FDA Briefing Book - TOBI

Tobramycin inhalation powder (NDA 201,688)
Briefing Document
AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
Prepared by Novartis Pharmaceuticals Corporation for the

September 5, 2012 Anti-Infective Drugs Advisory
Committee Meeting
Document type:
Briefing document
Document status:
Final
Release date:
August 2, 2012
Number of pages:
135
Novartis
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Briefing document
TIP/tobramycin inhalation powder
Table of contents
3
4
Table of contents ................................................................................................................. 2

List of tables ........................................................................................................................ 5
List of figures ...................................................................................................................... 8
List of abbreviations .......................................................................................................... 11
Executive summary ........................................................................................................... 13
1.1
Cystic fibrosis: burden of disease and unmet medical need .................................. 13
1.2
Development of tobramycin inhalation powder (TIP) ........................................... 13
1.3
Overview of clinical studies .................................................................................. 15
1.3.1
Study C2301 .......................................................................................... 16
1.3.2
Study C2302 .......................................................................................... 17
1.3.3
Study C2303 .......................................................................................... 18
1.3.4
Evaluation of efficacy in Phase III studies ............................................ 20
1.4
Overview of microbiology- susceptibility and emerging pathogens ..................... 22
1.5
Summary of safety ................................................................................................. 23
1.6
Device usability ..................................................................................................... 24
1.7
Conclusions Benefit/Risk ................................................................................... 25
Introduction and background ............................................................................................. 26
2.1
Cystic fibrosis: burden of disease .......................................................................... 26
2.2
Pseudomonas aeruginosa infection and treatment ................................................ 26
2.3
CF patients need less burdensome treatment options to improve adherence ........ 27
2.4
Tobramycin inhalation powder (TIP) .................................................................... 29
2.5
Regulatory history ................................................................................................. 29
2.5.1
U.S. ........................................................................................................ 29
2.5.2
Global .................................................................................................... 30
Product description ............................................................................................................ 30
Pharmacology .................................................................................................................... 34
4.1
Pharmacokinetics and pharmacodynamics ............................................................ 34
4.1.1
Clinical pharmacokinetics ..................................................................... 34
4.1.2
TIP pharmacokinetics in Phase I studies ............................................... 35
4.1.3
TIP pharmacokinetics in Phase III studies ............................................ 37
4.1.4
Population pharmacokinetics of TIP ..................................................... 37
4.1.5
Pharmacodynamics ............................................................................... 39
4.2
Summary ................................................................................................................ 41
The selected dose: 112 mg twice daily .............................................................................. 41
5.1
Dose selection rationale ......................................................................................... 41
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5.2
Dose selection results ............................................................................................ 42
Design and analysis of Phase III program ......................................................................... 42
6.1
Overview................................................................................................................ 42
6.2
Considerations for the design of the Phase III program ........................................ 43
Summary of the efficacy data by study ............................................................................. 44
7.1
Study C2301 .......................................................................................................... 44
7.1.1
Study C2301 design .............................................................................. 44
7.1.2
Study C2301 execution ......................................................................... 45
7.1.3
Study C2301 analysis and relationship to disposition........................... 46
7.1.4
Study C2301 disposition and demographics ......................................... 48
7.1.5
Study C2301 relative change in FEV1 % predicted .............................. 50
7.1.6
Study C2301 relative change in FEV1 % predicted over 3 cycles ........ 51
7.1.7
Study C2301 absolute change in FEV1 % predicted ............................ 52
7.1.8
Study C2301 FEV1 % predicted sensitivity analyses ............................ 52
7.1.9
Study C2301 change in colony forming units ....................................... 53
7.1.10
Study C2301 changes in other clinical endpoints ................................. 54
7.2
Active-controlled trial: Study C2302..................................................................... 55
7.2.1
Study C2302 design .............................................................................. 55
7.2.2
Study C2302 execution ......................................................................... 55
7.2.3
Study C2302 analysis ............................................................................ 55
7.2.4
7.2.5
7.2.6
Study C2302 colony forming units changes ......................................... 61
7.2.7
Study C2302 other efficacy endpoints .................................................. 62
7.2.8
Study C2302 efficacy results in age groups .......................................... 65
7.3
Study C2303 .......................................................................................................... 67
7.3.1
Study C2303 background ...................................................................... 67
7.3.2
Study C2303 design .............................................................................. 68
7.3.3
Study C2303 execution challenge ......................................................... 69
7.3.4
Study C2303 analysis ............................................................................ 71
7.3.5
7.3.6
7.3.7
Study C2303 relative change in FEV1 % predicted sensitivity
analyses ................................................................................................. 77
7.3.8
Study C2303 additional supportive analyses: individual patterns ........ 78
7.3.9
Study C2303 Bayesian analysis ............................................................ 81
7.3.10
Study C2303 absolute change in FEV1 % predicted ............................. 82
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7.3.11
Study C2303 change in P. aeruginosa colony forming units ............... 83
7.3.12
Study C2303 changes in other clinical endpoints .............................. 84
7.3.13
Study C2303 Health-related quality of life ........................................... 85
7.4
Comparison of outcomes for Studies C2301 and C2303....................................... 86
7.4.1
Change in FEV1 % predicted in Cycle 1 ............................................... 86
7.4.2
Clinical variability in change from baseline in FEV1 % predicted ....... 87
7.4.3
Absolute change analyses for FEV1 % predicted .................................. 88
7.4.4
P. aeruginosa suppression in the lungs ................................................. 88
7.4.5
Anti-pseudomonal antibiotic use........................................................... 89
7.4.6
Hospitalizations ..................................................................................... 89
7.5
Study C2303E1 ...................................................................................................... 90
7.5.1
Study C2303E1 design .......................................................................... 90
7.5.2
Study C2303E1 population ................................................................... 90
7.5.3
Study C2303E1 sustained improvements in lung function
assessments ........................................................................................... 90
7.5.4
Study C2303E1 hospitalizations and use of anti-pseudomonal
antibiotics .............................................................................................. 91
7.6
Overall efficacy conclusions.................................................................................. 92
Overview of clinical microbiology .................................................................................... 94
8.1
Rationale for inhaled antibiotics in CF patients .................................................... 94
8.2
Limitations of establishing susceptibility interpretive criteria (breakpoints)
for inhaled tobramycin in CF patients ................................................................... 94
8.3
MICs of P. aeruginosa isolates in TIP Studies...................................................... 95
8.3.1
Study C2301 .......................................................................................... 95
8.3.2
Study C2302 .......................................................................................... 96
8.3.3
Study C2303 .......................................................................................... 98
8.4
Treatment emergent pathogens .............................................................................. 99
8.5
Microbiology conclusions ................................................................................... 100
Overview of safety .......................................................................................................... 100
9.1
Safety populations, evaluations, and patient exposure ........................................ 101
9.2
Adverse events ..................................................................................................... 102
9.2.1
Common adverse events (AEs) in Study C2302 (primary safety
population) .......................................................................................... 102
9.2.2
Common adverse events in the placebo-controlled studies Study
C2301 (first cycle) and Study C2303 .................................................. 105
9.3
Serious adverse events, death, and other clinically significant adverse events ... 106
9.3.1
Serious adverse events ........................................................................ 106
9.3.2
Deaths .................................................................................................. 108
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10
11
12
13
9.3.3
Adverse events leading to discontinuation .......................................... 110
9.4
Safety areas of special interest ............................................................................. 112
9.4.1
Adverse events associated with dry powder inhalation (cough and
dysphonia) ........................................................................................... 112
9.4.2
Cough events ....................................................................................... 112
9.4.3
Audiology testing ................................................................................ 115
9.5
Clinical laboratory evaluations ............................................................................ 116
9.5.1
Clinical chemistry in Study C2302 (primary safety population) ........ 116
9.5.2
Clinical chemistry in individual placebo-controlled studies (C2301
and C2303) .......................................................................................... 117
9.5.3
Urinalysis ............................................................................................ 118
9.6
Summary of safety data from uncontrolled studies ............................................. 118
9.6.1
Study C2301 Cycles 2 and 3 ............................................................... 118
9.6.2
Study 2303E1 ...................................................................................... 118
9.7
Post-marketing experience................................................................................... 119
9.8
Additional studies to further evaluate safety of tobramycin inhalation powder .. 119
9.9
Safety summary ................................................................................................... 120
Device usability study results .......................................................................................... 120
Benefit and risk conclusions ............................................................................................ 122
References ....................................................................................................................... 125
Appendix 1 Manufacturing process development ........................................................ 130
13.1 Comparability data for Phase III and Improved spray drying processes ............. 131
13.1.1
Aerodynamic particle size distribution (APSD) ................................. 131
13.1.2
Delivered dose ..................................................................................... 134
13.1.3
Physical characterization ..................................................................... 135
13.2 Conclusion ........................................................................................................... 135
List of tables
Table 1-1
Table 3-1
Table 4-1
Table 4-2
Table 4-3
Phase III clinical studies initiation and completion dates .................. 15

Composition of the drug product .......................................................... 31
Serum and sputum pharmacokinetic parameters of TIP (112 mg)
vs. TOBI (300 mg) - Study TPI001 ...................................................... 36
Summary of serum tobramycin concentrations across studies
C2301, C2302 and C2303 at the end of a 28-day dosing cycle ............ 37
Predicted mean Cmax and Ctrough at steady state for subjects with
a range of values of BMI or FEV1% predicted at baseline................... 38
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Table 4-4
Table 7-1
Table 7-2
Table 7-3
Table 7-4
Table 7-5
Table 7-6
Table 7-7
Table 7-8
Table 7-9
Table 7-10
Table 7-11
Table 7-12
Table 7-13
Table 7-14
Table 7-15
Table 7-16
Table 7-17
Table 7-18
Summary of sputum tobramycin concentrations across studies

C2302 and C2303 at the end of a 28-day dosing cycle ......................... 40
Demographics, by treatment group Study C2301 (All
Randomized Safety population) ............................................................ 48
Baseline characteristics, by treatment group Study C2301 (All
Safety population) ................................................................................. 49
Relative change in FEV1 % predicted from baseline to pre-dose
Day 28 of Cycle 1 Study C2301 (SIA ITT population) ..................... 50
Study C2301 sensitivity analyses with additional imputation
methods (SIA population, n=61) ........................................................... 52
Study C2301 Significance test (p-values) with non-parametric
methods (SIA population, n=61) ........................................................... 52
Study C2301 estimates with non-parametric methods (SIA
population, n=61) .................................................................................. 52
Study C2301 sensitivity analyses in all treated patients (All
Randomized Safety population, n=95) .................................................. 53
Demographic summary by treatment group Study C2302 (All
Disease characteristics by treatment group Study C2302 (All
FEV1 % predicted relative change from baseline to pre-dose Day
28 of Cycle 3 Study C2302 (ITT population) .................................... 59
New anti-pseudomonal antibiotic use and hospitalizations due to
respiratory events during the study, by treatment group - Study
C2302 .................................................................................................... 63
Duration of administration of study drug - Study C2302 (All
Treatment satisfaction from modified Treatment Satisfaction
Questionnaire for Medication - Study C2302 (ITT population) ........... 65
Analysis of covariance of relative change in FEV1 % predicted
from baseline to pre-dose Day 28 of Cycle 3 for patients aged 20 or
older - Study C2302 (ITT population) .................................................. 66
Change in P. aeruginosa sputum density (mean (SD) log10 CFU/g)
from baseline for the sum of all 3 biotypes after 3 cycles (end of
on- treatment, Week 21), by age - Study C2302 (ITT population) ....... 66
Summary of efficacy outcomes by age group Study C2302 (ITT
population) ............................................................................................ 67
Demographic summary, by treatment group - Study C2303 (All
randomized Safety population) ............................................................. 73
Baseline characteristics, by treatment group - Study C2303 (All
randomized Safety population) ............................................................. 74
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Table 7-19
Table 7-20
Table 7-21
Table 7-22
Table 7-23
Table 7-24
Table 7-25
Table 7-26
Table 7-27
Table 7-28
Table 7-29
Table 7-30
Table 8-1
Table 8-2
Table 8-3
Table 8-4
Table 8-5
Table 8-6
Table 9-1
Table 9-2
Table 9-3
Relative change of FEV1 % predicted from baseline to Day 29 in

key analysis populations - Study C2303 ............................................... 76
Study C2303 sensitivity analyses with additional imputation
methods ................................................................................................. 77
Study C2303 significance test (p-values) with non-parametric
methods ................................................................................................. 77
Study C2303 estimates with non-parametric method ........................... 78
Analyses on relative change in FEV1 % predicted by treatment
actually received - Study C2303 ........................................................... 78
Relative change from baseline to Day 29 in FEV1 % predicted with
outlier excluded from key analysis populations - Study C2303 ........... 81
Summary of placebo data ...................................................................... 81
Bayesian analyses of relative change from baseline in FEV1 %
predicted on Day 29 incorporating historical placebo information Study C2303 .......................................................................................... 82
Absolute change of FEV1 % predicted from baseline to Day 29 in
key analysis populations - Study C2303 ............................................... 83
Change in P. aeruginosa sputum density from baseline to Day 29
(ITT population) - Study C2303 ........................................................... 83
Relative change in FEV1 % predicted from baseline to pre-dose
Day 28 of Cycle 1 (Studies C2301 and C2303) .................................... 86
Between treatment comparison of change in P. aeruginosa sputum
density (Log10 CFU/g) from baseline to end of dosing in Cycle 1
Studies C2301 and C2303 (ITT population) ......................................... 89
Summary of Tobramycin MICs for P aeruginosa (maximum MIC
per patient) - Study C2301 (ITT population) ........................................ 95
Summary of Tobramycin MICs for P aeruginosa (maximum MIC
per patient) - Study C2302 (ITT population) ........................................ 96
Clinical outcomes in patients with baseline maximum MICs 8
g/mL and 128 g/mL - Study C2302 (ITT population)................... 98
Summary of tobramycin MICs for P.aeruginosa (maximum MIC
per patient) - Study C2303 (Safety population) .................................... 98
Frequency of emergence of pathogens of potential relevance Studies C2301 (ITT population) and C2303 (Safety population) ......... 99
Frequency of emergence of pathogens of potential relevanceStudy C2302 (ITT population) ............................................................ 100
Population groupings for safety assessments ...................................... 101
Patient exposure to study treatments ................................................... 101
Adverse events by preferred term regardless of relationship to
treatment (at least 2% in any group) - Study C2302 (primary safety
population) .......................................................................................... 103
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Table 9-4
Table 9-5
Table 9-6
Table 9-7
Table 9-8
Table 9-9
Table 9-10
Table 9-11
Table 9-12
Table 9-13
Table 9-14
Table 9-15
Table 13-1
Adverse events with an occurrence >2 events/cycle, adjusted for

exposure - Study C2302 (primary safety population) ......................... 104
Cycle 1 adverse events (on-treatment and off-treatment, at least 5%
in any group), regardless of study drug relationship, by preferred
term and treatment group - Study C2301 (all randomized safety
population) .......................................................................................... 105
Adverse events (on-treatment and off-treatment, at least 5% in any
group), regardless of study drug relationship, by preferred term and
treatment group - Study C2303 (safety population) ............................ 106
Serious adverse events by preferred term (at least 2 patients in
total) regardless of relationship to treatment - Study C2302
(primary safety population) ................................................................. 106
Cycle 1 serious adverse events (on-treatment and off-treatment),
regardless of study drug relationship, by system organ class,
preferred term and treatment group - Study C2301 (all randomized
safety population) ................................................................................ 107
Serious adverse events (on-treatment and off-treatment), regardless
of study drug relationship, by preferred term and treatment group Study C2303 (all safety population) ................................................... 108
Deaths in all completed studies ........................................................... 109
Discontinuations due to adverse events (at least 2 patients in total)
by preferred term regardless of relationship to treatment - Study
C2302 (primary safety population) ..................................................... 111
Cough events by cycle - Study C2302 (primary safety population) ... 112
Airway reactivity: acute decrease in percent predicted FEV1 from
pre-dose to 30-minute post-dose at any visit - Study C2302
(Primary safety population)................................................................. 114
Airway reactivity: acute decrease in percent predicted FEV1 from
pre-dose to 30-minute post-dose by treatment group - Study C2301
(All safety population) ........................................................................ 114
Treatment emergent abnormal lab events in selected lab parameters
- Study C2302 (Primary safety population) ........................................ 116
Powder manufacturing process development summary ...................... 130
List of figures
Figure 3-1
Figure 3-2
Figure 3-3
Tobramycin drug substance .................................................................. 31

Scanning electron micrograph of PulmoSphere particles ..................... 32
T-326 Dry Powder Inhaler (T-326 Inhaler) .......................................... 33
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Figure 4-1
Figure 4-2
Figure 7-1
Figure 7-2
Figure 7-3
Figure 7-4
Figure 7-5
Figure 7-6
Figure 7-7
Figure 7-8
Figure 7-9
Figure 7-10
Figure 7-11
Figure 7-12
Figure 7-13
Figure 7-14
Figure 7-15
Figure 7-16
Figure 7-17
Figure 8-1
Mean serum concentration-time profiles of tobramycin after

administration of TOBI (300 mg) and escalating doses of TIP (28,
56, 84, and 112 mg) to CF patients ....................................................... 36
Tobramycin serum exposure is consistent for TIP manufactured by
the improved process and TIP used in the Phase III program.
Concentrations for TIP improved (circles) are in the range of
probable (90%) concentrations for TIP Phase III (gray). Average
profile for TIP improved (dashed line) is consistent with average
profile for TIP Phase III (solid line) ...................................................... 39
Design of Study C2301 ......................................................................... 45
Study C2301 patient disposition (all randomized patients) .................. 46
Relative change from baseline in percent predicted FEV1 in Cycles
1-3 Study C2301 (SIA population) .................................................... 51
Between treatment comparison of change from baseline in P.
aeruginosa sputum density (Log10 CFU) Study C2301 (ITT
population) ............................................................................................ 54
Design of Study C2302 ......................................................................... 55
Patient disposition in Study C2302 ....................................................... 56
Relative change from baseline in FEV1 percent predicted in Cycles
1-3 Study C2302 (ITT population) .................................................... 60
aeruginosa sputum density (Log10 CFUs) Study C2302 (ITT
population .............................................................................................. 61
Study C2302 Kaplan-Meier curve of time to first antipseudomonal antibiotic use, by treatment group (ITT population)....... 62
Design of Study C2303 ......................................................................... 69
Patient disposition in Study C2303 ....................................................... 73
Histogram of relative change in FEV1 % predicted from baseline to
Day 29 in the TIP group - Study C2303 (observed population, n =
27) ......................................................................................................... 79
Histogram of relative change in FEV1 % predicted from baseline to
Day 29 in the placebo group - Study C2303 (observed population,
n= 28) .................................................................................................... 79
Study C2301 Histograms ...................................................................... 80
Study C2303 Cystic Fibrosis Quality of Life domain scores ................ 85
Meta analysis: 2 TIP studies and 2 TOBI studies (Observed data at
Day 29) .................................................................................................. 88
Relative change in FEV1 % predicted from baseline in Study
C2303 and in Study C2303E1 ............................................................... 91
Distribution of tobramycin MICs of all P. aeruginosa isolates with
TIP treatment - Study C2302 (ITT population) .................................... 97
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Figure 8-2
Figure 13-1
Figure 13-2
Figure 13-3

TOBI treatment (Study C2302, ITT population) .................................. 98
APSD: Phase III, Improved (pre-validation) and Improved
(validated) process batches ................................................................. 132
Mass per stage for NGI data at flow rate of 60 LPM .......................... 133
Delivered dose uniformity................................................................... 134
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List of abbreviations
AE
ALP
ALT
ANCOVA
ANOVA
APSD
AST
ATS
AUC
AUCinf
b.i.d.
BMI
BOCF
BUN
CF
CFF
CFQ-R
CFTR
CFU
CI
Cmax
CRO
Ctrough
DMC
DPI
DSPC
EMA
EU
FDA
FEV1
GCP
HCP
IFU
ITT
LS
MedDRA
Adverse event
Alkaline phosphatase
Alanine aminotransferase
Analysis of covariance
Analysis of variance
Aerodynamic particle size distribution
Aspartate aminotransferase
American Thoracic Society
Area under the curve
Area under the curve extrapolated to infinity
bis in diem/twice a day
Body mass index
Baseline observation carried forward
Blood urea nitrogen
Cystic fibrosis
Cystic Fibrosis Foundation
Cystic fibrosis questionnaire - revised
Cystic fibrosis transmembrane conductance regulator
Colony forming units
Confidence interval
Maximum concentration
Contract Research Organization
Trough concentration
Data Monitoring Committee
Dry powder inhaler
1,2-distearoyl-sn-glycero-3-phosphocholine
European Medicines Agency
European Union
Food and Drug Administration
Forced expiratory volume in 1 second
Good Clinical Practice
Health care professionals
Instructions for use
Intent-to-treat
Least squares
Medical Dictionary for Regulatory Affairs
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MIC
MIC50
MIC90
mITT
MRSA
N, n
NDA
NGI
OIA
PFOB
PFT
PK
p.o.
PopPK
PP
SAE
SCV
SD
SE
SIA
T
TIP
Tmax
TOBI
TSQM
ULN
Minimum inhibitory concentration

Minimum inhibitory concentration required to inhibit the growth of 50 % of
organisms
Minimum inhibitory concentration required to inhibit the growth of 90 % of
organisms
Modified intent-to-treat
Methicillin-resistant Staphylococcus aureus
Number of patients in study/treatment group
New Drug Application
Next Generation Impactor
Original interim analysis
perfluorooctyl bromide
Pulmonary function test
Pharmacokinetics
per os
Population pharmacokinetics
Per-protocol
Serious adverse event
Small colony variants
Standard deviation
Standard error
Sensitivity interim analysis
Elimination half-life
Tobramycin inhalation powder hard capsule 28 mg
Time of maximum concentration
Tobramycin inhalation solution 300 mg/5 mL
Treatment Satisfaction Questionnaire for Medication
Upper limit of normal
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Executive summary
1.1
Cystic fibrosis: burden of disease and unmet medical need
Cystic fibrosis (CF) is the most common life-shortening monogenetic disease affecting
Caucasians. It is a multi-organ disease in which a mutation in the transmembrane conductance
regulator (CFTR) gene affects chloride-channel proteins and chloride ion transport in a variety
of tissues, most notably in the lungs and pancreas. It is estimated that there are approximately
30,000 CF patients in the United States and about 60,000 worldwide. In the US the median
predicted age of survival for people with CF is 38.3 years (CFF Patient Registry Report
2011).
CF is characterized by a gradually progressive obstructive lung disease due to the
accumulation of viscous endobronchial secretions in the airways, which are associated with
impaired mucociliary clearance and increased susceptibility to endobronchial infections.
Infection with Pseudomonas aeruginosa (P. aeruginosa) in the lungs is particularly
debilitating and life-threatening due to the damage it causes to lung tissue and consequent
increase in breathing difficulties. The infections often become recurrent and then chronic,
resulting in an increasing frequency of hospitalization in adolescence and early adulthood.
The acquisition of chronic P. aeruginosa in the lungs of CF patients is associated with
accelerated lung function decline.
The treatment burden for CF patients (and their families) is extremely high, with a median of
7 therapies per day (Sawicki et al 2009). Typically, maintenance therapy includes a range of
inhaled and systemic medications including antibiotics, bronchodilators, mucolytics, and
pancreatic enzymes. These treatments, along with physiotherapy and exercise, often take
several hours each day (Sawicki et al 2009). This overall treatment burden, applicable to all
CF patients, has significant adverse consequences and is a major challenge in clinical practice.
Adherence with the large and demanding daily treatment regime is a recognized problem in
the CF community. Modi et al (2006) reported adherence rates of 36% for inhaled nebulized
antibiotics, suggesting a substantial need for improvement. In addition to low adherence with
respect to dosing frequency, studies have also found low adherence to treatment-related
processes, such as nebulizer cleaning and disinfection. It was noted by Briesacher et al (2011),
that only 7% of patients achieve 4 or more of the 6 treatment cycles per year that should be
used for inhaled tobramycin inhalation solution.
There remains a high clinical need to ease this treatment burden. The need to improve the
burden is substantially more than just patient convenience. A central goal is improving low
rates of adherence as this will result in better clinical outcomes (Eakin et al 2011, Briesacher
et al 2011).
1.2
Development of tobramycin inhalation powder (TIP)
In the almost 15 years since its approval by the Food and Drug Administration (FDA) in
1997, Novartiss TOBI (tobramycin inhalation solution, USP) has become a standard of care
for treatment of CF patients with P. aeruginosa. The use of a nebulized solution of
tobramycin, however, may also be subject to limited patient adherence. The nebulization time
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for one dose of TOBI with the labeled device and compressor is approximately 15-20
minutes, and this must be done twice a day. This does not include the additional time required
to prepare the dose, assemble and disassemble the nebulizer and compressor, and clean and
disinfect the nebulizer (recommended every other treatment day). This adds approximately
10-15 additional minutes per treatment, for a total of approximately 50 to 70 minutes per day,
noting that patients may need to use and maintain additional nebulizers for their other inhaled
treatments.
Tobramycin inhalation powder (TIP) (proposed trade name TOBI Podhaler) was designed
to make delivery of inhaled tobramycin simpler, faster, and more portable. TIP is an
inhalation powder hard capsule formulation of tobramycin (28 mg tobramycin per capsule)
administered via the T-326 Inhaler (proposed trade name Podhaler), a hand-held, manuallyoperated, breath-activated, dry powder inhaler (DPI).
The proposed indication for TIP is the same as the approved indication for TOBI: the
management of CF patients with P. aeruginosa. The recommended dosage of TIP for both
adults and pediatric patients 6 years of age and older is the inhalation of the contents of four
28 mg capsules (112 mg) twice daily; the 112 mg dose has been found to deliver tobramycin
to achieve comparable exposure to the 300 mg dose of TOBI (see Section 1.3). TIP is
administered in the same dosing regimen as TOBI: twice daily in alternating periods of 28
days. After 28 days of therapy, patients stop therapy for the next 28 days, and then resume
therapy for the next cycle of 28 days on/28 days off treatment.
In contrast to TOBI, TIP is administered in approximately 5 minutes per dose (inhalation of
the contents of 4 capsules using the T-326 Inhaler). The time saved in dose administration per
treatment cycle is 9-14 hours (10-15 minutes saved per dose 2 doses per day 28 days).
This does not include the time saved on nebulizer/compressor set-up and
maintenance/cleaning - approximately 10 additional hours per treatment cycle. It has been
reported (Rosenfeld et al 1998) that treatment burden can reduce adherence to therapy, which
in turn can lead to worse outcomes for the patient.
The T-326 Inhaler also has a simple cleaning regimen wiping the exterior of the mouthpiece
with a dry cloth after use. The patient is supplied with a new inhaler for use every 7 days,
minimizing the risks of contamination associated with a nebulizer. TIP also has significant
benefits over TOBI with regard to storage (no refrigeration needed) and portability (no power
source required to operate the delivery device, unlike the nebulizer/compressor). These
features offer CF patients more freedom to participate in their daily work and school
activities.
Thus, TIP is a tobramycin formulation option that delivers the same active ingredient to the
lungs as TOBI, with comparable safety and efficacy, in a faster, simpler way. TIP is aimed at
reducing the treatment burden and providing increased portability for patients.
TIP received its first global approval in Chile in 2010, and is currently approved for use in 37
countries including the EU, Canada, and Switzerland (see Section 2.5). It has been launched
so far in 20 countries.
The New Drug Application for TIP was submitted to the US FDA on December 21, 2011 and
is currently under review with an action date of October 21, 2012.
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1.3
Overview of clinical studies
Study TPI001, a Phase I trial in CF patients, demonstrated that a 112 mg (4 x 28 mg) twice
daily (b.i.d.) dry powder dose of TIP yielded a comparable systemic pharmacokinetic profile
to the approved 300 mg b.i.d. nebulized dose of TOBI. This dose was therefore selected for
use in subsequent studies. The primary clinical data comes from three Phase III studies (and
one extension), performed in more than 650 randomized CF patients aged 6 years and older:
Study C2301: A double-blind randomized study of TIP vs. placebo in CF patients aged 621 years (with no prior exposure to inhaled anti-pseudomonal antibiotics for at least 4
months) for 1 cycle (28 days on/28 days off treatment), followed by additional 2 cycles of
open label TIP treatment.
Study C2302: An open label randomized study of TIP vs. TOBI in CF patients aged 6
years (with no prior exposure to inhaled anti-pseudomonal antibiotics for 1 month) across
3 cycles.
Study C2303: A double-blind randomized study of TIP vs. placebo in CF patients aged 621 years (with no prior exposure to inhaled anti-pseudomonal antibiotics for at least 4
months) for 1 cycle.
Study C2303E1: An open-label extension in which patients received TIP for an additional
three treatment cycles.
The timing of the studies is shown in Table 1-1.

Table 1-1
Phase III clinical studies initiation and completion dates
Study
First patient / first visit
Last patient / last visit
Study C2301
Study C2302
Study C2303
Study C2303E1*
September 22, 2005

February 6, 2006
June 4, 2009
August 12, 2009
February 28, 2007

March 12, 2009
May 6, 2011
October 6, 2011
*open-label extension to Study C2303
Studies C2301 and C2302 made up the originally planned Phase III development program as
agreed with FDA in 2004. Study C2303 was an additional clinical study performed to fulfill a
request made by FDA in 2007 to generate clinical data to support improvements made to one
step of the drug product manufacturing process (bulk spray-dried powder manufacture, see
Section 7.3.1 and Section 13 - Appendix 1). Of note, the qualitative and quantitative
formulation and scale of manufacture of the drug product were unchanged, and the available
comparative technical data suggested that the aerosol performance and all physicochemical
characteristics pertinent to in vivo performance were very closely matched and comparable to
the drug product used for Studies C2301 and C2302.
Global recruitment of Study C2303 proved to be extremely challenging due to the placebocontrolled design and the requirement for CF patients who were effectively TOBI-nave, i.e.
patients who had not used inhaled anti-pseudomonal antibiotics for 4 months prior to
screening. Due to the wider usage of TOBI globally, such patients were no longer available in
the U.S. and many European countries as they had been for Study C2301 a few years prior.
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After all recruitment efforts were exhausted, Study C2303 was terminated in 2011 prior to full
enrollment.
Each of the Phase III studies is summarized below.
1.3.1
Study C2301
Study design and patient population

Study C2301 was a three-cycle trial in CF patients aged 621 years with P. aeruginosa, with
forced expiratory volume at 1 second (FEV1) 25% and 80% predicted. The first cycle was
double-blind and placebo-controlled with patients randomized to TIP (4 x 28 mg twice a day)
or placebo at a 1:1 ratio. Upon completion of the first cycle, all patients received TIP for
Cycles 2 and 3. Each cycle consisted of 28 days on treatment followed by 28 days off
treatment. Patients were required to have received no inhaled anti-pseudomonal antibiotics
within 4 months prior to screening or systemic anti-pseudomonal antibiotics within 28 days
prior to start of study drug.
The primary objective was to demonstrate the efficacy of a 28-day b.i.d. dosing regimen of
TIP versus placebo, as measured by the relative change in FEV1 % predicted from baseline
(Cycle 1, Day 1) to the end of Cycle 1 dosing (Cycle 1, Day 28). The secondary and
exploratory objectives were to assess the safety and efficacy of TIP over 3 cycles, including
lung function, change in sputum P. aeruginosa density, new anti-pseudomonal antibiotic
usage and hospitalizations.
Planned enrollment was for 140 CF patients. An interim analysis was pre-planned in the
protocol when the 80th randomized patients completed Cycle 1 dosing.
The study was terminated at the interim analysis upon recommendation from an external Data
Monitoring Committee (DMC) who concluded, based on pre-established stopping criteria,
that the trial conclusively demonstrated benefit in the active treatment arm compared to
placebo. The primary efficacy endpoint of Study C2301 entails a population of 61 patients
from the original analysis set of 79 (see additional details in Section 7.1).
Results
Lung function
The primary efficacy endpoint in this study was relative change from baseline in FEV 1 %
predicted after 28 days of treatment. Treatment with TIP during Cycle 1 resulted in
statistically significant improvement in FEV1 % predicted compared with placebo (betweentreatment difference 13.29%, 95% confidence interval [CI] 5.31, 21.28, p=0.0016) which is
judged clinically relevant. When patients in the placebo group switched to TIP in Cycle 2, the
relative change in FEV1 % predicted from baseline increased to the level of the TIP group and
was maintained over time.
Microbiology- P. aeruginosa sputum density
For reduction of sputum P. aeruginosa density, the greatest differences between TIP and
placebo for the sum of all biotypes were seen at Day 28 of Cycle 1; P. aeruginosa was
decreased by 2.86 log10 colony forming units (CFU)/g in the TIP group vs. 0.16 log10 CFU/g
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in the placebo group (treatment difference of 2.7 log10 CFU/g and 95% CI of 1.79, 3.60, p
<0.001). After switching from placebo to TIP starting in Cycle 2, the results were generally
similar in the original TIP and placebo groups. P. aeruginosa density generally rebounded
after 28 days off-treatment and then decreased again after 28 days on-treatment.
Anti-pseudomonal antibiotic use and hospitalization
Fewer patients on TIP required new anti-pseudomonal antibiotics (any route of
administration) or were hospitalized for respiratory exacerbations compared with those on
placebo. The percentage of patients needing new anti-pseudomonal antibiotics (other than
study drug) in Cycle 1 was 20.4% in the placebo group compared to 13.0% in the TIP group.
In addition, the duration of new anti-pseudomonal antibiotic usage was longer in the placebo
group than in the TIP group [mean duration: 18.2 (placebo) vs. 13.3 (TIP) days]. The
percentage of patients with respiratory-related hospitalizations was greater in the placebo
group than that in the TIP group (12.2%, placebo vs. 0, TIP). The average number of days of
hospitalization for respiratory exacerbations in Cycle 1 was 12.3 in the placebo group.
1.3.2
Study C2302

Study C2302 was a multi-center, randomized, open-label, parallel-group, active-controlled
study, comparing the safety and efficacy of TIP with TOBI in CF patients aged 6 years and
above with P. aeruginosa, and with FEV1 25% and 75% predicted. The primary objective
was to evaluate safety (see Section 1.5). The protocol defined a secondary objective to
compare the efficacy of TIP with TOBI over three cycles, by assessing non-inferiority using
the relative change from baseline in FEV1 % predicted at Cycle 3 Day 28 pre-dose. Given the
rare patient population and study size feasibility, non-inferiority as it is currently understood
was not a feasible objective for this study. The study was powered to reject a difference of 6%
or higher in favor of TOBI using the lower limit of the one-sided 85% CI.
A total of 553 patients were randomized and 517 received study drug.
Results
Lung function
TIP and TOBI improved lung function comparably over 3 cycles. The lower limit of the onesided 85% CI was higher than the predefined 6% margin (as were the 90% and 95% CIs),
indicating that treatment with TIP was similar to treatment with TOBI with regard to FEV1 %
predicted (85% CI -0.67, 2.96). The lower limit of the 95% CI was -1.74. The similarity of
results for TIP and TOBI were also maintained after allowing for differences in
discontinuations and anti-pseudomonal antibiotic usage rates.
Microbiology - P. aeruginosa sputum density
Reductions in P. aeruginosa density were comparable in the TIP and TOBI groups. The mean
decreases from baseline for the sum of all biotypes at Day 28, for the first and second cycles
were similar: Cycle 1 (1.78 vs. 1.30 log10 CFU/g for TIP and TOBI, respectively), Cycle 2
(1.62 vs. 1.10 log10 CFU/g for TIP and TOBI, respectively). For Cycle 3, the decrease was
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1.60 log10 CFU/g in the TIP group and 0.92 log10 CFU/g in the TOBI group. In both treatment
groups, P. aeruginosa density rebounded at the end of the 28-day off-treatment phase but then
decreased again during the 28-day on-treatment phase to comparable levels across each cycle
of treatment. The microbiologic effect of TIP was maintained across the 3 cycles.
There was little difference between treatment groups with regard to hospitalization for
respiratory events. In both treatment groups more than 50% of patients used new antipseudomonal antibiotics during the study, a higher proportion of patients in the TIP treatment
group used new antibiotics (64.9%) compared with those in the TOBI group (54.5%). The
mean duration of treatment, however, was shorter in the TIP treatment group (30.9 days)
compared with the TOBI treatment group (33.4 days). The difference in the rate of use does
not appear to have been driven by events of a higher clinical severity as the rates of
respiratory events leading to hospitalization (24.4% TIP vs. 22.0% TOBI) and rates of new IV
anti-pseudomonal antibiotic use were similar for the TIP (34.7%) and TOBI (33.0%)
treatment groups. Antibiotic use is discussed further in Section 7.2.7.1.
Administration time
The mean treatment administration time was significantly lower for TIP than TOBI (5.6
versus 19.7 minutes, p<0.0001). This difference does not include the additional set-up and
cleaning time for nebulizers.
Treatment Satisfaction Questionnaire for Medication
The patient reported outcome for assessments of effectiveness, convenience and global
satisfaction in the Treatment Satisfaction Questionnaire for Medication (TSQM) were
consistently greater for the TIP group than TOBI at all visits. Side effect ratings showed no
difference between treatment groups.
1.3.3
Study C2303

As noted earlier, Study C2303 was performed to obtain additional clinical data (requested by
FDA) following minor improvements to one step of the drug product manufacturing process
(described further in Section 7.3.1 and Section 13 - Appendix 1); the improvements were
aimed at making the spray-drying part of the process (preparation of bulk powder) more
consistent and efficient.
Similar in design to the first cycle of Study C2301, Study C2303 (initiated nearly 4 years
later) was a double-blind, placebo-controlled, randomized study performed in CF patients
with P. aeruginosa aged 621 years, with FEV1 25% and 80% predicted. Patients were
required to have received no inhaled anti-pseudomonal antibiotics within 4 months prior to
screening or systemic anti-pseudomonal antibiotics within 28 days prior to start of study drug.
Patients were randomized in a 1:1 ratio to TIP (4 x 28 mg b.i.d.) or placebo for 1 cycle.
The primary objective of the study was to evaluate the efficacy of TIP for the treatment of
infections with P. aeruginosa in CF patients, assessed by relative change from baseline FEV1
% predicted to Day 29, compared to placebo. In addition, there was a pre-planned analysis of
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the primary endpoint data using absolute change in FEV1 % predicted from baseline.
Secondary objectives were to evaluate the safety profile of TIP, the pharmacokinetic
properties of tobramycin, and the change in sputum P. aeruginosa density.
Recruitment proved to be extremely challenging due to the placebo-controlled design and the
requirement for CF patients who were effectively TOBI-nave, i.e. patients who had not
used inhaled anti-pseudomonal antibiotics for 4 months prior to screening. Access to such
patients was limited by the more widespread use of inhaled anti-pseudomonal antibiotics since
the time Study C2301 was conducted. For this reason, the study could not be performed in the
US or in many European countries and was instead largely conducted in the Baltic states and
Eastern Europe/Russia. Also, some health authorities or ethics committees did not permit a
placebo-controlled study in CF, particularly in pediatric patients. The study was therefore
largely done in different countries, with different healthcare systems, than Study C2301. After
global recruitment efforts were exhausted over a period of approximately two years, the study
was terminated with 62 patients randomized out of the planned 100 patients.
Results
Lung function
For the primary endpoint, relative change in FEV1 % predicted from baseline to Day 29 in the
intent-to-treat (ITT) population, the difference between TIP and placebo was 5.9% (95% CI 2.2, 14.0). While numerically supportive of efficacy, statistical significance was not reached
(p=0.148) in this underpowered study.
The following additional factors adversely affected the estimate of treatment effect for the
primary endpoint:
An imbalance in missing spirometry data affected the TIP group more than the placebo
group (6 vs. 1 patient). The baseline observation carried forward (BOCF) approach to
impute these missing data in the primary analysis created a bias against TIP,
Following the ITT principle, two patients who had actually received placebo instead of
TIP (due to a dispensing error at the study site) were included in the TIP analysis group,
One TIP patient an atypical patient (7 year old, with marked failure to thrive and screening
FEV1 of 33% predicted) was an extreme low outlier in terms of spirometry and drug levels
(indicating he did not successfully receive expected amounts of tobramycin).
A pre-planned analysis of absolute change (recommended by the FDA) in FEV1 % predicted
from baseline was statistically significant for the ITT population with a least squares (LS)
mean between-treatment difference of 4.4% predicted, 95% CI 0.0, 8.8: p=0.050. The
absolute change in FEV1 analysis is less sensitive to the effect of extreme values than relative
change, and provides important supportive evidence for the efficacy of TIP in Study C2303.
For the relative change analysis, when the factors described are appropriately taken into
account in sensitivity analyses, a higher treatment effect was observed. The point estimate of
effect was improved, reaching statistical significance in some cases (refer to Sections 7.3.7,
7.3.8 and 7.3.9).
Microbiology- P. aeruginosa sputum density
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The density of P. aeruginosa biotypes in the sputum decreased by 2.3 log10 CFU/g in the TIP
group and did not change in the placebo group; the mean difference was -2.4 (95% CI -3.18, 1.54, p<0.001).
Few patients (6) received new anti-pseudomonal antibiotics, 3 in each treatment group; if the
study drug dispensing error is taken into account, 2 TIP and 4 placebo patients received new
anti-pseudomonal antibiotics. The placebo treatment group had on average 13 days of
antibiotic use, while the TIP treatment group had 8.3 days of use. Hospitalization due to
respiratory events occurred only for one patient taking placebo. These results are discussed
further in Section 7.3.12.
Cystic Fibrosis Quality of Life Questionnaire
The results of the Cystic Fibrosis Quality of Life Questionnaire (CFQ-R), a disease-specific
patient-reported outcome tool, showed trends indicative of improvements (i.e. median change
of >8 score points from baseline to Day 29) in Respiratory Symptoms, Role Functioning,
Treatment Burden and Health Perceptions in the TIP group, compared to virtually no change
in these domains in the placebo group. A striking result was observed for the treatment burden
which improved by 11.1 points, consistent with the rationale for developing TIP.
Study C2303E1 extension study
Study C2303E1 was an open-label, single-arm extension to Study C2303 which provided the
opportunity for all the patients who completed Study C2303 to receive three additional cycles
of treatment with TIP. In total 94.5% of patients completed 3 cycles and the data from this
study demonstrated sustained efficacy of TIP with respect to the maintenance of FEV1 %
predicted improvements and suppression of P. aeruginosa across 3 cycles. The magnitude of
improvement in lung function for patients switched from placebo to TIP was similar to that
observed with TIP in the core study. The mean relative change from the core study baseline in
FEV1 % predicted was statistically significantly higher at all post-baseline time points during
the extension study, with the highest mean ( standard deviation [SD]) increase from baseline
in mean FEV1 % predicted of 17.3 (23.56)% (p<0.001) which occurred at the end of dosing
Cycle 4 (Day 29).
The decrease from baseline (using initial core Study C2303 baseline) in P. aeruginosa sputum
density for the sum of all biotypes was greater at all post-baseline time points and statistically
significant at all timepoints except at follow-up (Visit 11, Week 33). The mean (SD)
decrease from baseline in P. aeruginosa sputum density for the sum of all biotypes ranged
from 3.5 to 3.9 log10 CFU/g at the end of the treatment periods and was the highest in Cycle 4
(Day 29) 3.9 (2.82) log10 CFU/g.
1.3.4
Evaluation of efficacy in Phase III studies
The Phase III studies demonstrated the efficacy of TIP relative to placebo (with Study C2301
showing highly significant FEV1 results and Study C2303, unavoidably smaller than planned,
showing trends toward significance for relative change in FEV1 % predicted and p<0.05 for
absolute change). TIP was compared to TOBI, in Study C2302, across a range of diseaserelevant endpoints. This study demonstrated that TIP is similar to TOBI in relative change
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from baseline in FEV1 % predicted (numerically 1.1 % points higher) with the lower limit of
the one-sided 85% CI being well above the pre-defined margin of 6 (the lower boundary is
less than -1% for 85% CI, and -1.74% for 95% CI).
Improvements from baseline in relative FEV1 % predicted were statistically significant vs.
placebo (estimated treatment effect 13.3% with 95% CI 5.3, 21.28) in Study C2301. In Study
C2303 relative change vs. placebo in FEV1 % predicted in the ITT population was 5.9% (95%
CI -2.2, 14.0). While numerically supportive of efficacy, statistical significance was not
reached (p=0.148) in this underpowered study.
In interpreting the apparently smaller treatment effect and lack of statistical significance in the
primary analysis of Study C2303, it is appropriate to take into account factors such as the
imbalance in imputation of missing data, the dispensing error, and an atypical patient (7 year
old, with marked failure to thrive and screening FEV1 of 33% predicted) with outlying data
(notably not receiving the expected amounts of tobramycin). Sensitivity analyses, both preplanned (observed data, Bayesian analysis, absolute change) and post-hoc (modified ITT, as
treated, and excluding outlier populations) addressing these factors showed larger estimated
treatment effects that in some cases had p values <0.05. The treatment effects and variability
observed across Studies C2301 and C2303 were comparable to those seen in the two previous
TOBI pivotal studies.
The pre-specified analysis of lung function by absolute change from baseline in FEV1 %
predicted showed a statistically significant treatment effect vs. placebo in Study C2303;
similar results were obtained for Study C2301 when performed post-hoc.
Microbiological results in all three Phase III studies demonstrated a decrease in P. aeruginosa
sputum density with the use of TIP. This decrease was greater than that observed with placebo
(difference statistically significant) and similar to that of TOBI. The effectiveness of TIP in
suppressing P. aeruginosa was demonstrated both with respect to mean reduction in log10
CFU/g and to the proportion of patients showing 0.5, 1.0 and 1.5 log decrease in CFU at the
end of the treatment period. These results show TIP to be microbiologically superior to
placebo and at least as effective as TOBI in reducing lung infection by P. aeruginosa.
The data from Study C2303E1 showed a sustained effect on lung function improvement and
P. aeruginosa suppression across three further treatment cycles.
The use of additional anti-pseudomonal antibiotics was less common with TIP than placebo.
TIP-treated patients had lower rates of hospitalization (zero) due to respiratory events than
patients who received placebo in the two placebo-controlled trials. In Study C2302,
hospitalization rates were similar for TIP- and TOBI-treated patients across 3 cycles of
treatment. Although there was a difference in use of anti-pseudomonal antibiotics in the TIP
vs. TOBI groups, this difference was not due to use of IV antibiotics, and the duration of
antibiotic use was lower for the TIP vs. TOBI treatment arms (see Section 7.2.7.1).
Patient-reported outcomes, including treatment satisfaction and quality of life assessments
showed trends in favor of TIP over placebo, and over TOBI for assessments related to
convenience and general treatment satisfaction.
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Regarding the effect of the minor improvements to one step of the drug product
manufacturing process, it is unlikely that these contributed to the observed variability between
Studies C2303 and C2301, considering:
The qualitative and quantitative composition, aerosol performance and physicochemical
characteristics of the drug product were unchanged, as evidenced by comparative
technical data,
Peak and trough tobramycin serum concentrations were similar across studies with similar
variability,
Tobramycin was delivered at levels many fold above the minimum inhibitory
concentrations,
Factors were identified that have a clear impact on the analysis of Study C2303, such as
the imbalance in imputation of missing data, the dispensing error in two patients, and the
patient with outlying FEV1 data,
The magnitude of the change from baseline in FEV1 % predicted resulting from TIP
treatment in Studies C2301 and C2303 falls within the expected degree of clinical
variability, based on previous TOBI data.
In summary, the results of the three Phase III studies support the approval of TIP at a dose of
4 x 28 mg b.i.d. in the 28 days on-off cyclical treatment of P. aeruginosa infection in CF
patients aged 6 years or older. This dose delivers an effective and safe dose of tobramycin to
the lungs and effectively suppresses P. aeruginosa, with relevant clinical benefits. TIP
provides comparable efficacy to TOBI, with a much shorter administration time, offering
patients an effective alternative treatment option to reduce treatment burden.
1.4
Overview of microbiology- susceptibility and emerging

pathogens
Tobramycin minimum inhibitory concentrations (MICs) for P. aeruginosa isolates were

analyzed in all three Phase III TIP studies, overall and by biotypes: biotype-1 (mucoid),
biotype-2 (non-mucoid/dry), and biotype-3 (small colony variants, SCV). Section 8 includes
MIC results during each study for the maximum MIC of tobramycin for all biotypes combined
per patient. Minimum inhibitory concentrations required to inhibit the growth of 50% of
organisms (MIC50s) remained stable, varying at most by one dilution, across visits on TIP
treatment in each of the three studies and on TOBI treatment in the active controlled trial,
Study C2302. Minimum inhibitory concentrations required to inhibit the growth of 90% of
organisms (MIC90s) varied across visits in the three studies. The higher MIC90s at some postbaseline visits reflected the presence of patients at these visits with pre-treatment isolates with
higher MICs.
An analysis of MIC data in Study C2302 showed in general similar MIC distribution curves
at the baseline and end of study visits. Clinical outcomes, including FEV1% predicted change
from baseline and hospitalization rates, were similar in patients with baseline maximum MICs
8 ug/mL compared to patients with baseline maximum MICs of 128 ug/mL.
In both TIP and TOBI treated patients, there were low rates of treatment-emergent clinically
relevant pathogens for CF patients including Alcaligenes/Achromobacter xylosoxidans,
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Aspergillus fumigatus, Staphylococcus aureus (including methicillin-resistant S. aureus

[MRSA]), Stenotrophomonas maltophilia, and Burkholderia spp.
1.5
Summary of safety
The pharmacokinetic profiles of TIP and TOBI are similar and therefore expected to have
comparable systemic safety profiles including ototoxicity and nephrotoxicity.
In Study C2301, TIP was shown to be safe and well tolerated, with a safety profile
comparable to placebo, except for cough and lung disorder (e.g., pulmonary or CF
exacerbation) which were less frequent with TIP treatment than with placebo and . There were
fewer serious adverse events (SAEs) on TIP than placebo and the only discontinuation due to
an adverse event (AE) across the three cycles of treatment occurred in the placebo group
(pulmonary exacerbation leading to death). Cough was reported in 13% of TIP and 26.5% of
placebo patients; pharyngolaryngeal pain (e.g. sore throat) was more frequently reported in
the TIP treatment group (10.9%) compared with the placebo treatment group (0%).
In Study C2302, an open label study in which more than 80% of patients had previous
exposure to TOBI, the AE profile of TIP was generally similar to TOBI with the majority of
AEs relating to the underlying diagnosis of CF. Cough, dysphonia, and dysgeusia were more
frequently reported in the TIP treatment group than in the TOBI treatment group. All of these
AEs, including cough, were most often mild to moderate. Serious and severe AEs were
closely matched between the TIP and TOBI groups. Cough is a common symptom of CF and
has been observed at similar rates with other inhaled therapies. The perception of the impact
of side effects as reported by the patients did not differ between TIP and TOBI, as measured
by the TSQM tool in all cycles.
In Study C2303 there were no new or unexpected safety events when compared to Study
C2301, and the discontinuation pattern was similar: one patient in the TIP group discontinued
due to an AE (pulmonary hemorrhage) and one patient treated with placebo discontinued due
to an AE (bronchitis). The nature and extent of AEs on TIP in both studies was consistent
with a CF patient population and the use of a dry powder formulation (related AEs such as
cough, dysphonia and dysgeusia).
The overall risk associated with the use of TIP appeared to be similar to that of TOBI,
particularly with respect to the most important aspects of systemic safety. The potential
differential tolerability relates to the events of cough, dysgeusia and dysphonia. Dysgeusia is
likely to be related to tobramycin itself, which has an unpleasant taste; notably no patients
discontinued from the studies due to dysgeusia. Dysphonia has already been reported with
nebulized therapy, including tobramycin nebulizer solution. The proportion of patients on TIP
with dysphonia appears to be higher compared to TOBI, however most events were mild and
only 3 of 308 patients on TIP in Study C2302 discontinued due to this AE. It is likely that
cough and dysphonia are local tolerability effects. Cough was most frequently reported in the
first treatment cycle and was not associated with bronchospasm. The number of patients
reporting cough AEs and the number of events among patients experiencing cough AEs in the
first cycle decreased over subsequent cycles suggesting that patients became more tolerant of
the effect.
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Increased airway reactivity, as indicated by post-dose bronchospasm (acute reduction in FEV1

% predicted of 20% or more) or assessed as an AE following inhalation of TIP or TOBI, was
observed in a small proportion of patients and occurred in 5.2% of TIP treated patients and
5.3% of TOBI treated patients in Study C2302.
There was no evidence of systemic toxicity, e.g. nephrotoxicity, following TIP treatment, and
the mean tobramycin serum levels recorded during all studies were well below those known to
be associated with renal toxicity.
There was no evidence of sensorineural hearing loss in Study C2301 or Study C2303. For
events which indicated a significant likelihood of ototoxicity, TIP and TOBI were well
matched. In Study C2302, the incidence of reporting of clinically significant hearing loss in
the TIP treatment group (4 patients) compared with the TOBI group (3 patients) approximated
the randomization ratio. For the majority of patients, these decreases were transient as were
hearing complaints such as tinnitus.
In summary, the safety profile of TIP is acceptable, and similar to the well-established profile
of TOBI, which is consistent with the similar systemic and local tobramycin exposures
provided by the two products.
1.6
Device usability
The T-326 Inhaler is a capsule-based dry powder inhaler requiring the basic use steps of
inserting a capsule into the inhaler, piercing the capsule by pressing a button, and delivering
the contents of the capsule by inhalation, similar to commercially available inhalers like
Spiriva HandiHaler.
The usability of the T-326 Inhaler was assessed in two user handling studies (human factors
engineering handling studies) performed in the US and EU, respectively. These studies,
performed in a total of 82 CF patients, or subjects representative of CF patients, aged 6 years
and older, evaluated the successful completion of the use steps described in the corresponding
Instructions For Use (IFU) using empty capsules. A usability assessment was made upon first
use and at the return visit after completing a 5-day period of simulated use at home (i.e.
patients completed all essential use steps including inhalation using empty capsules). The
return visit investigated whether patients could still use the product correctly and occurred
approximately one week after training was provided. Throughout both studies, children and
adults demonstrated correct use of the T-326 Inhaler. The subjects understood the operation of
the inhaler, and the majority of users preferred it to a nebulizer.
The results of these two studies demonstrated that the T-326 Inhaler is safe and can be used
effectively by the intended user population. Each use error and finding observed in these two
studies was assessed and the required mitigations were implemented. A few deviceindependent errors, typically observed with dry powder inhalers, such as exhaling fully prior
to inhalation, inhaling twice from each capsule, and checking the capsules after use,
demonstrated room for improvement through more extensive training, though the simulated
use with empty capsules may have affected the outcome from these studies. Adherence to the
instructions will be further reinforced by the in-depth and personalized training typically
provided at CF centers.
Please refer to Section 3 for details on the device and Section 10 for additional discussion.
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1.7
Conclusions Benefit/Risk
TIP has a favorable benefit/risk profile that is comparable to TOBI and provides an alternative
treatment option for heavily treatment-burdened CF patients. The safety and efficacy of TIP is
comparable with TOBI, and TOBI is supported by over 10 years of use in clinical practice,
and recommended in Cystic Fibrosis Foundation (CFF) and ECFS treatment guidelines.
Compared to placebo, TIP treatment resulted in suppression of pulmonary P. aeruginosa
infection and subsequent improvement in lung function, together with a decrease in additional
anti-pseudomonal antibiotic use and hospitalizations due to respiratory events. Compared to
TOBI, TIP treatment resulted in similar suppression of pulmonary P. aeruginosa infection and
improvement in lung function. Use of IV anti-pseudomonal antibiotics and hospitalizations
due to respiratory events were similar. TIP provided comparable efficacy to TOBI 300 mg
administered by nebulizer, but with a faster administration time that results in approximately
70% shorter administration time, not including further time savings for relative to setup,
cleaning, and disinfection of the TOBI nebulizer.
The data from Studies C2301 and C2303 fell within the expected range of clinical variability,
particularly when Study C2303 is adjusted for key sensitivity parameters, with the point
estimate of effect in the 8-10% range, and support the conclusion that the proposed dose is
effective. The minor improvements to one step of the TIP manufacturing process did not
affect the qualitative or quantitative composition, aerosol performance, or other
physicochemical characteristics of the drug product pertinent to in vivo action and were not a
likely contributor to the observed variability between Studies C2303 and C2301.
The T-326 Inhaler used for administration of TIP offers a considerably shorter administration
time compared with TOBI, which increases patient satisfaction and reduces treatment burden.
In two user handling studies, children and adults demonstrated safe and effective use of the T326 Inhaler. Thus, TIP offers an important alternative therapeutic option for the CF patient to
obtain the clinical benefits of inhaled tobramycin in a faster, simpler and more portable way.
The risks associated with TIP use are anticipated to be similar to TOBI, given that the same
active compound (tobramycin) is delivered to the lungs in both products and that the systemic
exposure of both is the same. TIP has a comparable safety profile to TOBI, and the increased
TIP-specific AEs (e.g., cough, dysgeusia and dysphonia) appear to be related to the dry
powder delivery. Of note, patients who experience mild to moderate cough following
inhalation still experienced the benefits of TIP, and in cases where tolerability proves to be
problematic, the option to switch back to nebulized tobramycin or to select an alternative
inhaled antibiotic remains.
In conclusion, the data summarized in this briefing document demonstrate that:
The dose of TIP is comparable to that of TOBI from a systemic exposure perspective.
The efficacy of TIP is superior to placebo.
TIP offers the well-established efficacy of TOBI, and with comparable systemic safety,
albeit with some increase in local AEs such as cough, dysgeusia, and dysphonia.
TIP substantially reduces CF patient treatment burden.
Thus, TIP is a treatment option that can contribute significantly to the improved care of
patients with CF.
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Briefing document
Introduction and background
2.1
Cystic fibrosis: burden of disease
Cystic fibrosis is an autosomal recessive disease and is the most common life-shortening
monogenetic disease affecting Caucasians (Cunningham and Taussig 2003). It is estimated
that there are up to 30,000 CF patients in the United States and about 60,000 worldwide
(Gibson et al 2003). CF is a complex multi-organ disease in which a mutation in the CF
transmembrane conductance regulator gene affects chloride-channel proteins and chloride ion
transport in a variety of tissues, most notably in the lungs and pancreas (Collins 1992). CF is
characterized by effects on the exocrine pancreas, intestine, respiratory tract, reproductive
system, hepatobiliary system, and exocrine sweat glands. Particularly important is a gradually
progressive obstructive lung disease due to the viscous endobronchial secretions which
accumulate in the airways and which are associated with impaired mucociliary clearance and
increased susceptibility to endobronchial infections. Pulmonary function tests (PFTs) are used
to monitor respiratory disease progression in CF, with the rate of decrease in FEV1 correlating
with the severity of disease progression (Corey et al 1997).
The most frequently reported respiratory symptoms associated with CF are cough, fatigue,
chest congestion and wheezing and difficulty breathing/shortness of breath (Goss et al 2009).
Cough may also be associated with gastroesophageal reflux, which is a recognized problem in
CF patients (Fathi et al 2009). Recurrent respiratory infections result in an increasing
frequency of hospitalization in adolescence and early adulthood. CF is also associated with
the production of viscous digestive secretions, along with pancreatic insufficiency, diabetes
and obstructive hepatobiliary disease.
Significant progress has been made in the treatment of CF over the last 20 years and the
median predicted age of survival has steadily improved, reaching 38.3 years by 2010, as
reported in the US Cystic Fibrosis Foundation Patient Registry. Despite the improvement in
median predicted survival, median age of death in the US is 26 years of age (CFF Patient
Registry Report 2007). CF pulmonary disease remains the leading cause for morbidity and
mortality in CF patients, and accounts for the majority of deaths (Ramsey et al 1999).
2.2
Pseudomonas aeruginosa infection and treatment
Infection with Pseudomonas aeruginosa (P. aeruginosa) in the lung is a major problem . Over
half of all CF patients (both children and adults) become chronically infected during their
lifetime. In adult patients, the rate can be up to 80% (CFF Patient Registry Report 2011). P.
aeruginosa infection is particularly debilitating and life-threatening in CF patients due to the
damage it causes to lung tissue and consequent increase in breathing difficulties. The
infections become chronic and this accelerates the progression of obstructive lung disease
(Ballmann et al 1998). P. aeruginosa infection is one of the most significant limiting factors
in the survival of patients with CF. Those who acquire chronic P. aeruginosa infection have a
2.6 times higher risk of death compared to patients without chronic P. aeruginosa infection
(Emerson et al 2002). Effective treatment of P. aeruginosa remains an essential clinical goal
in the treatment of CF and the use of the antibiotic tobramycin delivered via the inhaled route
remains central to this clinical need.
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Inhalation antibiotic therapy offers a good alternative to systemic (intravenous or

intramuscular) administration, delivering high concentrations of antibiotic directly to the site
of infection in the endobronchial space, while minimizing systemic bioavailability and the
AEs such as oto- and nephrotoxicity, which are associated with systemic aminoglycosides.
Tobramycin solution for inhalation via a nebulizer (TOBI) was first approved in the United
States in 1997 for the management of CF patients 6 years of age and older with P. aeruginosa
infection. TOBI is now approved in 43 countries. The recommended administration of TOBI
is by repeated cycles of 28 days on-drug at a nebulized dose of 300 mg twice daily, followed
by 28 days off-drug. The use of inhaled tobramycin has become a standard of care option for
the treatment of chronic P. aeruginosa infection and is advocated by the Cystic Fibrosis
Foundation (Campbell and Saiman 1999, Flume et al 2007, Flume et al 2007), the European
consensus (Heijerman et al 2009), and the Cystic Fibrosis Trust (Cystic Fibrosis Trust 2011).
Inhaled aztreonam (Cayston) is also an inhaled antibiotic therapy used to treat P. aeruginosa
infection in CF patients in the United States.
2.3
CF patients need less burdensome treatment options to improve

adherence
The treatment burden for CF patients (and their families) is extremely high. Maintenance
therapy includes a range of inhaled and systemic medications along with physiotherapy and
exercises and often takes several hours each day to perform. In addition to inhaled antibiotics,
other treatments that may be a part of a CF patients regimen include:
pancreatic enzymes to aid digestion (especially of fats); vitamin supplements due to
malabsorption; nutritional supplements to aid growth/maintenance of a suitable body mass
index (BMI),
drugs (e.g., DNAse, hypertonic saline) and physical therapies to aid clearance of the viscid
mucus from the lungs,
bronchodilators (both beta-agonists and anticholinergics, and inhaled corticosteroids for
some patients) and other drugs used for their anti-inflammatory purposes (e.g.,
azithromycin or ibuprofen) to improve pulmonary function.
The overall time required to administer all the required treatments (including bronchodilators,
antibiotics and mucolytics), as well as perform physiotherapy and exercise, can be as long as
2 to 3 hours each day (Bell and Robinson 2007). The high level of daily treatment activity
applies for CF patients regardless of age or disease severity. Among the 204 respondents in
the Project on Adult Care in CF, the median number of daily therapies reported was 7, and the
respondents reported a median of three inhaled and three oral therapies on the day prior to the
survey (Sawicki et al 2009). The mean reported time spent on treatment activities was 108
minutes per day. This is a substantial treatment burden for a chronic disease, and is associated
with poor compliance with therapy (Arias Llorente et al 2008).
Adherence with the large and demanding daily treatment regimen is a recognized and
significant problem in the CF community. Only 61.8% of patients in a cross-sectional study
were adherent to their respiratory medications, whereas adherence to digestive medications
was about 90% (Arias Llorente et al 2008). Despite the benefits of inhaled antibiotics, Modi et
al (2006) reported adherence rates of 36% for inhaled antibiotics based on daily phone diary
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entries, suggesting the need for significant improvements in adherence. In addition to low
adherence to dosing frequency, studies have also found low adherence to treatment process,
such as nebulizer cleaning (Lester et al 2004, Blau et al 2007). Related to this, studies have
found most nebulizers to be contaminated by bacteria, including P. aeruginosa and
Staphylococcus aureus (Blau et al 2007, Rosenfeld et al 1998).
Complexity of treatment and duration of administration are cited among the most important
factors affecting the adherence in several review articles (Weiner et al 2008, Abbott et al
2009). Perceived increases in treatment burden have been associated with increasing numbers
of nebulized therapies and increased airways clearance time, irrespective of gender, age, or
pulmonary function. A longitudinal study in patients with CF showed that over a 12-week
period the mean number of days on which nebulized antibiotics were used as prescribed was
31.6% (Latchford et al 2009), while 8.8% of patients in the cross-sectional study said that they
did not take respiratory medications because they did not have time (Arias Llorente et al
2008). This supports anecdotal data obtained through CF patient focus group meetings in
which CF patients indicated that their adherence with medication could be improved by
decreasing the administration times.
Therefore, there remains a high clinical need to ease the treatment burden in patients with CF.
The need to improve the burden is substantially more than just patient convenience. A central
issue is improving low rates of adherence because this has been associated with better clinical
outcomes (fewer exacerbations, slower lung function decline, lower morbidity). In a study of
804 patients with CF, only 7% had high TOBI use (defined as 4 cycles/year vs. 6
recommended cycles/year with full adherence). Those patients with high TOBI use had a
decreased risk of hospitalization relative to those with low use (2 cycles) with an adjusted
odds ratio of 0.40. This further highlights the low adherence rates with TOBI and
demonstrates that better outcomes are achieved when patients are more adherent to therapy
(Briesacher et al 2011). Although not demonstrable in controlled clinical trials, improvements
in adherence with administration or delivery in medication could lead to improved efficacy in
the day-to-day clinical management of CF patients where adherence is typically substantially
worse than in clinical trials.
Although highly successful in the treatment of P. aeruginosa infections in CF patients, the use
of a nebulized solution of tobramycin is associated with limited adherence. The nebulization
time for one dose of TOBI (one 5 mL vial; 60 mg/mL) with the PARI LC PLUS and the
DeVilbiss Pulmo-Aide compressor is approximately 15-20 minutes, twice a day. Newer
mesh nebulizers are faster, but have not been approved to be used with TOBI and may result
in important differences in dose delivery. Furthermore, the described times do not include the
additional time required to prepare the dose, assemble the nebulizer and compressor, and
disassemble, clean, and disinfect the device afterwards. These unaccounted activities have
been found to add at least an additional 10-15 minutes per treatment (VanDevanter and Geller
2011), for a total of approximately 50 to 70 minutes per day. Furthermore, in a study
evaluating the performance of different nebulizers, Rottier et al (2009) found decreases in
performance of both eFlow and LC Plus nebulizers over time, as well as considerable
differences between them with respect to particle sizes. This emphasizes the complexity and
challenges presented by nebulizers and highlights the need for a simpler and faster treatment
option.
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2.4
Tobramycin inhalation powder (TIP)
Novartis developed TIP as a faster, simpler, more portable treatment option to reduce the
significant treatment burden for CF patients requiring treatment for their pulmonary P.
aeruginosa infection.
TIP is an inhalation powder hard capsule formulation of tobramycin (28 mg tobramycin per
capsule), administered via the T-326 Inhaler, a hand-held, manually-operated, breathactivated, DPI.
The proposed indication for TIP is the management of cystic fibrosis patients with P.
aeruginosa. This is the same indication as TOBI. The recommended dosage of TIP for both
adults and pediatric patients 6 years of age and older is the inhalation of the contents of four
28 mg capsules twice daily. TIP is administered in the same dosing regimen as TOBI: twicedaily in alternating periods of 28 days. After 28 days of therapy, patients stop TIP therapy for
the next 28 days, and then resume therapy for the next cycle of 28 days on/28 days off
treatment.
In contrast to TOBI, which takes about 15-20 minutes per dose, TIP can be administered in
approximately 5 minutes. The time saved in dose administration per treatment cycle is
approximately 9-14 hours. Assembly, cleaning and disinfection as needed for a nebulizer is
not required for TIP, saving approximately another 10 hours per treatment cycle. TIP also has
significant benefits over TOBI with regard to storage and portability and can be used without
an external power source. TIP can be stored at room temperature for at least 36 months (TOBI
has to be refrigerated for prolonged storage). TIP delivers the same active ingredient as TOBI
at comparable tobramycin exposure in a faster, simpler way aimed at reducing the treatment
burden and thereby facilitating adherence.
2.5
Regulatory history
2.5.1
U.S.
An Investigational New Drug (IND) application for TIP was filed by Chiron Corporation, the
original sponsor, on May 23, 2003. The Phase III program supporting approval was agreed
with FDA in 2004, and consisted of Study C2301, a three cycle efficacy study with placebo
control in the first cycle; and Study C2302, a safety study with both TIP and TOBI arms. In
April 2006, Novartis acquired Chiron and took over the development of TIP and the ongoing
Phase III studies.
In November 2007, Novartis met with FDA to discuss minor improvements to one step of the
manufacturing process for TIP (described in Section 7.3.1 and Section 13 - Appendix 1),
required to ensure a robust and reproducible process for commercialization, noting that the
qualitative and quantitative formulation of the drug product was unchanged. Novartis also
presented comparative technical data on the physicochemical and aerodynamic characteristics
of the drug product as manufactured by the Phase III and improved processes. While Novartis
believed that these data adequately supported comparability, the FDA requested additional
clinical data to confirm equivalent efficacy and safety of the product manufactured with the
improved process with the product used in the Phase III studies (C2301 and C2302).
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A new clinical study was proposed to meet the FDA request. On further discussion, FDA
specified that a placebo control and the inclusion of patients nave to inhaled tobramycin
needed to be essential elements of the study. Thus, the final design, incorporating FDA
feedback, was a one-cycle study of TIP (from the improved process) vs. placebo. This study,
Study C2303, which became the second placebo-controlled efficacy study in the TIP program
and the third Phase III study required for New Drug Application (NDA) submission in the US,
had its first patient visit in June 2009.
After extensive efforts to overcome the severe difficulty in global recruitment for Study
C2303, due to its placebo-controlled design and requirement for patients who had not taken
inhaled tobramycin within 4 months prior to screening, Novartis met with FDA in February
2011 to discuss these challenges as well as the prospect of having to conclude the study with
fewer than the planned 100 patients. Shortly after this meeting, having exhausted all the
possibilities for recruitment, Novartis terminated recruitment for Study C2303 and completed
the study with 62 patients.
Novartis submitted the TIP NDA on December 21, 2011, with Studies C2301, C2302, and
C2303 constituting the Phase III clinical development program.
2.5.2
Global
As of early August 2012, TIP is approved in 37 countries. The first filing for market
authorization of TIP (as TOBI Podhaler) took place in the European Union (EU) in
December 2009 via the Centralized Procedure. It was approved by the European Commission
in July 2011. Additional approvals were obtained in Canada (April 2011), Switzerland
(February 2012) and Australia (February 2012).
With the exception of Russia, where the Health Authority requested the results of Study
C2303, based on the participation of Russian patients, the approvals to date have been based
on Studies C2301 and C2302, and comparative technical data to support the minor
manufacturing process improvement. The results of Study C2303 were requested for
submission as a post-approval commitment by the European Medicines Agency (EMA) and
were submitted in December 2011.
Product description
TIP, an inhalation powder hard capsule formulation of tobramycin (28 mg tobramycin per
capsule) is to be administered via the T-326 dry powder inhaler. The inhalation powder is
composed of porous particles (PulmoSphere) with a size range appropriate for lung
delivery.
Drug substance
Tobramycin (Figure 3-1) belongs to the aminoglycoside class of antibiotics. The compound is
a member of a broad-spectrum antibiotic complex, nebramycin, isolated from the fungus
Streptomyces tenebrarius.
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Figure 3-1
Tobramycin drug substance
Drug product
TIP is manufactured from tobramycin, sulfuric acid, 1,2-distearoyl-sn-glycero-3phosphocholine (DSPC), calcium chloride, perfluorooctyl bromide (perflubron, PFOB), and
water using the Novartis proprietary PulmoSphere formulation technology. These are
combined to produce an oil-in-water emulsion which is then spray dried. During spray drying
of this emulsion, water and PFOB are removed by evaporation, leaving porous particles. The
composition of TIP is presented in Table 3-1.
Table 3-1
Composition of the drug product
Ingredient
Tobramycin
Sulfuric Acid
1,2-distearoyl-sn-glycero-31
phosphocholine (DSPC)
Calcium Chloride
2
Water for injection
2
Perflubron
Theoretical amount
per capsule
63%
22%
14%
1%
-
Function
Active ingredient
Salt forming agent and pH
adjuster
Wall forming agent
Wall forming agent
Processing aid
Processing aid and pore forming
agent
DSPC is a component of endogenous lung surfactant belonging to the lecithin class of compounds,
and widely used to formulate drug products administered by pulmonary, oral, intravenous,
intramuscular, and dermal routes
2
Removed to residual levels during processing
The particles exhibit a characteristic sponge-like morphology that results in significantly

lower inter-particle cohesive forces than solid non-porous particles (Figure 3-2). This
facilitates powder fluidization and dispersibility without the need to blend with larger carrier
particles as in traditional dry powder formulation technology. The lack of lactose dilution and
the gain in delivery efficiency commensurate with engineered particles enables a larger drug
load per capsule and delivery of larger lung doses via inhalation.
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Briefing document
Figure 3-2
Scanning electron micrograph of PulmoSphere particles
The bulk powder is then filled into transparent hypromellose capsules which are individually
sealed in aluminum blister packs.
For a summary of the TIP manufacturing process development, please see Section 13 Appendix 1.
Delivery device and use
TIP is delivered to the lung by the T-326 Inhaler, which is a hand-held, manually-operated,
breath-activated, capsule based unit dose dry-powder inhaler (DPI) that uses no stored power
sources or electronics (Figure 3-3).
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Figure 3-3
T-326 Dry Powder Inhaler (T-326 Inhaler)
To administer the drug, the patient inserts the capsule into the chamber of the device by
removing and replacing the mouthpiece, piercing the capsule by pressing the button, inhaling
twice and inspecting the capsule for confirmation of delivery. Inspiratory flow produced by
inhalation evacuates the powder from the pierced capsule, disperses it into the inspiratory air
stream, and delivers the aerosol into the lung. The resistance of the T-326 Inhaler (0.08
cmH2O0.5/LMP) and the selected capsule fill mass ensure that most patients (including
pediatric patients as young as 6 years old) can empty the contents of the capsule with a single
inhalation. The second inhalation ensures that even patients with low inspired volume are also
able to inhale the full capsule content.
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One dose consists of inhaling the contents of four capsules. Two doses are taken each day
(morning and evening).
The intended commercial packaging contains the medication required for a 28 day treatment
and supports the established 28 day on off cycle treatment. Each 4-week (28 day supply) kit
contains:
Four weekly boxes: each weekly box contains 7 blister cards (one for each day of the
week). Each blister card contains 8 capsules per blister card (4 for the morning dose and 4
for the evening dose) and one T-326 Inhaler in its case
1 reserve T-326 Inhaler in its case.
The usability of the T-326 Inhaler was assessed in two summative user handling studies
(human factors engineering handling studies) performed in the US and EU, respectively.
These studies evaluated the successful completion of the use steps described in the
corresponding IFU. A usability assessment was made on first use and at the return visit after
completing a 5-day period of simulated use at home. The return visit was intended to
investigate whether patients could still use the product correctly. These studies were done in
82 CF patients, or subjects representative of CF patients, aged 6 years and older. Throughout
both studies, children and adults were able to demonstrate good use of the T-326 Inhaler. The
subjects understood the operation of the T-326 Inhaler, and the majority of users preferred the
T-326 Inhaler to a nebulizer. Additional information regarding the human factors engineering
studies can be found in Section 10.
Pharmacology
4.1
Pharmacokinetics and pharmacodynamics
4.1.1
Clinical pharmacokinetics
The pharmacokinetics (PK) of tobramycin after intravenous administration have been

extensively described in the literature (Neu 1976, Pechere and Dugal 1976, Pechere and
Dugal 1979). After parenteral administration, tobramycin distributes throughout extracellular
water and highly perfused tissues and has an apparent volume of distribution in the range of 7
to 35 L (0.1-0.6 L/kg). Binding of tobramycin to serum proteins is negligible (Gordon et al
1972), thus tobramycin free drug concentrations are not expected to be affected by any
changes in serum protein concentrations. Tobramycin is not metabolized and is excreted
unchanged principally by glomerular filtration with some tubular re-absorption. Tobramycin
is cleared from serum with a half-life of the first elimination phase of approximately two
hours; this half-life is dependent upon renal function, and increases with decreasing creatinine
clearance.
Tobramycin is not absorbed to any appreciable extent when administered via the oral route
(Neu et al 1976). Thus, the systemic exposure to tobramycin after inhalation is expected to
result from pulmonary absorption of the dose fraction delivered to the lungs. Therefore, the
PK behavior of systemically absorbed tobramycin resulting from the inhalation route is
expected to be the same as in intravenous administration. Based on the similar exposure to
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TOBI and overall low systemic exposure, metabolism, and elimination (renal impairment)
assessments were not performed with TIP.
Tobramycin PK has been characterized for TOBI (Geller et al 2002, Cheer et al 2003). The
mean SD serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose
of TOBI by CF patients was 0.95 0.5 g/mL and the mean SD sputum concentration of
tobramycin was 1237 1090 g/g ten minutes after inhalation (Geller et al 2002). Tobramycin
did not accumulate in serum or sputum after multiple 300 mg b.i.d. TOBI administration. The
absolute bioavailability of TOBI was estimated to be 11.7% based on cross-study comparison
of clearance estimates after inhalation of TOBI and intravenous administration of tobramycin
(Geller et al. 2002).
PK information for TIP has been collected from a healthy volunteer lung deposition study
(INH-007) and a dose-escalation study in CF patients (TPI001); sparse PK data was collected
from three Phase III studies C2301, C2302 and C2303. All these PK data are summarized
below.
4.1.2
TIP pharmacokinetics in Phase I studies
Regional lung distribution of a prototype TIP formulation and of the approved TOBI
formulation in healthy volunteers was investigated by gamma scintigraphy using Technetium
(99mTc)-labeled formulations of both TIP and TOBI (Study INH-007, published as Newhouse
et al 2003). The distribution data from this study showed that 34% of the TIP dose and 5% of
the TOBI dose (dosing with the nebulizer was stopped after 15 minutes) were deposited in the
lungs. The ratio of peripheral to central lung deposition (P/C ratio) was calculated as an index
of regional lung deposition of tobramycin. The relative distribution of radiolabel within the
central, intermediate, and peripheral airways was similar for TIP and TOBI. Tobramycin
deposition was greater in the peripheral than the central airways for both TIP and TOBI, as
indicated by a mean SD P/C ratio of 1.6 0.4 for TIP and 1.5 0.4 for TOBI.
In the dose-escalation study in CF patients (Study TPI001, published as Geller et al 2007),
tobramycin was rapidly absorbed after inhalation of a single dose of TIP (28 mg, 56 mg, 84
mg and 112 mg of tobramycin). Pharmacokinetic samples were taken at pre-dose and 0.5, 1,
2, 4, 8, 12 hours after the start of the first tidal breath during inhalation of study treatment.
Maximum serum concentrations were observed at approximately 1 hour post dose, with a
terminal half-life of approximately 3 hours. A single dose of 112 mg TIP showed comparable
systemic and sputum exposure, variability and elimination half life (T1/2) to the approved 300
mg dose of TOBI in CF patients (Table 4-1, Figure 4-1). Variability in sputum tobramycin PK
was substantially higher than observed for serum (Table 4-1), consistent with previous studies
of inhaled tobramycin in CF patients (Geller et al 2002). The range of tobramycin maximum
concentration (Cmax) in sputum was 86 3609 g/g for 112 mg TIP and 20 4737 g/g for
300 mg TOBI. Taking the variability into account, the range of sputum levels, along with the
comparable serum exposure (which effectively comes from only the portion of the dose
entering the lungs), demonstrated that 112 mg TIP resulted in lung exposure that was similar
to 300 mg TOBI, and therefore the 112 mg dose was selected for subsequent Phase III studies
(See also Section 5.1).
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Table 4-1
Serum and sputum pharmacokinetic parameters of TIP (112 mg) vs.

TOBI (300 mg) - Study TPI001
Serum
n
Tmax (h)
Sputum
TOBI
(300 mg)
TIP
(112 mg; 4 x 28mg
capsules)
TOBI
(300 mg)
TIP
(112 mg; 4 x 28mg
capsules)
20
12
20
11
1 (0.5-2)
1 (0.5-2)
0.5 (0.5-2.0)
0.5 (0.5-1.0)
0.92 (0.40, 2.10)
0.90 (0.38, 2.11)
402 (58, 2806)
640 (104, 3936)
AUC0-12h (g.h/mL)
4.27 (1.82, 9.99)
4.29 (2.20, 8.37)
461 (34, 6265)
877 (137, 5622)
AUCinf (g.h/mL)
4.77 (2.19, 10.40)
4.74 (2.51, 8.96)
1008 (307, 3306)
1599 (796, 3214)
3.1 (2.0, 4.7)
3.2 (2.5, 4.0)
2.5 (0.6, 10.7)
2.7 (0.9, 8.2)
Cmax (g/mL)
T1/2 (h)
Data are presented as geometric mean (90% CI), except for Tmax, which is presented as median
(range)
Figure 4-1
Mean serum concentration-time profiles of tobramycin after

administration of TOBI (300 mg) and escalating doses of TIP (28, 56,
84, and 112 mg) to CF patients
For clarity, error bars ( one SD) are displayed for TOBI 300 mg (blue) and TIP 112 mg (red) dose
groups only
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4.1.3
TIP pharmacokinetics in Phase III studies
Sparse PK samples were collected in the Phase III studies. In Study C2301, serum PK
samples were collected at pre-dose and 1-h post-dose; in Study C2302, PK samples were
collected at pre-dose, 0 2 h post-dose, and 2 5 h post-dose; in Study C2303, PK samples
were collected at pre-dose, 0 1 h post-dose, 1 2 h post-dose, and 2 6 h post-dose.
As expected, serum tobramycin concentrations after multiple b.i.d. inhalation of 112 mg of
TIP (Study C2301, Study C2302, Study C2303) were low relative to the systemic levels
recommended for avoidance of the toxicity associated with intravenous tobramycin therapy
(peak and trough levels exceeding 12 g/mL and 2 g/mL, respectively) (Sweetman 2011).
The highest mean serum tobramycin concentrations of TIP observed in Phase III studies were
1.61 (90% CI 0.59 4.41) g/mL for peak (at 1 hour post-dose) and 0.31 (90% CI 0.11
0.82) g/mL for trough (pre-dose) concentrations (Table 4-2), which were approximately sixfold lower than the respective toxicity-associated systemic levels. Minimal accumulation of
tobramycin in serum, consistent with the short half-life, was observed based on trough
concentration levels after multiple b.i.d. administration in the Phase III studies.
While comparison of tobramycin pharmacokinetics between TIP from the improved process
(Study C2303) and TIP produced prior to the improvement of the manufacturing process
(Studies TPI001, C2301 and C2302) was not possible due to the sparse sampling schedule of
the Phase III studies, comparison of tobramycin concentration data at the end of a 28-day
treatment period across Phase III studies shows that steady-state peak and trough
concentrations are similar across studies with similar variability (Table 4-2 for serum and
Table 4-4 for sputum).
Table 4-2
Summary of serum tobramycin concentrations across studies C2301,

C2302 and C2303 at the end of a 28-day dosing cycle
C2302
C2301
C2302
C2303
TOBI 300 mg
TIP 112 mg
TIP 112 mg
End of cycle,
approximate peak
1.02 (0.38, 2.73)
1.61 (0.59, 4.41)
1.21 (0.64, 2.28)
TIP 112 mg,

improved
manufacturing
process
1.40 (0.60, 3.25)
End of dosing cycle

trough (pre-dose)
0.27 (0.08, 0.87)
0.24 (0.03, 2.08)
0.31 (0.11, 0.82)
0.26 (0.04, 1.81)
Peak collected at
0 2 h post-dose
n=6
Peak collected at
1 h post-dose
n=71-76
Peak collected 0
2 h post-dose
n=11 - 12
Peak collected 0 1 h
post-dose
n=29-30
Tobramycin
concentration
(g/mL)
Comments
Data presented as geometric mean (90% confidence intervaI).

For Studies C2301 and C2302, PK concentration data included two dosing cycles; for study C2303,
concentration data included one dosing cycle
4.1.4
Population pharmacokinetics of TIP
Population pharmacokinetic (PopPK) analysis of data from Study TPI001, Study C2301 and
Study C2302 indicated that age (range 6 to 58 years), gender and renal function (minimum
creatinine clearance was 63.9 mL/min in the model population) do not affect the PK of
tobramycin after TIP administration. BMI and lung function (forced expiratory volume in one
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second as percentage of the predicted value at baseline - FEV1% predicted) were identified as
covariates affecting the apparent volume of distribution of central compartment (Vd/F).
However, model-based simulations showed that changes in BMI or FEV1% predicted over the
90% range of their sample distributions in the PK population changed tobramycin peak
(Cmax) and trough (Ctrough) concentrations by less than 20% (Table 4-3). These mean
predicted Cmax and Ctrough values were at least 7.6-fold and 5.1-fold lower, respectively,
than the systemic concentration levels associated with tobramycin therapy toxicity (i.e.: >12
g/mL for Cmax, >2 g/mL for Ctrough). Given the wide safety margin, the <20% effect of
BMI and FEV1% predicted on the concentration levels of tobramycin after administration of
112 mg b.i.d. TIP are not expected to be clinically relevant.
Table 4-3
Predicted mean Cmax and Ctrough at steady state for subjects with a
range of values of BMI or FEV1% predicted at baseline
Covariate
Mean Cmax (g/mL) [95% PI]
Mean Ctrough (g/mL) [95% PI]
BMI (13.3 kg/sq m) (5%)

BMI (25.1 kg/sq m) (95%)
FEV1% predicted (29.7%) (5%)
FEV1% predicted (102.5%) (95%)
1.57 [0.65 - 3.01]

1.3 [0.56 - 2.56]
1.22 [0.52 - 2.49]
1.48 [0.64 - 2.97]
0.32 [0.04 - 1.02]

0.38 [0.06 - 1.19]
0.39 [0.07 - 1.16]
0.32 [0.05 - 0.97]
th
th
When BMI was varied between 5 and 95 percentiles of its sample distribution in the PK model
population, FEV1% predicted was fixed at population median 62.1%. When FEV1% predicted was
th
th
2
varied between 5 and 95 percentile, BMI was fixed at population median 18.8 kg/m . PI: predictive
interval.
A population PK modeling approach (posterior predictive check) was used to show that serum
exposure to tobramycin from TIP, as manufactured by the improved process used in Study
C2303 (Section 13 - Appendix 1), is statistically equivalent to the exposure predicted by the
population PK model developed with data from Studies TPI001, C2301 and C2302 prior to
the manufacturing process improvement. This approach evaluates whether the concentrations
observed in Study C2303 (TIP from the improved manufacturing process) were consistent
with the population PK model of TIP, using visual predictive check as well as statistical
diagnostic tests on concentrations simulated with the model. Examination of covariates of
patients in Study C2303 showed that distributions of their BMI, FEV1% predicted, age and
creatinine clearance at baseline were within the range of values of CF patients in the three
studies used for developing the population PK model, thus justifying comparison with
simulated concentrations. A distribution of serum concentrations was then generated using the
population PK model based on the TIP dosing regimen and covariates of patients in Study
C2303. As illustrated by the visual predictive check plot (Figure 4-2), variability and central
tendency of observed concentrations of tobramycin in Study C2303 were in agreement with
the concentrations predicted from the population PK model. Statistical tests (normalized
prediction distribution error tests) also indicated that the predicted and the observed
distributions of concentrations are consistent. Therefore tobramycin systemic exposure from
administration of TIP manufactured via the improved process was statistically equivalent to
the exposure expected after inhalation of TIP prior to the process improvement. Thus, the
dose fraction delivered to the lungs following inhalation of TIP, and the resulting serum
exposure, were not affected by the improvements to the manufacturing process.
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Figure 4-2
Tobramycin serum exposure is consistent for TIP manufactured by

the improved process and TIP used in the Phase III program.
Concentrations for TIP improved (circles) are in the range of probable
(90%) concentrations for TIP Phase III (gray). Average profile for TIP
improved (dashed line) is consistent with average profile for TIP
Phase III (solid line)
Left panel: data from Day 1. Right panel: data from Day 28. White circles: observed data from Study
C2303; dashed line: cubic spline fit of the data; solid line: mean of predicted concentrations by
population PK model; gray area: 5th and 95th percentiles of the predicted concentration distribution
4.1.5
Pharmacodynamics
No formal pharmacodynamic assessments were performed for TIP. The pharmacodynamic

experiences with parenteral tobramycin and TOBI are extrapolated to TIP and verified in the
Phase III studies. The pharmacodynamic effect of interest for TIP, as for TOBI, is the
bactericidal effect of tobramycin on P. aeruginosa in the lungs of the patients, which in turn
will result in improvement of lung function and other clinical parameters. The basic rationale
for inhaled tobramycin is to deliver high concentrations of antibiotic directly into the lungs,
that are multiples of the MIC of P. aeruginosa.
The antibacterial effects of aminoglycosides are known to be concentration dependent.
Tobramycin kills bacteria, including P. aeruginosa, in a concentration-dependent manner, and
the higher the peak concentration of the drug the greater the degree of bacterial killing
(Moriarty et al 2007).
For the management of CF patients with P. aeruginosa, both the concentration and bioactivity
of the tobramycin in the lung are key factors. It has been shown that sputum may counteract
the bioactivity of antibiotics in several ways. Components of in vitro sputum are known to
bind aminoglycosides, thereby potentially reducing their bioactivity (Levy et al 1983;
Mendelman et al 1985). Sputum has a high ionic strength and contains macromolecules and
high concentrations of divalent cations, all of which contribute to the in vitro inhibition of
tobramycin activity. In vitro studies demonstrated that in the presence of sputum, a 10-fold
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excess of tobramycin was required to suppress the growth of P. aeruginosa. These findings
contributed to the argument that in order to achieve optimal efficacy in sputum,
aminoglycosides should be used at considerably higher doses than needed for similar
antibacterial effects elsewhere in the body (Mendelman et al 1985). In early studies of
tobramycin, a sputum concentration of tobramycin greater than 128 g/g were proposed to be
adequate for therapy as it was found to be at least 10-fold higher than the MIC of 90% of
patient isolates studied at that time (Eisenberg et al 1997).
TIP treatment achieves high concentrations of tobramycin in sputum with levels comparable
to, or greater than, those observed for TOBI. The geometric mean (90% CI) of sputum Cmax
values after single dose of 112 mg TIP and 300 mg TOBI were 640 (104, 3936) g/g and 402
(58, 2806) g/g, respectively, in Study TPI001 (Table 4-1). In Studies C2302 and C2303
where subjects provided expectorated sputum samples at collection windows of pre-dose, 0
0.5 h and 0.5 2 h post-dose after multiple dosing, similar high sputum peak concentrations
were achieved (Table 4-4).
In comparison to MIC values in Study C2302, at baseline and at end of Cycle 3 dosing (Week
21), 91.2% and 86.4% of TIP patients, respectively, had P. aeruginosa isolates (including all
biotypes) with MIC values of 64 g/mL or less; these were at least 13-times lower than the
mean sputum concentration of tobramycin seen within 0.5 hour of the dose (geometric mean
865 g/g), Table 4-4). In Study C2303, at baseline and at the end of the one month treatment
cycle (Day 29), 96.9% and 100% of the TIP patients, respectively, had P. aeruginosa isolates
(any biotype) with MIC values of 8 g/mL or less; these were at least 100-times lower than
the mean sputum tobramycin concentration observed within 0.5 hour of the dose (geometric
mean 870 g/g, Table 4-4).
These data indicate that inhalation of TIP results in local sputum concentrations that are much
higher than the MIC values in most, if not all, patients. This provides support that TIP allows
local delivery of tobramycin to achieve a high concentration in the lungs to maximize the
therapeutic effect at the infection site.
Table 4-4
Summary of sputum tobramycin concentrations across studies C2302

and C2303 at the end of a 28-day dosing cycle
Tobramycin
concentration (g/g)
C2302
C2302
C2303
TOBI 300 mg
TIP 112 mg
TIP 112 mg,

improved manufacturing
process
End of dosing cycle,

approximate peak
768 (145, 4081)
865 (179, 4172)
870 (75, 10077*)
End of dosing cycle

trough
91 (18, 446)
67 (12, 374)
262 (15, 4578*)
Peak collected 0 0.5

h post-dose
n=4-6
Peak collected 0 0.5 h

post-dose
n=9-13
Peak collected 0 0.5 h

post-dose
n=26-27
Comments
Data presented as geometric mean (90% CI)

For Studies C2301 and C2302, PK concentration data included two dosing cycles; for study C2303, concentration
data included one dosing cycle
* Large CI due to three samples of extreme high values.
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4.2
Summary
As an inhalation drug product, TIP delivers high concentrations of tobramycin directly to the
lungs while minimizing systemic exposures. Since tobramycin has negligible gastrointestinal
absorption, systemic exposure to tobramycin after inhalation is expected to result from
pulmonary absorption of the dose fraction delivered to the lungs, which is ~34% of the
nominal TIP dose. In CF patients, tobramycin was rapidly absorbed after inhalation of single
doses of TIP, with maximum serum tobramycin concentrations observed at approximately 1
hour post dose and a T1/2 of about three hours. A single dose of 112 mg TIP showed
comparable systemic exposure to the approved 300 mg dose of TOBI, and therefore was
selected for Phase III studies. Mean peak and trough serum tobramycin concentrations
observed after inhalation of 112 mg of TIP were at least 7- and 5-fold lower than the
established systemic toxicity levels (peak concentration 12 g/mL, trough concentrations 2
g/mL), respectively (Sweetman 2011).
Population PK analysis indicated that age, gender, renal function, lung function and BMI did
not have clinically relevant effects on the PK of tobramycin after TIP administration, and no
dose adjustment is warranted. Also, analysis using the population PK model demonstrated that
TIP manufactured by means of an improved manufacturing process resulted in serum
tobramycin exposure that was consistent with those of the Phase III process (Section 13
Appendix 1). Comparison across studies of tobramycin serum exposure after inhalation of TIP
also showed that overall tobramycin systemic exposures were within the same range, and
were multiple folds below toxicity thresholds. In effect, the serum exposures to tobramycin
are comparable for TIP (from either manufacturing process) and TOBI.
Sputum assessments indicated that inhalation of TIP resulted in local sputum concentrations
that are on average 13- to 100-fold higher than the MIC values at baseline in most patients.
These data provide support that TIP allows local delivery of tobramycin to achieve a high
concentration in the lungs to maximize the therapeutic effect at the site of intrapulmonary
infections.
The selected dose: 112 mg twice daily
5.1
Dose selection rationale
The rationale, as agreed with the FDA, for selecting the dose was based upon PK parameters
of TIP in serum rather than pharmacodynamic endpoints in order to build on the extensive
clinical experience gained with TOBI over the decade since its launch. Systemic exposure was
used as the dose selection endpoint in view of the high variability in sputum concentrations of
tobramycin (observed also for TOBI). Systemic exposure is thought to reflect lung deposition
and lung absorption since oral bioavailability of tobramycin resulting from the swallowed
portion of the dose is negligible and thus the serum PK reflects the lung exposure. Results of
the scintigraphy study Study INH-007 showed that administration of this formulation of TIP
resulted in successful delivery of tobramycin to the lung and achieved similar relative
distributions of the dose in the central and peripheral airways when compared to TOBI
(Section 4.1.2).
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Given the known systemic safety profile of aminoglycosides, the goal was to choose a dose
with comparable serum exposure to TOBI with the expectation of achieving a similar safety
profile with respect to oto- and nephrotoxicity (the principal safety concerns with systemic
administration of aminoglycosides). In addition, selection of a TIP dose with similar lung
exposure to TOBI would be expected to produce similar clinical benefits although clinical
data would be required to validate this.
5.2
Dose selection results
To identify a suitable dose for the Phase III program, Study TPI001 was performed. This
randomized, open-label, sequential cohort, active controlled, single-dose, dose escalation trial,
was designed to determine the dose of TIP that would show the most comparable systemic
exposure to the current standard of care TOBI treatment of 300 mg, inhaled twice daily. A
further goal of the study was to demonstrate that the selected dose would have a similar lung
exposure to that achieved with TOBI dose 300 mg.
The selected dose 4 x28 mg TIP was accepted by the Division at the October 6, 2004 End of
Phase 2 meeting. The 112 mg (4 x 28 mg) b.i.d. dose of TIP yielded comparable systemic PK
and safety profile to the approved 300 mg dose of TOBI (Section 4.1.2). The subsequent
Phase III clinical trial Study C2302 compared the safety and efficacy of 4 x 28 mg TIP and
300 mg TOBI, and the efficacy of this TIP dose was evaluated in two double-blind, placebocontrolled trials (Studies C2301 and C2303).
Since this is a new formulation of inhaled tobramycin, it was decided to follow the same dose
regimen as was established for TOBI i.e. twice-daily dosing in cycles of 28-day ontreatment/28-day off-treatment.
Design and analysis of Phase III program
6.1
Overview
The Phase III clinical development program initially consisted of Studies C2301 and C2302,
which began in September 2005 and February 2006, respectively. These two studies, along
with comparative technical data supporting the manufacturing process improvements, formed
the basis of health authority approval of TIP in the EU, Canada, Australia, Switzerland, and a
number of other countries.
Study C2303 was added to the program in response to an FDA request for additional clinical
data in support of the minor improvements to the drug product manufacturing process, as
described in Section 13 - Appendix 1. This study, which began in June 2009, was followed by
two open-label extension studies, C2303E1 (completed) and C2303E2 (ongoing), to provide
further efficacy and safety data.
The design of the three Phase III studies was as follows:
C2301: Double blind study of TIP vs. placebo in CF patients aged 6-21 years for 1 cycle,
followed by 2 cycles of open label TIP treatment. Patients had no exposure to inhaled antipseudomonal antibiotics within 4 months prior to screening,
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C2302: Open label study of TIP vs. TOBI in CF patients aged 6 years for 3 cycles of
treatment. Patients had no exposure to inhaled anti-pseudomonal antibiotics within 28
days prior to study drug administration,
C2303: Double blind study of TIP vs. placebo in CF patients aged 6-21 years for 1 cycle
of treatment. Patients had no exposure to inhaled anti-pseudomonal antibiotics within 4
months prior to screening,
C2303E1 and C2303E2: open-label extensions of 3 cycles each during which all
patients received TIP.
The studies were performed in more than 650 CF patients, which constitutes one of the largest
ever CF clinical development programs. A total of 425 patients received at least one dose of
TIP. All trials utilized the intended dosing regimen (cycles of 28 days on treatment and 28
days off treatment), dose (4 x 28 mg b.i.d.) and delivery device (T-326 inhaler). Patients had
CF, P. aeruginosa infection and FEV1 % predicted in the range 25-80% predicted (75% in
Study C2302).
6.2
Considerations for the design of the Phase III program
The Phase III development program for TIP was designed with the following objectives:
1. To demonstrate superiority of TIP to placebo with respect to efficacy (lung function,
microbiological activity and clinical outcomes (Studies C2301 and C2303) and sustained
efficacy over 3 cycles,
2. To demonstrate clinical comparability between inhaled tobramycin delivered as a DPI
(TIP) vs. the nebulized solution (TOBI) with respect to safety, lung function,
microbiological activity and PK (Study C2302),
3. To confirm the efficacy and safety of the drug product following an improvement to the
manufacturing process (Study C2303),
4. To provide further evidence of the patient benefit provided by TIP using tools such as the
TSQM and Cystic Fibrosis Questionnaire-Revised (CFQ-R).
The design reflected the original TOBI studies by using the relative change in FEV1 %
predicted from baseline as the primary efficacy endpoint. Within the limits of current clinical
practice, the inclusion and exclusion criteria in Studies C2301 and C2303 (placebo-controlled
trials) were designed to include a patient population similar to that used in the original TOBI
registration studies, most notably with respect to being essentially naive to TOBI treatment
(no exposure to inhaled anti-pseudomonal antibiotics within 4 months prior to screening).
Study C2303 was added to the clinical program to meet the Agencys request for further
clinical data following a minor improvement to one step of the drug product manufacturing
process. FDA requested a placebo control arm and the inclusion of patients nave to inhaled
tobramycin as essential elements of the study. The final design, incorporating FDA feedback,
was a one-cycle study of TIP (from the improved process) vs. placebo. The three studies are
described further in the sections below.
The following features of the three Phase III trials are noted:
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Studies C2301 and C2302 were stratified according to age, region, and FEV1 at screening.
Study C2302 was also stratified according to macrolide use. Study C2303 was stratified
according to age and FEV1 at screening,
Relative change from baseline in FEV1 % predicted (together with additional spirometry
measures) was assessed as the primary efficacy endpoint after 28 days treatment (for
Studies C2301 and C2303) and at 5 months-end of Cycle 3 dosing for Study C2302 (as a
key secondary endpoint),
Absolute change in FEV1 % predicted was recommended by FDA as a pre-specified
sensitivity analysis for Study C2303 (and was analyzed retrospectively for Study
C2301),
Microbiological assessments (conducted at a blinded independent Contract Research
Organization [CRO]) of P. aeruginosa CFU density, tobramycin MIC, and the semiquantitative assessment of other bacterial pathogens were collected monthly for up to 2
months (Study C2303) and up to 6 months in the other studies,
The use of other anti-pseudomonal antibiotics (other than inhaled) was permitted as a
treatment option if necessary. This was used as a measure of efficacy as such antibiotic
treatment is directed at the relief of pulmonary exacerbations,
Hospitalizations related to respiratory events (a proxy for exacerbations) were collected to
support the data for the relative change from baseline in FEV1 % predicted,
Patient reported outcomes were assessed over 6 months (TSQM in Study C2302), and
over 2 months (CFQ-R in C2303), in support of the patient benefit anticipated for TIP, in
addition to measurement of treatment administration time of TIP and TOBI,
TOBI, the only approved inhaled antibiotic in this indication in the US at the time the
development program was started, was used as the active comparator (Study C2302) for
the treatment of chronic infection.
Summary of the efficacy data by study
7.1
Study C2301
7.1.1
Study C2301 design
Study C2301 was a double blind, placebo controlled, 1:1 randomized, three-cycle, two arm
trial in CF patients aged between 6 and 21 years, with FEV1 values from 25% to 80%
(inclusive) predicted, who were infected with P. aeruginosa. Patients were required to have
received no inhaled anti-pseudomonal antibiotics in the four months prior to screening. The
first cycle was double blind and placebo controlled. Upon completion of the first cycle, all
patients received open-label TIP for Cycles 2 and 3. Study C2301 had a placebo control only
in the first cycle given the ethical challenge inherent in treating CF patients with a chronic
lung infection with placebo.
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Figure 7-1
Design of Study C2301
TIP = tobramycin inhalation powder

X = Standard of care in off-treatment period
The primary objective of Study C2301 was to demonstrate the efficacy of a 28-day b.i.d.
dosing regimen of TIP versus placebo, as measured by the relative change in FEV1 %
predicted from baseline (Week 1/Cycle 1, Day 1) to the end of Cycle 1 dosing (Week 5/Cycle
1, Day 28). The secondary objectives were to assess the safety and efficacy of TIP when
administered to patients who were dosed for more than one cycle. A post hoc analysis of
absolute change was also done to provide comparison to Study C2303 (see Section 7.4.3).
Planned enrollment was for 140 CF patients with a protocol planned interim analysis when 80
patients had completed Cycle 1, in order to refine the sample size (based on the blinded
review of SD of the primary endpoint measurement) as well as to assess efficacy.
7.1.2
Study C2301 execution
Study C2301 was initiated in September 2005. In September 2006, a voluntary partial clinical
hold was implemented on the placebo-controlled cycle of Study C2301 due to levels of Slyso-PC (a degradant/hydrolysis product of excipient DSPC) above International Conference
on Harmonisation guidelines for qualification in some placebo batches. Only the placebo was
affected due to the presence of a higher proportion of the excipient giving rise to the
degradation product in the placebo. No patients were randomized to active or placebo
treatment after the clinical hold.
To support future use of the placebo formulation in clinical development of TIP, Novartis
completed a 2-week inhalation toxicity study in rats to qualify S-lyso-PC to support the
clinical trial and help set specification limits for intended marketed use in active batches with
S-lyso-PC. S-lyso-PC (with and without tobramycin) was well tolerated when compared to air
control and did not produce alterations in respiratory function and microscopic pathology.
Based on the results of this study, the FDA agreed to a lift of the partial clinical hold.
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However, Study C2301 was not restarted due to a Data Monitoring Committee (DMC)
recommendation to stop the study based on results from the pre-planned interim analysis (see
Section 7.1.3.1).
7.1.3
Study C2301 analysis and relationship to disposition
7.1.3.1
Disposition and Original Interim Analysis
The study disposition and analysis populations are shown in Figure 7-2. A total of 102
patients (6 21 years of age, with baseline FEV1 25%-80% predicted, infected with P.
aeruginosa) were enrolled and randomized and 95 subsequently received study drug (TIP: 46,
placebo: 49). In total, 84.8% of TIP and 81.6% of placebo patients completed the study.
Figure 7-2
Study C2301 patient disposition (all randomized patients)

Randomized
n=102
7 discontinued
Screen failure
3
Prematurely withdrew 4
TIP
All treated patients
n=46
Removed
from Latin
America
N=10
Original
Interim
Analysis
N=39
Sensitivity
interim
analysis
n=29
Placebo
All treated patients
n=49
Removed
from Latin
America
N=8
7 Discontinued
Inappropriate
enrollment
2
Protocol Deviation 1
Other
4
39 (84.8%)
completed
Original
Interim
Analysis
N=40
Sensitivity
interim
analysis
n=32
9 Discontinued
Adverse event/death
Consent withdrawn
Inappropriate
enrollment
Protocol Violation
Other
1
5
1
1
1
40 (81.6%)
completed
A pre-planned interim analysis, referred to here as the Original Interim Analysis (OIA), was
conducted in November 2006 by an external, independent Data Monitoring Committee CRO
(DMC CRO), and the results were reviewed by an external, independent Data Monitoring
Committee (DMC). Novartis remained blinded to the data.
The primary objectives of the interim analysis were to (a) estimate the common standard
deviation for sample size re-estimation, (b) evaluate efficacy of TIP versus placebo for
potential stopping of the study, and (c) assess safety in terms of AEs, airway reactivity, and
bronchospasm.
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The interim analysis meeting was conducted when the approximately 80th randomized patient
completed Cycle 1 dosing. The clinical database was locked and the DMC interim analysis
meeting was held based on the 79 dosed patients (see Figure 7-2). The timing of the interim
analysis was contemporaneous to the partial clinical hold, and sufficient patients had been
recruited and dosed up to the time of the hold that the interim analysis could proceed as
planned.
Following the review of the results from this OIA, the DMC communicated to Novartis that
based on the pre-established stopping criteria, the trial showed results that conclusively
demonstrated a benefit in the treatment arm compared to the placebo arm. The DMC
recommended stopping the study (which at that time was still on partial clinical hold as
described in Section 7.1.2).
7.1.3.2
Spirometry quality at Latin American study sites
In late 2006, around the time of the OIA, a blinded review of PFT data from some study
centers located in Latin America raised concerns regarding the quality of source PFT data
from these sites. Subsequently, Novartis personnel conducted site audits at three active sites in
the Latin American region and two active sites in Europe. Findings from two of the sites in
Latin America raised concerns regarding compliance with acceptable PFT calibration
practices.
Novartis set up an external, independent Expert Panel of pulmonologists to review, in a
blinded manner, the source PFT data from all Latin American centers in the OIA. An assigned
independent contract research organization (CRO), in conjunction with Novartis and the chair
of the Expert Panel, created a spirometry calibration checklist which was used to document
adherence with acceptable PFT calibration practices and to the technical criteria of the
American Thoracic Society (ATS)/National Lung Health Education Program (NLHEP). These
steps were discussed with FDA and endorsed by the DMC prior to implementation.
Using the spirometry calibration checklist, the assigned CRO conducted an audit of all Latin
American study centers in the OIA to assess overall adherence to the study protocol for
spirometry equipment calibration. The independent Expert Panel, using the completed
spirometry calibration checklists, determined the acceptability of calibrations in a blinded
manner. The Expert Panel also reviewed the source PFT data from those Latin American
patients with acceptable calibration, and rated their PFT quality using the previously defined
quality criteria developed by the Panel members. Those with unacceptable PFT data
according to these criteria were excluded from a revised analysis set.
In view of the unacceptable spirometry data a Sensitivity Interim Analysis (SIA) (n=61) of the
OIA data (n=79) was performed by the DMC CRO, following a revised statistical addendum
to the DMC charter, to ensure robustness of statistical inference from the OIA. The following
criteria were used in deciding if subjects were included in the SIA:
Subjects must have had acceptable calibrations at Screening day, Day 1, Day 8 and Day
28.
In addition to calibrations, subjects must have satisfied quality review at baseline
(Screening day or Day 1 pre-dose) and post-baseline (Day 8 or Day 28 pre-dose of Cycle
1).
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7.1.3.3
Sensitivity Interim Analysis
The SIA was performed excluding the spirometry data deemed not to be reliable. The SIA
population was used for the primary efficacy analysis as this population had the most robust
spirometry data. Among 79 patients included in the OIA, all 53 patients from North
America/Europe plus 8 from Latin America who met the calibration and FEV1 data quality
criteria based on independent external expert review panel were included in the SIA, giving a
total of 61 patients (see Figure 7-2). Data from 18 (of 79) patients, all from Latin America,
were excluded.
The DMC reviewed the SIA results, and in keeping with their initial review of the OIA,
communicated to Novartis in November 2007 that Study C2301 had met the pre-determined
stopping boundaries for efficacy, and that there was no need to re-start the study. Shortly
thereafter, Novartis formalized the decision not to re-start Study C2301, and informed FDA in
early 2008.
In Study C2301, the primary analysis for claiming superiority was based on observed data
without data imputation for three patients (2 in TIP arm and 1 in the placebo arm) with
missing data, based on discussion with FDA. This analysis used the sensitivity interim
analysis (SIA) ITT population (all patients who received at least one full dose of TIP and were
included in the SIA) using an ANCOVA model with factors of treatment, baseline %
predicted FEV1, age and region.
Based on the recommendations by the DMC and the agreement with FDA, the primary
efficacy endpoint of Study C2301 is presented using the SIA ITT (n=61) population in this
document.
7.1.4
Study C2301 disposition and demographics
As shown in Figure 7-2 above, 102 patients were randomized and 95 (93%) received study
drug. Seventy-nine (83.2%) completed the study.
The demographics and baseline disease characteristics are shown in Table 7-1 and Table 7-2.
The proportion of patients who prematurely discontinued the study drug was similar between
the two treatment groups (15.2% in the TIP group and 18.4% in the placebo group). Patient
baseline demographics and disease characteristics were comparable between treatment groups
for the all randomized safety population. Overall, patients were evenly distributed across age
groups and gender: 47.4% were below 13 years of age, 55.8 % were females. With respect to
pulmonary function, 40.6% of patients had a FEV1 % predicted below 50% at baseline.
Table 7-1
Demographics, by treatment group Study C2301 (All Randomized

Safety population)
TIP
(N=46)
Placebo
(N=49)
Total
(N=95)
21 ( 45.7%)
25 ( 54.3%)
24 ( 49.0%)
25 ( 51.0%)
45 ( 47.4%)
50 ( 52.6%)
46
13.4
49
13.2
95
13.3
Age group (years)

6 - <13
13 - <22
Age (years)
n
Mean
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SD
Min
Median
Max
TIP
(N=46)
Placebo
(N=49)
Total
(N=95)
4.42
6.0
14.0
21.0
3.91
6.0
13.0
21.0
4.14
6.0
13.0
21.0
19 ( 41.3%)
27 ( 58.7%)
23 ( 46.9%)
26 ( 53.1%)
42 ( 44.2%)
53 ( 55.8%)
0 ( 0.0%)
0 ( 0.0%)
37 ( 80.4%)
8 ( 17.4%)
1 ( 2.2%)
0 ( 0.0%)
1 ( 2.0%)
43 ( 87.8%)
4 ( 8.2%)
1 ( 2.0%)
0 ( 0.0%)
1 ( 1.1%)
80 ( 84.2%)
12 ( 12.6%)
2 ( 2.1%)
46
146.1
17.41
115.0
150.8
180.5
49
147.7
16.25
106.0
149.0
173.5
95
146.9
16.75
106.0
150.0
180.5
46
37.1
14.68
18.8
36.3
75.9
49
38.4
12.45
14.2
37.9
61.4
95
37.8
13.52
14.2
37.0
75.9
Sex
Male
Female
Race
Asian
Black
Caucasian
Hispanic
Other
Height (cm)
n
Mean
SD
Min
Median
Max
Weight (kg)
n
Mean
SD
Min
Median
Max
Table 7-2
Baseline characteristics, by treatment group Study C2301 (All Safety

population)
TIP
(N=32)
Placebo
(N=37)
Total
(N=69)
31
54.0
18.31
26.3
52.0
79.1
35
57.8
17.90
25.1
61.6
84.0
66
56.0
18.06
25.1
61.2
84.0
32
54.7
18.89
24.1
56.4
37
58.5
20.03
23.4
61.0
69
56.7
19.46
23.4
59.3
FEV1% predicted at screening

n
Mean
SD
Min
Median
Max
FEV1% predicted at baseline
n
Mean
SD
Min
Median
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Max
TIP
(N=32)
Placebo
(N=37)
Total
(N=69)
96.2
98.2
98.2
3 ( 8.1%)
11 (29.7%)
18 (48.6%)
5 (13.5%)
4 ( 5.8%)
24 (34.8%)
34 (49.3%)
7 (10.1%)
FEV1 % predicted at baseline distribution n (%)

<25
25 - <50
50 - 80
>80
1 ( 3.1%)
13 (40.6%)
16 (50.0%)
2 ( 6.3%)
Baseline was defined as the last measurement prior to the first dosing of study medication (screening or pre-dose
Day 1 of Cycle 1); for example, if pre-dose Day 1 was missing, the non-missing screening value was used.
With respect to concomitant medications, mucolytics (especially dornase alfa) were

administered to approximately two third of patients in both treatment groups (58.7% for TIP
group and 73.5% for placebo). Selective 2-adrenoreceptor agonists were administered in
about half of patients in both treatment groups and in particular salbutamol (in 41.3% of
patients from the TIP group and 46.9% of patients from the placebo group). Macrolides were
used by 9.5% of the subjects in Cycle 1 (azithromycin: 4.3% in TIP group and 12.2% in
placebo group, erythromycin: 2.2% in TIP group and none in placebo group).
7.1.5
Study C2301 relative change in FEV1 % predicted
The primary efficacy endpoint in this study was relative change from baseline in FEV1 %
predicted after 28 days of treatment (in Cycle 1 of Study C2301) (Table 7-3). The primary
analysis for claiming superiority is based on the SIA ITT population using an analysis of
covariance (ANCOVA) model with factors of treatment, baseline FEV1 % predicted, age and
region. This analysis was based on observed data without imputation of missing data for three
patients (two in the TIP arm and 1 in the placebo arm). Treatment with TIP during Cycle 1
resulted in statistically significant improvements in FEV1 % predicted compared with placebo
(LS mean 14.0% vs. 0.7%, respectively; between-treatment difference 13.3%, 95% CI 5.3,
21.3, p=0.0016). This met the pre-planned stopping criterion in the DMC charter.
Table 7-3
n
Mean(1)
LS Mean(2)
Relative change in FEV1 % predicted from baseline to pre-dose Day 28

of Cycle 1 Study C2301 (SIA ITT population)
TIP
N=29
Placebo
N=32
27
13.2
14.0
31
-0.6
0.7
Difference (SE)
95% CI of difference
P-value
13.8 (3.95)
13.3 (3.98)
(5.9, 21.7)
(5.3, 21.3)
0.0010
0.0016
(1) Mean, p-value, mean difference, and its 95% CI are calculated from ANOVA with treatment in the model.
(2) Least square mean, p-value, least square mean difference, and its 95% CI are calculated from ANCOVA with
treatment, baseline value, age and region in the model.
SE = standard error, n is number of subjects with value at baseline and Day 28.
The analysis is based on observed data only, no imputation is performed for missing data
The t-test was conducted as a pre-defined sensitivity analysis to the ANCOVA model.
It is noted that this analysis is based on observed data without imputation for three patients
with missing data. A different approach for missing data, consistent with that used in the
primary analysis for Study C2303, was performed as a post-hoc analysis by imputing zero
relative change from baseline for patients with missing Day 28 measurements. The result was
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similar (LS mean 12.6% vs. 0.1% respectively for TIP and placebo; between-treatment
difference 12.5, 95% CI 4.9, 20.0, p=0.0016).
The improvement in the TIP group was maintained over the subsequent two cycles of
treatment. When the Cycle 1 placebo group was switched to TIP in Cycle 2, the relative
change from baseline in FEV1 % predicted increased to 11.7% which is approximately the
level of that seen in the group who also received TIP in Cycle 1 (10.6% in Cycle 2); this was
maintained with TIP treatment in Cycle 3. The magnitude of the treatment effect was
consistent with the range expected based on TOBI Phase III placebo-controlled trials.
7.1.6
Study C2301 relative change in FEV1 % predicted over 3 cycles
As shown in Figure 7-3 below, results from Study C2301 indicated that the effect of treatment
with TIP was maintained across the 3 treatment cycles with comparable improvements in
Cycle 3 with respect to the change from baseline in FEV1 % predicted to those in Cycle 1.
The LS mean relative change from baseline in FEV1 % predicted to the end of dosing was
14.0% in Cycle 1 and 15% in Cycle 3.
The relative change from baseline to pre-dose values in FEV1 % predicted over 3 cycles in
Study C2301 is presented graphically in Figure 7-3.
Figure 7-3
Relative change from baseline in percent predicted FEV1 in Cycles 1-3

Study C2301 (SIA population)
Note: The vertical bar is 95% CI. On-treatment phases: from Week 0 to 4, Week 8 to 12, Week 16 to
20. Off-treatment phases: from Week 5 to 8, Week 12 to 16 and Week 20 to 24. Last off-treatment
phase not shown. The x-axis is not linear over the first four weeks.
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7.1.7
Study C2301 absolute change in FEV1 % predicted
In light of an FDA recommendation to assess absolute change in FEV1 % predicted in Study

C2303, a post-hoc analysis of absolute change from baseline in FEV1 % predicted in Cycle 1
of Study C2301, using observed data and an analysis of variance (ANOVA) model identical
to the analysis of relative change was performed. The changes were 6.38% on TIP and -0.52%
on placebo and in the ANOVA showed an estimated between-treatment difference of 6.9%
(95% CI 2.4, 11.4, p=0.0033).
7.1.8
Study C2301 FEV1 % predicted sensitivity analyses
As described in Sections 7.3.7 to 7.3.9 sensitivity analyses were performed for the primary
endpoint of Study C2303. For comparative purposes, a number of similar post-hoc analyses of
Study C2303 were performed. These and those already described in the previous sections, are
shown in Table 7-4 and provide further support for the efficacy of TIP is this study.
Table 7-4
Study C2301 sensitivity analyses with additional imputation methods

(SIA population, n=61)
Point estimate
95% CI
p-value
13.3
12.5
5.3, 21.3
4.9, 20.0
0.0016
0.0016
13.4
12.4
5.5, 21.3
4.9, 20.0
0.0009
0.0017
Primary analysis- Observed cases

ITT with BOCF (imputing missing data with
zero)
Multiple imputation
Least favorable mean imputation (imputing
with placebo mean)
Three different non-parametric analyses were conducted to investigate the sensitivity to

distributional assumption of the primary analysis assessing both the ITT population with
missing data imputed with zero (BOCF) and the observed cases. The results are presented in
Table 7-5 and Table 7-6. Non-parametric analyses for both the observed cases and the ITT +
BOCF all resulted in nominal p-values at or lower than 0.0057. These further analyses support
the significance of the primary analysis.
Table 7-5
Study C2301 Significance test (p-values) with non-parametric methods

(SIA population, n=61)
Observed cases
BOCF
Table 7-6
ANCOVA
Randomization
-based method
Wilcoxon rank
sum test
ANCOVA of
ranks
0.0016
0.0016
0.0022
0.0023
0.0032
0.0050
0.0049
0.0057
Study C2301 estimates with non-parametric methods (SIA population,

n=61)
ANCOVA
Observed cases
BOCF (imputing missing
Non-parametric method
Estimate
95% CI
HodgesLehmann
estimate
95% CI
13.3
12.5
5.3, 21.3
4.9, 20.0
11.86
11.14
4.12, 20.94
1.22, 16.31
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ANCOVA
Estimate
95% CI
HodgesLehmann
estimate
95% CI
data with zero)
Additionally, sensitivity analyses were performed for the All Randomized Safety population
(n=95) which includes all treated patients. The first analysis (Observed cases) included nonmissing and valid spirometry data obtained at Day 29; the second analysis used a BOCF
approach to impute missing or invalid data. It should be noted that the latter analysis which
imputes missing data with zero for a high number of patients with invalid FEV1 % predicted
values due to procedural issues does not adequately reflect the treatment effect but is provided
here for completeness and consistency with the Study C2303. The results shown in Table 7-7
provide further support for the efficacy of TIP in this study.
Table 7-7
Study C2301 sensitivity analyses in all treated patients (All

Randomized Safety population, n=95)
Observed cases
ITT with BOCF (imputing missing data with
zero)
7.1.9
Point estimate
95% CI
p-value
14.5
8.9
7.0, 21.9
3.7, 14.0
0.0003
0.0009
Study C2301 change in colony forming units
P. aeruginosa density in sputum was measured at Day 1 and Day 28 for Cycles 1-3. Results
were reported as log10 colony-forming units [CFU] per gram of sputum. Absolute change in
density from baseline to each post-baseline time point in Cycles 1-3 was calculated and the
mean change determined in each treatment group, both for the sum of the biotypes and for
each individual biotype present at baseline. In the All Randomized Safety population (n=95),
the greatest differences between the TIP placebo groups were seen at Day 28 of Cycle 1, with
a decrease of 2.96 log10 CFU/g in the TIP group vs. 0.16 log10 CFU/g in the placebo group for
the sum of all biotypes (difference, -2.70, 95% CI, -3.60, -1.79, p < 0.001). Similarly, biotype
1 (mucoid) decreased by 2.61 log10 CFU/g in the TIP group vs. 0.43 log10 CFU/g in the
placebo group and biotype 2 (non-mucoid/dry) decreased by1.91 log10 CFU/g in the TIP
group vs. 0.15 log10 CFU/g in the placebo group. There were too few SCVs to report
separately in the analysis. After switching from placebo to TIP starting at Cycle 2, the results
were generally similar between the TIP/TIP/TIP and placebo/TIP/TIP groups with a general
trend showing that the P. aeruginosa density rebounded after 28 days off-treatment and then
decreased after 28 days treatment.
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Figure 7-4

aeruginosa sputum density (Log10 CFU) Study C2301 (ITT
population)
Note: the vertical bar is 95% CI. Overall density is used, and it is defined as the sum of biotypes
(mucoid, dry and small colony variant).
In order to further assess the suppressive action of TIP compared to placebo, the percentage of
patients with at least a 0.5, 1.0 or 1.5 reduction in log10 CFUs is shown for Cycle 1, below.
0.5 log10 CFU reduction: TIP 78.6%, placebo 38.9%
1.5 log10 CFU reduction: TIP 64.3%,placebo 13.9%
7.1.10
Study C2301 changes in other clinical endpoints
7.1.10.1 Anti-pseudomonal antibiotic usage and respiratory-related

hospitalizations in Cycle 1
In the 95 patients who received study treatment, the percentage of patients receiving new antipseudomonal antibiotics (other than study drug) in Cycle 1 was greater in the placebo group
than in the TIP group (10 patients [20.4%] vs. 6 patients [13.0%]). In addition, the duration of
usage in Cycle 1 was longer in the placebo group than that in the TIP group (mean duration
per patient in days: 18.2 vs. 13.3).
The percentage of patients with respiratory-related hospitalizations in Cycle 1 was greater in
the placebo group than that in the TIP group (6 patients, 12.2% vs. 0). The average number of
days of hospitalization in Cycle 1 was 12.3 in the placebo group.
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7.2
Active-controlled trial: Study C2302
7.2.1
Study C2302 design
Study C2302 was a multi-center, randomized, open-label, parallel-group, active-controlled

study, comparing the safety and efficacy of TIP with TOBI in CF patients with P. aeruginosa
infection.
The primary objective was to evaluate the safety of twice-daily (b.i.d.) dosing of TIP
delivered with the T-326 Inhaler, compared with TOBI delivered with the PARI LC PLUS jet
nebulizer and DeVilbiss PulmoAide compressor or suitable alternative compressor delivering
similar air pressure/flow through the nebulizer, across 3 cycles of treatment (each cycle 28
days on-, 28 days off-treatment). The open-label design was necessitated by the very different
modes of delivery (dry powder inhaler vs. nebulizer). Patients were randomized 3:2 to
increase the TIP safety database.
The study had a pre-planned inclusion of the natural efficacy comparisons between TIP and
TOBI, including a comparison of the change from baseline in FEV1 % predicted. The study
was one of the largest ever in the rare CF population. As specified in the protocol, noninferiority would be assessed using the relative change from baseline in FEV1 % predicted at
Cycle 3 Day 28 pre-dose, with a lower limit of the one-sided 85% CI below a predefined 6%
margin. The design is outlined below:
Figure 7-5
7.2.2
Study C2302 execution
There were no unusual or exceptional issues in relation to the execution of this study.
7.2.3
Study C2302 analysis
In Study C2302, safety was the primary objective. For this objective a sample size of 300
patients in the TIP group is sufficient to observe at least one AE that is as likely as 1 in 100
with a high likelihood. In addition, a comparison between TIP and TOBI for relative change
in FEV1 % predicted was performed using an inferential analysis, and comparing the lower
bound of the CI for the estimated contrast with a margin of 6% pre-defined in the protocol.
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Reflecting the feasible study size, a claim of non-inferior efficacy was based on the one-sided
85% CI in the ITT population (lower limit greater than -6%). Sensitivity analyses based on
one-sided 90% and 95% CIs from the same ANCOVA model were provided and in addition,
the non-inferiority inferential analysis was performed for the Per Protocol (PP) population.
Sensitivity analyses were conducted to assess the effect of patient discontinuation on the
comparison in FEV1 % predicted at the end of Cycle 3 between TIP and TOBI in Study
C2302.
7.2.4
A total of 553 patients (6 years of age, with baseline FEV1 25%-75% predicted, infected
with P. aeruginosa) were enrolled and randomized and 517 subsequently received study drug
(TIP: 308, TOBI: 209). In total, 73.1% of TIP and 81.8% of TOBI patients completed the
study.
Figure 7-6
Patient disposition in Study C2302
The main reason for discontinuation in both treatment groups was AEs, with the majority of
discontinuations occurring during the first cycle (14.3% for TIP and 13.4% for TOBI in cycle
1). A post-hoc analysis of the discontinuations by age group in Study C2302 showed that in
patients 20 years the discontinuation rate was 33% in the TIP group compared with 19% in
the TOBI group, while in patients aged 13 - <20 years the discontinuation rates in the TIP and
TOBI groups were matched at 18% and 17% respectively. In contrast to the oldest age group,
the discontinuation rates in the small group of patients aged <13 years were 4% in the TIP and
17% in the TOBI groups (1 vs. 3 patients). These data, although in smaller numbers in the
younger age groups, tend to suggest that discontinuations during treatment with TIP were
similar to TOBI in patients aged <20 years, whereas in patients aged 20 years, a higher rate
of discontinuation during treatment with TIP compared with TOBI occurred. Overall, the
similar rate of discontinuations during treatment with TIP compared with TOBI in patients
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aged less than 13 years and in the 13 - <20 years of age group may suggest that factors not
universally applicable to the TIP tolerability profile led to a higher discontinuation rate in
older patients.
The reason that more patients over 20 years old discontinued is not clear, although the open
label design may have had an influence. Patients treated in Study C2302 with TOBI would
most likely have continued to receive TOBI when they discontinued the study, whereas
patients treated with TIP would most likely have swapped to TOBI when they discontinued.
Thus there could have been a differential effect on the decision to discontinue. This may be of
relevance in older patients who have become accustomed to TOBI and who rely on it for their
well-being especially as more than two-thirds of patients entering the trial had been on prior
nebulized tobramycin.
The baseline demographic and disease characteristics are shown below in Table 7-8 and
Table 7-9 respectively.
Table 7-8
Demographic summary by treatment group Study C2302 (All

Randomized Safety population)
Age group (years)

6 - <13
13 - <20
20
Age (years)
Mean (SD)
TIP
N=308
TOBI
N=209
28 (9.1)
66 (21.4)
214 (69.5)
18 (8.6)
48 (23.0)
143 (68.4)
25.9 (11.36)
25.2 (10.20)
Sex
Male
Female
171 (55.5)
137 (44.5)
115 (55.0)
94 (45.0)
Race
Asian
Black
Caucasian
Hispanic
Other
2 (0.6)
3 (1.0)
279 (90.6)
20 (6.5)
4 (1.3)
2 (1.0)
1 (0.5)
189 (90.4)
17 (8.1)
0 (0.0)
Region
North America
1
Europe and rest of world
Latin America
195 (63.31)
104 (33.77)
9 (2.92)
131 (62.68)
71 (33.97)
7 (3.35)
20.7 (3.96)
20.4 (3.45)
BMI (kg/m )
Mean (SD)
1
Rest of world including Australia and Israel.
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Table 7-9
Disease characteristics by treatment group Study C2302 (All

Chronic macrolide use

Yes
No
1
Screen FEV1 % predicted
25% - < 50%
50% - 75%
1
Baseline FEV1 % predicted
Mean (SD)
Last use of antipseudomonal antibiotics prior to first dose
(month)
0 to 1
> 1 to 3
> 3 to 6
>6
never used
2
P. aeruginosa Tobramycin MIC
> 8 g/mL
8 g/mL
TIP
N=308
n (%)
TOBI
N=209
n (%)
187 (60.71)
121 (39.29)
125 (59.81)
84 (40.19)
128 (41.56)
180 (58.44)
89 (42.58)
120 (57.42)
52.9 (14.20)
52.8 (15.95)
78 (25.32)
171 (55.52)
33 (10.71)
11 (3.57)
15 (4.87)
46 (22.01)
112 (53.59)
24 (11.48)
9 (4.31)
18 (8.61)
68 (22.08)
240 (77.92)
48 (22.97)
160 (76.56)
MIC; minimum inhibitory concentration.

1
Randomization is based on screen FEV1 % predicted. Baseline FEV1 was defined as the last measurement prior
to the first dose of study drug.
2
Maximum MIC of all P. aeruginosa bio-types.
The two treatment groups were well matched for age, sex, race and BMI. Patients were
predominantly aged 20 years or over, Caucasian, and with slightly more males than females.
Four patients 60 years of age and above were enrolled in the study. Disease characteristics and
history were similar for the two treatment groups; patients had a mean FEV1 % predicted of
53% at baseline, and approximately half had used anti-pseudomonal drugs between 1 and 3
months prior to the start of the study. The most frequent anti-pseudomonal antibiotic used
prior to screening was tobramycin, at a rate over 80% (any route) and its use was well
matched between treatment groups.
7.2.5
The results of the relative change in FEV1 % predicted from baseline to the end of dosing in
Cycle 3 for the ITT population are presented below (Table 7-9). The estimated treatment
difference and its CI were assessed using an ANCOVA model with treatment, region, and
macrolide use (Yes, No) as factors and age and baseline FEV1 % predicted as covariates.
Non-inferiority is shown if the lower bound of the CI is greater than the pre-defined noninferiority margin (-6%).
There was a slightly greater increase in mean and LS mean post-baseline values for FEV1 %
predicted in the TIP treatment group as compared with the TOBI treatment group (LS Mean
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difference 1.1%). The lower limit of the one-sided 85% CI is well above the pre-defined -6%
margin (one-sided 85% CI (-0.67, 2.96)). This was also the case for the lower limits of the
one-sided 90% and 95% CIs (one-sided 90% CI (-1.10, 3.39), 95% CI (-1.74, 4.03)). These
results were supported by the per-protocol (PP) analysis in which the LS mean difference in
relative change from baseline in FEV1 % predicted was 1.2% (85% one-sided CI -1.03, 3.36;
90% one-sided CI -1.54, 3.88; 95% one-sided CI -2.31, 4.65).
These data suggest that TIP and TOBI were similar with respect to their effect on FEV1 %
predicted in this population of patients with experience using inhaled tobramycin. The limited
change from baseline on TIP suggests patients switching from TOBI to TIP had stable control
of FEV1.
Table 7-10
n
1
LS Mean
2
Mean
FEV1 % predicted relative change from baseline to pre-dose Day 28 of

Cycle 3 Study C2302 (ITT population)
TIP
N=308
TOBI
N=209
Difference
(SE)
85% one-sided CI of
difference
227
5.8
3.1
171
4.7
2.3
1.1 (1.75)
0.8 (1.92)
(-0.67, 2.96)
(-1.22, 2.77)
Least square (LS) mean, least square mean difference (TIP - TOBI), and its one-sided 85% confidence interval
(CI) are calculated from ANCOVA with treatment, baseline FEV1 % predicted, age, chronic macrolide use, and
region in the model.
2
Mean, mean difference, and its one-sided 85% CI are calculated from ANOVA with treatment in the model.
Two-sided 70% CI is presented.
SE = standard error, n is number of patients with values at baseline and Day 28 of Cycle 3.
The analysis is based on observed data only, no imputation is performed for missing data.
Claim of non-inferiority efficacy is based on the one-side 85% CI in the ITT population (lower limit is greater than 6%).
The relative change from baseline in FEV1 % predicted over the 3 treatment cycles in Study
C2302 is displayed graphically below. At each measured time the mean FEV1 % predicted
showed a relative increase from baseline for both the TIP and TOBI groups. The relative
increase at Week 2 was approximately 7% in both groups (Cycle 1 Day 8). This was the peak
effect as the increase at Week 5 was approximately 3% (Day 28 pre-dose). The relative
increase in FEV1 % predicted was maintained with comparable effects to those seen at Week 5
during Cycles 2 and 3. There was little difference between the TIP and TOBI groups.
The differences in FEV1% predicted from baseline to the end of Cycle 3 between Studies
C2301 and C2302 are expected based on the differences in the study populations, i.e. the
Study C2302 patients were predominantly on inhaled tobramycin prior to the study and so a
stable FEV1 would be expected.
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Figure 7-7
Relative change from baseline in FEV1 percent predicted in Cycles 1-3

Study C2302 (ITT population)
The pattern of FEV1 % predicted change by age group is described in Section 7.2.8.
As a form of sensitivity analysis (in view of the imbalance between TIP and TOBI in
discontinuations), the analysis of relative change from baseline in FEV1 % predicted by
treatment and cycle in the ITT population and also in patients aged 20 years or older (who had
the larger discontinuation rate) was performed using various methods of imputation for Study
C2302 (See Section 7.2.3). These methods included both single and multiple imputation
methods. For the different imputation methods used, TIP and TOBI continued to show
comparable results with the point estimate of difference between TIP and TOBI being within
2% for all methods used except Goulds ranking procedure (Goulds: -2.2% with BOCF, 2.6% with last observation carried forward [LOCF], -2.8%) (Gould 1980) and the predicted
mean imputation method (+3.5%). This similarity was maintained in patients aged 20 years or
over with results ranging from -3.5% to +2.3% for all approaches except the Goulds ranking
procedure. Thus the discontinuations do not detract from the overall finding that TIP and
TOBI have a similar effect on FEV1 % predicted.
The effect of the new use of anti-pseudomonal antibiotics was also assessed. The difference in
rate of use of new anti-pseudomonal antibiotics between TIP and TOBI did not appear to alter
the conclusion that TIP and TOBI had a similar effect on FEV1 % predicted. The FEV1 %
predicted relative change from baseline to Day 28 of Cycle 3 in the ITT population of Study
C2302 after adjusting for new anti-pseudomonal use (by including it as an additional factor in
the ANCOVA model) in all patients showed little difference between treatment groups
(adjusted LS mean of 5.8 for TIP and 4.7 for TOBI). Looking at the relatively large sub-group
of patients aged 20 years or over, in whom there was higher antibiotic use on TIP also showed
little difference between treatment groups (adjusted LS mean of -1.1 for TIP and -0.9 for
TOBI). To further evaluate the possible effect of new use of anti-pseudomonal antibiotics
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(TIP 64.9%, TOBI 54.5%), FEV1 % predicted for patients not using any new antipseudomonal antibiotics was assessed. After 3 cycles the FEV1 % predicted change from
baseline was 5.2% for TIP (n=103) and 3.8% for TOBI (n=83). When assessed for patients
not using new oral antibiotics (since the oral antibiotic use drove the overall difference) after
3 cycles the FEV1 % predicted change from baseline was 5.3% for TIP (n=127) and 4.9% for
TOBI (n=104).
7.2.6
Study C2302 colony forming units changes
Figure 7-8 shows the mean changes from baseline in P. aeruginosa sputum density (log 10
CFU/g) for the sum of all biotypes in the TIP and TOBI groups. Reductions in P. aeruginosa
density were comparable in both groups. The mean decreases from baseline to Day 28 (end of
on-treatment cycle) for the first and second cycles were similar: Cycle 1 (1.78 vs. 1.30 log10
CFUs for TIP and TOBI, respectively), Cycle 2 (1.62 vs. 1.10 log10 CFU/g for TIP and TOBI,
respectively). For Cycle 3, the mean decreases were 1.60 log10 CFU/g in the TIP group and
0.92 log10 CFU/g for the TOBI group. In both treatment groups, P. aeruginosa density
rebounded at the end of the 28-day off-treatment phase but then decreased again during the
28-day on-treatment phase to comparable levels across each cycle of treatment. The
microbiologic effect of TIP was maintained across the 3 cycles.
Figure 7-8

aeruginosa sputum density (Log10 CFUs) Study C2302 (ITT
population
Note: the vertical bar is 95% CI. Overall density is used, and it is defined as the sum of biotypes
(mucoid, dry and small colony variant).
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In order to further assess the suppressive action of TIP and TOBI, the percentage of patients
with at least a 0.5, 1.0 or 1.5 reduction in log10 CFUs after 3 cycles was conducted. This
showed that the percentage of patients in each category of change was similar.
0.5 log10 CFU reduction: TIP 63.1%, TOBI 53.2%
1.0 log10 CFU reduction: TIP 56.1%, TOBI 43.7%
1.5 log10 CFU reduction: TIP 46.5%,TOBI 33.3%
The pattern of CFU change by age group is described in Section 7.2.8.
7.2.7
Study C2302 other efficacy endpoints
7.2.7.1
Anti-pseudomonal antibiotic use and hospitalizations
Over half of the patients in both treatment groups used new anti-pseudomonal antibiotics (all
routes of administration) during the study, with a higher proportion in the TIP treatment
group. The Kaplan-Meier plot of time to first new anti-pseudomonal antibiotic use after the
start of study drug showed the estimated proportion of patients using new anti-pseudomonal
antibiotics to be slightly higher in the TIP treatment group (65%) than in the TOBI group
(55%) for the duration of the study (Figure 7-9). According to the Kaplan-Meier estimates,
over 50% of patients in both groups had used new anti- pseudomonal antibiotics by Day 112,
with a median time to first use of 89 days for TIP vs. 112 days for TOBI.
Figure 7-9
Study C2302 Kaplan-Meier curve of time to first anti-pseudomonal

antibiotic use, by treatment group (ITT population)
The difference in the rate of new anti-pseudomonal antibiotic use of 10.4% does not appear to
have been driven by events of a higher clinical severity, as most were oral agents. The rates
of new IV anti-pseudomonal antibiotic use were matched between treatment arms (34.7% in
TIP treated patients vs. 33.0% in TOBI treated patients). There was little difference between
treatment groups with regard to hospitalization for respiratory events (24.4% on TIP and
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22.0% on TOBI, were hospitalized. The mean and median duration of hospitalization,
respectively, was 30.9 and 36 days for patients in the TIP group and 33.4 and 27.5 days in the
TOBI group. The median time to hospitalization was 199 and 190 days for patients in the TIP
and TOBI groups, respectively. These data tend to suggest that the difference seen for new
anti-pseudomonal antibiotic use is largely driven by the use of oral agents for milder events
(i.e. those not needing IV antibiotics and/or hospitalization).
The open label design might have influenced this pattern of antibiotic use. It seems unlikely
that the difference of 10% in oral antibiotic use would lead to clinically important differences
in outcomes. This conclusion is supported by a study by (Sheldon et al 1993) in which
regularly repeated cycles of 10-day treatment with oral ciprofloxacin did not significantly
change FEV1 results, and did not prevent hospital admissions or reduce the number of courses
of intravenous antibiotics throughout the year. It is further supported by the sensitivity
analyses of FEV1 % predicted outcomes for TIP and TOBI allowing for the difference in
antibiotic use (Section 7.2.5). It is noted that among patients who used anti-pseudomonal
drugs during the study, 73.3% of those in the TIP group and 62.6% of those in the TOBI
group had reported use of oral ciprofloxacin prior to the study start, a difference of 10.7%,
which is similar to that observed for new antibiotic use as a whole in the study.
Table 7-11
New anti-pseudomonal antibiotic use and hospitalizations due to

respiratory events during the study, by treatment group - Study C2302
TIP
N=308
TOBI
N=209
Any new use of anti-pseudomonal antibiotics

All routes n (%)
IV
Mean (SD) - days
Median - days
200 (64.9)
107 (34.7)
30.9 (23.34)
26.0
114 (54.5)
69 (33.0)
33.4 (24.42)
27.5
Hospitalizations due to respiratory events

n (%)
Mean (SD) - days
Median - days
75 (24.4)
15.6 (13.31)
14.0
46 (22.0)
15.3 (10.23)
14.5
The differences in new anti-pseudomonal antibiotic use by age group are noted in Section
7.2.8.
Administration time
As expected, the mean duration of drug administration was significantly less for TIP than
TOBI at each visit and overall (Table 7-12). LS mean duration of administration for TOBI
was constant throughout the study. In the TIP group, the mean duration of administration
decreased from Week 1 (Cycle 1 Day 1) to Cycle 1 Day 8, after which it remained constant.
This is thought to be due to training/familiarity. The median time of administration of TIP
ranged from 3.5-6.0 minutes (18.0-20.0 minutes for TOBI).
TIP was approximately 14 minutes faster to administer than TOBI in this study, a reduction in
treatment time of 28 minutes per day (13 hours per month). The administration time excluded
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the time required to set-up, clean and disinfect the nebulizer, so that only actual administration
times were compared. Thus the true gain with respect to treatment burden is greater.
Table 7-12
Duration of administration of study drug - Study C2302 (All

TIP
N=308
n, LS Mean
Visit
Week 1
Week 2
Week 5
Week 9
Week 13
Week 17
Week 21
304,
284,
258,
265,
234,
238,
208,
Average over visits
8.6
6.1
5.5
5.7
5.6
5.9
5.3
5.6
TOBI
N=209
n, LS Mean
207,
196,
185,
183,
165,
174,
152,
20.8
20.0
20.2
19.8
19.5
20.1
20.1
19.7
LS Mean
Difference (SE)
P-value
-12.2 (0.45)
-13.9 (0.35)
-14.7 (0.38)
-14.1 (0.38)
-13.9 (0.43)
-14.2 (0.51)
-14.8 (0.49)
-14.1 (0.30)
<0.0001
n is the number of patients with values at the visit. SE= standard error
Least square mean, least square mean difference (TIP TOBI), and p-value are calculated from
repeated measures model with treatment, baseline FEV1 % predicted, age, chronic macrolide use,
region, visit, visit-by-treatment interaction in the model.
1
Week 1 is excluded.
P-value is testing the average effect of TIP versus TOBI over the visits
7.2.7.2
Treatment satisfaction
The modified Treatment Satisfaction Questionnaire for Medication tool has a total of 18 items
with responses to nearly all items rated on a five-point or seven-point rating scale; higher
rating indicates higher level of satisfaction. Items 1-14 are factored into four domains or subscales: Effectiveness, Side Effects, Convenience, and Global Satisfaction. Note that the scale
scores are transformed into continuous data scores, with possible range 0% to 100%.
Between-treatment comparison is performed using repeated measures model assuming unstructured variance-covariance matrix. The repeated measures model is defined as:
Response = continuous baseline FEV1 % predicted + continuous baseline age (in years) +
categorical chronic macrolide use (user, nonuser) + categorical region (North America, EU
and Latin America) + treatment + visit + treatment-by-visit-interaction,
where Response is the score from the questionnaires including: a) effectiveness score; b) side
effects score; c) convenience score; d) global satisfaction score; and (e) scores from items 15,
16, 17 and 18.
LS mean assessments of effectiveness, side effects, convenience and global satisfaction were
similar at weeks 5, 13 and 21 within each treatment group, indicating that patient satisfaction
was constant over the duration of the study. Assessments for effectiveness, convenience and
global satisfaction were consistently greater for the TIP group than TOBI at all visits,
indicating a higher level of satisfaction, and for these domains the differences were
statistically significant for the mean of all visits assessment (LS mean difference of 9.36 for
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effectiveness, 24.35 for convenience and 5.20 for global satisfaction). Side effect ratings
(which assessed impact of events) showed no difference between treatment groups.
Table 7-13
Treatment satisfaction from modified Treatment Satisfaction

Questionnaire for Medication - Study C2302 (ITT population)
TIP
N=308
n, LS mean
TOBI
N=209
n, LS mean
LS mean
Difference (SE)
P-value
Effectiveness
Week 5
Week 13
Week 21
Average over visits
264, 75.1
241, 74.5
221, 74.5
74.8
189, 65.8
170, 65.0
162, 65.5
65.4
9.35 (1.60)
9.53 (1.71)
8.99 (1.87)
9.36 (1.46)
<0.0001
Side Effects
Week 5
Week 13
Week 21
Average over visits
263, 92.1
239, 92.9
215, 90.7
92.1
190, 92.3
170, 93.2
158, 93.0
92.6
-0.20 (1.42)
-0.23 (1.37)
-2.36 (1.71)
-0.50 (1.22)
0.6833
Convenience
Week 5
Week 13
Week 21
Average over visits
264, 83.4
241, 82.2
221, 82.6
82.7
190, 59.1
170, 58.4
162, 57.7
58.4
24.32 (1.66)
23.77 (1.77)
24.95 (1.83)
24.35 (1.55)
<0.0001
Global Satisfaction
Week 5
Week 13
Week 21
Average over visits
264, 76.6
241, 76.4
221, 74.8
76.2
190, 71.1
170, 71.1
162, 72.1
71.0
5.48 (1.75)
5.31 (1.83)
2.78 (2.17)
5.20 (1.66)
0.0018
Mean scores for individual questions remained relatively consistent for each treatment cycle.
The questions with the greatest difference between the TIP and TOBI treatment groups were
9, 10, 11 (relating to ease and convenience of medication use, not altered in the modified
questionnaire) and questions 17 and 18 (relating to use of the delivery device away from
home, and care of the delivery device, additional questions added by Chiron).
The between treatment comparisons for questions 15, 16, 17 and 18 all showed a significant
difference in favor of TIP at each cycle (p<0.0001), and for the entire study period
(p<0.0001). These questions related to the use and upkeep of the inhalation devices, and were
questions added by Chiron, because the original questionnaire did not cover the use of the
device.
7.2.8
Study C2302 efficacy results in age groups
A series of post hoc analyses using Study C2302 data evaluated relative change from baseline
in FEV1 % predicted, CFU changes and anti-pseudomonal antibiotic use by age group.
Specifically, analyses were performed in patients aged 20 years to assess the relative
efficacy of TIP and TOBI in adult CF patients with chronic P. aeruginosa infection of the
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lungs (in view of the difference in discontinuations in this age group). The ANCOVA analysis
results in patients aged 20 years is presented in the table below.
Table 7-14
Analysis of covariance of relative change in FEV1 % predicted from

baseline to pre-dose Day 28 of Cycle 3 for patients aged 20 or older Study C2302 (ITT population)
TIP
(N=214)
n
Adjusted
144
Unadjusted 144
TOBI
(N=143)
Mean LSMean n
0.3
0.3
-1.1
0.3
Difference TIP-TOBI
Mean LSMean LSMean (SE)
116
116
0.9
0.9
-0.3
0.9
-0.7 (2.10)
-0.6 (2.22)
85% CI
90% CI
95% CI
(-2.89, 1.47) (-3.40, 1.98) (-4.17, 2.75)

(-2.88, 1.72) (-3.43, 2.27) (-4.24, 3.08)
Baseline was defined as the latest measurement prior to the first dosing of study medication.
Change from baseline = post-baseline pre-dose value - baseline value.
Least square (LS) means and confidence intervals (CI) are calculated from an ANCOVA model with baseline
FEV1 % predicted, age, chronic macrolide use, region, treatment as factors.
85% CI, 90% CI and 95% CI are from one-sided CIs using the same analysis.
This analysis is consistent with the comparison made in the whole population, with an
adjusted LS mean treatment difference of -0.7 (85% CI -2.89, 1.47), with the 85%, 90% and
95% CIs all having a lower level greater than the protocol pre-specified boundary for noninferiority of -6%. This analysis indicates that TIP is similar to TOBI with respect to FEV1 %
predicted in the 20 years ITT sub-population. Differences in relative change in FEV1 %
predicted between treatment groups (assessed by LS means controlling for baseline severity)
decreased with advancing age. Treatment differences for TIPTOBI were 4.7%, 95% CI 6.6,
15.9 for the 6-13 years group; 3.7%, 95% CI 3.6, 11.0 for 13-20 years group; and 0.8%,
95% CI 5.2, 3.6 for the >20 years group. It is noted that the patient numbers are lower in the
younger age groups.
The mean (SD) change in P. aeruginosa density for the sum of all three biotypes was also
assessed by age group in Study C2302, on Day 28 of Cycle 3 in the ITT population.
Table 7-15
Change in P. aeruginosa sputum density (mean (SD) log10 CFU/g)

from baseline for the sum of all 3 biotypes after 3 cycles (end of ontreatment, Week 21), by age - Study C2302 (ITT population)
Age group
TIP
TOBI
6 - < 13
13 - < 20
20
-2.54 (2.01)
-1.21 (2.03)
-1.63 (2.02)
-1.23 (1.08)
-0.69 (1.96)
-0.73 (1.81)
Reduction in P aeruginosa sputum density were similar in the 20 years sub-group compared
to the 13 - <20 years sub-group. Additionally TIP is at least as effective as TOBI in any
subgroup. The data for TOBI also show an effect at least as good in the 20 years sub-group
as in the sub-group aged 13 - <20 years.
Furthermore, for both biotype-1 (mucoid) and biotype- 2 (non-mucoid/dry) a decrease in P.
aeruginosa density was observed for all age groups in both the TIP and TOBI groups.
In particular, the results from Study C2302 for the 20 years subgroup are comparable to the
whole study population for categorical CFU suppression after 3 cycles confirming the benefit
of TIP and TOBI in older patients as follows:
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0.5 log10 CFU reduction: TIP 65%, TOBI 52%,

log10 CFU reduction: TIP 58%, TOBI 42%,
1.5 log10 CFU reduction: TIP 48%, TOBI 34%.
In Study C2302, use of new anti-pseudomonal antibiotics was comparable in the two
treatment arms for the 13 - <20 year and 20 year age groups (respectively 65% and 67% for
TIP and 44% and 55% for TOBI), indicating that there was no loss of efficacy of either TIP or
TOBI in the older age group. For the youngest age group of 6-13 years, the rates of new antipseudomonal antibiotic use on TIP and TOBI were 46% and 83%, respectively.
Similarly, the results for new IV anti-pseudomonal antibiotic (indicating more clinically
severe events) were comparable within each treatment arm for all age groups, as well as
between the 2 treatment groups. These were 32%, 32% and 36% on TIP and 39%, 31% and
33% on TOBI for the 6-13, 13 - <20 and 20 year old age groups, respectively.
Hospitalization for respiratory events were comparable within each treatment arm for the 13 <20 and 20 year age groups. Hospitalizations were also comparable between the TIP and
TOBI groups for the 13 - <20 and 20 year age groups (respectively 27%, 23% on TIP and
27%, 18% on TOBI), whereas the hospitalization rate in the TIP group was numerically lower
than in the TOBI group for the youngest patients studied (29% and 44%, respectively). There
was little difference in the mean duration of hospitalization (17.2 days for TIP vs. 14.0 days
for TOBI in patients aged 20 years or older). A summary of efficacy outcomes by age group
in Study 2302 is shown in Table 7-16.
Table 7-16
Summary of efficacy outcomes by age group Study C2302 (ITT

population)
Age Group
6 to <13
20
13 to <20
Endpoint
Units
TIP
TOBI
TIP
TOBI
TIP
TOBI
Hospitalizations
(respiratory events)
Mean duration of
hospitalization
New anti-pseudomonal
antibiotic use
n (%)
8
(28.6)
17.8
8
(44.4)
16.4
18
(27.3)
10.4
13
(27.1)
17.2
49
(22.9)
17.2
25
(17.5)
14
46.4
83.3
65.2
43.8
67.3
54.5
32
39
32
31
36
33
43.7
28.9
30.6
46.4
29.8
30.8
New IV antipseudomonal antibiotic

use
Duration of new antipseudomonal antibiotic
use
days
% of
patient
s
% of
patient
s
days
7.3
Study C2303
7.3.1
Study C2303 background
After the Phase III Studies C2301 and C2302, minor manufacturing improvements were made
to the bulk powder manufacturing step of TIP drug product manufacture. The improvements
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in emulsion preparation and powder collection in this step were necessary to produce bulk
spray-dried powder with consistency commensurate with a commercial manufacturing
process. These improvements did not change the overall manufacturing process. In vitro
results showed comparable aerosol performance (e.g., mass per stage, delivered dose
uniformity) and physicochemical characteristics of materials from each of the processes. A
first set of comparability data was shared with FDA at a meeting in November 2007. The
Division requested that Novartis provide additional clinical data to supplement the available
technical comparative data. Study C2303 was conducted to fulfill this request. Additional
information about the manufacturing process improvement including in vitro data is provided
in Section 13 - Appendix 1.
The results of this in vitro comparison are supported by the results of Study C2303.
Tobramycin exposure in serum and sputum remained comparable following the improvements
in the manufacturing process. It is also noted that tobramycin is delivered at multiple folds
above the minimum inhibitory concentrations to conductive and respiratory areas of the lung
where P. aeruginosa colonies are present. Results for the key efficacy endpoints in Study
C2301 (Phase III process batches) and Study C2303 (improved process batches) remained
within the expected range for the clinical trial results. Materials from the validated process are
intended for commercial supply.
7.3.2
Study C2303 design
As Studies C2301 and C2302 were nearly complete when FDA requested additional clinical
data, incorporation of drug product from the improved process into these trials was no longer
feasible. A new clinical study, Study C2303, was designed to meet the FDAs request. The
design initially proposed by Novartis was a two-arm study of TIP (Phase III) vs. TIP
(improved). However, FDA requested a placebo controlled study and the inclusion of patients
nave to inhaled tobramycin (to be similar to the original TOBI studies). Thus, the final
design, incorporating FDA feedback, was a one-cycle study of TIP (from the improved
process) vs. placebo.
Similar in design to the first cycle of Study C2301, Study C2303 was a double-blind, placebocontrolled, randomized study performed in TOBI-naive patients. Eligible patients met the
following criteria: 6 to 21 years of age, FEV1 25-80% predicted, confirmed diagnosis of CF
and P. aeruginosa infection, and no recent use of anti-pseudomonal antibiotics (inhaled within
4 months of screening, or systemic within 28 days of study drug administration). Patients
were randomized in a 1:1 ratio to TIP (4 x 28 mg b.i.d.) or placebo for 28 days on-treatment
and 28 days off-treatment for 1 cycle. The design is outlined below:
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Figure 7-10
The primary objective of the study was to evaluate the efficacy of TIP after minor
improvements in the manufacturing process for the treatment of infections with P. aeruginosa
in CF patients, assessed by relative change in FEV1 % predicted from baseline to Day 29,
compared to placebo.
The use of relative change from baseline was adopted to maintain consistency with Study
C2301. In addition, and in response to an FDA recommendation, there was a pre-planned
sensitivity analysis of the primary endpoint data using absolute change. Secondary objectives
were to evaluate the safety profile of TIP, the pharmacokinetic properties of tobramycin, and
the effect of TIP on the density of microorganisms in sputum samples of patients.
7.3.3
Study C2303 execution challenge
Enrollment in Study C2303 commenced in June 2009. Recruitment proved to be extremely

challenging due to the placebo-controlled design and requirement for TOBI-naive patients
with chronic P. aeruginosa infection, i.e. no use of other inhaled anti-pseudomonal antibiotics
permitted for 4 months prior to screening. This was more challenging than for Study C2301
due to the more extensive availability of inhaled tobramycin, and an apparent evolution across
4 years in ethical standards for CF studies globally with respect to acceptance of a placebocontrolled arm.
Only sites outside of the United States were able to participate, as discussions with US
investigators and the CFF revealed that a reliable, TOBI-naive population no longer existed in
the US. The enrollment challenges were similar across most European/Rest of World
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countries due to the absence of TOBI-naive patients and/or the actual (e.g. Argentina, Chile
and S. Africa) or expected rejection of the study by HAs or ethics committees due to the
placebo arm. Such recruitment challenges were initially described to FDA during the preNDA meeting in December 2009.
Over 40 countries in which Novartis internal monitoring units are located and where
compliance with Good Clinical Practice (GCP) could have been expected were included in the
feasibility assessments carried out on four separate occasions. However, only six countries
agreed to participate in this study: Bulgaria, Estonia, Latvia, Lithuania, Romania and Russia.
In a further final effort, it was possible to include Egypt and India, subject to ensuring patient
access to inhaled tobramycin and provision of lifetime inhaled tobramycin supply to these
patients.
The key reasons for the inability of the majority of countries to commit patients to Study
C2303 were as follows:
TOBI or other inhaled anti-pseudomonal therapy was already in use for the treatment of P.
aeruginosa infection in CF. This included Canada, Denmark, Finland, France, Germany,
Italy, Luxemburg, Netherlands, Norway, Sweden, Switzerland, the United Kingdom, and
the United States.
Local health authorities or ethics committees would consider it unethical to allow placebocontrolled studies in CF, particularly in pediatric patients. The standard of care typically
ensures that any patient with chronic P. aeruginosa infection receives adequate
suppressive anti-pseudomonal therapy. This included Argentina, Austria, Belgium, Chile,
Czech Republic, Greece, Ireland, Poland, Portugal, Slovakia, S. Africa, Spain and Turkey.
Study sites elsewhere in the Latin American region were not included based on a similar
determination that it would not be possible to find TOBI-naive patients at sites of adequate
quality or not possible to achieve approval from ethics committees.
In effect, recruitment into this study was considered feasible and ethical only in those
countries where CF patients had no or very limited access to inhaled anti-pseudomonal
therapy (especially TOBI) due to specific local health care circumstances.
Novartis also explored a range of other countries which could potentially have a suitable CF
population i.e. a number of CF patients but no substantive access to inhaled anti-pseudomonal
therapy. However, none of these countries were ultimately selected as they did not have
acceptable infrastructure or local regulation to meet Novartis standards for implementation of
global development trials. These countries included Croatia, Georgia, Jordan, Pakistan, Saudi
Arabia, Serbia, and Ukraine.
Some countries declined participation during the feasibility assessment due to local
circumstances such as an uncertain local reimbursement plan or a negligible CF population.
These included Australia, China, Japan, and New Zealand. In addition, Australia and New
Zealand do not have tobramycin-naive patients, based on treatment with compounded
tobramycin solutions. These countries also expressed ethical concerns about the study.
Russia is the only country from the list with active sites that was considered to have the
potential for adding more sites. To further aid in recruitment, a patient referral program to
refer eligible patients from remote areas to the participating centers, e.g. in Moscow, was
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implemented. Despite these measures, Russia had to reduce their original patient commitment
from 31 to 22 randomized patients due to the difficulty in finding suitable patients.
In early 2010, as part of its vigorous and continuous re-assessment of feasibility, Novartis
identified Egypt and India as countries where CF patients exist and where the prospect of
providing GCP-compliant data existed. As a result, in August and September 2010, Novartis
received the required Ethics Committee and Health Authority approvals to conduct Study
C2303 in India and Egypt, respectively. These countries were only able to provide a small
number of patients.
With the addition of Egypt and India, Novartis had exhausted the sources of countries with
GCP-compliant sites, and eligible patients naive to inhaled anti-pseudomonal antibiotics who
could participate in this placebo-controlled study. Based on this exhaustive search for eligible
patients, it was evident that reaching the originally planned enrollment of 100 patients in
Study C2303 was not possible. This situation was discussed with FDA during a Type A
meeting in February 2011. Given that all options had been exhausted, the study recruitment
was closed, despite recruiting substantially fewer patients than planned, recognizing the
unavoidable risk posed to the statistical power of the study.
7.3.4
Study C2303 analysis
In Study C2303, the primary analysis of relative change in FEV1 % predicted from baseline
(or screening if baseline data missing) was based on an ITT analysis which included patients
with observed data and patients with missing data. The patients with missing data were
imputed with zero relative change from baseline based on discussion with FDA. The primary
analysis was based on an analysis of variance (ANOVA) model with factors of treatment,
screening FEV1 % predicted (<50% and 50 %) and age (<13 and 13 years) that was
suggested by FDA. If screening FEV1 was missing it was imputed by the baseline value;
however three patients had no screening or baseline values and so were excluded from all
change from baseline analyses. Supportive analyses were performed using an unadjusted two
sample t-test, as well as several other imputation methods for missing data.
The significant recruitment difficulties described above led to stopping recruitment at the
maximum feasible recruitment. Despite screening 103 patients (with a majority unsuitable due
to spirometry or microbiology results) the study randomized 62 of the planned 100 patients
and so was underpowered.
Study C2303 had various challenges which complicated the analyses and the interpretation of
the results, namely:
There was a marked imbalance between treatment groups in the number of patients with
missing spirometry data requiring imputation with zero relative change from baseline in
the primary analysis (six in the TIP arm and one in placebo). In fact, most of these patients
(five out of seven with 4 on TIP and 1 on placebo) were missing the assessment due to
unacceptable (judged by the central over-read) spirometry measurements. This would not
seem to be related in any way to the treatment, and it can be noted that 4 of these 5
patients continued treatment in the extension study. Given the treatment imbalance, the
pre-specified imputation rule of zero change from baseline would seem likely to have
resulted in under-estimation of the true treatment effect.
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Two patients randomized to TIP that actually received placebo, due to investigator error,
were included in the ITT analysis as TIP patients.
In addition, other challenges included:

One TIP-treated patient was an extreme low outlier in terms of both drug exposure and
spirometry data: his very low tobramycin PK levels indicated that he did not receive the
expected amounts of tobramycin (akin to the mis-dispensed patients). This patient had a
screening FEV1 of 0.33 L (33% predicted), with a relative change from baseline in FEV1
% predicted of -36.7% at Day 29.
A related issue is the use of relative change from baseline instead of absolute change as
the primary variable because the relative change can exaggerate such extreme values.
Therefore sensitivity analyses were performed to explore the stimated treatment effect. Some
were, pre-planned before unblinding (observed data set, absolute change, Bayesian analysis)
and others were post-hoc (modified ITT, as treated, excluding outlier analysis sets) to evaluate
the effect of these issues and complications.
The following analyses were pre-planned:
In addition to the ITT population, the observed cases analysis set to match Study C2301
was a pre-planned analysis population that excluded patients with missing or unacceptable
FEV1 measurements at Day 29.
Absolute change from baseline in FEV1 % predicted also was analyzed. Patients with
missing data at Day 29 were imputed with 0 change as in the primary analysis of relative
change. This pre-planned analysis was suggested by FDA.
A Bayesian analysis that uses prior information on placebo patients was performed in
view of the reduced sample size in this study. This was a pre-planned analysis that had
been proposed to FDA before database lock/unblinding.
The following analyses were post-hoc:
The modified ITT population is a post-hoc defined analysis set that excludes patients with
unacceptable (i.e. not meeting ATS/ERS criteria as judged by the blinded central overread) FEV1 measurements at Day 29, as this was not viewed as being related in any way to
treatment or outcome (the other 2 patients with missing values were maintained in this
analysis set).
Analysis based on the safety population (analyzed as actually treated, not as randomized)
was performed to evaluate the effect of the two patients who were incorrectly treated.
A post hoc analysis excluding a potential outlier was performed to evaluate the impact of
that value.
Analysis was performed based on nonparametric methods that include Wilcoxon rank
sum test, ANCOVA of ranks and a randomization based method which do not require an
assumption about the distribution of underlying data.
In addition to imputing with zero relative change from baseline, other imputation
approaches also were used, e.g. multiple imputation, imputing with placebo mean etc.
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7.3.5
In total, 95.2% of patients completed the study. Baseline demographics and disease
characteristics were generally similar in the two treatment groups, but a higher proportion of
patients were female in the TIP group (70%) than the placebo group (59%). Also, there were
more patients on TIP (23.3%) than placebo (12.5%) with a screening FEV1 % predicted value
<50%. Ongoing medical conditions were more frequently reported in the TIP group (50.0%)
than in the placebo group (40.6%).
Figure 7-11
Patient disposition in Study C2303
The differences in the ITT and safety populations is due to the mis-dispensation of study drug to 2
patients.
Table 7-17 and Table 7-18 provide the baseline demographics and disease characteristics.
Table 7-17
Variable
Demographic summary, by treatment group - Study C2303 (All

randomized Safety population)
TIP
N=30
Placebo
N=32
Total
N=62
30
12.9
4.25
12.5
32
12.9
4.68
14.0
62
12.9
4.44
13.0
Age (years)
n
Mean
SD
Median
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TIP
N=30
Placebo
N=32
Total
N=62
6- 21
6- 20
6- 21
15 (50.0)
15 (50.0)
15 (46.9)
17 (53.1)
30 (48.4)
32 (51.6)
9 (30.0)
21 (70.0)
13 (40.6)
19 (59.4)
22 (35.5)
40 (64.5)
29 (96.7)
1 (3.3)
32 (100.0)
0 (0.0)
61 (98.4)
1 (1.6)
30
34.6
13.56
32.3
11.0- 62.5
32
36.2
15.15
32.8
12.0- 70.0
62
35.4
14.31
32.7
11.0- 70.0
30
143.5
17.48
141.5
106- 168
32
145.5
22.09
151.0
107- 184
62
144.5
19.86
149.0
106- 184
30
16.1
3.26
15.5
9.1- 22.1
32
16.4
3.41
16.3
8.6- 25.4
62
16.2
3.32
16.1
8.6- 25.4
Variable
Min-Max
Age category (years), n (%)
< 13 years
>= 13 years
Sex, n (%)
Male
Female
Race, n (%)
Caucasian
Asian
Weight (kg)
n
Mean
SD
Median
Min-Max
Height (cm)
n
Mean
SD
Median
Min-Max
2
Body mass index (kg/m )

n
Mean
SD
Median
Min-Max
Body Mass index: weight (kg) / [height (m) ]
Table 7-18
Baseline characteristics, by treatment group - Study C2303 (All

randomized Safety population)
Variable
TIP
N=30
Placebo
N=32
Total
N=62
25
61.8
17.50
71.2
31.0 - 80.2
25
63.1
18.66
65.1
21.5 - 107.8
50
62.4
17.92
67.7
21.5 - 107.8
7 (23.3)
17 (56.7)
1 (3.3)
5 (16.7)
4 (12.5)
19 (59.4)
2 (6.3)
7 (21.9)
11 (17.7)
36 (58.1)
3 (4.8)
12 (19.4)
Screening FEV1 % predicted

n
Mean
SD
Median
Min - Max
Screening FEV1 % predicted, n (%)
>=25% - < 50%
>=50% - <=80%
< 25% or >80%
Missing
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Variable
TIP
N=30
Placebo
N=32
Total
N=62
29
59.1
18.18
66.4
28.9 - 79.3
30
59.3
16.61
62.9
26.6 - 86.1
59
59.2
17.25
64.9
26.6 - 86.1
30
7.4
1.55
7.9
3.4 - 9.1
57
7.4
1.52
7.9
3.3 - 9.1
3 (9.4)
29 (90.6)
4 (6.5)
58 (93.5)
Baseline FEV1 % predicted

n
Mean
SD
Median
Min - Max
Baseline P. aeruginosa sputum density (log10 CFU)

n
Mean
SD
Median
Min - Max
27
7.4
1.53
7.9
3.3 - 9.0
Baseline P. aeruginosa tobramycin MIC, n (%)

> 8 g/mL
<= 8 g/mL
1 (3.3)
29 (96.7)
Any values that are listed as missing at Screening and/or Baseline FEV 1 % predicted can include data that was
captured but identified as unacceptable.
a
Overall density, defined as the sum of biotypes (mucoid, dry and small colony variant).
MIC = Minimum inhibitory concentration.
Baseline was defined as the last measurement prior to the first dose of study drug.
While there were no major differences between treatment groups for any particular preferred
terms, the TIP group did have an apparent higher burden of illness, as judged by the rate of
these prior medical conditions. With regard to concomitant medications 17% of TIP patients
in Study C2303 used beta-agonists, compared with >40% in the other arms of Studies C2301
and C2303, and the patients used more mucolytics (TIP arms 73% vs. 59%) and more
macrolides (TIP arms 17% vs. 6.5%) respectively for Study C2303 and Study C2301.
7.3.6
The primary endpoint was the relative change in FEV1 % predicted from baseline to Day 29 in
the ITT population, as calculated using an ANOVA model. Seven patients with missing (2) or
unacceptable (5) Day 29 spirometry measurements had their primary endpoint data imputed
with zero as recommended by the FDA. Three patients without acceptable screening or
baseline values (due to inadequate spirometry) were excluded from all change from baseline
analyses.
The results are presented in Table 7-19. The mean relative change with TIP in the case
adjusted for baseline FEV1% predicted and age (8.2%), as well as in the unadjusted case
(8.3%) is larger than with placebo (2.3% and 2.4%, respectively).
The LS mean difference between TIP and placebo was 5.9% (95% CI -2.2, 14.0), but a
statistically significant difference was not reached (p=0.148 for adjusted case, and p=0.151 for
unadjusted case)
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Table 7-19
Treatment
Relative change of FEV1 % predicted from baseline to Day 29 in key

analysis populations - Study C2303
---- Treatment ----LS

#
Mean
SE
Comparison
---------------- Treatment difference ----------------LS

#
Mean
SE
95% CI
p-value
FEV1 % predicted, ITT population (adjusted analysis: ANOVA)
TIP
31
8.2
2.93
TIP-Placebo
5.9
4.03
( -2.2, 14.0)
Placebo
28
2.3
3.13
1
FEV1 % predicted, ITT population (unadjusted analysis: two-sided two-sample t-test)
0.148
TIP
31
8.3
2.68
TIP-Placebo
5.8
4.00
Placebo
28
2.4
2.98
1
FEV1 % predicted observed cases population (adjusted analysis: ANOVA)
( -2.2, 13.8)
0.151
TIP
25
10.3
3.42
TIP-Placebo
7.9
4.49
Placebo
27
2.4
3.35
FEV1 % predicted, modified ITT population (adjusted analysis: ANOVA)
( -1.2, 16.9)
0.086
TIP
Placebo
( -1.6, 15.9)
0.107
27
27
9.7
2.5
3.30
3.30
TIP-Placebo
7.1
4.35
LS Mean = least squares mean, SE = standard error of the mean, CI = confidence interval.
# In the unadjusted analysis LS mean = Arithmetic mean.
In the adjusted analysis, analysis model: response (% change) = treatment + Screening FEV 1 % predicted (<50
and >=50) + age (<13 and >=13) + error.
In the unadjusted analysis, analysis model: response (% change) = treatment + error.
In ITT population, patients with missing or unacceptable Day 29 spirometry measurements have relative change
from baseline of FEV1 % predicted imputed using zero.
In observed cases analysis set, patients with missing or unacceptable FEV 1 measurements are excluded from
analysis.
In modified ITT population, patients with unacceptable FEV1 measurements are excluded from analysis.
Significance for the FEV1 % predicted is reached for p-values <= 0.05.
1
Pre-planned analysis.
A range of pre-specified analyses were performed to assess the effect of the imputation
methods used.
The pre-planned observed cases analysis excludes all 7 patients with missing spirometry data
at Day 29 pre-dose values and this is presented in Table 7-19. The results show a treatment
effect of 7.9 and p-value of 0.086. The primary analysis of Study C2301 was based on
observed cases.
Of the 7 patients with missing spirometry data at Day 29, 5 patients (TIP 4, placebo 1) had
performed spirometry, but the spirometry curves were deemed unacceptable when evaluated
during the centralized spirometry over-read. In addition, 4 of these 5 patients continued into
the first extension study. Since the failure to achieve technically acceptable spirometry curves
was not considered to be related to treatment or outcome, and because the majority continued
on active treatment, it might be considered appropriate to consider a less conservative
imputation scheme. Therefore a modified ITT (mITT) population was defined in which these
5 patients were excluded from the analysis and the remaining 2 patients (who discontinued
early) were imputed with 0 relative change from baseline as in the primary analysis. These
data show a treatment effect of 7.1 (p-value 0.107).
Overall, these results indicate that the imputation method for missing data can have a
substantial effect on the estimate of treatment effect, and suggest that the primary analysis is
likely to have been too harsh and under-estimated the true treatment effect.
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7.3.7
Study C2303 relative change in FEV1 % predicted sensitivity analyses
Table 7-20 shows the results of the sensitivity analyses with additional imputation methods
for Study C2303. These provided estimates of treatment effect in the range 5.9-7.9.
Multiple imputation with BOCF for missing data due to discontinuation probably provides the
most reasonable imputation scheme. As described in the previous section, of the 7 patients
without spirometry data at Day 29, only 2 were due to discontinuation. The other 5 were
because of unacceptable spirometry readings. The primary analysis using BOCF for all 7
patients (6 in TIP and 1 in Placebo) basically assume treatment failure for all of them which is
probably not a reasonable approach and can potentially under-estimate the treatment effect.
Using BOCF for the 2 patients who discontinued and multiple imputation for the other 5
patients is probably a better method and reflects a scenario thats closer to the truth.
A separate multivariate normal models for both treatment groups, each including screening
FEV1, baseline FEV1, baseline age, and FEV1 relative change from baseline, multiple
imputation was applied for the 5 patients with unacceptable spirometry. Once again, the
remaining 2 patients (who discontinued early) were imputed with 0 relative change from
baseline. For subjects with missing values due to unacceptable spirometry, this approach will
tend to impute values that are similar to those in subjects with complete data who have similar
baseline covariates. Further, as the imputation process is conducted a number of times, the
technique accounts for the additional uncertainty associated with missing values.
Table 7-20
Study C2303 sensitivity analyses with additional imputation methods
Observed cases
Primary analysis ITT with BOCF (imputing
missing data with zero)
Multiple imputation
Multiple imputation with BOCF for missing
due to discontinuation
Least favorable mean imputation (imputing
with placebo mean)
Point estimate
95% CI
p-value
7.9
5.9
-1.2, 16.9
-2.2, 14.0
0.086
0.148
7.7
6.9
-1.2, 16.7
-1.7, 15.4
0.090
0.118
6.3
-1.7, 14.3
0.120
Three different non-parametric analyses were also conducted to investigate the sensitivity to
distributional assumption of the primary analysis using both the ITT population with missing
data imputed with zero (BOCF) and the observed cases. The results are presented in
Table 7-21 and Table 7-22. These additional analyses provide results which are in line with
those of the primary analysis.
Table 7-21
Study C2303 significance test (p-values) with non-parametric methods
Study C2303 observed

cases
Study C2303 ITT + BOCF
ANCOVA
Randomization
-based method
Wilcoxon rank
sum test
ANCOVA of
ranks
0.086
0.088
0.092
0.088
0.148
0.153
0.239
0.233
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Table 7-22
Study C2303 estimates with non-parametric method

ANCOVA
Study C2303 observed

cases
Study C2303 ITT + BOCF
7.3.8
Estimate
95% CI
HodgesLehmann
estimate
95% CI
7.9
-1.2, 16.9
7.84
-1.05, 18.61
5.9
-2.2, 14.0
4.45
-4.95, 10.40
Study C2303 additional supportive analyses: individual patterns
The primary efficacy analysis and other sensitivity analyses were performed using the ITT
population, such that patients were analyzed according to their randomized treatment
allocation. To assess the effect of 2 patients who were assigned to TIP actually receiving
placebo, analyses of data for relative change from baseline in FEV1 % predicted, based on the
actual treatment received (i.e. equivalent to the Safety population) were performed
(Table 7-23 and Table 7-24).
Analysis using the same imputation method as for the primary analysis. The adjusted
treatment difference was 6.7% (p=0.098).
Analysis for the mITT population, i.e. with exclusion of the 5 patients who had missing
data due to technically unacceptable spirometry curves, and with the remaining 2 patients
with missing data imputed with 0 relative change from baseline. The adjusted treatment
difference was 8.2% (p=0.064).
Analysis for the ITT population with multiple imputation for the 5 patients who had
missing data due to technically unacceptable spirometry curves, and the 2 patients with
missing data due to discontinuation imputed with 0 relative change from baseline. The
adjusted treatment difference was 7.7% (p=0.076).
Analysis for the observed cases population, where all patients with missing post-baseline
data were excluded. The adjusted treatment difference was 8.8% (p=0.056).
Table 7-23
Analyses on relative change in FEV1 % predicted by treatment actually

received - Study C2303
Analysis
ITT population with patients analyzed by treatment actually
received
Modified ITT population with patients analyzed by treatment
actually received
Observed cases population with patients analyzed by treatment
actually received
LS mean difference
TIP-placebo
95% CI
P-value
6.7
-1.3, 14.7
0.098
8.2
-0.5, 16.9
0.064
8.8
-0.2, 17.8
0.056
Across these three analyses the mean change in FEV1 % predicted from baseline to Day 29
was in the range of 8.8-11.1% for TIP and 2.1-2.4% for placebo.
To further examine the pattern of FEV1 response at Day 29, histograms of change from
baseline for FEV1 % predicted were produced for the TIP group and placebo group in Study
C2303. For these histograms, the mis-dispensed patients were kept in the assigned ITT group.
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Figure 7-12
Histogram of relative change in FEV1 % predicted from baseline to Day

29 in the TIP group - Study C2303 (observed population, n = 27)
Figure 7-13
Histogram of relative change in FEV1 % predicted from baseline to Day

29 in the placebo group - Study C2303 (observed population, n= 28)
The histogram for relative change in FEV1 % predicted shows that one patient on TIP had a
much lower change than the rest of the TIP patients (Figure 7-12). This patient was a 7 year
old male from Egypt with a weight of 11 kg and a BMI of 9 kg/m 2 (height of 110 cm). This
child appeared to have a disease-induced failure to thrive. He had a screening FEV1 of 0.33 L
(33% predicted, which is severe for such a young child), with a -36.7% relative change from
baseline in FEV1 % predicted at Day 29 without any evidence of a severe exacerbation. He
had spirometry values available only for screening and Day 29 pre-dose values (although Day
29 values noted in the technical over read prior to the database lock were borderline
acceptable), and a missing baseline value. In addition to outlying FEV1 values, he had low
outlying PK values consistent with the technical evaluations of his device and capsules
indicating inappropriate use of the device and study medication. To aid comparisons, the
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equivalent distribution of results is shown in Figure 7-14 for Study C2301. This shows no
such extreme low outlier on TIP and a balanced distribution of results for placebo, visually
similar to that seen in C2303.
Figure 7-14
Study C2301 Histograms
Analyses were performed using the ITT population, observed cases method and the Modified
ITT population excluding this outlier (i.e. outlying with respect to FEV1 values and PK data),
to assess the effect of this one patient on the results of the study. These data demonstrated a
treatment difference of 7.3 for the ITT population (p=0.058). For the observed data set the
treatment difference was at 9.8 (p=0.023). For the modified ITT population excluding the
outlier, the treatment difference of 8.9 was (p=0.032). Of note, the 2 mis-dispensed patients
are analyzed here as though they received TIP treatment, when they actually received placebo
treatment.
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Table 7-24
Treatment
Relative change from baseline to Day 29 in FEV1 % predicted with

outlier excluded from key analysis populations - Study C2303

#
Mean
SE
---------------- Treatment difference ----------------Comparison
LS Mean
SE
95% CI
p-value
FEV1 % predicted, ITT population excluding outlier (adjusted analysis: ANOVA)

TIP
30
10.4
2.81
TIP-Placebo
7.3
3.77
( -0.3, 14.8)
Placebo
28
3.1
2.92
FEV1 % predicted, observed cases population excluding outlier (adjusted analysis: ANOVA)
0.058
TIP
24
13.1
3.25
TIP-Placebo
9.8
4.15
(1.4, 18.1)
Placebo
27
3.4
3.08
FEV1 % predicted, modified ITT population excluding outlier (adjusted analysis: ANOVA)
0.023*
TIP
Placebo
0.032*
26
27
12.4
3.5
3.14
3.05
TIP-Placebo
8.9
4.03
(0.8, 17.0)
Model: response (% change) = treatment + Screening FEV1 % predicted (<50 and >=50) + age (<13 and >=13) +
error.
* denotes a statistically significant difference between TIP and Placebo.
7.3.9
Study C2303 Bayesian analysis
To account for the unavoidably smaller than planned sample size, a Bayesian analysis (which
was pre-specified and had been proposed to FDA before un-blinding) was performed. This
analysis used historical placebo information from three previous studies on TIP and TOBI to
adjust the placebo effect estimate.
The set of studies were identified prior to database lock and the patient populations in these
three studies were similar to the current study. Implementation consisted of two steps: 1) a
meta-analysis of the historical data to form an informative prior for the control group effect
and 2) Applying a Bayesian approach in an analysis of the new study incorporating the prior
for the placebo effect, which was formed in step 1. A summary of the placebo data is shown
in Table 7-25 below.
Table 7-25
Summary of placebo data
Study
TIP (Study C2301)
1
TOBI1 (PC-TNDS-002)
1
TOBI2 (PC-TNDS-003)
1
2
Number of patients
Primary efficacy variable

2
(N)
Mean
31
109
141
-0.57
1.07
-0.51
SD
13.61
16.65
14.11
TOBI (tobramycin inhalation solution) pivotal study

Relative change in FEV1% predicted.
This method (Neuenschwander et al 2010) first uses a Bayesian normal random effect model
for the meta-analysis of historic control data. The results of the meta-analysis, specifically the
posterior distribution for , the placebo effect, were used to form the corresponding normal
prior distribution for the new study. In this case, the prior mean was calculated to be 0 and
prior SD=152/20. Based on a patient level SD of 15, which was assumed in the planning of the
trial, the prior is worth approximately 20 placebo patients i.e. the total of 281 historical
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placebo patients contributed 20 virtual placebo patients distributed as normal with mean 0 and
SD 15.
Using the above informative prior for the mean of the placebo effect in this study and together
with a non-informative prior for the mean of the TIP effect, a Bayesian analysis was
constructed for the mean difference between the TIP and placebo arms. The result of the
Bayesian analysis is presented in the table below (Table 7-26).
Table 7-26
Bayesian analyses of relative change from baseline in FEV1 %

predicted on Day 29 incorporating historical placebo information Study C2303
Population set
Treatment
Treatment
Mean SD
ITT
TIP
Placebo
31
28
8.27
1.38
2.73
2.20
6.89
3.53
-0.06
13.84
0.0264
Observed cases
TIP
Placebo
25
27
10.25
1.35
3.21
2.28
8.90
3.95
1.11
16.64
0.0131*
Modified ITT
TIP
Placebo
27
27
9.50
1.35
3.05
2.27
8.16
3.82
0.65
15.66
0.0167*
Difference
Mean SD
Posterior
95% CI
P(Diff<0
|data)
SD is the standard deviation from the Bayesian posterior distribution of the estimate of the population mean,
which is similar to the standard error (SE) of the mean estimate in the traditional analysis.
P(Diff<0/Data) is derived from the Bayesian posterior distribution of the estimate of the population mean, which is
similar to the one-sided p-value in the traditional analysis.
Historical placebo information based on placebo patients in TIP study C2301 and TOBI studies 002 and 003 were
used to construct the prior distribution of the mean effect in the placebo arm.
These data demonstrated a treatment difference of 6.9 in the primary analysis set which is
very close to statistical significance (1-sided p=0.026 which is equivalent to 2-sided p=0.052).
For the modified primary analysis set and observed data set the treatment differences were
statistically significant with a treatment effect of 8.2 and 8.9, respectively (1-sided p=0.017
and p=0.013).
The Bayesian analysis was more powerful and helpful in two aspects. In Study C2303, there
was a higher placebo effect than in previous studies. By using prior historical placebo
information, the Bayesian analysis adjusted the placebo effect estimate by integrating placebo
data from previous studies after a process of down-weighting to take into account study to
study variability. Additionally, the inclusion of 20 virtual placebo patients increased the
sample size and reduced the variability of the treatment effect estimate.
7.3.10
Study C2303 absolute change in FEV1 % predicted
As recommended by FDA, there was a pre-specified analysis for absolute change in FEV1 %
predicted (Table 7-27), as the relative change in FEV1 % predicted can be exaggerated by
extreme values. Importantly, all populations showed statistically significant betweentreatment differences in favor of TIP, despite the imbalance in missing data, the outlier and
the inclusion in the TIP group of the 2 patients who actually received placebo. For the
adjusted analysis in the ITT population, absolute changes from baseline were 4.9% in the TIP
group vs. 0.5% in the placebo group; the LS mean difference between TIP and placebo was
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4.4% (p=0.0496). LS mean between-treatment differences were 5.6% (p=0.025) for the
observed cases population and 5.1% (p=0.035) for the modified ITT population.
Table 7-27
Treatment
Absolute change of FEV1 % predicted from baseline to Day 29 in key

analysis populations - Study C2303
#
Mean
SE
Comparison
---------------- Treatment difference ----------------LS

Mean
SE
95% CI
p-value
FEV1 % predicted, ITT population (adjusted analysis: ANOVA)
TIP
31
4.9
1.59
TIP-Placebo
4.4
2.18
Placebo
28
0.5
1.70
FEV1 % predicted, observed cases population (adjusted analysis: ANOVA)
(0.0, 8.8)
0.050*
TIP
25
6.1
1.84
TIP-Placebo
5.6
2.42
Placebo
27
0.5
1.80
FEV1 % predicted, modified ITT population (adjusted analysis: ANOVA)
( 0.7, 10.5)
0.025*
TIP
Placebo
( 0.4, 9.8)
0.035*
27
27
5.7
0.6
1.78
1.79
TIP-Placebo
5.1
2.35
In the adjusted analysis, analysis model: response = treatment + Screening FEV1 % predicted (<50 and >=50) +
age (<13 and >=13) + error.
1
Pre-planned analysis
These data, using exactly the same spirometry values as for the relative change, show a
statistically significant result despite the numerous challenges encountered in the study. This
provides important supportive evidence for the efficacy of TIP in Study C2303 with respect to
lung function.
7.3.11
Study C2303 change in P. aeruginosa colony forming units
Summaries of P. aeruginosa density in sputum (log10 CFU/g) at screening, baseline, Day 29,
Day 57 and at end of study were done. For all biotypes and sum of all biotypes the greatest
decrease in the TIP group and the greatest difference to placebo was seen at Day 29 (end ontreatment Cycle 1). Changes in the TIP group on Day 57 were smaller (as expected for the
off-treatment period) than on Day 29 overall and for all biotypes, but still larger than in the
placebo group.
The findings for P. aeruginosa sputum density is shown in Table 7-28. The mean difference
was -2.4 (95% CI -3.18, -1.54, p=0.002).
Table 7-28
Treatment
Change in P. aeruginosa sputum density from baseline to Day 29 (ITT

population) - Study C2303
N
-- Treatment -Mean
SE
Comparison
-------------- Treatment difference -------------Mean

SE
95% CI
p-value
P.aeruginosa sputum density (log10 CFU/g)

TIP
Placebo
14
27
-2.31
-0.01
0.34
0.26
TIP-Placebo
-2.29
0.387
( -3.08, -1.51)
<0.0001
P. aeruginosa sputum density refers to overall density, defined as the sum of biotypes (mucoid, dry and small
colony variant).
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N= number of patients with data at baseline and Day 29 visit
In order to further assess the suppressive action of TIP compared to placebo, the percentage of
patients with at least a 0.5, 1.0 or 1.5 reduction in log10 CFUs by cycle was conducted. This
showed that the percentage of patients in each category of change was greater in the TIP
treatment group than in the placebo treatment group (end of on treatment cycle 1) were as
follows:
1.5 log10 CFU reduction: TIP 71.4%,placebo 0%
Taken as a whole, these data demonstrate that TIP is effective in suppressing pulmonary P.
aeruginosa. The changes in MICs are addressed in Section 8.
7.3.12
Study C2303 changes in other clinical endpoints
7.3.12.1 Anti-pseudomonal antibiotic use and hospitalization

Six patients received new anti-pseudomonal antibiotics, 3 patients in each treatment group.
Also, analysis by different routes of administration were similar in the two treatment groups.
However, differences in the duration of new anti-pseudomonal antibiotics were observed in
the treatment groups. The 3 placebo patients had on average 13 days of use, while the 3 TIP
patients had on average 8.3 days of use. Hospitalization due to respiratory events occurred
only for one patient in the placebo group.
One of these 6 patients receiving anti-pseudomonal antibiotics was a patient who in error
received placebo instead of active treatment. Consequently, if the data were presented based
on treatment received (i.e. the safety population) the usage would be 2 (6.7%) TIP patients (2
out of 30 patients in the safety population) versus 4 (12.5%) placebo patients (4 out of 32
patients in the safety population).
Of the 3 patients in the TIP arm, only one patient, the one mis-dispensed placebo instead of
active treatment, used an anti-pseudomonal antibiotic as treatment for an AE of bronchitis
(colistin inhaled and ciprofloxacin per os (p.o.), administered on the day of study
discontinuation Day 19). One patient had meropenem and tobramycin IV from days 35 to 50
as pre-planned routine (at that care center) for prophylaxis against pulmonary exacerbations
and another patient had ciprofloxacin p.o. from Day 50-57 (in the absence of any AE
reported). All 3 patients on placebo used anti-pseudomonal antibiotics due to respiratory
related events AEs, two patients received ciprofloxacin p.o., and one patient received
cefoperazone and netilmicin IV during hospitalization (described below).
If the pre-planned prophylactic antibiotics use is excluded from consideration as an efficacy
marker (because it did not denote a clinical deterioration /exacerbation) together with the misdispensed patient, then the relative use of anti-pseudomonal antibiotics to treat clinical
worsening is one patient in the TIP group (3.3%) vs. 4 placebo patients (12.5%).
Thus, overall the lower use of new anti-pseudomonal antibiotics is similar to Study C2301
and favours TIP over placebo.
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The reason for the relatively low number of these events (anti-pseudomonal antibiotic use and
hospitalization) is unclear and may be due the nature of clinical practice in the countries in
which the study was conducted. It may also relate to the relatively low number of prior
antibiotic users in this study population (25% in the TIP group and 30% in the placebo group)
compared with the previous comparable study (Study C2301 - 89.1% in the TIP group and
87.8% in the placebo group).
7.3.13
Study C2303 Health-related quality of life
7.3.13.1 CFQ-R
The results of the Cystic Fibrosis Quality of Life Questionnaire (CFQ-R), a validated diseasespecific patient-reported outcome showed trends indicating improvements (i.e. median change
of >8 score points from baseline to Day 29) in Respiratory Symptoms, Role Functioning,
Treatment Burden and Health Perceptions in the TIP group, as compared with virtually no
change in these domains in the placebo group. These are displayed in Figure 7-15.
Figure 7-15
Study C2303 Cystic Fibrosis Quality of Life domain scores
A striking result was observed for the treatment burden, which improved by 11.1 points,
consistent with the rationale for developing TIP i.e. making it easier to take their treatment.
Another important result was on the the Respiratory Symptoms Scale, on which the observed
difference between treatments on Day 29 was 11.1 (TIP 66.7, placebo 55.6). This difference is
substantially larger than the published minimal important difference (MID; Quittner et al
2000) for this sub-scale and is consistent with the positive trends in FEV1 % predicted and
sputum CFU, but was not statistically significant in the small patient group.
Between-treatment comparisons of the CFQ-R scores, by age, domain and validated and
unvalidated languages was evaluated. Overall, statistically significant differences for
validated languages were observed only for the Health Perceptions scale on Day 29 (p=0.023)
and the Weight scale on Day 57 (p=0.046). The translations of the CFQ-R in Bulgaria,
Estonia, Latvia, Lithuania and Romania had not been validated prior to the study and
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consequently only a proportion of patients in the trial were using previously validated
translations of the CFQ-R. Note however, that forward and backward translations of the
CFQ-R were performed.
7.4
Comparison of outcomes for Studies C2301 and C2303
As noted in the PK section, comparable amounts of tobramycin were delivered to the patients
lungs and systemic circulation in studies C2301 and C2303, supporting the similarities
between these studies.
As displayed in the demographic and disease baseline tables for Studies C2301 and C2303
(Tables 7-1, 7-2, 7-17, and 7-18) similar populations appeared to have been recruited to each
trial, although the baseline FEV1 was slightly higher in Study C2303.
7.4.1
Change in FEV1 % predicted in Cycle 1
The primary efficacy endpoint for Study C2301 and Study C2303 was the relative change
from baseline in FEV1 % predicted after 28 days (which corresponded to the end of Cycle 1
dosing in Study C2301).
For Study C2301, data are presented for the SIA ITT population. The primary analysis in
Study C2301 used observed data, with no imputation of missing values. Although the primary
analysis for Study C2303 imputed missing values, an analysis using observed data was also
performed for the sake of consistent comparison.
As shown in Table 7-29 below, there was a greater increase in mean and LS mean postbaseline values in the TIP group compared with the placebo group in Study C2301. The
difference between the TIP and placebo treatment groups was greater than 13% and was
statistically significant (p=0.0016) and crossed the pre-defined efficacy stopping boundary for
the study (critical value of 2.848 and significance level of 0.0044).
In the smaller than planned Study C2303, the primary analysis was based on an ITT analysis,
which included patients with observed data and patients with missing data. The patients with
missing data (six in the randomized TIP arm and one in placebo) were imputed as zero
relative change from baseline based on discussions with FDA. This analysis showed
numerically superior improvements in FEV1 % predicted for TIP as compared with placebo
(LS mean 8.2% and 2.3%, respectively; between-treatment difference 5.9%, 95% CI - 2.2,
14.0, p=0.148).
A prospectively-planned sensitivity analysis was also performed for relative change in FEV1
% predicted using observed data (in order to aid comparisons to Study C2301 which used
only observed data), with no imputation of missing values. For comparability with the results
of Study C2301, the results of this analysis are presented in Table 7-29. The change from
baseline observed for TIP was 14.0% in Study C2301 and 10.3% in Study C2303, a difference
of approximately 4% points. The difference in treatment effects in each study was
approximately 5 percentage points (13 vs. 8).
Table 7-29
Relative change in FEV1 % predicted from baseline to pre-dose Day 28

of Cycle 1 (Studies C2301 and C2303)
TIP
Placebo
Difference (SE)
P-value
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C2301 (SIA ITT population)
n
1
Mean
2
LS Mean
27
13.21
13.97
31
-0.57
0.68
13.79 (3.95)
13.29 (3.98)
(5.87, 21.70)
(5.31, 21.28)
0.0010
0.0016
27
2.4
2.5
7.7 (4.46)
7.9 (4.49)
(-1.2, 16.7)
(-1.2, 16.9)
0.089
0.086
C2303 (Observed cases population)

n
1
Mean
2
LS Mean
25
10.3
10.3
Mean, p-value, mean difference, and its 95% confidence interval (CI) are calculated from ANOVA with treatment
in the model.
2
Least square (LS) mean, p-value, least square mean difference, and its 95% CI are calculated from ANCOVA
with treatment, baseline value, age and region (region in C2301 only) in the model.
SE = standard error, n is number of patients with value at baseline and Day 28.
The analysis was based on observed data only, no imputation was performed for missing data.
Other matching analyses between studies are found in Table 7-4 and Table 7-19, These show
a consistent pattern of higher point estimates of effect, ranging 12.4 - 13.4, in Study C2301
than seen in Study C2303 where the range was 5.9 7.9.
7.4.2
Clinical variability in change from baseline in FEV1 % predicted
In comparing Studies C2301 and C2303, the estimated treatment effect between the two
studies are numerically different, but a significant difference could not be detected.
The point estimate of the treatment effect of one study lies within the 95% CI of the other
study. Additionally a test of treatment by study interaction, i.e., a test of the null hypothesis
that the treatment effects in the two studies are the same, yields a non-significant p-value of
0.18. As further indication that the range of response in Studies C2301 and C2303 falls within
the range expected due to clinical variability, the previous TOBI pivotal studies (002 and
003), which used the same TOBI formulation and had matching designs and study populations
were reviewed. In the TOBI studies, the estimated treatment effects based on analysis of
observed data 28 days after treatment were 13.9% (95% CI 8.0%, 19.8%) and 10.2% (95% CI
6.3%, 14.1%). Thus for TOBI variation in treatment estimates were also observed with no
significant study by treatment interaction (p-value of 0.15).
The approximate difference in treatment effect vs. placebo in the two TIP studies was 5
percentage points (13% - 8%) vs. a treatment effect of 4 percentage points (14% - 10%) for
the two TOBI studies. This supports the view that the range of variation observed between the
two TIP studies falls within the expected range of clinical variability for tobramycin studies as
shown in the figure below.
Additionally, although the observed treatment effect in Study C2303 was at the lower end of
the expected effect, it is not entirely unlikely. For example, assuming the true treatment effect
is in the 10%~11% range, the probability of observing a treatment effect that is worse than
what is observed in Study C2303 is in the range of 24% ~32%.
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Figure 7-16
7.4.3
Meta analysis: 2 TIP studies and 2 TOBI studies (Observed data at Day
29)
Absolute change analyses for FEV1 % predicted
Post-hoc analysis of absolute change from baseline in FEV1 % predicted in Cycle 1 of Study
C2301, using observed data and an adjusted ANOVA showed an estimated between-treatment
difference of 6.9% (95% CI 2.40, 11.40, p=0.0033). The treatment effect was similar to that
seen in the equivalent analysis for Study C2303 (5.6%, 95% CI 0.7, 10.5, p=0.025).
Similarly, the absolute change in FEV1 % predicted using the observed data in Study C2301
was 6.38 for TIP and -0.52 for placebo. For comparison, the equivalent changes in Study
C2303 were 6.1 for TIP and 0.5 for placebo. Thus the observed data for absolute change show
comparable results across these 2 studies.
Absolute change from baseline in FEV1 % predicted showed a statistically significant
treatment effect in both studies, and the treatment effects in the two studies were also judged
to be clinically similar.
Thus, in summary the degree of difference seen between Studies C2301 and C2303 falls
within the expected range, reflecting similar variability in the 2 identical placebo-controlled
TOBI Studies.
7.4.4
P. aeruginosa suppression in the lungs
As the rationale for use of an inhaled antibiotic in CF patients is to suppress P. aeruginosa

infection in the lungs, the change from baseline in P. aeruginosa sputum density was an
important efficacy endpoint in the Phase III studies.
In Studies C2301 and C2303, one cycle of TIP treatment resulted in a statistically significant
reduction of P. aeruginosa density in sputum, while placebo had a minimal effect. A
reduction was achieved for all biotypes present at baseline. Changes in P. aeruginosa density
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in sputum in treatment Cycle 1 of Study C2301 and from baseline to Day 29 in Study C2303
are presented in Table 7-30. In both placebo-controlled studies, there was essentially no
change in the placebo group but marked decreases occurred in the TIP groups. The differences
between TIP and placebo were statistically significant in both studies.
In both studies, there was a 2 log10 reduction in CFU/g from baseline to the end of Cycle 1 ontreatment period in the TIP group. These data demonstrate comparability in the two studies
with respect to suppression of P. aeruginosa.
Table 7-30
Treatment
C2301
TIP (N=46)
Placebo (N=49)
C2303
TIP (N=32)
Placebo (N=30)
Between treatment comparison of change in P. aeruginosa sputum

density (Log10 CFU/g) from baseline to end of dosing in Cycle 1
Studies C2301 and C2303 (ITT population)
N
LS mean
Difference (SE)
p-value
28
36
-2.86
-0.16
-2.70 (0.453)
(-3.60, -1.79)
<0.001
14
27
-2.31
-0.01
-2.29 (0.387)
(-3.08, -1.51)
<0.0001
Least square means, p-values, LS mean differences, and their 95% CI are calculated from ANCOVA
model with treatment and baseline value as factors.
SE = standard error.
n are the number of subjects with values at both baseline and end of dosing in Cycle 1.
Sputum density is Log10 CFU/g of the sum of all biotypes.
7.4.5
Anti-pseudomonal antibiotic use
Use of new anti-pseudomonal antibiotics was assessed in Studies C2301 and C2303. In Cycle
1 of Study C2301, 20.4% of patients in the placebo group and 13.0% of patients in the TIP
group used new anti-pseudomonal antibiotics. The mean duration of use in Study C2301 was
greater in the placebo group compared with the TIP group (18.2 days and 13.3 days,
respectively). When new anti-pseudomonal antibiotic use was summarized according to actual
treatment received, the rates were 12.5% and 6.7% in the placebo and TIP groups,
respectively.
7.4.6
Hospitalizations
No patients in the TIP treatment groups of Studies C2301 or C2303 required hospitalization
due to respiratory events in Cycle 1. Although some caution in interpretation is required due
to the small patient populations (particularly in Study C2303), hospitalization rates in placebo
groups differed between studies: 12.2% (6 of 49 patients) and 3.3% (1 of 30 patients of
patients in the placebo groups were hospitalized in Study C2301 and Study C2303,
respectively. The mean duration of hospitalization was 12.3 days in Study C2301; the single
patient hospitalized in Study C2303 had a stay of 10 days. The difference in hospitalization
rates for the placebo arms may explain the difference in use of antibiotics in general between
the two studies. Patients in Study C2303 may have had a lower severity of illness requiring
less use of antibiotics. Differences could also be related to differences in local medical
practice and the propensity to use antibiotics and hospital care.
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7.5
Study C2303E1
7.5.1
Study C2303E1 design
Study C2303E1 was an open-label extension to Study C2303, which provided the opportunity
for all the patients to receive three additional cycles of treatment with TIP. This was an open
label extension with a single TIP treatment arm across 3 cycles. It was open to all patients
who successfully completed the core study.
7.5.2
Study C2303E1 population
In total, 52 (94.5%) of the 55 patients who entered the extension (from the 59 who completed
the core study) completed the study, with one patient having AEs leading to discontinuation.
This high completion rate compares favorably with the rate of 84.8% seen in the 3 cycles of
the TIP arm in the similar C2301 study.
The demographics, as expected, were closely similar to the core study and reflected the
intended patient population for the trial. The mean age of patients was 12.9 years and nearly
one-half of patients were less than 13 years of age (26 patients, 47.3%). Most subjects were
Caucasian (54 patients, 98.2%) and nearly two-thirds of patients were female (35 patients,
63.6%). The mean FEV1 % predicted at entry to this extension study had risen to 67%, as
compared to 60% mean FEV1 % predicted for the same patients at the start of the core study.
7.5.3
Study C2303E1 sustained improvements in lung function assessments
The efficacy data showed a progressive increase in FEV1 across the 3 cycles of active
treatment, with no apparent loss of effect. The mean relative change from the core study
baseline in FEV1 % predicted was statistically significantly higher at all post-baseline time
points during the extension study, with the highest mean (SD) increase from baseline in
mean FEV1 % predicted of 17.3 (23.56)% (p<0.001) which occurred at the end of dosing
Cycle 4 (Day 29).
The mean relative change from core study baseline in FEV1 % predicted according to
treatment received in the core study during Cycle 1 and at all post-baseline time points during
the extension study is displayed in Figure 7-17.
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Figure 7-17
Relative change in FEV1 % predicted from baseline in Study C2303

and in Study C2303E1
Start of Study C2303E1
The vertical bar is the 95% CI

Week is defined from the start of treatment in Study C2303 study. The patient population shown is the Safety
population for Study C2303E1.
Core TIP = Patients who received TIP in both the C2303 and C2303E1 studies. Core Placebo = Patients who
received Placebo in Study C2303 and TIP in the C2303E1 extension study.
On: On-treatment phase, Off: Off-treatment phase.
The patients treated with placebo in the core study showed a progressive improvement in
FEV1 % predicted during the extension study, irrespective of the on-off cycles until the end of
Week 21. The degree of improvement in lung function in the (original) placebo group
regardless of the on-off cycles of TIP treatment in the first 3 cycles (core and 1st two cycles of
the extension) is striking, but the reason for this is not clear. This might relate to improved
compliance to the overall treatment (including standard care medication) due to the close
supervision within the clinical trial.
7.5.4
Study C2303E1 hospitalizations and use of anti-pseudomonal

antibiotics
In total, 5 (9.1%) of patients were observed with new anti-pseudomonal antibiotic use across 3
cycles of treatment, with only 3 patients (5.5%) using IV anti-pseudomonal antibiotics. This
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compares favorably to the 9.4% rate of use of new anti-pseudomonal antibiotics observed in a
single cycle in the core study, and the 13.0% rate observed on TIP in the first cycle of the
C2301 study. The 3.6% rate of hospitalization for respiratory events across 3 cycles (2
patients) is notably low for this CF population, considering the results of the earlier studies
(12.2% in 3 cycles of Study C2301).
7.6
Overall efficacy conclusions
The appropriate dose and its efficacy of TIP was demonstrated across 4 studies.
The PK data for tobramycin from Study TPI001 showed that the 112 mg b.i.d. dose of TIP
was comparable to the 300 mg b.i.d. dose of TOBI with respect to systemic exposure and
was similar with regard to lung exposure, given that the systemic exposure derives from
the inhaled portion of the dose. The PK data indicate a comparable exposure to
tobramycin from TIP in all 3 pivotal studies and that this exposure in sputum and serum
was comparable to TOBI. The data therefore, demonstrate that a clinically adequate
amount of tobramycin (i.e. an amount comparable to TOBI) is delivered to the lungs and
that this is associated with a sustained, statistically significant reduction in P. aeruginosa
levels. The PK data also demonstrated low systemic exposure of tobramcyin across all
three studies. For example mean trough serum concentration at the end of the 4-week
treatment cycle of TIP in Study C2303 was 0.41 g/mL, which was five-fold lower than
the recommended maximum trough level of 2 g/mL (Sweetman et al 2011).
The three Phase III studies demonstrated the efficacy of TIP relative to placebo (Study C2301
and Study C2303) and TOBI (Study C2302) across a range of disease-relevant endpoints,
which show the following:
Improvements from baseline in relative FEV1 % predicted that were statistically
significant vs. placebo in Study C2301 and greater with TIP than placebo in Study C2303.
Although Study C2303 showed an apparent smaller treatment effect, which was not
statistically significant in the primary analysis, this may have been due to this study being
underpowered, in addition to a number of other confounding factors. Sensitivity analyses
to address these factors showed larger treatment effects with nominal p values < 0.05 in
some cases. The treatment effects observed across both TIP studies were comparable to
those seen in earlier TOBI pivotal studies.
The relative change from baseline in FEV1 % predicted across Studies C2301 and
C2303 is consistent with that observed across 2 TOBI placebo controlled studies.
The absolute change in FEV1 % predicted analysis between studies Studies C2301
and C2303 are similar: 6.38% on TIP and -0.52% on placebo in study C2301 versus
6.1% on TIP and 0.5% on placebo in study C2303.
The data from Study C2303-Extension 1 show a sustained effect on FEV1 across 3
further cycles.
Absolute change from baseline in FEV1 % predicted showed a statistically significant
treatment effect vs. placebo in Study C2301 and Study C2303 in all analysis populations
and it was similar in both studies.
TIP was also shown to be comparable to TOBI in relative change from baseline in FEV1
% predicted
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Decreases from baseline in P. aeruginosa sputum density with TIP were statistically
significantly greater than for placebo, in two placebo-controlled studies (C2301 and
C2303) and comparable to those for TOBI in the active-controlled study (C2302). These
data support the underlying rationale for the use of TIP, i.e. delivering sufficient
tobramycin to the lungs to suppress P. aeruginosa.
The use of additional anti-pseudomonal antibiotics was less common with TIP than
placebo.
patients who received placebo in the two placebo-controlled trials. Hospitalization rates
were similar for TIP- and TOBI-treated patients across 3 cycles of treatment.
Data from subgroup analyses showed no overall differences in efficacy across
demographic subgroups (defined by region, age, gender and race)
TIP was faster to administer than TOBI by 28 minutes per day (13 hours per month) plus
the estimated 10-15 minutes required to prepare the dose, assemble the nebulizer and
compressor and disassemble and clean the device afterwards (VanDevanter and
Geller2011).
In providing a portable, simple treatment/formulation option to CF patients that
significantly reduces their very high treatment burden, TIP has the potential to
improve adherence, which may lead to better outcomes.
Although Study C2303 study was performed at different times from Study C2301 (starting
2009 and 2005 respectively but with similar designs in Cycle 1 and similar population
demographics), results for key efficacy endpoints were not inconsistent taking into account
the logistic challenges and reduced sample size for Study 2303. The magnitude of the change
from baseline resulting from TIP treatment in studies C2301 and C2303 falls within the
expected degree of clinical variability, based on previous TOBI data; it is unlikely that the
minor improvements to one step of the drug product manufacturing process contributed
significantly to the variability between these studies, especially considering that tobramycin is
delivered at levels many fold above the minimum inhibitory concentrations in most patients.
TIP provided equivalent efficacy to TOBI 300 mg b.i.d. administered by nebulizer, but with a
much shorter administration time and greater convenience. TIP therefore offers patients a
suitable treatment option to help successfully manage their disease.
In summary, the results of the three pivotal studies support the approval of TIP at a dose of 4
x 28 mg b.i.d. in the 28 days on-off cyclical treatment of P. aeruginosa infection lung
infections in CF patients aged 6 years or older. This dose delivers an appropriate amount of
tobramycin to the lungs and effectively suppresses P. aeruginosa, providing relevant clinical
benefits.
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Overview of clinical microbiology
CF patients chronically infected with P. aeruginosa have approximately 105-107 P.

aeruginosa CFUs per gram of sputum. This bacterial population is not homogeneous and
thought to exist in a biofilm. Diverse biotypes (colony morphology) often derived from the
same strain are usually found in respiratory tract specimens from CF patients, particularly
from those with chronic infections. These different biotypes may have different antibiotic
susceptibilities (Ratjen et al 2009). The density of P. aeruginosa, including the relative
proportion of the different biotypes may vary both during treatment with chronic inhaled
antibiotics and during systemic antibiotic treatment.
8.1
Rationale for inhaled antibiotics in CF patients
In contrast to treatment of infections with systemic antibiotics in other patient populations

which aim to eradicate the pathogen, in CF patients P aeruginosa is not eradicated by chronic
suppressive therapy, regardless of MIC. Thus, while aerosolized tobramycin acts as an
antibiotic reducing the burden of organisms, eradication is not possible in the unique milieu of
the chronically infected CF lung.
The core rationale for the use of high dose inhaled tobramycin is to serve as a chronic
suppressive therapy for P aeruginosa infection in CF patients leading to clinical benefit
without systemic toxicity. Clinical benefit includes an improvement of lung function, decrease
in exacerbations leading to less hospitalizations and IV antibiotic use, and improved quality of
life.
TIP was specifically developed for administration of inhaled tobramycin to achieve a
comparable concentration profile to TOBI in the serum and also in the respiratory tract of CF
patients. The Phase III studies were designed to demonstrate safety and efficacy of TIP, with
regard to clinical and microbiological endpoints.
8.2
Limitations of establishing susceptibility interpretive criteria

(breakpoints) for inhaled tobramycin in CF patients
In general, in order to define susceptibility of a pathogen to an antibiotic, clinical breakpoints

established for systemic treatment are calculated by using models based on serum levels that
can safely be achieved. A single-compartment pharmacokinetic assumption cannot be applied
to inhaled antibiotic therapy in CF, as the site of infection is a complex compartment
consisting of the inflamed lung and associated bacterial biofilms (Govan 2006). This is
reflected in the approved US label for TOBI, which states that susceptibility breakpoints
established for parenteral administration of tobramycin do not apply to aerosolized
administration of TOBI. Phase III studies with TOBI have not shown an association between
MIC and clinical or microbiological response to inhaled tobramycin (Smith et al 2003).
Furthermore, inhaled antibiotics reach levels in the airways that are 10 100 fold greater than
the serum concentrations achieved after systemic administration, making systemic breakpoints
of limited relevance.
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8.3
MICs of P. aeruginosa isolates in TIP Studies
In TIP Studies C2301 and C2303, CF patients were mainly children and adolescents, and most
had no prior exposure to inhaled antibiotics, including TOBI. In TIP study C2302, patients
were from all age groups, but a majority (nearly 70%) were adults and most had used inhaled
antibiotics, mainly TOBI, before being enrolled in the study. The differences in prior use of
anti-pseudomonal antibiotics (including tobramycin) explain the differences in baseline
tobramycin MICs.
8.3.1
Study C2301
Table 8-1 shows summary results for a given study visit for the maximum tobramycin MIC of
all biotypes per patient. The MIC90 was greater in the TIP/TIP/TIP arm at the screening (32
g/mL, vs. 2 g/mL, placebo/TIP/TIP) and baseline visits (32 g/mL, vs. 8 g/mL,
placebo/TIP/TIP) suggesting some imbalance between the two groups in regard to infection
with less susceptible strains prior to study start.
Table 8-1
Summary of Tobramycin MICs for P aeruginosa (maximum MIC per

patient) - Study C2301 (ITT population)
Tobramycin MIC (g/mL)
Visit
TIP/TIP/TIP
placebo/TIP/TIP
Range
MIC50
MIC90
Range
MIC50
MIC90
Screening
44
0.12->512
32
45
0.12-4
Baseline
44
0.12->512
0.5
32
48
0.25-512
Week 5
29
0.12->512
512
44
0.25-16
0.5
Week 21
28
0.25->512
512
30
0.12-256
32
Week 25
30
0.12->512
32
37
0.12->512
During the study tobramycin MIC50s (maximum per patient) were stable ranging from 0.5- 1
g/mL.
In the TIP/TIP/TIP arm, at the end of the first (Week 5) and third (Week 21) on-treatment
cycles, the MIC90 (maximum per patient) was 512 g/mL, but then returned to 32 g/mL
(same as screening) at the end of the third (Week 25) off-treatment cycle. The high MIC90s
(maximum per patient) in the TIP/TIP/TIP arm at Weeks 5 and 21 were determined by 4
patients, 2 who persistently had isolates with MICs of 512 g/mL from screening or
baseline, then leaving one patient each at Week 5 and Week 21 whose MIC of 512 g/mL
only occurred post-baseline. The MIC90 (maximum per patient) for the remaining patients
(excluding the two with MICs > 512 g/mL present pre-treatment) was 64 g /mL at both
Week 5 (N=27) and 21 (N=26). In the PCB/TIP/TIP arm there was one patient at baseline
and none at Week 5 with an MIC > 512 g/mL. So when comparing TIP to PCB during the
first cycle, excluding the one patient on PCB with a pre-treatment MIC of > 512 g/mL would
not impact the MIC90 at Week 5.
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8.3.2
Study C2302
Table 8-2 shows tobramycin MICs for P aeruginosa (maximum MIC per patient). Patients
with P aeruginosa isolates with a broad range of MICs were included in this study. As Study
C2302 included patients with more exposure to inhaled tobramycin prior to study start than in
Study C2301, the baseline maximum MIC90 was 3-4 dilutions greater compared to Study
C2301.
Table 8-2
Summary of Tobramycin MICs for P aeruginosa (maximum MIC per

patient) - Study C2302 (ITT population)
Visit
TIP
TOBI
Range
MIC50
MIC90
Range
MIC50
MIC90
Screening
306
0.12->512
64
206
0.12->512
128
Baseline
308
0.12->512
64
208
0.12->512
128
Week 5
239
0.12->512
512
173
0.12->512
64
Week 21
199
0.12->512
256
154
0.12->512
256
Week 25
201
0.12->512
256
155
0.12->512
64
During the study there were minimal changes in MIC50 values across visits for TIP and TOBI
patients, ranging from 2-4 g/mL (max MIC per patient). At Week 21, representing 3 cycles
of exposure to tobramycin, for both the TIP and TOBI arms the MIC90s (maximum MIC per
patient) were similar, 256 g/mL. At Weeks 5 and 25, the MIC90 (maximum per patient) for
the TIP arm was greater than for the TOBI arm. A further analysis of this difference showed
the following.
Week 5:
in the TIP arm, there were 26 patients (of 239 total) with a maximum MIC of their
isolates 512 g/mL. Thirteen of those 26 patients had isolates at screening and/or
baseline MICs of 256 ug/mL; for the remaining patients (n=226), the MIC90 was
128 ug/mL.
in the TOBI arm, there were 12 patients (of 173 total) with a maximum MIC of
their isolates of 512 ug/mL. Nine patients had isolates at screening and/or
baseline with MICs 256 g/mL. Excluding these patients, the MIC90 at Week 5
was 64 g/mL.
Week 25:
in the TIP arm there were 19 patients (of 201 total) with a maximum MIC of their
isolates 512 g/mL. Fourteen patients had screening and/or baseline MICs of
256 g/mL. Excluding these patients, the MIC90 (maximum per patient) was 128
g/mL.
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in the TOBI arm there were 9 patients (of 155 total) with maximum MIC of their
isolates at Week 25 of 512 g/mL. Seven patients had isolates at screening and/or
baseline with MICs of 256 g/mL. Excluding these patients, the MIC90 at Week
25 was 64 g/mL.
When considering patients that entered the study with isolates with MICs 256 g/mL and
also had similar high MICs at later visits, the differences in MIC90s seen at these later visits in
TIP vs. TOBI patients are lessened to 1 dilution. Figure 8-1 and Figure 8-2 below display the
distribution of MICs for patients (maximum MIC of isolates per patient) in Study C2302 at
baseline and end of study (Week 25) in the TIP and TOBI groups. MIC distribution curves are
generally similar at the two timepoints and also for TIP compared to TOBI patients. The small
but greater percentage of patients in the TIP arm with MICs 256 g/mL at Week 25 included
patients who persistently had isolates with MICs 256 g/mL from the time of screening or
baseline.
Figure 8-1
Distribution of tobramycin MICs of all P. aeruginosa isolates with TIP

treatment - Study C2302 (ITT population)
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Figure 8-2

TOBI treatment (Study C2302, ITT population)
Table 8-3 shows the change in FEV1% predicted and hospitalizations for respiratory
exacerbations comparing patients who had baseline maximum MICs 8 g/mL to those
with maximum MICs at baseline 128 g/mL. These data do not show any worsening of
these clinical outcomes for patients with higher vs lower MICs.
Table 8-3
Clinical outcomes in patients with baseline maximum MICs 8 g/mL

and 128 g/mL - Study C2302 (ITT population)
TIP/TIP/TIP (N=308)
Change in FEV1 % predicted from baseline to week 21

Subgroup MIC
Subgroup total
LS mean
8 g/mL
179
3.7
128 g/mL
18
3.6
Hospitalizations for respiratory exacerbations
Subgroup MIC
Subgroup total
n (%)with event
(N)
8 g/mL
240
58 (24.2)
128 g/mL
27
5 (18.5)
8.3.3
TOBI/TOBI/TOBI (N=209)
Subgroup total
135
18
LS mean
1.7
5.5
Subgroup total
n (%) with event
160
24
35 (21.9)
6 (25.0)
Study C2303
Table 8-4 shows tobramycin MICs for P. aeruginosa as the maximum MIC per patient. This
analysis includes data for the safety population so changes in MICs could be analyzed by
treatment given. Screening and baseline MIC50s were 0.5g/mL in both treatment groups. The
MIC90 was similar for the two groups at the baseline visit, 4 g/mL. At the screening visit
there was a difference in MIC90, but this difference is due to only 2 more patients with MICs
of 16 g/mL in the placebo vs. TIP group.
Table 8-4
Summary of tobramycin MICs for P.aeruginosa (maximum MIC per

patient) - Study C2303 (Safety population)
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Visit
TIP
placebo
Range
MIC50
MIC90
Range
MIC50
MIC90
Screening
30
0.12-128
0.5
32
0.12-128
0.5
16
Baseline
30
0.12-64
0.5
32
0.12-64
0.5
Day 29
16
0.12-8
0.5
31
0.12-512
64
Day 57
23
0.12-512
1.0
28
0.12-512
0.5
32
In both the TIP and placebo groups, MIC50s remained stable throughout the study, ranging
from 0.5-1 g/mL. MIC90 only increased by 1 dilution from baseline during the study in TIP
treated patients. In this study, there were higher MIC90s at some visits in the placebo arm.
There were 4 patients in the placebo arm with MICs 64 g/mL at Week 5, and 3 with MICs
32 g/mL at Week 9. Two of these patients had MICs 64 g/mL at screening or baseline.
Therefore the elevated MIC90s seen at the post-baseline visits in the placebo group are
accounted for by 2 patients who had elevated MICs prior to study start and also had
specimens at weeks 5 and 9. Given the small number of patients in this study, just a few
patients can affect the MIC90.
8.4
Treatment emergent pathogens
Table 8-5 shows the frequency of treatment emergent pathogens of clinical relevance to CF
patients in the placebo controlled studies, C2301 and C2303. Frequency is shown as number
of patients with the pathogen at > 1 visit.
Table 8-5
Frequency of emergence of pathogens of potential relevance - Studies

C2301 (ITT population) and C2303 (Safety population)
Study C2301
Pathogen
TIP/TIP/TIP
(N=46)
n (%)
Pbo/TIP/TIP
(N=49)
n (%)
Acaligenes/Achromobacter
1 (2.2%)
xylosoxidans
Aspergillus fumigatus
2 (4.1%)
2 (4.1)
1
Burkholderia spp.
Staphylococcus aureus
3 (6.5)
3 (6.1)
MRSA
1 (2.2)
1 (2.0)
Stenotrophomonas
1 (2.2)
2 (4.1)
maltophila
1
One patient had Burkholderia spp. isolated at one visit
Study C2303
TIP
(N=30)
n (%)
Placebo
(N=32)
n (%)
1 (3.3)
1 (3.1)
-
Table 8-6 shows the frequency of treatment-emergent pathogens of potential clinical

relevance to CF patients in Study C2302. Frequency is shown as number of patients with the
pathogen isolated from respiratory tract specimens obtained at 2 or more visits. The frequency
of treatment-emergent pathogens was low and similar in all treatment groups.
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Table 8-6
Frequency of emergence of pathogens of potential relevance- Study

C2302 (ITT population)
Pathogen
Acaligenes/Achromobacter xylosoxidans
Aspergillus spp
Aspergillus fumigatus
Burkholderia spp.
Staphylococcus aureus (all)
MRSA
Stenotrophomonas maltophila
1
TIP (N=308)
n (%)
TOBI (N=209)
n (%)
4 (1.3)
6 (2.9)
14 (4.5)
1
11 (3.6)
4 (1.3)
16 (5.2)
10 (4.8)
7 (3.3)
5 (2.4)
8 (3.8)
2 patients had Burkholderia spp. isolated at 1 visit.
The frequency of persistent isolation of treatment emergent pathogens was low and similar in
both treatment arms.
8.5
Microbiology conclusions
The tobramycin MIC50 for P aeruginosa was 0.5- 1 g/mL at the start of the placebocontrolled studies C2301 and C2303, and 2 g/mL at the start of active-controlled Study
C2302. Once study treatment began, MIC50s remained stable, varying at most by 1 dilution,
across visits on TIP treatment in each of the 3 studies and on TOBI treatment in the active
controlled trial, C2302. MIC90s varied across visits in each of the 3 studies. The higher
MIC90s at some visits in the TIP/TIP/TIP vs. placebo/TIP/TIP arms in Study C2301 and the
TIP vs. TOBI arms in study C2302 reflected the presence, in a number of patients, of pretreatment isolates with similarly high MICs. In Study C2303, at some visits higher MIC90s
were seen in the placebo arm, also accounted for by patients with pre-treatment isolates with
similarly high MICs.
MIC distribution curves were also generally similar between baseline and end of study visits
in Study C2302. Collectively, these data do not show the emergence of high MICs on TIP or
TOBI during the studies. Furthermore, no differences were noted in clinical efficacy outcomes
of change in FEV1 % predicted or hospitalizations in patients with MICs 8 g/mL compared
to those MICs 128 g/mL.
The frequency of treatment-emergent pathogens of potential clinical relevance was low and
similar for both TIP and TOBI treated patients in Study C2302.
Overview of safety
The TIP dry powder formulation was designed to match the pharmacokinetic profile of TOBI
and thus have a similar safety profile to the nebulized formulation. The safety of TIP has been
evaluated in Phase III studies comparing it to both TOBI and placebo. In summary:
Systemic effects of TIP were minimal and consistent with those previously described for
TOBI.
Local AEs, such as cough and dysphonia are tolerability issues but not associated with
significant safety risk.
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SAEs were comparable between TIP and TOBI.
Data obtained from post-marketing experience of TIP are consistent with the safety profile
observed in clinical trials.
9.1
Safety populations, evaluations, and patient exposure
Safety populations
Study C2302, the primary safety study in the TIP development program, was an open label
study in which patients received 3 cycles of TIP or TOBI. A cycle was defined as 28 days on
treatment followed by 28 days off treatment. Data from randomized patients who received at
least one dose of study drug are included in the safety analyses of this trial. Data from placebo
controlled studies are also presented to provide additional safety information. Table 9-1
describes the populations included in the safety analyses.
Table 9-1
Population groupings for safety assessments
Studies
Population
Studies
Number of patients
(safety population)
Comparison of TIP vs.

TOBI (Primary safety
population)
Patients > 6 years of age

with no exposure to antipseudomonals 1 month
prior
C2302
517
(308 TIP and 209 TOBI treated
patients)
Comparison of TIP vs.

Placebo (Supportive
Safety population )
Patients 6-21 years of

age who had not received
inhaled anti-pseudomonal
agents within 4 months of
screening
C2301
(Cycle 1)
and C2303
157
(76 TIP and 81 placebo treated
patients)
Uncontrolled clinical trial

data
Patients in C2301
randomized to TIP or
placebo in Cycle 1
receiving open label TIP
in Cycles 2 and 3
Patients completing
C2303 enrolled in study
C2303E1
C2301
(Cycles 2
and 3) and
C2301E1
87 C2301
55 C2303E1 (previously
enrolled in study C2303)
Evaluations
Patient Exposure
Overall, 425 CF patients were treated with TIP in the Phase III development program.
Exposure to the study treatments is summarized in Table 9-2.
Table 9-2
Exposure to:
Patient exposure to study treatments

Number (%) of
subjects with
C2301
C2302
C2303
Total
87 (100.0)
83 (95.4)
78 (89.7)
308 (100.0)
278 (90.3)
249 (80.8)
30 (100.0)
25 (83.3)
0
425 (100.0)
386 (90.8)
327 (76.9)
TIP
>= 1 dose
>= 28 days
>= 56 days
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Exposure to:
Number (%) of
subjects with
C2301
C2302
C2303
Total
>= 84 days
36 (41.4)
218 (70.8)
254 (59.8)
>= 1 dose
>= 28 days
>= 56 days
>= 84 days
49 (100.0)
39 (79.6)
0
0
N/A
32 (100.0)
28 (87.5)
0
0
81 (100.0)
67 (82.7)
0
0
>= 1 dose
>= 28 days
>= 56 days
>= 84 days
N/A
209 (100.0)
201 (96.2)
175 (83.7)
160 (76.6)
N/A
209 (100.0)
201 (96.2)
175 (83.7)
160 (76.6)
Placebo
TOBI
84 days of exposure corresponds to a 24-week study period with 28 days on treatment followed by a 28 days off
treatment for 3 cycles.
9.2
Adverse events
AEs observed in the Phase III program generally reflect the underlying disease, CF, and
occurred at similar rates among patients treated with TIP and TOBI in the primary open label
safety study, and TIP and placebo in the placebo-controlled studies.
9.2.1
Common adverse events (AEs) in Study C2302 (primary safety

population)
Table 9-3 describes AEs which occurred in at least 2.0% of the patients in any treatment
group in Study C2302.
In both the TIP and TOBI treatment groups, the most frequently reported AEs by Medical
Dictionary for Regulatory Affairs (MedDRA) preferred term were cough and lung disorder,
both events associated with CF. Lung disorder was a preferred term used by the investigators
to capture events related to CF exacerbations. Cough is a common event associated with CF
and was reported in 41.8% of patients at baseline.
Cough, lung disorder, dyspnea, pyrexia, oropharyngeal pain, dysphonia, chest discomfort, and
dysgeusia were reported by a higher percentage of patients (difference of 3% or more) in the
TIP group than in the TOBI group, while abdominal pain was more frequently reported in the
TOBI group.
The 95% CIs for AE incidence rates showed considerable overlap among patients treated with
TIP and TOBI for all events, with the exception of cough and dysphonia: cough 95% CI
(42.7, 54.1) and (24.9, 37.9) for TIP and TOBI, respectively and dysphonia 95% CI (10.0,
18.0) and (1.7, 7.4) for TIP and TOBI, respectively. These events are further detailed in
Section 9.4 (Safety areas of special interest).
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Table 9-3
Adverse events by preferred term regardless of relationship to

treatment (at least 2% in any group) - Study C2302 (primary safety
population)
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
Total
N=517
n (%)
Patients with AE(s)
278 (90.3)
176 (84.2)
454 (87.8)
Cough
Lung disorder
Sputum increased
Dyspnoea
Pyrexia
Oropharyngeal pain
Dysphonia
Haemoptysis
Headache
Nasal congestion
Nausea
Rales
Rhinorrhoea
decreased
Upper respiratory tract
infection
Wheezing
Chest discomfort
Fatigue
Vomiting
Sinusitis
Pulmonary congestion
Decreased appetite
Weight decreased
Musculoskeletal chest
pain
Throat irritation
Abdominal pain
Diarrhoea
Sinus headache
Dysgeusia
Forced expiratory volume
decreased
Nasopharyngitis
Abdominal pain upper
Blood glucose increased
Insomnia
Rhinitis
Arthralgia
Epistaxis
Pain
149 (48.4)
104 (33.8)
53 (17.2)
48 (15.6)
48 (15.6)
43 (14.0)
42 (13.6)
40 (13.0)
35 (11.4)
25 (8.1)
23 (7.5)
22 (7.1)
22 (7.1)
21 (6.8)
65 (31.1)
63 (30.1)
35 (16.7)
26 (12.4)
26 (12.4)
22 (10.5)
8 (3.8)
26 (12.4)
25 (12.0)
15 (7.2)
20 (9.6)
13 (6.2)
15 (7.2)
17 (8.1)
214 (41.4)
167 (32.3)
88 (17.0)
74 (14.3)
74 (14.3)
65 (12.6)
50 (9.7)
66 (12.8)
60 (11.6)
40 (7.7)
43 (8.3)
35 (6.8)
37 (7.2)
38 (7.4)
21 (6.8)
18 (8.6)
39 (7.5)
21 (6.8)
20 (6.5)
20 (6.5)
19 (6.2)
18 (5.8)
17 (5.5)
16 (5.2)
15 (4.9)
14 (4.5)
13 (6.2)
6 (2.9)
10 (4.8)
12 (5.7)
15 (7.2)
9 (4.3)
10 (4.8)
8 (3.8)
10 (4.8)
34 (6.6)
26 (5.0)
30 (5.8)
31 (6.0)
33 (6.4)
26 (5.0)
26 (5.0)
23 (4.4)
24 (4.6)
14 (4.5)
13 (4.2)
13 (4.2)
13 (4.2)
12 (3.9)
12 (3.9)
4 (1.9)
17 (8.1)
4 (1.9)
6 (2.9)
1 (0.5)
2 (1.0)
18 (3.5)
30 (5.8)
17 (3.3)
19 (3.7)
13 (2.5)
14 (2.7)
11 (3.6)
10 (3.2)
9 (2.9)
9 (2.9)
9 (2.9)
8 (2.6)
8 (2.6)
8 (2.6)
8 (3.8)
8 (3.8)
1 (0.5)
5 (2.4)
5 (2.4)
4 (1.9)
4 (1.9)
2 (1.0)
19 (3.7)
18 (3.5)
10 (1.9)
14 (2.7)
14 (2.7)
12 (2.3)
12 (2.3)
10 (1.9)
Preferred term
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Preferred term
Bronchitis
Dyspnoea exertional
Lower respiratory tract
infection
Lymphadenopathy
Myalgia
Nasal mucosal disorder
Productive cough
Rash
Constipation
Sinus congestion
Tinnitus
Back pain
Hypoglycaemia
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
Total
N=517
n (%)
7 (2.3)
7 (2.3)
7 (2.3)
7 (3.3)
0 (0.0)
2 (1.0)
14 (2.7)
7 (1.4)
9 (1.7)
7 (2.3)
7 (2.3)
7 (2.3)
7 (2.3)
7 (2.3)
6 (1.9)
6 (1.9)
6 (1.9)
3 (1.0)
3 (1.0)
1 (0.5)
5 (2.4)
0 (0.0)
7 (3.3)
5 (2.4)
5 (2.4)
9 (4.3)
5 (2.4)
7 (3.3)
5 (2.4)
8 (1.5)
12 (2.3)
7 (1.4)
14 (2.7)
12 (2.3)
11 (2.1)
15 (2.9)
11 (2.1)
10 (1.9)
8 (1.5)
Preferred terms are sorted in descending order of frequency in the TIP column
A patient with multiple occurrences of the same preferred term was counted only once for that preferred term
MedDRA Version 14.0 was used for coding
Table 9-4 shows all occurrences of AEs corrected by exposure. For most events, there is a
difference between treatment groups of 2 events/cycle or less. Cough and dysphonia are the
only events in which there is a clinically meaning full difference between treatment groups.
Table 9-4
Adverse events with an occurrence >2 events/cycle, adjusted for

exposure - Study C2302 (primary safety population)
Preferred term
Adverse events
Cough
Lung disorder
Sputum increased
Dyspnoea
Haemoptysis
Pyrexia
Dysphonia
Oropharyngeal pain
Headache
Nasal congestion
Nausea
TIP/TIP/TIP
N=308
n (event rate)
1958 (119.0)
TOBI/TOBI/TOBI
N=209
n (event rate)
1069 (92.1)
273 (16.6)
157 (9.5)
75 (4.6)
65 (4.0)
60 (3.7)
58 (3.5)
55 (3.3)
55 (3.3)
44 (2.7)
33 (2.0)
24 (1.5)
103 (8.9)
87 (7.5)
45 (3.9)
32 (2.9)
34 (2.9)
31 (2.7)
11 (1.0)
27 (2.3)
35 (3.0)
15 (1.3)
25 (2.2)
All AEs which occurred after the first dose are summarized, a subject may have multiple occurrences of the same
event. All events are calculated. Event rate is calculated as the number of events/(days of exposure/28)* 100.
MedDRA Version 14.0 was used for coding.
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9.2.2
Common adverse events in the placebo-controlled studies Study

C2301 (first cycle) and Study C2303
9.2.2.1
Study C2301
The most common AEs reported during Cycle 1 for the TIP and Placebo groups are
summarized in Table 9-5. A cut-off of 5% in any group was chosen because of the small
sample size. As also observed in Study C2302 (Primary safety population), the most
commonly reported AEs with TIP in Cycle 1 were associated with CF: cough and lung
disorder. Overall, AEs tended to occur with a higher frequency in the placebo group, with the
exception of pharyngolaryngeal pain, which had a higher incidence in the TIP group.
Table 9-5
Cycle 1 adverse events (on-treatment and off-treatment, at least 5% in

any group), regardless of study drug relationship, by preferred term
and treatment group - Study C2301 (all randomized safety population)
TIP
(N=46)
n (%)
Placebo
(N=49)
n (%)
Total
(N=95)
n (%)
Any preferred term
23 (50.0)
37 (75.5)
60 (63.2)
Cough
Lung disorder
Pharyngolaryngeal pain
Productive cough
Pyrexia
Dysgeusia
Nasopharyngitis
Headache
6 (13.0)
5 (10.9)
5 (10.9)
1 (2.2)
3 (6.5)
3 (6.5)
1 (2.2)
0
13 (26.5)
6 (12.2)
0
4 (8.2)
2 (4.1)
1 (2.0)
3 (6.1)
3 (6.1)
19 (20.0)
11 (11.6)
5 (5.3)
5 (5.3)
5 (5.3)
4 (4.2)
4 (4.2)
3 (3.2)
Preferred term
Preferred terms are sorted in descending order of frequency in the Total column
It is notable that cough was reported less frequently on TIP (13.0% of patients) than on
placebo (26.5% of patients), while being more frequently reported in Study C2302 for 1 cycle
of TIP (37.7%) compared to TOBI (21.5%). The factors influencing the higher reporting rate
for cough across the first cycle in the open-label Study C2302 compared to the blinded Study
C2301 are unclear. Notable differences between these studies include age groups, prior TOBI
experience and open-label design.
9.2.2.2
Study C2303
In Study C2303, hypoacusis was the most frequent reported AE by patients in each group (3
TIP patients vs. 2 placebo patients) (Table 9-6). Audiology findings are discussed in Section
9.4.3.
Cough was reported by patients in the TIP group only (3 patients, 10.0%), whereas respiratory
tract infection viral (3 patients, 9.4%) and respiratory tract infection (2 patients, 6.3%) were
reported by patients in the placebo group only.
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Table 9-6
Adverse events (on-treatment and off-treatment, at least 5% in any

group), regardless of study drug relationship, by preferred term and
treatment group - Study C2303 (safety population)
Preferred term
TIP
(N=30)
n (%)
Placebo
(N=32)
n (%)
Total
(N=62)
n (%)
Any preferred term
8 (26.7)
11 (34.4)
19 (30.6)
Hypoacusis
Cough
Respiratory tract infection
viral
3 (10.0)
3 (10.0)
0
2 (6.3)
0
3 (9.4)
5 (8.1)
3 (4.8)
3 (4.8)
2 (6.3)
2 (3.2)
The safety population in Study C2303 was defined as all randomized patients who received at least one dose of
study drug
Preferred terms are sorted in descending order of frequency in the Total column
MedDRA version 14.0 was used for coding.
9.3
Serious adverse events, death, and other clinically significant

adverse events
9.3.1
Serious adverse events
Serious adverse events in the primary safety population (C2302)

SAEs reported for at least 2 patients in total are summarized for Study C2302 (Primary safety
population) in Table 9-7. The percentage of patients with SAEs was similar between the two
treatment groups; 27.6 % of patients treated with TIP reported SAEs compared to 29.2% of
patients treated with TOBI. The most frequently reported SAE in both treatment groups was
lung disorder consistent with the underlying disease condition. There were no differences
between treatment groups regarding the types of SAE reported, including the incidence of
cough SAEs.
Table 9-7
Serious adverse events by preferred term (at least 2 patients in total)

regardless of relationship to treatment - Study C2302 (primary safety
population)
Preferred term
Patients with SAE(s)
Lung disorder
Haemoptysis
Cough
Bronchitis
Dyspnoea
Sputum increased
Pulmonary function test decreased
Fatigue
Cystic fibrosis lung
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
Total
N=517
n (%)
85 (27.6)
61 (29.2)
146 (28.2)
60 (19.5)
8 (2.6)
7 (2.3)
6 (1.9)
5 (1.6)
5 (1.6)
4 (1.3)
3 (1.0)
2 (0.6)
39 (18.7)
4 (1.9)
5 (2.4)
1 (0.5)
4 (1.9)
1 (0.5)
3 (1.4)
0
2 (1.0)
99 (19.1)
12 (2.3)
12 (2.3)
7 (1.4)
9 (1.7)
6 (1.2)
7 (1.4)
3 (0.6)
4 (0.8)
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Preferred term
Lower respiratory tract infection
Lung infection pseudomonal
Pneumonia
Pneumonia bacterial
Sinusitis
Dyspnoea exertional
Epistaxis
Abdominal pain
Distal intestinal obstruction syndrome
Pyrexia
Bronchopneumonia
Lung abscess
Pseudomonas infection
Forced expiratory volume decreased
Weight decreased
Bronchiectasis
Hypoxia
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
Total
N=517
n (%)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
0
0
0
2 (1.0)
1 (0.5)
2 (1.0)
2 (1.0)
1 (0.5)
0
1 (0.5)
1 (0.5)
1 (0.5)
2 (1.0)
2 (1.0)
1 (0.5)
2 (1.0)
1 (0.5)
1 (0.5)
1 (0.5)
3 (1.4)
2 (1.0)
2 (1.0)
4 (0.8)
3 (0.6)
4 (0.8)
4 (0.8)
3 (0.6)
2 (0.4)
3 (0.6)
2 (0.4)
2 (0.4)
3 (0.6)
3 (0.6)
2 (0.4)
3 (0.6)
2 (0.4)
2 (0.4)
2 (0.4)
3 (0.6)
2 (0.4)
2 (0.4)
Preferred terms are sorted in descending order of frequency in the TIP column.
A patient with multiple occurrences of the same preferred term is counted only once in the preferred term.
Serious adverse events in the placebo controlled studies

SAEs reported during Cycle 1 for the TIP and Placebo group in Study C2301 are summarized
in Table 9-8. All SAEs were more frequently reported for placebo patients during Cycle 1 of
treatment. The most common SAEs were respiratory disorders, with only lung disorder
occurring in TIP and more frequently in the placebo group.
Table 9-8
Cycle 1 serious adverse events (on-treatment and off-treatment),

regardless of study drug relationship, by system organ class,
preferred term and treatment group - Study C2301 (all randomized
safety population)
MedDRA system organ class

Preferred term
TIP
(N=46)
n (%)
Placebo
(N=49)
n (%)
Total
(N=95)
n (%)
Any MedDRA
system organ class
Total
3 (6.5)
7 (14.3)
10 (10.5)
Total
Hepatitis B
Pneumonia
Investigations
0
0
0
2 (4.1)
1 (2.0)
1 (2.0)
2 (2.1)
1 (1.1)
1 (1.1)
Total
2 (4.1)
2 (2.1)
Infections and infestations
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MedDRA system organ class

Preferred term
TIP
(N=46)
n (%)
Placebo
(N=49)
n (%)
Total
(N=95)
n (%)
1 (2.0)
1 (1.1)
1 (2.0)
1 (1.1)
3 (6.5)
3 (6.5)
0
0
0
0
0
4 (8.2)
4 (8.2)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
7 (7.4)
7 (7.4)
1 (1.1)
1 (1.1)
1 (1.1)
1 (1.1)
1 (1.1)

decreased
Sputum abnormal
Respiratory, thoracic and
mediastinal disorders
Total
Lung disorder
Cough
Dyspnoea exertional
Haemoptysis
Productive cough
Sputum discolored
MedDRA system organ classes are presented alphabetically; preferred terms are sorted within system organ
class in descending order of frequency in the Total column.
A patient with multiple occurrences of the same SAE is counted only once in the SAE category.
A patient with multiple AEs within a system organ class is counted only once in the Total row.
SAEs reported for the TIP and placebo groups in Study C2303 are summarized in Table 9-9.
Two SAEs (lower limb fracture and pneumonia) were reported by 1 patient each in the
placebo group.
Table 9-9
Serious adverse events (on-treatment and off-treatment), regardless

of study drug relationship, by preferred term and treatment group Study C2303 (all safety population)
TIP
N=30
n (%)
Placebo
N=32
n (%)
Total
N=62
n (%)
Patients with SAE(s)
2 (6.3)
2 (3.2)
Lower limb fracture

Pneumonia
0
0
1 (3.1)
1 (3.1)
1 (1.6)
1 (1.6)
Preferred term
Preferred terms are sorted in descending order of frequency in the TIP treatment group.
9.3.2
Deaths
Overall, deaths were rare in the TIP studies. A listing of the patients who died during all of the
completed studies and within 30 days of termination of treatment are listed by reason in Table
9-10. Data are summarized from the study databases and from a review of cases reported in
the ARGUS clinical safety database.
Five patients enrolled in the completed studies died, including one patient who died prior to
the start of study treatment (Table 9-10). For the four deaths that occurred during study (3 TIP
and 1 placebo patient), all had occurred more than 30 days after the last dose of study
medication. The four respiratory-related deaths (1 prior to study treatment, 2 on TIP and 1 on
placebo) are consistent with CF comorbidities.
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For the two cases of respiratory-related deaths occurring during the study in the TIP treatment
group, both had severe lung function impairment at baseline (percent predicted FEV1 below
40%). FEV1 values were relatively stable during the first cycle of treatment and had a
tendency towards a slight decline during the second cycle. In the first patient, P. aeruginosa
lung infection appeared to be well controlled (decrease in CFUs of over 2 logs, last
tobramycin MIC measured was 2 g/mL), but the patient had in addition, multiple infections
with MRSA, Achromobacter (both present at baseline) and Stenotrophomonas maltophilia.
During off-treatment period of Cycle 2, the patient had an episode of pneumonia that
precipitated lung function deterioration and led to acute respiratory failure, causing the
premature death.
In the second patient, P. aeruginosa infection appeared to be relatively stable during the study
(biotype dry CFU 6x108). Tobramycin MIC increased from 128 at screening, to 512 g/mL
during the Cycle 1 treatment period. At Week 17, the final sputum culture had an MIC of 16.
It is noteworthy that other pathogens had been detected in patients sputum at various visits:
Chryseobacterium indologenes, filamentous mold other than Penicillium/Aspergillus,
Klebsiella oxytoca and E. coli. During the off-treatment period of Cycle 2 the patient had an
episode of lung exacerbation (lung disorder) that precipitated the patients deteriorating
condition. The investigator assessed the event as not being related to study medication. In the
absence of any microbiology data during the lung disorder it remains unclear which of the
multiple lung infections led to the premature death.
Table 9-10
Deaths in all completed studies
Study/ Treatment Group

Patient No.
Age, Race, Gender
Treatment duration
Prior to study treatment
Study C2302/
randomized to TIP
PID C2302-0004-00303
27 year old Caucasian
female
Randomized, but not
dosed
During study treatment
period
Study C2301/ Placebo
PID C2301-0501-00211
female
Died Day 48 of study
having discontinued study
medication on Day 8 due
to pulmonary
exacerbation
Study C2302/ TIP
PID C2302-0706-00303
male
Cause of death
Comments
Attributed relationship
to study drug by
Investigator
Respiratory failure
secondary to disease
progression
The patient was

randomized and found to
be clinically unstable and
did not receive her first
dose
Not applicable
Decompensated chronic
cor pulmonale
Hypoxic ischemic brain

damage
Suspected
Following an accidental
overdose of a recreational
drug
Not suspected
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Study/ Treatment Group
Patient No.
Age, Race, Gender
Treatment duration
(off-treatment Cycle 2)
having received the last
dose of study medication
more than 30 days
previously (Day 85)
Cause of death
PID C2302-0165-00301
21 year old Hispanic male
more than 30 days
previously (Day 84)
Lung disorder (pulmonary

exacerbation) leading to
respiratory failure
Not suspected
PID C2302-0017-00301
female
more than 30 days
previously (Day 93)
Acute respiratory failure

secondary to pneumonia
and infection with P.
aeruginosa and
Stenotrophomas
maltophilia
Not suspected
Comments
Attributed relationship
to study drug by
Investigator
PID: patient identification number
9.3.3
Adverse events leading to discontinuation
Discontinuations due to adverse events in Study C2302 (primary safety

population)
Discontinuation of study medication due to AEs reported for at least 2 patients in total are
summarized for Study C2302 (Table 9-11). AEs resulting in study discontinuation were more
frequent in the TIP treatment group. Cough and dyspnea were more common causes of
discontinuation in the TIP group compared to the TOBI group, while in the TOBI treatment
group lung disorder and PFT decreased were the most common AEs leading to
discontinuation.
It is important to note that C2302 was an open label study. Patients 6 - <13 years of age had
overall a low discontinuation rate due to AEs, with patients in the TIP group (3.6%)
discontinuing less than those in the TOBI group (11.1%); patients 13 - <20 years of age had
slightly higher discontinuation rates due to AEs (TIP 7.6% vs. TOBI 4.2%) and patients above
20 years of age discontinued due to AEs more in the TIP group (17.3%) than in the TOBI
group (9.1%). The pattern of AEs leading to discontinuation did not appear to be related to the
AE rates across age groups.
The most frequent AEs leading to discontinuations in the TIP group were cough and dyspnea.
Relatively few cases of lung disorder (MedDRA preferred term for the reported term lung
exacerbation) have led to discontinuations and do not drive the imbalance in the
discontinuation rates between TIP and TOBI.
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Table 9-11
Discontinuations due to adverse events (at least 2 patients in total) by

preferred term regardless of relationship to treatment - Study C2302
(primary safety population)
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
Total
N=517
n (%)
Patients discontinued due to AE
46 (14.9)
17 (8.1)
63 (12.2)
Cough
Dyspnoea
Lung disorder
Chest discomfort
Bronchospasm
Dysphonia
Cystic fibrosis lung
Pyrexia
Musculoskeletal chest pain
Haemoptysis
Throat irritation
Pulmonary function test decreased
Rash
Sputum increased
12 (3.9)
8 (2.6)
7 (2.3)
5 (1.6)
3 (1.0)
3 (1.0)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
2 (0.6)
1 (0.3)
1 (0.3)
0
0
2 (1.0)
4 (1.9)
6 (2.9)
0
0
0
0
0
1 (0.5)
1 (0.5)
0
4 (1.9)
1 (0.5)
2 (1.0)
2 (1.0)
14 (2.7)
12 (2.3)
13 (2.5)
5 (1.0)
3 (0.6)
3 (0.6)
2 (0.4)
2 (0.4)
3 (0.6)
3 (0.6)
2 (0.4)
5 (1.0)
2 (0.4)
2 (0.4)
2 (0.4)
Preferred term
Preferred terms are sorted in descending order of frequency in the TIP/TIP/TIP column.
A higher percentage of patients discontinued TIP treatment than TOBI treatment due to AEs
in each of the cycles, although the difference between the treatment groups was less in Cycles
2 and 3 (Cycle 1; 6.5% and 3.8% for TIP and TOBI, respectively, Cycle 2; 3.2% and 1.9%,
respectively, Cycle 3; 1.0% and 0%, respectively).
Despite the frequent occurrences of the AEs of cough and lung disorder, relatively few led to
study discontinuation, and discontinuations due to AEs became more infrequent in both
treatment groups with time.
Of the 12 TIP patients that discontinued due to cough, only 5 discontinued due to cough only,
the other patients having multiple AEs leading to discontinuation, which were most frequently
respiratory system related events.
The percentage of patients discontinuing was greater in the off-treatment periods for both TIP
and TOBI (9.7% and 5.3% of patients discontinued during off-treatment periods in the TIP
and TOBI groups, respectively, compared to 1.0% and 0.5%, respectively, in the on-treatment
periods. Discontinuations during the on-treatment period were highest during Cycle 1 and
decreased afterwards. This suggests that most patients remained on-treatment, if they tolerated
it well during the first treatment period.
The majority of the SAEs leading to discontinuation were lung disorders in both TIP and
TOBI treatment groups. Fourteen patients in the TIP treatment group (4.5%) and 6 patients in
the TOBI group (2.9%) experienced SAEs which led to discontinuation.
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Although the discontinuation rate due to AE is numerically higher in the TIP treatment group,
events leading to discontinuation among TIP patients were generally mild to moderate and
non-serious. These events do not significantly impact the benefit risk profile of the drug.
Discontinuations due to adverse events in the placebo controlled studies
In Study C2301, one placebo treated patient discontinued study medication due to an AE
(pulmonary exacerbation) on Day 8 of Cycle 1. No other AE discontinuations were reported.
The reason for the strikingly low rate of discontinuations due to AEs in this study compared to
the higher rates in Study C2302 is not clear.
In Study C2303, one patient treated with TIP discontinued due to pulmonary hemorrhage and
one patient mis-dispensed treatment with placebo (randomized to receive TIP but erroneously
received placebo) discontinued due to bronchitis.
9.4
Safety areas of special interest
In this section, safety issues of interest will be presented. The events of interest have been
selected based on AEs that occurred more frequently in the TIP group than in the TOBI group
(cough, dysphonia), other AEs considered medically relevant (airway reactivity), and adverse
drug reactions associated with systemic aminoglycoside exposure (ototoxicity).
9.4.1
Adverse events associated with dry powder inhalation (cough and

dysphonia)
9.4.1.1
Dysphonia
In Study C2302, among patients receiving TIP, most dysphonia reports occurred during Cycle
1 in the on-treatment period. In the subsequent on periods, the frequency of reports decreased
with few reports occurring in any of the off periods. Three patients (1% of TIP treated
patients) discontinued due to dysphonia; all were also taking concomitant inhaled
corticosteroids.
9.4.2
Cough events
Cough is a common event associated with CF. In Study C2302 the baseline reporting rate for
cough was similar in both treatment groups (42.9% in the TIP group, 40.2% in the TOBI
group). During the treatment periods, cough events were reported by a greater percentage of
patients in the TIP treatment group (48.4%) than in the TOBI group (31.1%) (Table 9-12).
During the first treatment cycle, the proportion of patients with cough was 37.7% in the TIP
group compared to 21.5% for TOBI (Table 9-12). In the second and third cycles the AE rates
for cough were 17.8% for TIP vs. 15.7% for TOBI and respectively, 23.5% for TIP and 11.7%
for TOBI.
Table 9-12
Cough events by cycle - Study C2302 (primary safety population)
Treatment Cycle
Treatment period
On
Off
TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
82 (26.6)
45 (14.6)
24 (11.5)
23 (11.1)
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TIP/TIP/TIP
N=308
n (%)
TOBI/TOBI/TOBI
N=209
n (%)
On and Off
116 (37.7)
45 (21.5)
On
Off
On and Off
30 (11.4)
20 (7.6)
47 (17.8)
18 (10.1)
11 (6.1)
28 (15.7)
On
Off
On and Off
14 (17.5)
22 (9.4)
55 (23.5)
10 (5.8)
13 (7.6)
20 (11.7)
Treatment Cycle
Treatment period
A patient with multiple occurrences of cough is counted only once.
Cough was reported as being severe in 2.6% of TIP treated patients and 1.9% of TOBI treated
patients, moderate in 22.4% and 14.4% of TIP and TOBI patients, respectively, and mild in
23.4% and 14.8% of TIP and TOBI patients, respectively.
Note that the exact timing of cough relative to the timing of dosing was not specifically
collected on the case report form (CRF) and so is not available for those patients where the
investigator did not report this. However, 29 patients treated with TIP reported cough
occurring after inhalation or with administration of study drug. Among these patients, 21
events were described as mild requiring no additional medication. Six post inhalation cough
events were described as moderate and 2 as severe. All were non-serious. Three of the 29
patients who discontinued due to cough reported cough after inhalation.
In Study C2302, the very different appearance and dosage administration practice between the
TIP administered by the T-326 and the TOBI Nebulizer Solution made blinding unfeasible.
The C2302 study population was comprised of a majority (approximately 80%) of TOBIexperienced patients, while none had prior experience with TIP. These factors may have
contributed to the disparate rates of cough for TIP and TOBI in C2302. The rate of cough
reported in the original TOBI pivotal registration studies are markedly higher than the rates
reported for the same product in the TOBI arm of C2302 (47% vs. 34%).
TIP was not associated with an excess of cough AEs when compared to rates in other
controlled studies of inhaled antibiotics for the treatment of CF (McCoy KS et al 2008, Geller
et al 2011).
Although cough was related to tolerability of the medication in Study C2302, it does not
appear to significantly alter the safety profile. FEV1 was measured before and after dosing at
study visits. An AE of cough was not associated with a clinically significant decrease in FEV 1
after dosing.
It is also noteworthy that no difference in the incidence or severity in hemoptysis events has
been reported between TIP and TOBI groups, despite the higher incidence in cough reported.
In the placebo-controlled studies, the incidence of cough was lower overall. In Study C2301,
cough was the most commonly reported AE during the first cycle of treatment (the doubleblind period of treatment) but was reported less frequently on TIP (13% of patients) than on
placebo (26.5% of patients). More patients in the placebo group had cough associated with
concurrent AEs indicative of an infection (e.g. fever, pulmonary exacerbations, sinus infection
or respiratory tract infection) than in the TIP group. Similar percentages of patients in the TIP
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group (32.6%) and placebo group (32.7%) reported cough as a baseline symptom. One cough
event was reported as an SAE by 1 (2.0%) placebo patient.
In Study C2303, cough events were reported by patients in the TIP group only (3 patients,
10.0% in the TIP group vs. no patients in the placebo group) (Table 9-6).
9.4.2.1
Airway reactivity results
Patients in Study C2302 who experienced a 20% decrease in percent predicted FEV1 from
pre-dose to 30 minutes post-dose are summarized in Table 9-13. The overall incidence of
bronchospasm in any cycle was comparable for both treatment groups. In the TIP group the
percentage of patients with this decrease in FEV1 was similar during all cycles of treatment. In
the TOBI treatment group there was a slightly higher percentage of affected patients during
Cycles 2 and 3 compared to Cycle 1.
Table 9-13
Airway reactivity: acute decrease in percent predicted FEV1 from predose to 30-minute post-dose at any visit - Study C2302 (Primary safety
population)
30-minutes post-dose
20% decrease
TIP/TIP/TIP
N=308
n/TOT (%)
TOBI/TOBI/TOBI
N=209
n/TOT (%)
16 / 307 (5.2)
11 / 209 (5.3)
TOT = the number of patients with FEV1 at pre-dose and post-dose measurements and n= the number of patients
with events
Three patients in the TIP treatment group of Study C2302 had bronchospasm reported as an
AE leading to discontinuation. All three had variations between pre- and post-dose FEV1
measurements of less than 10%. These events were reported as being suspected by the
investigator of being related to the study drug.
Patients in Study C2301 who experienced a 20% decrease in percent predicted FEV1 from
pre-dose to 30 minutes post-dose are summarized in Table 9-14. Airway reactivity was found
in two patients using TIP (one patient in the TIP group on Day 1 of Cycle 1 and one patient on
Day 28 of Cycle 2 who had taken placebo in the first cycle), and in 4 patients receiving
placebo in Cycle 1 (2 instances on Day 1 and Day 28, respectively). None of the instances
was reported as an AE or led to the study discontinuation of a patient.
Table 9-14
Cycle 1
Airway reactivity: acute decrease in percent predicted FEV1 from predose to 30-minute post-dose by treatment group - Study C2301 (All
safety population)
Day 1
Day 8
Day 28
Cycle 2
Day 1
Relative change
(1)
from Pre-dose
TIP/TIP/TIP
N=32
n (%)
Placebo/TIP/TIP
N=37
n (%)
Number of patients
20 % decrease
Number of patients
20 % decrease
Number of patients
20 % decrease
31
1 (3.2)
27
0
26
0
35
2 (5.7)
36
0
34
2 (5.9)
Number of patients
27
29
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Day 28
Cycle 3
Day 1
Day 28
Relative change
(1)
from Pre-dose
TIP/TIP/TIP
N=32
n (%)
Placebo/TIP/TIP
N=37
n (%)
20 % decrease
Number of patients
20 % decrease
0
24
0
0
30
1 (3.3)
Number of patients
20 % decrease
Number of patients
20 % decrease
24
0
24
0
28
0
28
0
(1)
Relative change = ((30-minute post-dose % predicted FEV1 pre-dose % predicted FEV1)/ pre-dose %
predicted FEV1)) x 100.
Bronchospasm was defined as the relative decrease of 20% or more in % predicted FEV1 from pre-dose to 30
minutes post-dose.
In Study C2303, one (4.8%) patient in the TIP group had a decrease in FEV1 20% on Day 1.
In the TIP group, 3 (14.3%) patients (Day 1) and 4 (16.7%) patients (Day 29) had decreases in
FEV1 <20%. Two (8.0%) patients in the placebo group had a decrease in FEV1 20% on Day
29. In the placebo group, 3 (11.5%) patients (Day 1) and 3 (12.0%) patients (Day 29) had
decreases in FEV1 <20%.
In general, the proportions of patients experiencing a 20% decrease in percent predicted
FEV1 from pre-dose to 30 minutes post-dose was small and comparable across treatments.
9.4.3
Audiology testing
9.4.3.1
Audiology data presentation and results
Ototoxicity is a known adverse drug reaction associated with systemic use of

aminoglycosides. Tinnitus, which can be an early symptom of ototoxicity was reported by
more patients on TOBI than placebo in the TOBI registration trials (TOBI USPI). In the TIP
development program, audiology testing was performed in patients at selected centers.
Clinically significant hearing loss was defined post-hoc as a decrease of 10-15 dB in at least 2
consecutive frequencies, or 20 dB or more at a single frequency and which was not transient.
The American Speech-Language-Hearing Association criteria have been used as a reference
(American Speech-Language-Hearing Association 1994), but were refined to be more
stringent and were consistent with the analyses performed in the TOBI analyses.
Approximately 80% patients in the audiology testing subgroup had normal hearing
assessments at baseline (79.5% and 78.6% of patients in the TIP and TOBI treatment groups,
respectively), with 20.6% and 14.3% having had a prior hearing event (complaints of tinnitus,
ear pressure or hearing loss) in the TIP and TOBI groups, respectively.
Overall, a clinically relevant decrease in hearing (10-15 dB in at least 2 consecutive
frequencies, or 20 dB or more at a single frequency) was measured in 4 TIP patients and 3
TOBI patients. Of the TIP patients, 3 patients had transitory changes (one of them having
abnormal hearing at baseline) and one patient had a persistent hearing loss as mentioned
above (also had abnormal hearing at baseline). Two of the three TOBI-treated patients had
abnormal hearing at baseline and none of them had follow-up audiometry testing.
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In Study C2301, 13 patients in the TIP group and 9 patients in the placebo group underwent
audiology testing. None of the patients reported hearing complaints (tinnitus, ear pressure, or
hearing loss) between baseline (Day 1 of Cycle 1) and Day 28 of Cycle 3. Two patients in the
TIP group had significant hearing loss (10-15 dB in at least 2 consecutive frequencies): one
patient had no subsequent audiometry testing and the other patient had a normal audiogram at
a subsequent visit.
In Study C2303, a total of 25 patients underwent audiology function testing on Day 29 (14
TIP patients vs.11 placebo patients). One patient in the placebo arm and one in the TIP arm
had a clinically significant decrease in audiograms, both resolved in the C2303 extension.
Overall, the majority of the measured hearing losses in patients in any study who underwent
audiology function testing were mild and transient and were not clinically significant.
9.5
Clinical laboratory evaluations
9.5.1
Clinical chemistry in Study C2302 (primary safety population)
Baseline
At baseline alkaline phosphatase (ALP) was elevated for 25.4% TIP and 33.0% TOBI patients
and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated for
between 10.5% and 18.6% of patients in both groups. Between 16% and 22.5% of patients in
both groups had elevations of total protein and glucose at baseline. These elevated baseline
values most likely reflect the patients CF related pancreatic and liver diseases. At baseline,
renal function markers, serum creatinine and blood urea nitrogen (BUN) were broadly similar
in the TIP and TOBI treatment groups.
Study C2302 (primary safety population)
Overall, there were no significant changes during the study in TIP and TOBI treatment
groups, with regards to renal function markers, serum creatinine and BUN.
The proportion of patients with treatment emergent abnormal changes in laboratory
parameters are summarized in Table 9-15.
Table 9-15
Treatment emergent abnormal lab events in selected lab parameters Study C2302 (Primary safety population)
Any time post-baseline

50% increase from baseline in serum creatinine
100% increase from baseline in BUN
(1)
>3xULN in AST
(1)
>3xULN in ALT
(1)
>1.5xULN in ALP
(1)
>2xULN in total bilirubin
(2)
Hy's law
TIP/TIP/TIP
N=308
n/TOT (%)
TOBI/TOBI/TOBI
N=209
n/TOT (%)
15 / 301 (5.0)
17 / 301 (5.6)
3 / 300 (1.0)
7 / 299 (2.3)
13 / 301 (4.3)
2 / 299 (0.7)
0 / 301 (0)
8 / 205 (3.9)
8 / 205 (3.9)
4 / 205 (2.0)
10 / 205 (4.9)
16 / 205 (7.8)
0 / 205 (0)
0 / 205 (0)
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TOT is the number of patients with values at both baseline and post-baseline
(1)
baseline 3xULN in AST/ALT, 2xULN in total bilirubin, ALP 1.5xULN
(2)
ALT >3xULN or AST >3xULN and total bilirubin >2xULN
Renal function tests

Treatment emergent abnormal changes in laboratory values were seen for less than 10% of
patients in either treatment group. The most common were increases in serum creatinine and
BUN from baseline.
During the study, 2 patients in the TIP treatment group and one patient in the TOBI treatment
group, presented with transient increases in serum creatinine values above upper normal limits
during the course of the study and a 50% increase as compared to baseline.
Of the patients with BUN above upper normal limits during the course of the study, 5 TIP
patients and 3 TOBI patients had increases of 100% or higher as compared to baseline. These
high values were transient in most of these patients and returned back to normal range values
at subsequent visits. In one TIP patient, the abnormal value was measured at follow-up visit
Week 25, the patient being at the end of the Cycle 3 offtreatment period, hence no
subsequent measurements were available. In addition to increased BUN values, a TOBI
patient also presented with a transient serum creatinine value above upper normal limits
during the course of the study and over a 50% increase as compared to baseline.
Overall, during the course of the study, there were no clinically significant differences
between the TIP and TOBI treatment groups, with regard to renal function markers, serum
creatinine and BUN (Table 9-15).
Liver function tests
Slightly more TOBI patients experienced increases >1.5 times upper limit of normal range for
ALP, but otherwise changes were comparable for both treatment groups. As expected (Goss et
al 2007), serum transaminases (ALT and AST) and ALP were reported above the upper limit
of normal in some patients at baseline, reflecting CF related liver disease (Table 9-15).
Fluctuations in transaminase levels were noted during the study, however there were no
notable differences between treatment groups. Further, no cases qualifying as per Hys law
(ALT >3x upper limit of normal (ULN) or AST >3xULN and total bilirubin >2xULN,
indicative of significant hepatotoxicity) occurred in either treatment group.
9.5.2
Clinical chemistry in individual placebo-controlled studies (C2301 and

C2303)
In Study C2301, changes from baseline in biochemistry variables for the TIP treatment group
were generally comparable to those seen in the placebo group. A higher percentage of patients
in the TIP group compared with the placebo group showed 100% increase from baseline in
BUN (10.9% for TIP vs. 4.2% for placebo, however, most of them remained within the
normal ranges). A higher percentage of patients in the placebo group showed 50% increase
from baseline in creatinine (4.3% for TIP vs. 10.4% for placebo), however, most of them
remained within the normal ranges.
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In Study C2303, a higher percentage of patients in the TIP group compared with the placebo
group showed 50% increase from baseline in creatinine (17.2% for TIP vs. 6.5% for
placebo), however they remained within the normal range.
9.5.3
Urinalysis
In Study C2302, 5 TIP-treated patients had positive protein (1+ or greater) urinalysis results
for at least 2 consecutive visits. Of these patients, 4 had positive assessments at screening. In
the TOBI treatment group, 3 patients had two consecutive urinalysis results positive for
protein, of whom one had a positive screening assessment.
In Study C2301 no patients had proteinuria for 2 consecutive visits. In Study C2303, one
patient treated with TIP had 2+ proteinuria at Day 29 and at Day 56 follow up.
Urine protein has been detected sporadically in a few CF patients participating in Phase III
TIP studies. Most of the events were mild and transient. The review of the profiles of the
patients has not revealed any risk factors and no particular pattern has been observed.
9.6
Summary of safety data from uncontrolled studies
9.6.1
Study C2301 Cycles 2 and 3
In Cycles 2 and 3 of Study C2301, all patients received open label TIP. The safety data
observed in Cycles 2 and 3 were consistent with events reported in Cycle 1. In Cycle 2,
patients randomized to placebo in the first cycle and starting TIP in the second cycle reported
increased numbers of local AEs compared to patients who had previously received TIP in
Cycle 1. Among patients new to TIP in Cycle 2, 5 (15.2%) patients reported cough compared
to 3 (10.7%) receiving the second cycle of TIP. Dysphonia was reported in 2 patients who
were new to TIP compared to 1 who received TIP in the first cycle, and dysgeusia was
reported in 4 patients (12.1) who were new to TIP vs. 2 (7.1) with previous TIP experience. In
Cycles 2 and 3, 8 SAEs were reported: 4 related to CF respiratory exacerbations, 1
pneumonia, 1 case of pancreatitis, 1 hospitalization due to abdominal pain, and 1 failure to
thrive. There were no deaths in Cycles 2 and 3 of Study C2301.
9.6.2
Study 2303E1
Study C2303E1, was an open-label extension of Study C2303. Fifty five patients who
completed Study C2303 received 3 cycles of TIP treatment. The safety data observed in the
extension study is similar to that observed in the randomized trials. Treatment-emergent AEs
(on- and off-treatment) were reported by less than one-half of patients (26 patients,
47.3%).The most commonly reported were cough (5 patients, 9.1%), respiratory tract
infection (5 patients, 9.1%), dysphonia (3 patients, 5.5%) and hypoacusis (3 patients, 5.5%).
Of the patients reporting hypocusis, only one of the patients had an associated change in
hearing as measured by audiology. Bone conduction was consistent with a conductive defect
and hearing returned to normal after discontinuation at follow up.
Patients receiving TIP for the first time (those treated with placebo in C2303) reported more
local AEs that those who had previous TIP experience. Cough was reported in 4 patients,
(13.8%) from the core placebo group vs. 1 patient (3.8%) in the core TIP group, dysphonia
was reported in 3 patients(10.3%) vs. 0 patients on TIP and placebo respectively.
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SAEs were reported by 3 patients who were hospitalized for the treatment of a moderate lung
infection, pneumonia and aspergillosis requiring systemic antifungal treatment. No deaths
occurred in this study.
9.7
Post-marketing experience
TOBI Podhaler has been approved in 37 countries and is currently available in 19 countries
including Canada and in the EU.
No marketing authorization withdrawal or suspension, no failure to obtain a marketing
authorization renewal, no restrictions on distribution, and no clinical trial suspension, for
safety reasons, have occurred at this time. In Switzerland, usage will be initially limited to
three consecutive treatment cycles until longer term safety data become available; patients
may resume therapy after one cycle off treatment.
For the time period since first approval, the estimated patient exposure calculated based on
worldwide sales volume is 1217.4 patient treatment years.
A total number of 136 cases were reported from November 25, 2010 until June 25, 2012.
The most frequent spontaneous reports reported by health care professionals (HCP) and nonHCP were cough, chest discomfort, dysphonia and dyspnea.
9.8
Additional studies to further evaluate safety of tobramycin

inhalation powder
Two sequential open-label extension studies to Study C2303 (C2303E1 and C2303E2) will
provide an additional 6 treatment cycles (48 weeks) of TIP and long-term safety data. These
extensions provided the opportunity for all the patients who completed placebo-controlled
Study C2303 to receive additional cycles of treatment with TIP. The results of Study
C2303E1 are described in Sections 7.5 and 9.6.2 of this briefing book. The results of Study
C2303E2 were not available in time for NDA submission.
As a post-approval commitment to the EMA, Novartis initiated an additional TIP postauthorization safety study (Study C2401) in 150 CF patients aged 6 years or older. The
purpose of this study is to provide long-term safety data for the use of TIP together with
supportive efficacy endpoints over a period of 6 cycles of treatment (a duration of 48 weeks).
Lastly, to further enhance the data with respect to the use of TIP in real-world conditions, an
additional study is planned (Study C2407) following the approval of TIP in the US. This study
would be a prospective observational study to gather information with respect to the safety
and effectiveness associated with the use of TIP in CF patients in routine clinical practice. It
will also assess treatment burden over time, adherence and persistence associated with inhaled
antibiotic treatments for chronic P. aeruginosa infection.
The design concept is for a long-term, prospective, observational study to be conducted at
approximately 75 US centers. The study would target enrollment of approximately 1000
patients (500 treated with TIP, 500 treated with another FDA-approved inhaled antipseudomonal therapy for pulmonary P. aeruginosa) over a two year enrollment period. Sites
would be selected based on their likelihood to have an eligible pool of patients to contribute to
this study (i.e. the number of CF patients seen annually).
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9.9
Safety summary
The proposed TIP dose was selected to provide comparable systemic exposure to TOBI. In
the primary safety Study C2302, the overall incidence of AEs was comparable between the
treatment arms. The most frequently reported preferred terms were cough and lung disorder
(generally a CF/pulmonary exacerbation) for both treatment groups. Cough, dysgeusia and
dysphonia may be associated with the use of TIP, indicating a different local tolerability
pattern from TOBI; however, cough was not associated with bronchospasm, hemoptysis, or
worse clinical outcome. There was no evidence of acute bronchospasm being more frequent in
TIP treated patients than in placebo or TOBI treated patients. In placebo-controlled studies,
local and systemic AEs were comparable to placebo and mostly related to the underlying
disease.
AEs associated with systemic exposure to aminoglycosides were rare. Few patients in any
treatment group demonstrated a clinically relevant decrease in hearing acuity or hearing
related AEs. In the development program, there was no evidence of nephrotoxicity.
The data from the TIP Phase III studies support the safety of the product in CF patients. Local
AEs tended to be mild and decrease over time while minimal systemic adverse effects attest to
the safety of the dry powder formulation. Post marketing experience of TIP confirms an
adverse reaction profile that is similar to TOBI. The totality of safety evidence supports a
positive benefit risk profile for the use of TIP in CF patients with P. aeruginosa.
10
Device usability study results
During the development of the T-326 Inhaler, the device user interface has been designed
and optimized in line with the 2011 FDA draft guidance, Applying Human Factors &
Usability Engineering to Optimize Medical Device Design (please see Section 3 for a picture
of the device and a description of its basic use steps). These development activities
culminated in two human factor validation testing studies which confirmed that CF patients,
independent of age, can safely and successfully perform all the steps required to inhale a full
dose and that the T-326 Inhaler is easy to use.
These two user handling studies (human factors validation testing) were performed in the US
and EU, respectively. These studies were done in a total of 82 subjects with 62 US-based CF
patients, or subjects representative of CF patients, aged 6 years and older, and 20 Europebased CF patients aged between 610 years old. The study subjects demonstrated the use of
the T-326 Inhaler by inhalation of four capsules (the intended dose of the drug product) using
empty capsules. Usability was evaluated based on pre-established criteria upon patients first
use and at the return visit after the patient completed a 5-day period of simulated twice-daily
use at home. Additionally patients were asked to provide subjective feedback. A total of 54
patients participated at the return visit, i.e. all 20 EU patients and a representative subset of 34
out of the 62 US patients. This approach was selected to investigate the effects of training
decay on the usability of the device.
Prior to conducting these two usability studies, healthcare professionals (HCPs) were
interviewed in order to establish the level of training that a patient or caregiver may receive
when prescribed TIP. The HCPs interviewed, who included registered nurses and respiratory
therapists in the US, said that they routinely train CF patients (and caregivers for younger
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patients) on how to use their drug delivery devices. This feedback is also representative of the
practice in the vast majority of CF care centers in the US.
The two usability studies showed that after a week of use, all subjects in the EU study and
94% in the US study, alone or with the assistance of their caregiver, were able to successfully
demonstrate the dosing procedure of removing 4 capsules from the blister card, piercing and
inhaling from each of the 4 capsules as required, and operating the device properly with
respect to dose preparation and inhalation, for a complete dose. This observation of a low
percentage of use errors (i.e. 6%) resulting in an unsuccessful complete dosing of all 4
capsules is superior to the known prevalence of critical/ essential step use errors in a
comparative marketed capsule based dry powder inhaler (Aerolizer) which ranged between
12-19.6%, as reported in studies by Molimard et al (2003) and Khassawneh et al (2008),
respectively.
The two usability studies combined demonstrated with 95% confidence that after 5 days of
use at home, a user is 99% likely to use the inhaler successfully to receive a full dose. The US
study demonstrated with 95% confidence that after 5 days of use at home, a user is 98% likely
to use the inhaler successfully to receive a full dose. These calculations are based on an upper
bound of a two-sided 95% confidence interval for binomially distributed proportions which is
suitable for testing in small sample sizes.
In addition to the demonstrated safe and effective use, 89% of the patients participating in the
two usability studies rated the inhaler as easy or very easy to use in a post-use
questionnaire. The study questionnaire results also showed that about 83% of subjects
preferred the T-326 Inhaler over use of a nebulizer mainly due to convenience and quick
administration, with approximately 7% of users still preferring to use a nebulizer.
At the return visit after 5 days of home use 96% of the subjects in the US study performed
11 of the 16 evaluated use steps correctly. The five use steps below demonstrated some room
for improvement which may be addressed through additional training. These occurences of
incorrect handling were randomly distributed, i.e. none of the study subjects made an error in
all five steps listed below.
the orientation of the device when piercing the capsule (piercing with the mouthpiece not
facing downwards).
exhaling fully prior to inhalation.
inhaling twice from each capsule.
checking the capsules after use, to be performed as instructed in the Instructions for Use
(IFU).
cleaning mouthpiece with a dry cloth.
Regarding the orientation of the device, this was associated with holding the inhaler
differently than instructed while piercing the capsules. Results of an in vitro study show that
orientation does not have an impact on dose delivery.
About half of the subjects (54%) did not appear to exhale fully prior to inhalation. This is a
device-independent use error and a known issue with a prevalence rate of 50% for commonly
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available inhalers as reported by Melani et al (2011) and correctable via further training and
reinforcement.
Four out of the 34 US subjects participating in the return visit forgot to inhale twice from each
capsule. Failure to inhale twice from each capsule is a device-independent use error which
does not in itself constitute a usability problem, as a capsule check is subsequently included in
the IFU and the majority of patients will be able to inhale the capsule content with one
inhalation.
After 5 days of home use, 17 of the 34 subjects forgot to check at least one of the four
capsules to see if they were emptied. Five of these subjects systematically forgot to check all
four capsules. This error may have been related to the use of empty capsules in this study
making inspection appear to be irrelevant.
The final cleaning step, consisting of wiping the device with a dry cloth, was not performed
by 26% of the subjects after 5 days home use. It emerged from the discussion with subjects
that failure to complete this step was related to the use of empty capsules.
Similar results have been obtained in the EU user study. The two studies combined
demonstrated that after use at home for 5 days, users successfully removed a capsule from the
blister card approximately 99% of the time (and the combined first use success rate was
~98%). Despite this high success rate, the child-resistant blister cards were found difficult to
open by some of the subjects. Following completion of the studies and assessment of the
results, the proposed labeling (Instructions for Use) was updated to more clearly communicate
a recommended blister opening technique to further improve the ease of opening the blister
card to retrieve capsules. The same blister design has been on the market for approximately
one year in Canada and Europe. During this period only two complaints on opening of the
blister card were received.
The use of the T-326 Inhaler has been found to be safe and effective for the intended users,
uses and use environments. The two studies demonstrated that a user will be able to operate
the device safely and successfully according to the IFU. Experience from one year of
commercial use of TIP in Europe and Canada support this conclusion. As per the previously
mentioned FDA draft guidance, each use error and finding was assessed for potential
additional mitigations and resulted in refinement of the wording in a few sections of the IFU.
Any residual risk is outweighed by the benefits that may be derived from device use, and is
likely to be reduced further by the in-depth and personalized training provided by respiratory
therapists or other members of the patients care team at CF centers.
11
Benefit and risk conclusions
There is a clear and significant unmet need for additional treatment options for CF patients
infected with P. aeruginosa. TIP reduces the treatment burden through faster, simpler delivery
of tobramycin with easier maintenance and better portability than the currently available
tobramycin formulation. Given the severe treatment burden in CF, this amounts to meaningful
benefit for a CF patient considering the extensive range of therapies needed in CF (antibiotics,
mucolytics, bronchodilators, enzymes) and regimens (chest physiotherapy).
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P. aeruginosa pulmonary infection in CF affects the majority of CF patients and is associated

with progressive lung disease that leads to increased morbidity and reduced survival.
Effective management of the infection can improve lung function, reduce respiratory related
morbidity, increase quality of life and prolong life expectancy. The current standard of
treatment is cyclical therapy with nebulized anti-pseudomonal antibiotics, in particular TOBI.
The benefits and risks of TIP are discussed in relation to this current standard of care.
The TIP development program demonstrated that the dose of 4 x 28 mg b.i.d. provides
effective delivery of tobramycin into the lungs of CF patients, matching the amount delivered
by TOBI, resulting in suppression of pulmonary P. aeruginosa infection and consequent
improvement in lung function, together with a decrease in anti-pseudomonal antibiotic use
and hospitalizations due to respiratory events.
TIP provided comparable efficacy to TOBI administered by nebulizer, but with better
portability, a simpler process and 70% shorter administration time, saving 13 hours per cycle.
The actual time reduction is greater since TIP also circumvents the need to assemble,
disassemble, clean, dry, and disinfect nebulizers and compressors. This overall reduction in
treatment burden is highly relevant to CF patients who are already time-poor and struggling
with their life/treatment balance.
The benefits of TIP were demonstrated by the following:
Improvements from baseline in FEV1 % predicted were greater with TIP than placebo
(with between-study differences comparable to those seen in earlier studies with TOBI),
and shown to be similar to TOBI.
Decreases from baseline in P. aeruginosa sputum density were greater for TIP than for
placebo and comparable to TOBI.
Use of additional anti-pseudomonal antibiotics was less common with TIP than placebo.
For the comparison of TIP vs. TOBI, although use of new anti-pseudomonal antibiotics
was higher with TIP vs. TOBI in Study C2302, the duration was similar and the use of
new IV anti-pseudomonal antibiotics was similar.
patients who received placebo in controlled trials. Hospitalization rates were similar for
TIP-and TOBI-treated patients.
Study C2301 demonstrated improvement in lung function (relative mean change from
baseline in FEV1 % predicted) during treatment with TIP to be significantly greater than that
observed with placebo after 28 days of treatment: the difference between TIP and placebo was
greater than 13% and was statistically significant (p=0.0016). When patients in the placebo
group switched to TIP in Cycle 2, the relative change in FEV1 % predicted from baseline
increased to the level of the TIP group and was maintained over time.
In Study C2302, the mean relative change from baseline in FEV1 % predicted after 3 cycles of
treatment with TIP was comparable to the same regimen of treatment with TOBI, the current
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standard of care. This remained the case even after allowing for differences in
discontinuations and anti-pseudomonal antibiotic usage rates.
In Study C2303, favorable and consistent FEV1 trends were shown for TIP compared to
placebo, although a statistically significant difference was not demonstrated for the prespecified ITT primary endpoint. The difference of 5.9% between TIP and placebo for the
relative change from baseline in FEV1 % predicted had a p-value of 0.148. Importantly, a preplanned analysis of absolute change from baseline in FEV1 % predicted in Study C2303 was
statistically significant for the ITT population with a LS mean between-treatment difference
of 4.4, 95% CI 0.0, 8.8: p=0.0496).
Taken together with data from Studies C2301 and C2302, the data from Study C2303 support
approval,
In Study C2303E1, the open-label extension to Study C2303, a progressive increase in FEV1
% predicted across the 3 cycles of active treatment was observed, with no apparent loss of
effect. Patients treated with placebo in Study C2303 showed a progressive improvement in
FEV1 % predicted during the extension.
Microbiological results in all three Phase III studies supported the use of TIP for the treatment
of P. aeruginosa infection by demonstrating a decrease in the overall sputum density for the
sum of biotypes, and for each of the different morphotypes. This decrease was greater than
placebo and comparable with TOBI.
MIC results during the studies showed that MIC50s remained stable. MIC distribution curves
(shown for Study C2302) were similar between baseline and end of study and between TIP
and TOBI. Apparent increases of MIC90s to higher levels reflected high pre-treatment MICs
in a number of patients. It cannot be concluded from these data that isolates with high MICs
emerged during the studies, though there is always a potential for MICs to increase for all
antibiotics. Furthermore, no difference in clinical outcomes were seen in patients with lower
vs higher MICs. These data are consistent to that previously reported for TOBI.
The safety of inhaled tobramycin (in the form of TOBI nebulizer solution) is now well
established over more than a decade of clinical use. Given that the systemic exposure to
tobramycin is comparable with TIP and TOBI and that the lung exposures are similar, the risk
profile for TIP is likely to be similar to that of TOBI.
TIP demonstrated no evidence of systemic toxicity, e.g. nephrotoxicity following TIP
treatment, and the mean tobramycin serum levels recorded during all studies were well below
those known to be associated with renal toxicity.
There was no evidence of sensorineural hearing loss in Study C2301 or Study C2303. For
events which indicated a significant likelihood of ototoxicity, TIP and TOBI were well
matched. In Study C2302, the incidence of reporting of clinically significant hearing loss in
the TIP treatment group was comparable to that in the TOBI group. For the majority of
patients, these decreases were transient as were hearing complaints such as tinnitus.
In Study C2301, TIP was shown to be safe and well tolerated, with a safety profile
comparable to placebo. Cough was reported less for TIP than for placebo. Pharyngolaryngeal
pain was more frequently reported in the TIP treatment group compared with the placebo
treatment group. There were no new or unexpected safety events in Study C2303 and the
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discontinuation pattern was similar to Study C2301. There were fewer SAEs on TIP than
placebo and the only discontinuation due to an AE across the three cycles of treatment
occurred in the placebo group (pulmonary exacerbation leading to death).
In the open-label Study C2302, the AE profile of TIP was generally similar to TOBI with the
majority of AEs relating to the underlying diagnosis of CF, but cough, dysphonia, and
dysgeusia were more frequently reported in the TIP treatment group than in the TOBI
treatment group. All of these AEs, including cough, were most often mild and moderate.
Serious and severe AEs were closely matched between the TIP and TOBI groups. Further, the
perception of the impact of side effects as reported by the patients did not differ between TIP
and TOBI, as measured with the TSQM.
Increased airway reactivity, as indicated by post-dose bronchospasm (acute reduction in FEV1
% predicted) or assessed as an AE following inhalation of TIP or TOBI was observed in a
small proportion of patients and occurred at similar rates for TIP, TOBI and placebo. There
was no apparent association between cough and bronchospasm.
The overall risk associated with the use of TIP appeared to be similar to that associated with
the use of TOBI, particularly with respect to the most important aspects of systemic safety.
The differential tolerability signal relates to the events of cough, dysgeusia and dysphonia.
Dysgeusia is likely to be related to tobramycin itself, which has an unpleasant taste; notably
no patients have discontinued from the studies due to dysgeusia. Dysphonia has already been
reported with nebulized therapy, including tobramycin nebulizer solution; the proportion of
patients on TIP with dysphonia appears to be higher based on the open-label Study C2302,
however most events were mild and only 3 patients on TIP discontinued due to dysphonia.
Dry powder inhalation itself may be associated with increased cough and dysphonia.
In summary, TIP has been shown to deliver a clinically relevant amount of tobramycin to the
lung and thereby to suppress growth of P. aeruginosa and improve lung function. The benefits
of TIP to patients with CF are characterized by marked improvements in speed, simplicity,
and portability, while retaining the efficacy of TOBI. Taken as a whole, the data from the TIP
clinical program provide confidence in a positive risk/benefit profile, and support approval of
this inhaled tobramycin formulation option for heavily burdened CF patients.
12
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13
Appendix 1 Manufacturing process development
Over the course of development the manufacturing process was improved, optimized,
validated, and commercialized, while maintaining the same composition, batch size, and
general manufacturing sequence and steps.
Powder for Phase III clinical supplies for Studies C2301 and C2302 (subsequently referred to
as Phase III process batches) was manufactured on the same spray dryer as Phase I supplies at
a 3 kg batch size. Improvements were then made to the Phase III bulk powder manufacturing
step to improve the physical stability of the emulsion, to reduce yield variability and increase
powder yield without changing batch size and composition. Spray drying conditions were
then optimized in order to produce powder with aerosol performance and other
physicochemical attributes that matched those of the Phase III batches. This is referred to as
the Improved (Pre-validation) process and was used to manufacture registration stability
batches and to supply clinical Study C2303.
The improvements were made to ensure consistency of the bulk spray-dried powder
commensurate with the needs and expectations of a commercial manufacturing process. The
improvements were:
Reduction of feedstock emulsion droplet size by approximately 0.4 m:
this increased the stability of feedstock during the spray-drying of a full 3 kg batch,
and
maintained consistency of the bulk powder characteristics across a full 3 kg batch
Improved design of powder collection hardware: this
reduced powder hold-up,
reduced variability of bulk powder characteristics, and
gave higher, more consistent yield
These process improvements were the subject of a meeting with FDA in November 2007.
The Improved powder manufacturing process was subsequently transferred to commercial
equipment of like design, keeping batch size constant, and validated. Spray drying ranges
were confirmed to achieve aerosol performance comparable to the Phase III clinical batches.
Drug product batches from the improved manufacturing process, both before and after
transfer to the commercial equipment and subsequent validation, were used in clinical study
C2303 requested by the Agency.
Table 13-1
Powder manufacturing process development summary
Clinical
study
Formulation
Manufacturing
process
nomenclature
Batch
size
Key changes compared to Phase III
C2301
C2302
C2303
CN1-002
CN1-002
CN1-002
Phase III
Phase III
Improved (prevalidation)
3 kg
3 kg
3 kg
n/a
n/a
1. Emulsion stabilized with smaller
droplet size
2. Powder hold-up and variability
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Clinical
study
C2303
Formulation
CN1-002
Manufacturing
process
nomenclature
Improved
(validated)
Batch
size
3 kg
Key changes compared to Phase III
reduced with changes in collection

hardware
Transfer to commercial equipment
of like design
For the commercial filling process, improvements to capsule handling and automation of fill
weight inspection were implemented to increase throughput. Otherwise, the capsule filling
process has retained the same steps from Phase I through to Commercial production
[improved (validated) process].
Filled capsules are individually packaged into laminated aluminum-aluminum blisters. This
packaging was used for clinical Phase III supplies, and registration stability and will be used
for commercial supplies.
The T-326 Inhaler remained unchanged throughout all of Studies C2301, C2302, C2303.
13.1
Comparability data for Phase III and Improved spray drying

processes
Comparability data for Phase III and improved process batches are provided in the following
sections.
13.1.1
Aerodynamic particle size distribution (APSD)
Aerodynamic particle size distribution (APSD) encompasses both the fluidization of powder
from the delivery device (captured via delivered dose measurements) and deagglomeration of
the powder. Therefore, APSD is considered the most relevant indicator of drug product
aerosol performance and is commonly accepted as the most relevant in vitro metric that
speaks to deposition of the inhaled powder in the lung.
13.1.1.1 APSD profiles
In the indicated population of CF patients, P. aeruginosa is present in both the conductive
zones of the bronchi and bronchioles and in the respiratory zones of the alveoli and
respiratory bronchioles (Bjarnsholt et al 2009). Therefore, the APSD stages 3 to 7 (plus filter)
provide an in vitro test analog of in vivo deposition, with respect to efficacy and encompass
aerodynamic sizes that cover both of these lung zones.
Figure 13-1 shows the resultant APSD profiles. Eighteen batches manufactured using the
Improved process (both pre-validation and validated), some of which were used in Study
C2303, were compared to the eighteen Phase III batches used in the clinical trials C2301 and
C2302. Each data point is a mean of 5 measurements (1 capsule each) utilizing the Next
Generation Impactor (NGI) at 60 LPM.
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Figure 13-1
APSD: Phase III, Improved (pre-validation) and Improved (validated)

process batches
The tolerance intervals in the figure above are 95% CIs with 99% coverage of Phase III
batches. The Improved process batches lie within 95% mean tolerance intervals of the Phase
III clinical batches and are considered equivalent.
13.1.1.2 Mass per stage
Figure 13-2 displays stage by stage individual capsule data for Phase III, Improved (prevalidation) and Improved (validated) process batches. It further underlines comparability
related to the key aerosol attributes of the drug product discussed above. Particularly notable
is that, almost without exception, the range of Phase III stage-by-stage aerosol data
encompass those of both the Improved (pre-validation) and Improved (validated) process
batches. The improved process is also more tightly controlled than the Phase III process,
which was one of the intents of the bulk powder process improvement.
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Figure 13-2
Mass per stage for NGI data at flow rate of 60 LPM
Dots to the left represent APSD data (on individual capsule basis) of Phase III batches.
Dots in the middle represent APSD data (on individual capsule basis) of Improved (pre-validation)
process batches.
Dots to the right represent APSD data (on individual capsule basis) of Improved (validated) process
batches.
F76 Presents the sum of Filter + Stage 7 + Stage 6.
The majority of the particles represented by throat, Stage 1 and Stage 2 can be considered
non-respirable and are likely to be deposited in the oropharynx and subsequently swallowed.
Small differences in means between the Phase III and Improved process lots are not expected
to affect drug product safety due to the very low oral bioavailability of tobramycin (<1%). It
is noted that, if considers a portion of the stage 2 deposition as being a contributor to lung
delivery, the Phase III data is more broad and variable than that from the improved process
and is encompassed within the Phase III range.
With respect to the respirable portion, there are essentially no differences in drug mass per
stage for stages 5, 6 and 7 and Filter.
The small differences in means for stages 3 and 4 in comparison to the Phase III process are
not of practical significance, particularly when one considers:
the ranges around each of the means.
the very small differences in absolute amounts of tobramycin relative to the mass of drug
on the stage.
the encompassment of the Improved (pre-validation) and Improved (validated) process
batch data by the Phase III batch data.
the effectiveness of the TIP drug product being based on its ability to deposit tobramycin
at levels above the minimum inhibitory concentrations (MICs) at the site of P. aeruginosa
colonies in the lung, i.e. in both the conductive zones of the bronchi and bronchioles and
in the respiratory zones of the alveoli and respiratory bronchioles (Bjarnsholt et al 2009).
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the in vivo delivery of tobramycin at multiple folds (for example in the range of 11-27X)
above the minimum inhibitory concentrations (which the drug product achieves) to the
lung where P. aeruginosa colonies are present.
the comparability in the clinical data from TIP and TOBI, despite the difference in
delivery systems.
13.1.2
Delivered dose
Delivered dose is an additional in vitro performance measure for inhaled products and data
comparing eighteen Phase III, and eighteen Improved process batches are shown in
Figure 13-3. For comparative purposes, the % label claim limits were fixed around the target
delivered dose of 102 mg (4 capsules per dose).
Figure 13-3
Delivered dose uniformity
The % label claim limits are shown for comparative purposes only.
All results met delivered dose testing requirements for uniformity as per the current
specifications. The mean delivered dose for the Improved (pre-validation and validated)
process batches are comparable with the Phase III process; though fractionally higher the
ranges overlap. Considering the nominal 102 mg delivered dose of tobramycin and the
comparability of APSD testing, this very slight difference is not considered to have any
clinical relevance. As mentioned in Section 13.1.1, APSD encompasses both delivered dose
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and deagglomeration aspects of drug product aerosol performance, and comparability was
demonstrated for this characteristic. Also notable is that the batch to batch variability is lower
for the Improved process compared to the Phase III process demonstrating an improvement in
delivered dose uniformity and process control.
13.1.3
Physical characterization
Multiple physicochemical characterization techniques were used to compare TIP

manufactured using the Phase III, Improved (pre-validation), and Improved (validated)
processes, respectively. Comparability was demonstrated in the numerous physicochemical
characteristics pertinent to in vivo behavior, including thermal (differential scanning
calorimetry), solid-state (x-ray-diffraction), homogeneity (Raman microscopy), purity and
assay (HPLC) and water content.
13.2
Conclusion
Subsequent to Phase III process supplies (used in Studies C2301 and C2302), manufacturing
improvements to the bulk powder manufacturing step were made in emulsion preparation and
powder collection to support future commercialization. Throughout these improvements, the
overall manufacturing process did not change. In vitro results show comparable aerosol
delivery characteristics (e.g., mass per stage, delivered dose uniformity) of materials from
each of the processes. Tolerance interval analysis of the APSD profiles presented
demonstrates statistical comparability; therefore, tobramycin delivery to the lung is expected
to be therapeutically equivalent for drug product produced from the Phase III process (used in
Studies C2301 and C2302) and the Improved (pre-validation and validated) process (used in
Study C2303). This is further supported by comparison of the solid-state, and other
physicochemical characteristics which provide additional confidence that, upon aerosol
delivery, uptake of drug in the lung will be comparable. A first set of comparability data was
shared with FDA at a meeting in November 2007. The Division requested that Novartis
provide additional clinical data to supplement the available technical comparative data. Study
C2303 was conducted to fulfill this request.
The results of this in vitro comparison are supported by the results of Study C2303.
Tobramycin exposure in serum and sputum remained comparable following the
manufacturing process improvements. Further perspective and context regarding the in vivo
similarity from Phase III batches and Improved (i.e. commercial) process batches is provided
via the striking comparability in the in vivo data from TIP and TOBI inhalation solution,
despite the many in vitro differences (nebulizer delivery vs. T-326; different patient inhalation
manoeuver between nebulizer and dry powder delivery device; solution versus powder
formulation; markedly different aerosol particle size distribution)
It is also noted that tobramycin is delivered at multiple folds above the minimum inhibitory
concentrations to conductive and respiratory areas of the lung where P. aeruginosa colonies
are present. Results for the key efficacy endpoints in C2301 (Phase III process batches) and
C2303 (improved process batches) remained within the expected range of clinical trial results.
Materials from the validated process are intended for commercial supply.

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Tobramycin inhalation powder (NDA 201,688)

Prepared by Novartis Pharmaceuticals Corporation for the

Table of contents ................................................................................................................. 2

Phase III clinical studies initiation and completion dates .................. 15

Summary of sputum tobramycin concentrations across studies

Relative change of FEV1 % predicted from baseline to Day 29 in

Adverse events with an occurrence >2 events/cycle, adjusted for

Tobramycin drug substance .................................................................. 31

Mean serum concentration-time profiles of tobramycin after

Distribution of tobramycin MICs of all P. aeruginosa isolates with

Minimum inhibitory concentration

Cystic fibrosis: burden of disease and unmet medical need

Development of tobramycin inhalation powder (TIP)

Overview of clinical studies

The timing of the studies is shown in Table 1-1.

Phase III clinical studies initiation and completion dates

First patient / first visit

Last patient / last visit

September 22, 2005

February 28, 2007

*open-label extension to Study C2303

Study design and patient population

Study design and patient population

Study design and patient population

Evaluation of efficacy in Phase III studies

Overview of microbiology- susceptibility and emerging

Tobramycin minimum inhibitory concentrations (MICs) for P. aeruginosa isolates were

Aspergillus fumigatus, Staphylococcus aureus (including methicillin-resistant S. aureus

Increased airway reactivity, as indicated by post-dose bronchospasm (acute reduction in FEV1

Introduction and background

Cystic fibrosis: burden of disease

Pseudomonas aeruginosa infection and treatment

Inhalation antibiotic therapy offers a good alternative to systemic (intravenous or

CF patients need less burdensome treatment options to improve

Tobramycin inhalation powder (TIP)

Tobramycin drug substance

Composition of the drug product

The particles exhibit a characteristic sponge-like morphology that results in significantly

Scanning electron micrograph of PulmoSphere particles

T-326 Dry Powder Inhaler (T-326 Inhaler)

Pharmacokinetics and pharmacodynamics

The pharmacokinetics (PK) of tobramycin after intravenous administration have been

TIP pharmacokinetics in Phase I studies

Serum and sputum pharmacokinetic parameters of TIP (112 mg) vs.

0.92 (0.40, 2.10)

0.90 (0.38, 2.11)

402 (58, 2806)

640 (104, 3936)

4.27 (1.82, 9.99)

4.29 (2.20, 8.37)

461 (34, 6265)

877 (137, 5622)

4.77 (2.19, 10.40)

4.74 (2.51, 8.96)

1008 (307, 3306)

1599 (796, 3214)

3.1 (2.0, 4.7)

3.2 (2.5, 4.0)

2.5 (0.6, 10.7)

2.7 (0.9, 8.2)

Mean serum concentration-time profiles of tobramycin after

TIP pharmacokinetics in Phase III studies

Summary of serum tobramycin concentrations across studies C2301,