Respiratory Medicine (2013) 107, 1558e1567

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Safety and efficacy of dual bronchodilation

with QVA149 in COPD patients: The
ENLIGHTEN study
Ronald Dahl a,*, Kenneth R. Chapman b, Michael Rudolf c,
Rajendra Mehta d, Pearl Kho e, Vijay K.T. Alagappan f,
Hungta Chen f, Donald Banerji f

a
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
b
Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, Canada
c
Department of Respiratory Medicine, Ealing Hospital NHS Trust and Imperial College, London, UK
d
Allergy and Asthma Care, Allergy and Asthma Care and Research Centre, Indore, India
e
Novartis Horsham Research Centre, Novartis, Horsham, UK
f
Novartis Pharmaceuticals Corporation, Novartis, East Hanover, NJ, USA

Received 18 February 2013; accepted 29 May 2013

Available online 16 July 2013

KEYWORDS Summary
Chronic obstructive Background: QVA149 is an inhaled, once-daily fixed-dose dual bronchodilator combination of
pulmonary disease; the long-acting b2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium
Safety; (NVA237) for the treatment of chronic obstructive pulmonary disease (COPD). We investigated
QVA149; the safety and efficacy of QVA149 over 52 weeks.
Lung function; Methods: This 52-week, multicenter, double-blind, parallel-group, placebo-controlled study
Bronchodilators randomized (2:1) patients with moderate-to-severe COPD to once-daily QVA149 (110 mg inda-
caterol/50 mg glycopyrronium) or placebo delivered via the Breezhaler
device. Primary
endpoint was safety and tolerability for treatment-emergent adverse events (AEs). Secondary
endpoints included safety based on vital signs, electrocardiograms (ECGs), laboratory evalua-
tions, and pre-dose forced expiratory volume in 1 s (FEV1).
Results: Of 339 patients randomized, QVA149 [n Z 226], placebo [n Z 113]; 76.9% male, mean
age: 62.6 years, post-bronchodilator FEV1: 57.4% predicted, 83.5% completed study. A smaller
percentage of patients discontinued in the QVA149 group (14.2%) compared with placebo
(21.2%). Overall incidence of AEs was similar in the QVA149 (57.8%) and placebo (56.6%) groups,

* Corresponding author. Tel.: þ45 784 59059.

E-mail address: ronadahl@rm.dk (R. Dahl).

0954-6111 ª 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.rmed.2013.05.016
Safety and efficacy of QVA149 in COPD patients 1559

with most AEs being mild to moderate in severity. The numerical differences in some AEs
observed could be at least in part explained by differences in baseline patient characteristics.
No clinically relevant differences were observed between treatment groups for vital signs or
ECG parameters. The five deaths reported were unrelated to study medication (QVA149,
n Z 4 [1.8%]; placebo, n Z 1 [0.9%]). QVA149 demonstrated rapid and clinically meaningful
bronchodilation sustained over 52 weeks versus placebo.
Conclusion: QVA149 demonstrated a good safety and tolerability profile, providing rapid and
sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD.
ClinicalTrials.gov identifier: NCT01120717.
ª 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.

Introduction Recent Phase III studies have demonstrated that QVA149

has an adverse event (AE) profile similar to placebo and
Long-acting inhaled bronchodilators relieve symptoms more provides significant, sustained, and clinically meaningful
effectively than short-acting bronchodilators and are cen- improvements in lung function compared with its mono-
tral to the management of patients with chronic obstruc- components or tiotropium [15]. QVA149 also improves lung
tive pulmonary disease (COPD) [1]. However, symptoms of function more effectively than twice-daily LABA plus
patients with COPD are often inadequately controlled by inhaled corticosteroid (ICS; salmeterol/fluticasone) in pa-
long-acting bronchodilator monotherapy. Hence, current tients with moderate-to-severe COPD [16].
guidelines/strategy recommend that combining broncho- The ENLIGHTEN study assessed the safety and efficacy of
dilators of different pharmacological classes may improve QVA149 over 52 weeks in patients with moderate-to-severe
efficacy and decrease the risk of side effects compared COPD [17].
with increasing the dose of a single bronchodilator [1].
Studies have shown that the complementary mechanisms of Methods
action of long-acting b2-agonists (LABAs) and long-acting
muscarinic antagonists (LAMAs) significantly improve bron-
Patients
chodilation in patients with COPD compared with respec-
tive monotherapies [2e6]. In the INTRUST I and II studies,
The study population comprised men and women 40 years
concurrent use of indacaterol and tiotropium once daily
of age with moderate-to-severe COPD [17] (Stage II or III
provided superior bronchodilation and reduced hyperinfla-
according to the GOLD 2008 criteria), a smoking history of
tion (reflected by increased resting inspiratory capacity)
10 pack-years, and a post-bronchodilator forced expira-
compared with tiotropium monotherapy [7]. However,
tory volume in 1 s (FEV1) of 30% and <80% of the predicted
there is currently no fixed-dose combination of a LABA and
normal and post-bronchodilator FEV1 to forced vital ca-
a LAMA available for the treatment of COPD.
pacity (FVC) ratio of <0.70 at screening. Patients were
QVA149, a fixed-dose combination of the LABA indaca-
required to have a total daily symptom score (obtained by
terol and the LAMA glycopyrronium (NVA237), is a novel,
adding the scores for the morning and evening symptoms,
once-daily dual bronchodilator for the maintenance treat-
ie, cough, wheezing, sputum production/color, shortness of
ment for COPD. Both monocomponents are approved as
breath) of 1 on 4 of the last 7 days prior to randomization.
once-daily maintenance treatment for patients with
Key exclusion criteria included COPD exacerbations that
moderate-to-severe COPD, and the safety and efficacy of
required treatment with antibiotics or oral steroids or
each have been demonstrated in various Phase II and III
hospitalization in the 6 weeks prior to screening or between
studies. Glycopyrronium has demonstrated rapid and sus-
screening and randomization, respiratory tract infection 4
tained improvements in lung function, dyspnea, improve-
weeks before or during screening, history of asthma and a
ments in health status, exercise endurance and reduced
clinically significant electrocardiogram (ECG) abnormality.
risk of exacerbations, with improvements similar to those
Further details of inclusion and exclusion criteria are
seen with tiotropium, and an acceptable safety profile
included in the online supplement [Supplement Table 1].
[8e10]. Overall, glycopyrronium was generally well toler-
This study was approved by institutional review boards
ated over a treatment period of 52 weeks in comparison
and ethics committees at participating centers, and was
with placebo and tiotropium [10]. Indacaterol has also
conducted in accordance with the Declaration of Helsinki
demonstrated rapid and sustained bronchodilation, im-
and Good Clinical Practice. All patients provided written
provements in symptom relief for dyspnea and health status
informed consent.
(as evaluated by Transition Dyspnea Index [TDI] and St
George’s Respiratory Questionnaire [SGRQ] scores, respec-
tively), and reduction in rescue medication use and exac- Study design and treatment
erbations, with an acceptable safety profile [11e13]. Long-
term safety of indacaterol for up to 52 weeks has been ENLIGHTEN was a multicenter, randomized, double-blind,
demonstrated in comparison with placebo and active parallel-group, placebo-controlled, 52-week study (Fig. 1)
comparators such as formoterol and tiotropium [11,14]. conducted in academic and clinical research centers in
1560
Figure 1
Europe, Canada, Asia (India, Korea), and South Africa
(ClinicalTrials.gov registration number: NCT01120717). The
study comprised a pre-screening wash-out period (up to 7
days) and a 14-day run-in period during which patients were
assessed for study eligibility and baseline patient diary data
(ie, mean daily total symptom scores were collected). At
the end of the screening period (Visit 3), patients were
randomized (2:1) to once-daily QVA149 110/50 mg or pla-
cebo. Randomization was stratified according to smoking
status (current/ex-smoker). QVA149 and placebo were
administered in the morning between 08:00 and 11:00 h via
the Breezhaler
device [18]. No patients received placebo
treatment in isolation at any time during the study: placebo
was included to patients’ established background COPD
therapy, for example, daily ICS. The short-acting broncho-
dilator salbutamol (albuterol) was provided for rescue use
throughout the study. Patients were not permitted to use
short-acting muscarinic antagonists or long-acting bron-
chodilators (LAMAs, LABAs, theophylline) before the
screening period (for at least 7 days for LAMAs and
theophylline; 48 h for LABA and LABA/ICS combinations) or
during the study. However, ICS use was maintained, ie,
patients taking combined LABA/ICS at screening were
transitioned to the equivalent ICS monotherapy.
Endpoints and assessments
The primary endpoint was safety and tolerability of 52-
week treatment with once-daily QVA149 compared with
placebo, in terms of frequency of treatment-emergent AEs.
Secondary endpoints were vital signs, electrocardiograms
(ECGs), laboratory evaluations, and the bronchodilator ef-
fect of QVA149 versus placebo based on the pre-dose FEV1
(mean of the values at 15 and 45 min pre-dose). FVC and
FEV1 measurements at all post-baseline time points were
assessed.
Safety and spirometry assessments (pre-dose and for up
to 1 h post-dose) were recorded when patients returned to
the clinic on Weeks 3, 6, 12, 26, 39, and 52 (Visits 4e9).
Safety assessments included recording all AEs, serious AEs
(SAEs), with their severity and relationship to study drug.
All treatment-emergent AEs were recorded and classified
R. Dahl et al.
Study design.
as AEs starting on or after the first administration of study
drug but not later than 7 days (30 days in the case of an
SAE) after the end of treatment period. These were coded
using MedDRA (Version 14 or higher). Deaths occurring
during the study in either group were adjudicated by an
external committee. Spirometry measurements were
taken at 45 and 15 min pre-dose and then at 30 and 60 min
post-dose. One spirometry measurement was taken in the
event of discontinuation. Patients were followed up for
safety an additional 30 days after the end of the treatment
period.
Statistical methods and populations for analysis
The sample size calculation was based on pre-trial esti-
mates that 226 patients would be required in the QVA149
group and 113 patients in the placebo group, assuming a
30% discontinuation rate over 12 months, in order to detect
a 1% or 2% AE incidence rate in the QVA149 treatment group
with 80% and 96% probability, respectively. This number
was also adequate to detect a 120-mL difference in pre-
dose mean FEV1 at Week 52 between QVA149 and placebo
(secondary objective), at 5% significance level with an
estimated 94% power. The safety population, comprising all
patients who received at least one dose of study drug and
analyzed according to treatment received, was used for
analysis of all safety endpoints. The primary endpoint of
AEs is presented as the number and percentage of patients
within each treatment group. To control for possible dif-
ferences in exposure between the treatment groups, AEs
were also presented with the total number of events per
patient-year for all AEs together. For QVA149-placebo
comparisons, 95% confidence intervals (CIs) were provided
together with the associated p-values. There were no ad-
justments made for multiplicity and no imputation was
done for the missing safety data. Efficacy endpoints
(spirometry) were analyzed using full analysis set (FAS),
which comprised all randomized patients who received at
least one dose of study drug, analyzed according to
the allocated treatment group. Additional details of the
statistical analysis are provided in the Supplementary
Appendix.
Safety and efficacy of QVA149 in COPD patients
Results
Patients
Of the 498 patients screened, 339 were randomized to
receive QVA149 (n Z 226) or placebo (n Z 113). Overall,
83.5% of patients completed 52 weeks of study treatment
(Fig. 2). A total of 338 patients were included in the safety
population and the FAS as one patient randomized to the
QVA149 group withdrew consent prior to receiving study
drug due to inability to perform spirometry maneuvers.
Baseline patient demographics and other clinical charac-
teristics were comparable across the two treatment groups,
with the notable exceptions that more patients in the
QVA149 group versus the placebo group had severe COPD
(31.1% vs 18.6%), used ICS at baseline (45.8% vs 38.9%),
respectively, and had a history of myocardial infarction,
stroke, and diabetes mellitus (Table 1). A higher percent-
age of patients discontinued in the placebo group (21.2%)
compared with the QVA149 group (14.2%); the primary
reasons for discontinuation were patients withdrawing
consent and AEs (Fig. 2).
COPD-related concomitant medications were continued
(as background allowable COPD medication) or initiated
after the start of study drug by 60.4% of patients in the
QVA149 group and 51.3% of patients in the placebo group.
The most common medications taken were ICS, which were
used by 44.4% of patients in the QVA149 group and 38.1% of
patients in the placebo group.
Long-term safety of QVA149 versus placebo
Treatment-emergent AEs
The overall incidence of AEs was similar for the QVA149
(57.8%) and placebo (56.6%) groups (Table 2), with an AE
rate per 100 patient-years of 232.0 and 222.4, respectively.
The most frequently reported AE was COPD worsening
(QVA149 28.0% vs placebo 25.7%, with an AE rate per 100
patient-years of 50.2 and 50.7, respectively). Cough and
lower respiratory tract infections were slightly more com-
mon for QVA149 compared with placebo, as were pneu-
monia, headache, and pyrexia AEs. Viral upper respiratory
Figure 2
1561
tract infection, upper respiratory tract infection, and hy-
pertension AEs were more common in the placebo group
than in the QVA149 group. There were no meaningful dif-
ferences between treatment groups for other AEs as they
occurred in few patients.
The majority of AEs reported in the QVA149 and placebo
groups were moderate (32.9% and 30.1%, respectively) or
mild (12.4% and 17.7%, respectively) in severity. Severe AEs
were reported in 12.4% and 8.8% of patients in the QVA149
and placebo groups, respectively (severe AEs for respira-
tory, thoracic, and mediastinal disorders: 5.3% and 3.5%,
respectively; infections and infestations: 4.0% and 1.8%,
respectively). AEs suspected to be related to study drug
based on investigator assessment were recorded in 5.3% of
patients in the QVA149 group and 7.1% of patients in the
placebo group. Cough was the most commonly reported AE
in the QVA149 group (n Z 7, 3.1%), but was not reported in
the placebo group. Treatment-related AEs were not re-
ported by more than two patients in either group. The
event rate of respiratory-related AEs was not statistically
significantly different for QVA149 compared with placebo
(0.42 vs 0.47, p Z 0.651). Cardio-cerebrovascular (CCV) AEs
were reported in 5.3% of QVA149-treated patients and 2.7%
of placebo-treated patients, with a CCV AE rate per 100
patient-years of 7.7 and 3.1, respectively. The most com-
mon CCV AE was congestive cardiac failure (QVA149 [n Z 3,
1.3%] vs placebo [n Z 0]), followed by supraventricular
extrasystoles (QVA149 [n Z 2, 0.9%] vs placebo [n Z 0]).
SAEs and deaths
The most common SAEs in both treatment groups were COPD
worsening (event rate per 100 patient-years: 6.8 for QVA149
and 5.2 for placebo), followed by pneumonia, which was
only reported in the QVA149 group (n Z 8, event rate: 3.6%,
odds ratio 5.70, p Z 0.074). A post-hoc analysis of serious
pneumonia events, when stratified by COPD severity, did not
provide any conclusive evidence that QVA149 resulted in a
higher incidence of pneumonia SAEs than placebo (event
rate: 3.6%, odds ratio 5.11, p Z 0.101). The rate of
respiratory-related SAEs was not statistically significantly
different between the QVA149 and placebo groups (event
rate: 4.9 vs 1.8, respectively, odds ratio Z 2.85, p Z 0.264).
Patient disposition.
1562 R. Dahl et al.

Table 1 Baseline demographics and clinical characteristics (safety population).

QVA149 (n Z 225) Placebo (n Z 113)
Mean (SD) age, years 62.5 (8.81) 62.9 (8.14)
Gender, male, n (%) 174 (77.3) 86 (76.1)
Race, n (%)
Caucasian 178 (79.1) 94 (83.2)
Asian 47 (20.9) 19 (16.8)
Mean (SD) duration of COPD, years 5.82 (5.74) 5.46 (5.10)
COPD severity [17], n (%)
Moderate 154 (68.4) 91 (80.5)
Severe 70 (31.1) 21 (18.6)
Very severe 0 1 (0.9)
COPD exacerbation historya, n (%)
0 154 (68.4) 72 (63.7)
1 56 (24.9) 32 (28.3)
2 15 (6.7) 9 (8.0)
ICS use at baseline, n (%) 103 (45.8) 44 (38.9)
Smoking status, n (%)
Ex-smoker 123 (54.7) 62 (54.9)
Current smoker 102 (45.3) 51 (45.1)
Mean (SD) number of smoking pack-years 36.3 (16.01) 38.1 (15.93)
History of cardiovascular disease, n (%)
Myocardial infarction 9 (4.0) 3 (2.7)
Stroke 6 (2.7) 2 (1.8)
Peripheral arterial disease 13 (5.8) 6 (5.3)
Coronary artery bypass graft 4 (1.8) 0
Type 2 diabetes mellitus, n (%) 28 (12.4) 9 (8.0)
Mean (SD) pre-bronchodilator FEV1, L 1.43 (0.52) 1.49 (0.52)
Mean (SD) post-bronchodilator FEV1, L 1.62 (0.52) 1.69 (0.51)
Mean (SD) post-bronchodilator % predicted FEV1 56.39 (13.27) 59.43 (12.50)
Mean (SD) post-bronchodilator FEV1 reversibility, % 15.74 (14.84) 15.59 (14.53)
Mean (SD) post-bronchodilator FEV1/FVC, % 53.36 (9.43) 55.04 (8.45)
SD Z standard deviation.
a
Number of COPD exacerbations in the previous year.

In the post-hoc analysis, the rate of respiratory related SAEs
events, when stratified by COPD severity, showed no sta-
tistically significant treatment difference between the
QVA149 and placebo groups (event rate: 4.9 vs 1.8,
respectively, odds ratio 2.58, p Z 0.345). Besides these
events, no specific SAEs occurred in >1% of patients in
either group. SAEs suspected to be related to study medi-
cation were reported by two patients in the QVA149 group
(two cases of COPD worsening, one case of pneumonia [one
patient reported both pneumonia and COPD worsening]); no
patients in the placebo group had an SAE suspected to be
related to study medication. Adjudicated CCV SAEs were
reported in five patients on QVA149 (2.2%; n Z 4 cardiac
disorders; n Z 1 nervous system disorder) and no patients
on placebo; two of these patients on QVA149 had major
adverse cardiovascular events (MACEs; Table 3). MACEs were
considered to be due to progression of the concomitant
diseases as they were recorded in patients with pre-existing
comorbid conditions. The rate per 100 patient-years for
MACEs was 1.0 in the QVA149 group and 0 in the placebo
group. The incidence of CCV SAEs was not statistically
significantly different between QVA149 and placebo (odds
ratio 3.43, p Z 0.258). In a post-hoc analysis, the incidence
of CCV SAEs, when stratified by COPD severity, was not
significantly different between the QVA149 and placebo
groups (odds ratio 3.25, p Z 0.284).
Five patients (QVA149 [n Z 4, 1.8%]; placebo [n Z 1,
0.9%]; Table 3) died during the treatment period and
within 30 days of the last treatment; no death was
thought to be related to study medication as determined
by the investigator. The rate of deaths per 100 patient-
years was 1.9 in the QVA149 group and 1.0 in the pla-
cebo group. There was no statistically significant differ-
ence in the time to death between treatment group
(hazard ratio 1.7, 95% CI 0.19, 15.36, p Z 0.638). The
adjudicated causes of deaths in the QVA149 group were
sudden death (one patient), COPD exacerbation with
pneumonia (one patient), and COPD exacerbation without
pneumonia (two patients). The adjudicated cause of
death in the placebo group was a road traffic accident
(one patient).
Discontinuation or hospitalization
AEs leading to permanent discontinuation of study drug
were reported in a similar proportion of patients in the
QVA149 (5.8%) and placebo (6.2%) groups; these were most
Safety and efficacy of QVA149 in COPD patients 1563

Table 2 Most frequent AEs (1.0% in the QVA149 treat- Table 3 SAEs, deaths and discontinuation of study drug.
ment group) by preferred term. QVA149 Placebo
Preferred term, n (%) QVA149 Placebo n Z 225, n (%) n Z 113, n (%)
n Z 225 n Z 113 Patients with any AE(s) 130 (57.8) 64 (56.6)
Any AE 130 (57.8) 64 (56.6) SAE(s) 37 (16.4) 12 (10.6)
COPD worseninga 63 (28.0) 29 (25.7) MACE 2 (0.9) 0
Cough 18 (8.0) 7 (6.2) Non-fatal stroke 1 (0.4) 0
Viral upper respiratory 18 (8.0) 15 (13.3) Heart failure requiring 1 (0.4) 0
tract infection hospitalization
Lower respiratory 15 (6.7) 4 (3.5) Deatha 4 (1.8) 1 (0.9)
tract infection Discontinuations due 13 (5.8) 7 (6.2)
Upper respiratory 12 (5.3) 9 (8.0) to AE(s)
tract infection Discontinued due 12 (5.3) 3 (2.7)
Upper respiratory tract 11 (4.9) 5 (4.4) to SAE(s)
infection bacterial Discontinued due 1 (0.4) 4 (3.5)
Pyrexia 10 (4.4) 1 (0.9) to non-SAE(s)
Headache 8 (3.6) 3 (2.7)
MACE Z major adverse cardiovascular event.
Pneumonia 8 (3.6) 0 a
Death Z number of patients who died between the first
Dizziness 7 (3.1) 1 (0.9) treatment day and 30 days after the last treatment.
Sinusitis 7 (3.1) 1 (0.9)
Oropharyngeal pain 6 (2.7) 1 (0.9)
Back pain 5 (2.2) 0 Additional safety parameters
Anxiety 4 (1.8) 0
Hypertension 4 (1.8) 6 (5.3) There were no clinically meaningful differences between
Muscle spasms 4 (1.8) 0 treatment groups or trends for any of the routine hema-
Nasopharyngitis 4 (1.8) 0 tology, biochemistry, or urinalysis parameters; analysis of
Urinary tract infection 4 (1.8) 1 (0.9) vital signs (pulse rate, systolic and diastolic blood pres-
Abdominal pain 3 (1.3) 0 sure); or serum potassium and blood glucose parameters.
Cardiac failure congestive 3 (1.3) 0 There were no clinically relevant between-treatment dif-
Dyspnea 3 (1.3) 1 (0.9) ferences in QTc interval, ventricular rate, RR-interval, PR-
Gastroesophageal 3 (1.3) 0 interval, QT-interval, or QRS duration at any time point,
reflux disease and least square (LS) mean treatment differences were less
Hypercholesterolemia 3 (1.3) 0 than 3 ms. No trend toward prolongation of the QTc interval
Oral candidiasis 3 (1.3) 2 (1.8) was seen in any treatment group.
Osteoarthritis 3 (1.3) 2 (1.8)
Rash 3 (1.3) 1 (0.9) Efficacy
a
Data on incidence of COPD exacerbations were combined
with AE data and reported under the preferred term of “COPD Spirometry
worsening” together with all other events with the same Pre-dose FEV1 at Week 52 was significantly improved in the
preferred term.
QVA149 group compared with the placebo group, with a
treatment difference of 0.189 L (p < 0.001; Fig. 3). QVA149
provided a significantly greater and clinically meaningful
commonly COPD worsening (n Z 5; 2.2%) and pneumonia increase in pre-dose FEV1 from Week 3 to Week 52 (treat-
(n Z 4; 1.8%) in the QVA149 group versus 0.9% and 0% in the ment differences in the range of 0.152e0.189 L; p < 0.001
placebo group, respectively. A lower proportion of patients at all time points vs placebo; Fig. 3).
on QVA149 discontinued due to non-serious AEs compared Bronchodilation with QVA149 at 60 min post-dose was
with placebo (0.4% vs 3.5%, respectively). Discontinuation significantly greater than placebo throughout the 52-week
due to a SAE was reported by 12 patients in the QVA149 treatment period, with a treatment difference ranging
group (5.3%) and three in the placebo group (2.7%). SAEs from 0.200 to 0.286 L (p < 0.001 at all time points; Fig. 4).
that led to permanent discontinuation of study drug were QVA149 also improved FVC versus placebo over the 52-
COPD worsening (n Z 4), pneumonia (n Z 4), cancer week treatment period, with statistical significance at all
(n Z 2), upper respiratory tract infection (n Z 1), cardio- time points (p < 0.001; Fig. 5).
respiratory arrest (n Z 1), pulmonary tuberculosis (n Z 1),
vertigo (n Z 1), and worsening of ischemic heart disorder Patient diary data
(n Z 1).
AEs that led to hospitalization or prolonged hospitali- Daily, daytime, and nighttime symptom scores
zation were reported in 15.1% patients in the QVA149 group Symptom scores improved from baseline significantly more
and 8.8% patients in the placebo group, with the most with QVA149 than placebo; for total daily symptom score
common cause being COPD worsening (5.3% of patients on (LS mean: 0.573, p Z 0.011), daytime symptom score (LS
QVA149 and 3.5% of patients on placebo). mean: 0.499, p Z 0.030), and nighttime symptom score
1564
Figure 3 Pre-dose FEV1 over 52 weeks.
(LS mean: 0.495, p Z 0.027). Over the 52 weeks of
treatment, QVA149 was also significantly better than pla-
cebo for percentage of days with “no daytime symptoms”
(QVA149-placebo LS mean: 5.294, p Z 0.012) and per-
centage of “days able to perform usual daily activities”
(QVA149-placebo LS mean: 8.134, p Z 0.028). The per-
centage of nights with “no nighttime awakenings” over 52
weeks was numerically better, although not significantly so
(QVA149-placebo LS mean: 6.319, p Z 0.081).
Rescue medication use
Patients on QVA149 used significantly less rescue medica-
tion compared with placebo (LS mean: 0.726 puffs/day,
p Z 0.002).
Discussion
The ENLIGHTEN study has provided the first detailed anal-
ysis of long-term safety with QVA149 versus placebo, as
Figure 4 FEV1 at 60 min post-dose over 52 weeks.
R. Dahl et al.
well as additional data on the long-term bronchodilatory
effects of QVA149 in patients with moderate-to-severe
COPD. QVA149 was well tolerated over the 52 weeks of
treatment, with the overall incidence of AEs being similar
between the QVA149 and placebo groups. Most of the AEs
reported were mild to moderate in severity and occurred in
only a small percentage of patients in both groups. These
data provide further support for the good safety profile for
QVA149, similar to data from previous studies where
QVA149 doses were well tolerated and had an AE rate
similar to placebo or active comparators [15,16]. Moreover,
QVA149 was not associated with any clinically relevant
changes in QTc interval, changes in pulse rate, urinalysis,
routine hematology, biochemistry, or blood pressure. This
supports previous findings where QVA149, even at supra-
therapeutic doses, had demonstrated no clinically relevant
effect on these parameters [19].
The incidences of SAEs seen in this study are not unex-
pected in patients with COPD. Similar frequencies of SAEs
have been observed in other studies with an established
standard of therapy for COPD [20e22]. The numerical
imbalance in the rates of SAEs and deaths between the
QVA149 and placebo groups are likely to be a consequence
of demographic imbalance between the groups. At base-
line, more patients in the QVA149 group had severe COPD;
used ICS; and had a history of myocardial infarction, stroke,
and diabetes mellitus. The higher percentage of patients
using ICS in the QVA149 group may be seen as a marker of
greater disease severity and/or tendency to suffer exac-
erbations. The use of ICS is also a risk factor for the
increased incidence of pneumonia seen in patients in the
QVA149 group [23]. Further, no imbalance in the rates of
SAEs and deaths was observed in either indacaterol or gly-
copyrronium monotherapy programs. The imbalances that
occurred in the current study are inconsistent with other
QVA149 studies and likely a result of the demographic
disparity between the two treatment groups [15,16].
The GOLD 2013 report indicates that as severity of COPD
increases from moderate to severe, hospitalization and
mortality rates can increase [1]. This may explain the
higher frequency of AEs leading to hospitalization in the
Safety and efficacy of QVA149 in COPD patients
Figure 5 FVC at 60 min post-dose over 52 weeks.
QVA149 group than in the placebo group. This is further
supported by the background (placebo) rates of SAEs
(deaths, pneumonia, cardiovascular events) seen in this
study, which are lower than that expected in a population
with COPD and in comparison to the SAE rates reported in
long-term COPD studies such as UPLIFT [24] and TORCH
[25,26]. The data may also be confounded by a higher
percentage of patients in the placebo arm discontinuing
treatment, reflecting their deteriorating condition. As a
result, patients continuing in the placebo arm in the pre-
sent study may represent a relatively healthy cohort of
patients with COPD.
The incidence of exacerbations of COPD over 12 months
of treatment was similar in the two treatment groups (6.8%
in the QVA149 group and 5.2% in the placebo group).
However, this study was not powered to detect a difference
in the event rate between groups as the patients with a
history of exacerbations in the past 6 weeks were specif-
ically excluded. As a result, 66.7% of the patients had no
history of exacerbations and were relatively stable at
baseline. This approach was adopted to minimize the effect
of exacerbations on the primary endpoint (treatment-
emergent adverse events) of the study. In a further study,
the SPARK study, where patients with a history of exacer-
bations were included, QVA149 reduced significantly all
exacerbations of COPD compared with glycopyrronium and
tiotropium, along with concomitant significant improve-
ments in lung function and health status [27]. The cardio-
and cerebrovascular profile of QVA149 was similar to pla-
cebo. While there was a numerical difference between the
treatment groups for the adjudicated causes of death, the
actual numbers of fatal AEs were too low to allow for any
meaningful interpretation.
The magnitude of the effect of QVA149 on pre-dose FEV1
relative to placebo is comparable to that seen in other
studies with this combination [15,16], and greater than that
observed with clinically comparable doses of indacaterol or
glycopyrronium monotherapy [8e10,15,16,28,29], suggest-
ing an additive effect when this LABA and LAMA are com-
bined as a fixed dose. Improvements in lung function were
1565
also paralleled by significant improvements in the per-
centage of days with “no daytime symptoms”, the per-
centage of “days able to perform usual daily activities”,
symptoms scores, and reduced use of routine rescue
medication for breakthrough symptoms. In previously re-
ported studies, the potent bronchodilator effect of QVA149
treatment was also paralleled by a greater improvement in
dyspnea [16,30] and health status [27] than other
treatments.
Conclusions
QVA149 demonstrated an overall good safety and tolera-
bility profile over 52 weeks of treatment in patients with
moderate-to-severe COPD. The observed numerical differ-
ences in some AEs and SAEs could be at least in part
explained by differences in baseline characteristics,
although this cannot be firmly established from this study.
QVA149 also demonstrated rapid and sustained bronchodi-
lation with concomitant improvements in patient symptoms
and reduced rescue medication use. These findings
demonstrate the potential of dual bronchodilation with
once-daily QVA149 as a safe and effective maintenance
treatment for patients with moderate-to-severe COPD.
Clinical trial
This study is registered at ClinicalTrials.gov with clinical
trial identifier number NCT01120717.
Conflict of interest statements
In the past 3 years, Professor Dahl has received compen-
sation for consulting with Boehringer-Ingelheim, Novartis,
Vectura, Roche, Elevation Pharma, and Norpharma; has
undertaken research funded by AstraZeneca, Boehringer-
Ingelheim, Chiesi, GlaxoSmithKline, Novartis, ALK-Abello,
and Stallergenes; has participated in educational activities
1566
sponsored by AstraZeneca, Boehringer-Ingelheim, Glax-
oSmithKline, ALK-Abello, Novartis, and Almirall.
In the past 3 years, Professor Chapman has received
compensation for consulting with Boehringer-Ingelheim,
CSL Behring, GlaxoSmithKline, Merck Frosst, Novartis,
Takeda, Pfizer, Roche, Schering Plough, and Grifols; has
undertaken research funded by AstraZeneca, Boehringer-
Ingelheim, CSL Behring, Forest Labs, GlaxoSmithKline,
Novartis, Parangenix, Roche, Takeda, and Grifols; and has
participated in continuing medical education activities
sponsored in whole or in part by AstraZeneca, Boehringer-
Ingelheim, GlaxoSmithKline, Grifols, Merck Frosst, Novartis,
Takeda, and Pfizer. He is participating in research funded
by the Canadian Institutes of Health Research operating
grant entitled Canadian Cohort Obstructive Lung Disease
(CanCOLD). Professor Chapman holds the GSK-CIHR
Research Chair in Respiratory Health Care Delivery at the
University Health Network, Toronto, Canada.
In the past 3 years, Dr Michael Rudolf has received
fees for consultancy work and speaking at meetings
from Almirall, AstraZeneca, Boehringer-Ingelheim, Glax-
oSmithKline, MSD, Napp, Novartis, and Pfizer and has
received travel grants for attending international meetings
from Almirall, Boehringer-Ingelheim, and Chiesi.
In the past 3 years, Dr Rajendra Mehta has received
compensation for doing clinical trials as Principal Investi-
gator from Novartis, AstraZeneca, Glenmark Pharma, Ran-
baxy, and Cipla and has participated in investigator
meetings sponsored by AstraZeneca, Novartis, and Glen-
mark Pharma.
Pearl Kho, Vijay KT Alagappan, Hungta Chen, and Donald
Banerji are employees of Novartis.
Acknowledgments
The authors thank the patients who participated and the
staff at the participating clinical centers. The study was
funded by Novartis Pharma AG, Basel, Switzerland. The
authors were assisted in the preparation of manuscript by
Saurabh Aggarwal and Mark J. Fedele (Novartis) and Shelley
Davies from CircleScience (Macclesfield, UK).
Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.rmed.2013.05.016.
References
[1] Global Initiative for Chronic Obstructive Lung Disease (GOLD).
Global strategy for the diagnosis, management, and preven-
tion of chronic obstructive pulmonary disease. At: http://
www.goldcopd.org; 2013 [accessed 08.02.13].
[2] van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J,
Disse B, et al. Comparison of tiotropium once daily, formoterol
twice daily and both combined once daily in patients with
COPD. Eur Respir J 2005;26(2):214e22.
[3] Rabe KF, Timmer W, Sagkriotis A, Viel K. Comparison of a
combination of tiotropium plus formoterol to salmeterol plus
fluticasone in moderate COPD. Chest 2008;134(2):255e62.
R. Dahl et al.
[4] Tashkin DP, Littner M, Andrews CP, Tomlinson L, Rinehart M,
Denis-Mize K. Concomitant treatment with nebulized for-
moterol and tiotropium in subjects with COPD: a placebo-
controlled trial. Respir Med 2008;102(4):479e87.
[5] Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein S,
Thirlwell J. Formoterol mono- and combination therapy with
tiotropium in patients with COPD: a 6-month study. Respir Med
2008;102(11):1511e20.
[6] van Noord JA, Aumann JL, Janssens E, Smeets JJ, Zaagsma J,
Mueller A, et al. Combining tiotropium and salmeterol in
COPD: effects on airflow obstruction and symptoms. Respir
Med 2010;104(7):995e1004.
[7] Mahler DA, D’Urzo A, Bateman ED, Ozkan SA, White T,
Peckitt C, et al., on behalf of the INTRUST-1 and INTRUST-2
Study Investigators. Concurrent use of indacaterol plus tio-
tropium in patients with COPD provides superior bronchodi-
lation compared with tiotropium alone: a randomised, double-
blind comparison. Thorax 2012;67(9):781e8.
[8] D’Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C,
Horton R, et al. Efficacy and safety of once-daily NVA237 in
patients with moderate-to-severe COPD: the GLOW1 trial.
Respir Res 2011;12:156.
[9] Beeh KM, Singh D, Di SL, Drollmann A. Once-daily NVA237
improves exercise tolerance from the first dose in patients
with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis
2012;7:503e13.
[10] Kerwin E, Hebert J, Gallagher N, Martin C, Overend T,
Alagappan VKT, et al. Efficacy and safety of NVA237 versus
placebo and tiotropium in patients with COPD: the GLOW2
study. Eur Respir J 2012;40(5):1106e14.
[11] Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D,
et al., INVOLVE (INdacaterol: Value in COPD: Longer Term
Validation of Efficacy and Safety) Study Investigators. Efficacy
of a new once-daily long-acting inhaled beta2-agonist inda-
caterol versus twice-daily formoterol in COPD. Thorax 2010;
65(6):473e9.
[12] Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H,
Yorgancioglu A, et al., INHANCE Study Investigators., et al.
Once-daily bronchodilators for chronic obstructive pulmonary
disease: indacaterol versus tiotropium. Am J Respir Crit Care
Med 2010;182(2):155e62.
[13] Buhl R, Dunn LJ, Disdier C, Lassen C, Amos C, Henley M, et al.
Blinded 12-week comparison of once-daily indacaterol and
tiotropium in COPD. Eur Respir J 2011;38(4):797e803.
[14] Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C,
Kramer B. Long-term safety and efficacy of indacaterol, a
long-acting beta(2)-agonist, in subjects with COPD: a ran-
domized, placebo-controlled study. Chest 2011;140(1):68e75.
[15] Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y,
Henley M, et al. Dual bronchodilation with QVA149 versus
single bronchodilator therapy: the SHINE study. Eur Respir J
2013. http://dx.doi.org/10.1183/09031936.00200212.
[16] Vogelmeier CF, Bateman ED, Pallante J, Alagappan VKT,
D’Andrea P, Chen H, et al. Efficacy and safety of once-daily
QVA149 compared with twice-daily salmeterol-fluticasone in
patients with chronic obstructive pulmonary disease (ILLUMI-
NATE): a randomised, double-blind, parallel group study.
Lancet Resp Med 2013;1(1):51e60.
[17] Global Initiative for Chronic Obstructive Lung Disease (GOLD).
Global strategy for the diagnosis, management, and preven-
tion of chronic obstructive pulmonary disease. At: http://
www.goldcopd.org; 2010 [accessed 24.08.12].
[18] Chapman KR, Fogarty CM, Peckitt C, Lassen C, Jadayel D,
Dederichs J, et al. Delivery characteristics and patients’
handling of two single-dose dry-powder inhalers used in COPD.
Int J Chron Obstruct Pulmon Dis 2011;6:353e63.
[19] van de Maele B, Fabbri LM, Martin C, Horton R, Dolker M,
Overend T. Cardiovascular safety of QVA149, a combination of
Safety and efficacy of QVA149 in COPD patients
indacaterol and NVA237, in COPD patients. COPD 2010;7(6):
418e27.
[20] Casaburi R, Mahler DA, Jones PW, Wanner A, San PG,
ZuWallack RL, et al. A long-term evaluation of once-daily
inhaled tiotropium in chronic obstructive pulmonary disease.
Eur Respir J 2002;19(2):217e24.
[21] Casaburi R, Kukafka D, Cooper CB, Witek Jr TJ, Kesten S.
Improvement in exercise tolerance with the combination of
tiotropium and pulmonary rehabilitation in patients with
COPD. Chest 2005;127(3):809e17.
[22] Yohannes AM, Willgoss TG, Vestbo J. Tiotropium for treatment
of stable COPD: a meta-analysis of clinically relevant out-
comes. Respir Care 2011;56(4):477e87.
[23] Singh S, Amin AV, Loke YK. Long-term use of inhaled cortico-
steroids and the risk of pneumonia in chronic obstructive
pulmonary disease: a meta-analysis. Arch Intern Med 2009;
169(3):219e29.
[24] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S,
et al. A 4-year trial of tiotropium in chronic obstructive pul-
monary disease. N Engl J Med 2008;359(15):1543e54.
[25] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,
Jones PW, et al. Salmeterol and fluticasone propionate and
survival in chronic obstructive pulmonary disease. N Engl J
Med 2007;356(8):775e89.
1567
[26] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,
Jones PW, et al. Cardiovascular events in patients with COPD:
TORCH study results. Thorax 2010;65(8):719e25.
[27] Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE,
Sandström T, Taylor AF, et al. Analysis of chronic obstructive
pulmonary disease exacerbations with the dual bronchodilator
QVA149 compared with glycopyrronium and tiotropium
(SPARK): a randomised, double-blind, parallel-group study.
Lancet Resp Med 2013;1(3):199e209.
[28] Feldman G, Siler T, Prasad N, Jack D, Piggott S, Owen R, et al.,
The INLIGHT 1 Study Group. Efficacy and safety of indacaterol
150 microg once-daily in COPD: a double-blind, randomised,
12-week study. BMC Pulm Med 2010;10:11.
[29] Renard D, Looby M, Kramer B, Lawrence D, Morris D,
Stanski DR. Characterization of the bronchodilatory dose
response to indacaterol in patients with chronic obstructive
pulmonary disease using model-based approaches. Respir Res
2011;12:54.
[30] Mahler D, Decramer M, D’Urzo AD, Worth H, White T,
Alagappan VKT, et al. Superior lung function with once-
daily QVA149 translates into improvements in patient-
reported breathlessness compared with placebo and tio-
tropium in COPD patients: the BLAZE Study. ATS 2013:
A6070.