Adherence to Fixed-Combination Versus
Unfixed Travoprost 0.004%/Timolol 0.5% for
Glaucoma or Ocular Hypertension:
A Randomized Trial
HOWARD S. BARNEBEY AND ALAN L. ROBIN

PURPOSE: To assess adherence to treatment with fixed-
combination travoprost 0.004%/timolol 0.5% (TTFC)
compared with separate containers of travoprost
0.004% and timolol 0.5% (TRAVDTIM; unfixed) using
electronic dosing aids.

DESIGN: Randomized, controlled, observer-masked
clinical trial.

METHODS: SETTING: Two US clinical sites. PATIENT
POPULATION: Eligible patients were adults diagnosed
with open-angle glaucoma or ocular hypertension.
Patients (n [ 81) were sequentially randomized 1:1 to
receive TTFC or TRAVDTIM for 12 months. INTERVEN-
TION: TTFC was administered once daily in the morning
or evening with a single dosing aid. Patients randomized
to TRAVDTIM administered TRAV once daily in the
evening and TIM once daily in the morning using separate
dosing aids. MAIN OUTCOME MEASURE: Adherence with
administered medication, as recorded by the dosing aids.

RESULTS: Mean ± SD patient age was 60 ± 10 years;
most patients were male and white. Compared with
TRAVDTIM (n [ 40), patients receiving TTFC
(n [ 41) were consistently adherent on a greater percent-
age of days through month 12 (60% vs 43%). At months
1, 3, 6, and 12, 80% adherence was achieved by 71% vs
38%, 53% vs 30%, 45% vs 16%, and 32% vs 11% of
patients receiving TTFC vs TRAVDTIM, respectively.
Significantly more patients were adherent on ‡80% of
days with TTFC compared with TRAVDTIM
(P < .001 to P [ .041). Both treatments reduced
IOP from baseline, and no safety issues were identified
in either group. Ocular hyperemia was the most common
treatment-related adverse event (n [ 3/group).

CONCLUSIONS: Patients receiving TTFC maintained
better treatment adherence compared with patients
Supplemental Material available at AJO.com.
Accepted for publication Dec 7, 2016.
From the Specialty Eyecare Centre, Bellevue, Washington (H.S.B.);
Department of Ophthalmology (A.L.R.) and Bloomberg School of
Public Health (A.L.R.), Johns Hopkins University, Baltimore,
Maryland; University of Maryland, Baltimore, Maryland (A.L.R.); and
University of Michigan, Ann Arbor, Michigan (A.L.R.).
Inquiries to Howard S. Barnebey, Specialty Eyecare Centre, 1920 116th
Ave NE, Bellevue, WA 98004; e-mail: hbarnebey@
specialtyeyecarecentre.com
0002-9394 © 2016 THE AUTHOR(S). PUBLISHED
http://dx.doi.org/10.1016/j.ajo.2016.12.002
receiving TRAVDTIM through 12 months of
on-therapy evaluation. This suggests that, for patients
requiring multiple IOP-lowering medications, a fixed
combination may provide improved long-term adherence
compared with unfixed therapy. (Am J Ophthalmol
2017;176:61–69. Ó 2016 The Author(s). Published by
Elsevier Inc. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).)
P
HARMACOLOGIC CONTROL OF INTRAOCULAR PRES-
sure (IOP) with topical ocular hypotensive medica-
tions is the standard of care for the initial treatment
of open-angle glaucoma and ocular hypertension.1
Elevated IOP can lead to optic nerve head damage, visual
field loss, or disability and blindness. Higher IOP levels
are associated with increased risk for disease progression
and glaucoma-related visual disability and blindness.2,3
Ocular hypotensive therapy is effective in slowing or
preventing progression of glaucoma and ocular
hypertension,4–7 and maintaining long-term IOP reduction
reduces the risk of vision loss. For some patients, a single
medication produces sufficient IOP reduction, although
many patients require treatment with more than 1 medica-
tion to achieve and maintain sufficiently low IOP.5,6
Patient adherence with IOP-lowering treatment is crucial
for the successful medical management of glaucoma; howev-
er, adherence with glaucoma medications is typically low and
decreases with time.8–10 Adherence is influenced by many
patient- and treatment-related variables, and treatment
complexity (ie, number of individual medications and daily
doses) is one of the only modifiable factors associated with
suboptimal treatment adherence. For example, compared
with combination medications, treatment regimens using
multiple individual medications are associated with lower
treatment adherence.11–16 Most fixed-combination therapies
provide 2 ocular hypotensive agents in a single formulation,
thereby simplifying treatment regimens and reducing the
number of daily instillations. An inherent disadvantage of
fixed combinations is that missed doses result in omission
of both medications rather than of a single agent.
Because better adherence with glaucoma therapy is asso-
ciated with reduced progression of visual field defects,17,18
BY ELSEVIER INC. 61
understanding and improving adherence among patients
with glaucoma or ocular hypertension is an important
aspect of treatment. Approaches to assess adherence
include patient surveys and self-reports, pharmacy refill
records, and electronic dosing aids, all of which have
advantages and disadvantages. For example, patients
frequently overestimate their treatment adherence,19 phar-
macy records cannot determine whether medications are
used, and dosing aids record accidental dispensing and
incorrectly instilled doses in addition to intentional,
correctly administered doses. A benefit of dosing aids is
that they provide a relatively objective record of the num-
ber and timing of drops dispensed using the device,
although they do not record whether or not the drop actu-
ally reached the eye.20
Our objective was to assess adherence through 12 months
of treatment with a fixed combination of the prostaglandin
analogue travoprost 0.004% and the b-blocker timolol
0.5% in a single bottle compared with 2 separate bottles
containing travoprost 0.004% and timolol 0.5% in eyes
with open-angle glaucoma or ocular hypertension using
electronic dosing aids.
METHODS

STUDY DESIGN: This was a randomized, controlled,
observer-masked clinical trial conducted at 2 sites in the
United States (Seattle, Washington, and Baltimore, Mary-
land) between March 2007 and January 2010 (www.
ClinicalTrials.gov identifier NCT00465803). The study
consisted of a screening visit followed by a washout period,
a postwashout eligibility visit, and on-therapy follow-up
visits conducted at days 30, 90, 180, and 365 (months 1,
3, 6, and 12, respectively).
The study was conducted in accordance with the Decla-
ration of Helsinki, Good Clinical Practice, and the Health
Insurance Portability and Accountability Act. Partici-
pating patients gave written informed consent for study
participation before enrollment. All study protocols and
consent forms were prospectively approved by Sterling
Institutional Review Board (Sterling Independent Ser-
vices, Inc, Atlanta, Georgia, USA), and the study and
data accumulation were carried out with approval from
the Institutional Review Board.

PATIENTS AND STUDY EYE SELECTION: Eligible patients
were at least 18 years old and diagnosed with open-angle
glaucoma (including open-angle glaucoma with pigment
dispersion and pseudoexfoliation) or ocular hypertension.
Additional inclusion criteria were discontinuation of all
IOP-lowering medications for the appropriate minimum
washout period, determined by ocular hypotensive class,
and mean postwashout IOP > _21 mm Hg in at least 1 eye
and mean IOP < _36 mm Hg in both eyes. The study eye
62 AMERICAN JOURNAL OF OPHTHALMOLOGY
was the qualifying eye (IOP > _21 mm Hg) at the eligibility
visit.
Key exclusion criteria were any form of glaucoma other
than open-angle glaucoma (with or without pigment
dispersion or pseudoexfoliation) or ocular hypertension;
any condition that precluded safe administration of a pros-
taglandin analogue or b-blocker; history of chronic or
recurrent severe inflammatory eye disease, clinically signif-
icant or progressive retinal disease, or severe ocular pathol-
ogy; history of ocular trauma or intraocular surgery
<
_6 months before screening; ocular laser surgery or ocular
infection/inflammation < _3 months before screening; best-
corrected visual acuity (BCVA) worse than 0.60 logMAR
in either eye; estimation of narrow angle (<10 degrees)
with the possibility of closure; cup-to-disc ratio >0.80 in
either eye; severe central visual field loss; and pregnancy,
potential of becoming pregnant during the study, or breast-
feeding. Patients using non–IOP-lowering medications
that may have affected IOP (eg, systemic b-blockers)
were required to have a stable dosing regimen for
>
_30 days before screening and throughout the study.

TREATMENTS: All eligible patients were sequentially
randomized to either the fixed combination of travoprost
0.004%/timolol 0.5% (TTFC; DuoTrav; Alcon Labora-
tories, Inc, Fort Worth, Texas, USA) or unfixed travoprost
0.004% (Alcon Laboratories, Inc) and timolol (as timolol
maleate 0.5%; Falcon Pharmaceuticals Ltd, Fort Worth,
Texas, USA) (TRAVþTIM) using a set of randomization
numbers developed to ensure a 1:1 assignment ratio. Study
medications were to be instilled in both eyes unless a
potential safety issue precluded administration in the
non–study eye. Patients receiving TTFC were instructed
to instill 1 drop of TTFC in each eye once daily at either
8 AM or 8 PM, in accordance with patient preference,
consistently for 12 months. Patients receiving
TRAVþTIM were instructed to instill 1 drop of TIM
once daily at 8 AM and 1 drop of TRAV once daily at 8 PM.
All study medications were supplied in identical opaque
bottles filled to 4.0 mL that were placed inside Travalert
Dosing Aids (Alcon Laboratories, Inc) with the reminder
functions turned off. Patients receiving TRAVþTIM
used a separate dosing aid for each medication. The dosing
aids recorded the time, date, and number of drops used in
each instillation; dosing aids were not capable of recording
misuse, such as removing medications from the aids or
dispensing but not instilling drops.

OUTCOMES AND ASSESSMENTS: The primary outcome
was adherence with medication administration over
12 months as recorded by the dosing aids. Patients were
defined as adherent with their assigned study treatment
on any given day if the associated dosing aid recorded at
least 1 drop dispensed at any time during the specified
24-hour period for that day; each of the 2 dosing aids
used in the TRAVþTIM group must have recorded at least
APRIL 2017
 Enrollment Enrolled (n=81)

Randomized (n=81)

Allocation
Allocated to fixed-combination Allocated to unfixed travoprost 0.004%
travoprost 0.004%/timolol 0.5% (n=41) + timolol 0.5% (n=40)

Follow-up
• Completed the study (n=36) • Completed the study (n=35)
• Discontinued the study (n=5) • Discontinued the study (n=5)
Inadequate intraocular pressure Inadequate intraocular pressure
control (n=2) control (n=1)
Sponsor request (n=2) Sponsor request (n=1)
Adverse event (n=1) Adverse event (n=1)
Noncompliance (n=1)
Patient decision to withdraw (n=1)

Analysis
• Intent-to-treat data set (n=41) • Intent-to-treat data set (n=40)
• Safety data set (n=41) • Safety data set (n=40)

FIGURE 1. Disposition of patients with open-angle glaucoma or ocular hypertension receiving fixed-combination travoprost
0.004%/timolol 0.5% or unfixed travoprost 0.004% D timolol 0.5%.

1 drop dispensed. The mean percentage of days on which
patients adhered to their dosing schedules was the primary
measure of adherence and was evaluated cumulatively over
fixed time intervals and for the overall duration of the
study. Cumulative adherence was calculated for intervals
of increasing duration (ie, through 1 month, 3 months,
6 months, and 12 months). Responder analyses were
performed to assess threshold levels of adherence. Patients
who discontinued the study early contributed data only to
the point of discontinuation.
Safety variables included IOP measurements, visual field
test results, gonioscopy evaluation findings, BCVA assess-
ments, ocular signs (cornea, iris/anterior chamber, lens,
eyelids, and conjunctiva), dilated fundus examinations
(vitreous, retina/macula/choroid, optic nerve, cup-to-disc
ratio), blood pressure, heart rate, and adverse events
(AEs). IOP was measured in both eyes at all study visits
by an independent operator and reader using a calibrated
Goldmann applanation tonometer, after completion of
BCVA and slit-lamp biomicroscopy assessments. Central
threshold visual fields were assessed at screening and month
12 with habitual correction by achromatic automated peri-
metry with a Humphrey Field Analyzer using a 24-2
threshold field test. Gonioscopy was performed at screening
and month 12 before instillation of dilating or miotic drops,
and gonioscopy was graded using the modified Shaffer
grading scale. BCVA was assessed at every study visit,
before IOP measurement, using an Early Treatment
Diabetic Retinopathy Study (ETDRS) chart at a viewing
distance of 10 feet. Ocular signs were assessed for both
eyes at every visit using slit-lamp biomicroscopy. Dilated
fundus examinations were conducted for both eyes at
screening and month 12 visits after completion of IOP
measurements. Systolic and diastolic blood pressures were
recorded at every visit after 5 minutes of resting; heart
rate measurements were based on a 60-second count. AE
information was collected during all on-therapy visits;
AEs were coded using the Medical Dictionary for Regulatory
Activities, version 13.0.

STATISTICAL ANALYSIS: Adherence was analyzed in the
intent-to-treat (ITT) population, defined as all patients
who instilled >_1 dose of study medication using the dosing
aid and who provided > _1 day of adherence information
from the dosing aid. Safety variables were assessed in the
safety population, which was defined as all patients who
instilled >
_1 dose of study medication using the dosing aid.
Patient demographics and baseline characteristics,
adherence outcomes, and safety variables were summarized
descriptively. Cumulative adherence was calculated for
various thresholds (50%, 60%, 70%, 80%, 90%, and
95%). All threshold levels were included in adherence cal-
culations for each cumulative time interval. Post hoc statis-
tical analyses of potential between-group differences in the
percentage of patients achieving various adherence thresh-
olds were performed using Fisher exact tests and x2 tests.

VOL. 176 ADHERENCE WITH TRAVOPROST/TIMOLOL 63

 Assuming a standard deviation (SD) of approximately
50% of the mean percent adherence rate and mean percent TABLE 1. Demographics of Patients With Open-Angle
adherence rates of 40%, 60%, and 80%, 80 patients (40 Glaucoma or Ocular Hypertension Randomized to
Fixed-Combination Travoprost 0.004%/Timolol 0.5% or
patients per treatment group) were determined to be suffi-
Unfixed Travoprost 0.004% þ Timolol 0.5%
cient to estimate treatment group differences within (Intent-to-Treat Population)
610%, 615%, and 620%, respectively, based on a
2-sided 95% confidence interval (CI). Fixed-Combination
Travoprost Unfixed Travoprost
Demographic 0.004%/Timolol 0.004% þ Timolol P
Characteristic 0.5% (N ¼ 41) 0.5% (N ¼ 40) Value

Age, years
RESULTS Mean 6 SD 58.7 6 10.2 61.5 6 9.3 .213a
Range 29–76 44–80

PATIENTS: Eighty-one patients were enrolled, random-
Distribution .439b
ized to treatment, and included in the ITT data set <65 27 (65.9) 23 (57.5)
(TTFC, n ¼ 41; TRAVþTIM, n ¼ 40; Figure 1). Mean >
_65 14 (34.1) 17 (42.5)
6 SD patient age was 60 6 10 years; 38% of patients Sex, n (%) .753b
(31/81) were > _65 years old. Most patients were male Male 28 (68.3) 26 (65.0)
(67%; 54/81) and white (89%; 72/81; Table 1). Patient Female 13 (31.7) 14 (35.0)
demographic and baseline characteristics were similar Race, n (%) .781c
between treatment groups. White 35 (85.4) 37 (92.5)
Ten patients discontinued the study (n ¼ 5 per treat- Black or African 4 (9.8) 3 (7.5)
American
ment group). Reasons for discontinuation in the TTFC
Native Hawaiian 1 (2.4) 0
group were inadequate IOP control (n ¼ 2), sponsor
or Pacific Islander
request (n ¼ 2), and AE (n ¼ 1). Reasons for discontinua- Other 1 (2.4) 0
tion in the TRAVþTIM group were inadequate IOP con-
trol, AE, nonadherence, sponsor request, and patient a
2-sided t test.
decision (n ¼ 1 each). x test.
b 2

ADHERENCE: Throughout 12 months of on-therapy
evaluation, patients receiving TTFC were adherent with
their dosing schedule on a greater percentage of days
compared with patients receiving TRAVþTIM
(Figure 2). In the first month of dosing, the cumulative
mean 6 SD percentage of days patients were adherent
with dosing was 79% 6 26% in the TTFC group and
67% 6 28% in the TRAVþTIM group. The cumulative
percentage of days through month 12 that patients were
adherent with dosing was 60% 6 28% and 43% 6 27%
with TTFC and TRAVþTIM, respectively.
Cumulative treatment adherence at thresholds of
50%–95% was consistently higher with TTFC compared
with TRAVþTIM (Figure 3). Significantly greater per-
centages of patients receiving TTFC demonstrated cumu-
lative adherence with dosing schedules on > _80% of days
through treatment months 1, 3, 6, and 12 compared with
patients receiving TRAVþTIM (P < .001 to P ¼ .041).
However, in both treatment groups, cumulative adherence
declined throughout the duration of the study. At 1 month
of treatment, 37% of patients in the TTFC group (15/41)
and 10% of patients in the TRAVþTIM group (4/40)
achieved adherence at a threshold level of 95% of days
(P ¼ .005). Patients receiving TTFC maintained adher-
ence on > _95% of days through month 3 (25%; 10/40),
month 6 (21%; 8/38), and month 12 (16%; 6/37), whereas
no patients receiving TRAVþTIM maintained cumulative
daily adherence above the 95% threshold at these time
c
Fisher exact test.
points. The threshold of adherence with dosing on >
_80%
of days was maintained through 12 months by 32% of
patients receiving TTFC (12/37) compared with 11% of
patients receiving TRAVþTIM (4/36; P ¼ .028).

SAFETY: The mean 6 SD duration of exposure to study
medications was 341 6 84 days in the TTFC group and
345 6 66 days in the TRAVþTIM group. Mean 6 SD
baseline IOP at the postwashout eligibility visit was similar
between treatment groups (TTFC, 26.8 6 4.4 mm Hg;
TRAVþTIM, 25.5 6 4.1 mm Hg). IOP change from base-
line was also similar between groups, ranging
from 7.7 mm Hg and 8.7 mm Hg at month 1
to 7.4 mm Hg and 7.3 mm Hg at month 12 with
TTFC and TRAVþTIM, respectively (Figure 4). There
were no trends or significant differences between treatment
groups with regard to changes from baseline in systolic or
diastolic blood pressure or heart rate at any visit.
A similar number of patients in each treatment group
experienced AEs, most of which were ocular in nature
and mild or moderate in intensity (Table 2). The most
common treatment-related AE in both groups was ocular
hyperemia (n ¼ 3 per group). Eye pain and eye irritation
were each reported for 2 patients receiving TTFC. Serious
AEs unrelated to treatment were reported for 3 patients:

64 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2017

 120 Fixed-combination travoprost 0.004%/timolol 0.5%
Unfixed travoprost 0.004% + timolol 0.5%

100
Cumulative Adherence,
Percentage of Patients 80
79
73
60 67 65
60
56
40 47 43

20
(41) (40) (40) (40) (38) (38) (37) (36)
0
1 Month 3 Months 6 Months 12 Months

FIGURE 2. Cumulative treatment adherence to fixed-combination travoprost 0.004%/timolol 0.5% vs unfixed travoprost
0.004% D timolol 0.5% by patients with open-angle glaucoma or ocular hypertension. Data reflect the percentage of patients consid-
ered adherent through each time point; results are presented as mean and standard deviation. Patient percentages are indicated within
top of bars; group sizes are indicated within bottom of bars.

Fixed-combination travoprost 0.004%/timolol 0.5%, n=41

Fixed-combination travoprost 0.004%/timolol 0.5%, n=40
Unfixed travoprost 0.004% + timolol 0.5%, n=40
Percentage of Patients, 1 Month

90
Percentage of Patients, 3 Months

90 Unfixed travoprost 0.004% + timolol 0.5%, n=40

80 85 P=0.003 80
83 81
70 76 70 78
73 71 73
60 P=0.007 60
63 63 63 P=0.041
50 50 58
51 53 P=0.001
P=0.005
40 40 45 43
30 38 37 P<0.001
30
20 30
23 20 25
10 10
10 10
0 0
0
0.5 0.6 0.7 0.8 0.9 0.95 0.5 0.6 0.7 0.8 0.9 0.95
Threshold Level of Adherence Threshold Level of Adherence

Fixed-combination travoprost 0.004%/timolol 0.5%, n=38 Fixed-combination travoprost 0.004%/timolol 0.5%, n=37
Percentage of Patients, 6 Months

90 Unfixed travoprost 0.004% + timolol 0.5%, n=38 Unfixed travoprost 0.004% + timolol 0.5%, n=36
Percentage of Patients, 12 Months

90
80 80
70 70
60 P=0.037 68
63 60
61
50 55 P=0.006 50
40 47 50 49
45 P=0.003 40 P=0.028
40
30 P=0.005* 30 38
32 32 32
20 28 P=0.025*
20
21
10 16 5 19 19
10 16
0 11 3
0
0 0
0.5 0.6 0.7 0.8 0.9 0.95 0.5 0.6 0.7 0.8 0.9 0.95
Threshold Level of Adherence Threshold Level of Adherence

FIGURE 3. Adherence to fixed-combination travoprost 0.004%/timolol 0.5% vs unfixed travoprost 0.004% D timolol 0.5% by
threshold level for patients with open-angle glaucoma or ocular hypertension at 1 month (Top left), 3 months (Top right), 6 months
(Bottom left), and 12 months (Bottom right). Patient percentages are indicated within bars. P values reflect the results of x2 tests
unless otherwise indicated. *P value from Fisher exact test.

VOL. 176 ADHERENCE WITH TRAVOPROST/TIMOLOL 65

 1 Month 6 Months
0
Intraocular Pressure Change
(40) (40) (38) (38)
From Baseline, mmHg
–2
–4
–6
–7.4
–7.7 –7.7
–8 –8.7
–10
–12
–14
Fixed-combination travoprost 0.004%/timolol 0.5%
Unfixed travoprost 0.004% + timolol 0.5%
FIGURE 4. Intraocular pressure change from baseline in pa-
tients with open-angle glaucoma or ocular hypertension
receiving fixed-combination travoprost 0.004%/timolol 0.5%
or unfixed travoprost 0.004% D timolol 0.5%. Results are
presented as mean and standard deviation. Mean intraocular
pressure changes are indicated within bottom of bars; group sizes
are indicated within top of bars.
syncope (TTFC group, n ¼ 1; severe), hip arthroplasty
(TRAVþTIM group, n ¼ 1; severe), and anemia
(TRAVþTIM group, n ¼ 1; moderate). No patients
discontinued the study because of a serious AE. One pa-
tient in the TTFC group discontinued the study because
of 3 moderate treatment-related AEs (eye irritation, ocular
hyperemia, and photophobia), and 1 patient in the
TRAVþTIM group discontinued because of 1 AE unre-
lated to treatment (alopecia; mild).
We identified no safety issues or trends in either treat-
ment group based on changes from baseline in visual field
tests, gonioscopy evaluations, BCVA assessments, ocular
signs, or fundus parameters. The overall safety profiles of
TTFC and TRAVþTIM were similar.
DISCUSSION
PATIENT ADHERENCE WITH IOP-LOWERING THERAPY FOR
glaucoma or ocular hypertension is a difficult challenge
for health care providers.9 Many individuals requiring med-
ical therapy for glaucoma are already on multiple systemic
prescription medications.21 This becomes more complex if
daily nutraceuticals and other over-the-counter medica-
tions are considered. Therapies requiring separate instilla-
tion of multiple individual medications increase
treatment complexity, which has been associated with
decreased treatment adherence. Adherence with treatment
regimens is multifactorial; however, the effect of treatment
complexity as a factor in adherence can be minimized with
use of fixed-combination therapies that provide multiple
medications in a single formulation. The purpose of this
study was to assess patient adherence with daily glaucoma
66
12 Months medication dosing schedules when receiving a fixed-
combination treatment (TTFC) compared with separate
(36) (35)
dosing of its unfixed components (TRAVþTIM) over
12 months.
The once-daily dosing of TTFC and TRAVþTIM was
the simplest treatment regimen possible (ie, 1 daily instil-
–7.4 –7.3
lation and 2 daily instillations, respectively) and, as such,
enabled the most direct comparison of adherence rates
between the fixed and unfixed medications without intro-
ducing additional variables. Compared with patients
receiving TRAVþTIM, patients receiving TTFC were
adherent with their dosing schedule on a greater percent-
age of days through 1, 3, 6, and 12 months of treatment,
although adherence was less than ideal. Furthermore,
significantly greater percentages of patients achieved
adherence at cumulative thresholds of 80%–95% with
TTFC compared with TRAVþTIM throughout the study.
Notably, between-group differences in adherence were
observed in the first month of treatment with regard to
both the percentage of days that patients were adherent
with their treatment regimen and the percentage of
patients achieving higher adherence thresholds. These
results were consistent with demonstrations that adherence
generally decreases with increasing treatment
complexity.11,12,15,16
Fixed-combination therapies simplify treatment admin-
istration for patients requiring multiple IOP-lowering med-
ications, potentially increasing adherence with dosing
regimens.22 In the current study, adherence declined over
time in both treatment groups, consistent with a previous
6-month assessment of adherence monitored using dosing
aids,8 but appeared to decrease at a more rapid rate with
TRAVþTIM than with the fixed-combination medica-
tion. This suggests that although fixed-combination thera-
pies with once-daily dosing may promote better adherence
over longer periods of time compared with separate instil-
lation of 2 medications at different times of day,12 fixed-
combination dosing does not address all factors that may
play a role in treatment adherence. In addition to treat-
ment complexity, other factors that may influence adher-
ence include age, income, race, education, health
awareness, health literacy, lifestyle, and number of
concomitant eye diseases.23–25 Several studies have
demonstrated that race is an important determinant of
treatment adherence.23,26,27 In the current study, most
patients in both treatment groups were white, and
patient race was not significantly different between
groups. Patient age was also similar between groups.
Nevertheless, important differences in treatment
adherence were observed with TTFC compared with
TRAVþTIM.
The IOP-lowering efficacy of TTFC and TRAVþTIM
has been demonstrated previously.28–31 IOP change from
baseline was not a primary outcome of the current study;
however, both treatment regimens effectively reduced
IOP from baseline. Both treatments were well tolerated,
AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2017
 was measured as a descriptive variable. The observation
TABLE 2. Summary of Treatment-Emergent Adverse Events that mean IOP measured at clinic visits did not correlate
in Patients With Open-Angle Glaucoma or Ocular with adherence rates may reflect the ‘‘white-coat compli-
Hypertension Receiving Fixed-Combination Travoprost
ance’’ phenomenon,32 in which patients increase adher-
0.004%/Timolol 0.5% or Unfixed Travoprost
0.004% þ Timolol 0.5% ence to treatment in anticipation of a clinic visit.33,34
White-coat compliance may confound long-term assess-
Fixed-Combination ment of IOP control, because short-term increases in
Travoprost Unfixed Travoprost adherence before a clinic visit can cause IOP to appear
0.004%/Timolol 0.004% þ Timolol
Adverse Eventsa 0.5% (N ¼ 41) 0.5% (N ¼ 40)
well controlled.35 Indeed, periods of poor adherence may
not be reflected in IOP measured at clinic visits because
Total adverse events, n 68 58
the IOP-lowering effects of many ocular hypotensive
Serious adverse events, n 2 1
agents are evident within hours after administration.19,36
Adverse events associated 3b 1
with discontinuation, n
A similar effect of increased compliance in anticipation
Treatment-related adverse of clinic visits was observed in a study that used
events, n (%) microelectronic monitoring to measure adherence with
Ocular hyperemia 3 (7.3) 3 (7.5) pill taking.33 Although adherence dropped significantly
Eye irritation 2 (4.9) 0 between clinic visits, spot checks revealed that drug levels
Eye pain 2 (4.9) 0 at clinic visits were within the therapeutic range. This led
Pruritus 1 (2.4) 1 (2.5) the authors to conclude that serum drug levels observed at
Photophobia 1 (2.4) 1 (2.5) follow-up visits do not represent long-term steady-state
Increased intraocular 1 (2.4) 0 serum concentrations.33
pressure
The possibility of overestimation of adherence with
Abnormal sensation in eye 0 1 (2.5)
treatment regimens is a potential limitation of this study.
Conjunctival hyperemia 0 1 (2.5)
Adverse events not related to
Dosing aids provide an advanced approach for measuring
treatment,c n (%) treatment adherence but cannot determine whether medi-
Meibomian gland 5 (12.2) 2 (5.0) cations were instilled. Patients were considered adherent
dysfunction on a given day if their dosing aids recorded at least 1
Nasopharyngitis 3 (7.3) 5 (12.5) drop dispensed in a 24-hour period; potential delivery of
Injury 3 (7.3) 2 (5.0) multiple drops by a dosing aid in a 24-hour period was
Foreign body sensation 3 (7.3) 0 not considered in adherence analyses. Patients elected to
Blurred vision 3 (7.3) 0 participate in the study and were therefore possibly health-
Gastroesophageal reflux 3 (7.3) 0 ier and more motivated than the general population.
disease
Furthermore, adherence with treatment may have been
Vitreous detachment 2 (4.9) 4 (10.0)
increased because of participation in a clinical trial.37
Increased intraocular 2 (4.9) 2 (5.0)
pressure
However, investigators made no additional attempts to
Eyelid erythema 2 (4.9) 0 educate patients on the importance of adherence
Stress at work 2 (4.9) 0 throughout the study, and no aids for promoting adherence
Hypertension 1 (2.4) 2 (5.0) were discussed or provided for either treatment group.
Blepharitis 1 (2.4) 2 (5.0) Morning vs evening dosing of TTFC was determined by
Conjunctival hyperemia 0 2 (5.0) individual patient preference and was not included in
Optic nerve disorder 0 2 (5.0) data analyses. The timing of daily instillations may have
a
influenced treatment adherence, which is reported to be
Incidence of adverse events is presented as number and
decreased with evening vs morning dosing.38,39 Lastly,
percentage of patients experiencing a Medical Dictionary for
Regulatory Activities–coded event. Patients experiencing multi-
group sizes were relatively small and patients were
ple coded events were counted for each event. predominantly white and were generally younger than
b
Three events were reported for a single patient. those in other studies, which may limit the
c
Adverse events not related to treatment and reported for >
_2 generalizability of study results to broader patient
patients within a treatment group. populations.

and no new safety concerns were identified with either

treatment regimen.
An interesting observation in this study was that, despite
improved adherence in the TTFC group, IOP was similar
between treatment groups at follow-up months 1, 6, and
12. IOP was not a predefined endpoint in this study, but
CONCLUSIONS
ADHERENCE IS A MULTIFACTORIAL ISSUE IN WHICH THE
complexity of treatment regimens plays an important role.
In patients with glaucoma or ocular hypertension who

VOL. 176 ADHERENCE WITH TRAVOPROST/TIMOLOL 67

require multi-agent therapy, TTFC may promote improved significant issue. Additional work outlining patterns of
adherence with treatment compared with TRAVþTIM. adherence and the relationship of adherence with daily
Based on this and other studies, there appears to be a clear activities and proximity to scheduled physical appoint-
role for fixed-combination medications when adherence is a ments will be described in future publications.

FUNDING/SUPPORT: THIS STUDY WAS SPONSORED BY ALCON RESEARCH, LTD, FORT WORTH, TEXAS, USA. THE STUDY SPONSOR
participated in study design and data analysis, provided feedback on manuscript drafts, and agreed with the decision to submit the manuscript for publi-
cation. Financial Disclosures: Howard S. Barnebey is a consultant to Alcon, Allergan, Aerie, and Biolight. Alan L. Robin is a consultant to Aerie Phar-
maceuticals, ForeSight Visions, Glaukos, Biolight, and Clearside, and is on the board of the Aravind Eye Foundation. All authors attest that they meet the
current ICMJE criteria for authorship.
Medical writing support was provided by Heather D. Starkey, PhD, of CHC Group, LLC (Chadds Ford, Pennsylvania, USA) and was funded by Alcon.

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