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12-Week, Randomized, Multicenter Study
Comparing Fixed-Combination
Brimonidine-Timolol and Timolol as
Adjunctive Therapy to Latanoprost
Robert D. Fechtner, MD1; Paul Harasymowycz, MD2; Donald R. Nixon, MD3;
Steven D. Vold, MD4; Fiaz Zaman, MD5; Julia Williams, MA6; David A. Hollander,
MD, MBA6
1Glaucoma
Division, UMDNJ-New Jersey Medical School, Newark, NJ, USA; 2University of
Montreal, Montreal, QC, Canada; 3Royal Victoria Hospital, Barrie, ON, Canada; 4BoozmanHof Regional Eye Clinic, Rogers, AR, USA; 5Houston Eye Associates, Houston, TX, USA;
6Allergan, Inc., Irvine, CA, USA
Study funded by Allergan, Inc.
Robert D. Fechtner, MD is a consultant to and has received research support from Allergan, Inc.
Drs. Paul Harasymowycz , Donald R. Nixon, Steven D. Vold, and Fiaz Zaman received research support
from Allergan, Inc. Ms. Julia Williams and Dr. David A. Hollander are employees of Allergan, Inc.
Introduction

Patients with glaucoma and ocular hypertension (OHT) frequently require multiple
IOP-lowering medications to control their intraocular pressure (IOP).
–
Over 20% of patients treated with a prostaglandin analog (PGA), the most efficacious class of
IOP-lowering medications, may be required to add another IOP-lowering medication to their
treatment regimen within a year of initiating treatment.1
–
Approximately 42% of patients in the Ocular Hypertension Treatment Study (OHTS) initial
medical treatment group were on 2 or more IOP-lowering medications at year 13.2

When multiple-drug therapy is needed, use of a fixed combination of 2 IOP-lowering
medications in 1 bottle may be preferred to enhance patient convenience and compliance. 3

The fixed combination of brimonidine 0.2%-timolol 0.5% (Combigan®; Allergan, Inc.) has been
demonstrated to reduce IOP more effectively than either brimonidine 0.2% or timolol 0.5%
used alone and to be better tolerated than brimonidine 0.2% monotherapy.4

Combigan® has also been shown to be as efficacious and well tolerated as concomitant use
of separate bottles of brimonidine 0.2% and timolol 0.5%.5

The efficacy and safety of Combigan® used as adjunctive therapy to PGAs such as
latanoprost has not been extensively studied.

The purpose of this study was to evaluate the additive IOP-lowering efficacy and safety of
Combigan® compared with timolol 0.5% when used as adjunctive therapy to latanoprost in
glaucoma and OHT patients who require additional IOP lowering.
Methods

This was a prospective, randomized, multicenter, investigator-masked, parallel-group
study.

Eligible patients were adults at least 18 years of age with a diagnosis of glaucoma or OHT
requiring treatment with IOP-lowering medication.

All patients were treated with latanoprost monotherapy once daily in the evening for at
least 4 weeks prior to the baseline visit.
– Patients on IOP-lowering medications at screening underwent a 4-week washout of all
medications other than latanoprost.
– Patients not on latanoprost at screening were run in on latanoprost for 4 weeks.

At the baseline visit, patients who had IOP ≥ 21 mm Hg in at least 1 eye continued on
latanoprost and were randomized to adjunctive treatment with twice-daily Combigan®
(n = 102) or timolol (n = 102) for 12 weeks.

IOP was measured at 8 AM and 10 AM at baseline, week 6, and week 12.

The primary efficacy endpoint was IOP lowering at peak effect (10 AM) at week 12.

Safety measures included adverse events (AEs).

Efficacy was evaluated in the worse eye (the eye with higher IOP at baseline) in the perprotocol population of patients with no major protocol violations.

IOP and change from baseline IOP at weeks 6 and 12 were analyzed by ANCOVA with
baseline IOP as the covariate.
Results: Patient Population and
Disposition
Patient Demographics
Combigan®
(n = 102)
Timolol
(n = 102)
Mean (SD) age, years
63.4 (11.3)
64.8 (10.8)
Female, n (%)
57 (55.9%)
45 (44.1%)
Black
26 (25.5%)
24 (23.5%)
Caucasian
57 (55.9%)
63 (61.8%)
Hispanic
17 (16.7%)
15 (14.7%)
2 (2.0%)
0 (0.0%)
Race/ethnicity, n (%)
Other
 Study completion rates were similarly high in each treatment group (93.1%, 95/102
in the Combigan® group and 94.1%, 96/102 in the timolol group).
 The per-protocol patient population represented 95.6% (195/204) of all randomized
patients.
Results: Mean Change From Latanoprost Baseline
IOP at 10 AM, Week 12 (Primary Endpoint)
Combigan®
(n = 94)
Timolol
(n = 94)
-8.3
(35.5%)
-6.2
(27.0%)
Mean Change From
Latanoprost Baseline IOP
at 10 AM, Week 12 (mm Hg)
0
-2
–
At 10 AM, baseline mean IOP was 23.4 mm Hg
in the Combigan® group and 23.0 mm Hg in the
timolol group (P = .229).
 At 10 AM, week 12, Combigan® provided
2.1 mm Hg greater IOP lowering
compared with timolol when used as
adjunctive therapy to latanoprost (P <
.001).
-4
-6
-8
-10
 There were no statistically significant
differences between treatment groups
in mean IOP at baseline on latanoprost.
P < .001 vs timolol.
Error bars, SEM.
Results: Percentage of Patients Achieving ≥ 30%
Reduction in IOP From Latanoprost Baseline at Week 12
Trough Effect (8 AM)
Peak Effect (10 AM)
80
60
40
P = .006 vs timolol.
53.1%
33.0%
20
0
Percentage of Patients
Percentage of Patients
80
60
P < .001 vs timolol.
68.1%
40
40.4%
20
0
Combigan®
(n = 96)
Timolol
(n = 94)
Combigan®
(n = 94)
Timolol
(n = 94)
 At week 12, patients treated with adjunctive Combigan® were significantly more
likely than patients treated with adjunctive timolol to achieve a ≥ 30% decrease
in IOP from latanoprost-treated baseline at both peak and trough effect.
Results: Percentage of Patients Achieving IOP
< 18 mm Hg at Week 12
Patients With IOP < 18 mm Hg at Both Peak and Trough
Percentage of Patients
80
P = .028 vs timolol.
60
59.6%
40
42.6%
20
0
Combigan®
(n = 94)
Timolol
(n = 94)
 At week 12, patients treated with adjunctive Combigan® were significantly
more likely than patients treated with adjunctive timolol to consistently
achieve IOP < 18 mm Hg at both peak (10 AM) and trough (8 AM) effect.
Safety Assessment
Incidence of Adverse Events, n (%)
Combigan®
(n = 102)
Timolol
(n = 102)
Any AE
15 (14.7%)
12 (11.8%)
Treatment-related AE
10 (9.8%)
4 (3.9%)
Ocular AE
9 (8.8%)
6 (5.9%)
Treatment-related ocular AE
8 (7.8%)
4 (3.9%)
Serious AE
0 (0.0%)
1 (1.0%)a
a
Determined to be unrelated to treatment.
 Both adjunctive study treatments were well tolerated.
 The overall incidence of AEs and treatment-related AEs was low in both treatment
groups.
 The rate of discontinuations due to AEs (not necessarily related to treatment) was
4.9% in the Combigan® group and 2.0% in the timolol group.
Discussion
 Achievement of a low target IOP minimizes the risk of vision loss in glaucoma.6,7
 For patients using a PGA who need lower IOP, the addition of a fixed combination
provides substantial additional IOP lowering while adding only 1 bottle and
2 drops to the patients’ daily regimen.
 In this study, glaucoma and OHT patients on latanoprost who added Combigan®
were significantly more likely that patients who added timolol alone to achieve
IOP < 18 mm Hg and 30% or larger reductions in IOP.
 Adjunctive Combigan® provided an 8.3 mm Hg reduction in IOP at peak effect at
week 12, approximately 2 mm Hg larger than the 6.2 mm Hg reduction provided
by adjunctive timolol (P < .001).
– The results are consistent with a previous study in which Combigan® reduced IOP
at least as effectively as fixed dorzolamide-timolol when used as adjunctive therapy
to a PGA.8
– In both studies, adjunctive use of Combigan® was well tolerated with few
discontinuations due to adverse events.
 Adjunctive Combigan® provides the IOP-lowering efficacy of 2 additional
medications while minimizing the number of drops used to maintain compliance.
Conclusions
 Combigan® reduced IOP significantly more effectively than
timolol when used as adjunctive therapy to latanoprost in
patients who needed additional IOP lowering.
 Adjunctive treatment with Combigan® and timolol was well
tolerated.
References
1. Covert D, Robin AL. Adjunctive glaucoma therapy use associated with travoprost, bimatoprost,
and latanoprost. Curr Med Res Opin. 2006;22(5):971-976.
2. Kass MA, Gordon MO, Gao F, et al; Ocular Hypertension Treatment Study Group. Delaying
treatment of ocular hypertension: the ocular hypertension treatment study. Arch Ophthalmol.
2010;128(3):276-287.
3. Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive
treatment in patients with glaucoma or ocular hypertension an evidence-based review.
Ophthalmology. 2005;112(6):953-961.
4. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixedcombination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or
ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230-1238.
5. Goñi FJ; Brimonidine/Timolol Fixed Combination Study Group. 12-week study comparing the fixed
combination of brimonidine and timolol with concomitant use of the individual components in
patients with glaucoma and ocular hypertension. Eur J Ophthalmol. 2005;15(5):581-590.
6. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship
between control of intraocular pressure and visual field deterioration. Am J Ophthalmol.
2000;130(4):429-440.
7. Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E; Early Manifest Glaucoma Trial
Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma
trial. Arch Ophthalmol. 2003;121(1):48-56.
8. Nixon DR, Yan DB, Chartrand JP, Piemontesi RL, Simonyi S, Hollander DA. Three-month,
randomized, parallel-group comparison of brimonidine-timolol versus dorzolamide-timolol fixedcombination therapy. Curr Med Res Opin. 2009;25(7):1645-1653.
Author Bio
ROBERT D. FECHTNER, MD
Professor/Director, Glaucoma Division
Institute of Ophthalmology and Visual
Science
New Jersey Medical School, UMDNJ
Newark, New Jersey
Robert D. Fechtner, MD graduated from the
University of Michigan School of Medicine.
He completed his residency at Albert
Einstein College of Medicine in 1989 and his
glaucoma fellowship at University of
California, San Diego under a National
Research Service Award from the National
Institutes of Health. He is now Professor of
Ophthalmology and Director of the
Glaucoma Division at the Institute of
Ophthalmology and Visual Science, New
Jersey Medical School in Newark.
Dr. Fechtner is an active member of
numerous scientific and medical
organizations. He has held committee
or leadership positions in the American
Academy of Ophthalmology, the
Association for Research in Vision and
Ophthalmology, the American Society
of Cataract and Refractive Surgery, the
American Glaucoma Society, the
International Society for Imaging of the
Eye and the Association of
International Glaucoma Societies. He
has served on the editorial boards of
American Journal of Ophthalmology,
Journal of Glaucoma, Review of
Ophthalmology, Video Journal of
Ophthalmology, and Eyenet. In addition
to a busy clinical and surgical practice,
Dr. Fechtner maintains an active
clinical research laboratory
concentrating on new technologies and
treatments. He has published over 150
peer-reviewed articles, book chapters
and abstracts.