Brimonidine and Timolol Fixed-Combination Therapy Versus ...

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 21, Number 4, 2005 © Mary Ann Liebert, Inc.

Brimonidine and Timolol Fixed-Combination Therapy Versus Monotherapy: A 3-Month Randomized Trial in Patients with Glaucoma or Ocular Hypertension E. RANDY CRAVEN,1 THOMAS R. WALTERS,2 ROBERT WILLIAMS,3 CONNIE CHOU,4 JANET K. CHEETHAM,4 and RHETT SCHIFFMAN,4 for the COMBIGAN STUDY GROUP

ABSTRACT Purpose: The aim of this study was to compare the safety and intraocular pressure (IOP)lowering efficacy of a fixed combination of brimonidine 0.2% and timolol 0.5% (fixed brimonidine/timolol) versus each drug used as monotherapy. Methods: Patients with glaucoma or ocular hypertension were randomized to receive fixed brimonidine/timolol BID (n 385), brimonidine 0.2% TID (n 382), or timolol 0.5% BID (n 392) in a multicenter, double-masked study. The primary outcome measure was decrease from baseline IOP. Results: Over all follow-up measurements, the mean decrease from baseline IOP ranged from 4.9 to 7.6 mmHg with brimonidine/timolol, from 3.1 to 5.5 mmHg with brimonidine, and from 4.3 to 6.2 mmHg with timolol. Mean IOP reductions from baseline were significantly larger with fixed brimonidine/timolol than with timolol at all follow-up measurements (P 0.026); the difference was greater than 1.5 mmHg at 10 AM (peak effect for each treatment). Mean IOP reductions from baseline were significantly larger with fixed brimonidine/timolol than with brimonidine at 8 AM, 10 AM, and 3 PM (P 0.001); the difference was greater than 1.5 mmHg. The rate of discontinuations owing to adverse events was 3.6% in the fixed timolol/brimonidine group. Conclusions: The fixed combination of brimonidine and timolol was well-tolerated and provided significantly better IOP control compared with either brimonidine or timolol used alone.

INTRODUCTION

E

(IOP) is a major risk factor in the progression of glauco-

LEVATED INTRAOCULAR PRESSURE

matous optic neuropathy. Studies have shown that lowering IOP in glaucoma slows the progressive loss of visual field.1–3 Recent studies have shown that every 1 mmHg of IOP lowering

1Glaucoma

Consultants of Colorado, Littleton, CO. Research, Austin, TX. 3Taustine Eye Center, Louisville, KY. 4Allergan, Inc., Irvine, CA. This study was supported by Allergan, Inc. ER Craven, TR Walters, and R Williams have no proprietary interests in the study drugs. C Chou, JK Cheetham, and R Schiffman are employees of Allergan, Inc. Results from this study were presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology, May 5–10, 2002, in Fort Lauderdale, Florida. 2Keystone

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338

decreases the risk of disease progression by approximately 10%.4,5 In the Advanced Glaucoma Intervention Study,6 patients who consistently achieved a target pressure of less than 18 mmHg had reduced deterioration of visual field compared to patients with higher IOP. First-line therapy for glaucoma is generally a single IOP-lowering agent. If monotherapy does not lower IOP sufficiently, a second drug can be added to the regimen.7,8 Although use of multiple medications increases the potential for adverse events and can lead to reduced compliance,9–11 many patients need more than one medication to reach their target IOP.5,12 For patients who require two drugs, administration of the drugs as a fixed combination in a single bottle provides a more convenient dosing regimen and improves the likelihood of patient compliance. In addition, combining the two medications in a single bottle diminishes the problem of washout, with potential diminution of efficacy owing to dilution of the first drug upon application of a second separately administered drug.13 Moreover, a single bottle containing two components minimizes the patient’s lifetime exposure to potentially damaging preservatives.14–16 Timolol is a nonselective beta-adrenergic receptor antagonist that lowers IOP by decreasing the production of aqueous humor by the ciliary epithelium.17 Brimonidine is a selective alpha2adrenoceptor agonist. Alpha-2 agonists have been shown to activate both postjunctional receptors in the ciliary body and prejunctional receptors on sympathetic nerve terminals in the eye that inhibit the release of endogenous neurotransmitters.18 These findings led to the suggestion that alpha-2 agonists might have a broader spectrum of action in the eye than beta-adrenergic receptor antagonists,18 and in fact, brimonidine was shown to lower IOP by a dual mechanism of decreasing aqueous inflow and increasing uveoscleral outflow.19 In light of their complementary mechanism of action, the fixed combination of brimonidine and timolol can be expected to be more effective in lowering IOP than monotherapy with either drug. Support for this hypothesis was provided by a study in normal human volunteers that demonstrated that brimonidine and timolol, administered concomitantly, reduce IOP to a greater extent than either drug alone.20 Other clinical studies have demonstrated increased IOP-lowering efficacy when brimonidine is used as an adjunctive therapy with beta-blockers.21–24

CRAVEN ET AL.

Brimonidine and timolol are often prescribed and used together in multiple-drug regimens. This study evaluates the safety and efficacy of a fixed combination of brimonidine and timolol in comparison with each of its components.

METHODS Study design Two prospective, 3-month, randomized, double-masked, parallel-group, phase III trials were conducted at 53 sites throughout the United States. The protocols were identical and the results of the two studies were similar, so the data were pooled to create a larger cohort for the present analysis. Both studies were conducted in compliance with the Declaration of Helsinki (1996) and in accordance with Institutional Review Board (IRB) regulations (United States [US] 21 Code of Federal Regulations [CFR] Part 56.103). Each participating investigator received IRB approval and obtained written, informed consent from patients at the screening visit prior to washout of any previous IOP-lowering medications and study entry. The first patient was enrolled in the study on January 14, 2000. All patients had completed 3 months of treatment by April 18, 2001.

Study population This study involved patients 18 years of age or older who required bilateral treatment for glaucoma or ocular hypertension. All patients were required to undergo washout of any IOPlowering medications prior to the baseline visit. Washout periods were 4 days for parasympathomimetics and carbonic anhydrase inhibitors, 2 weeks for sympathomimetics and alpha-agonists, and 4 weeks for beta-blockers (alone or in combination), topical prostaglandins, and topical prostamides. Patients had to have a baseline IOP (after washout) between 22 mmHg and 34 mmHg in each eye, with no more than a 5 mmHg difference between eyes, and a best-corrected visual acuity of 20/100 or better in each eye to be eligible for study entry. All determinations of patient eligibility were based on the judgment of the participating investigator. Key exclusion criteria included active ocular disease, functionally significant or pro-

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FIXED-COMBINATION THERAPY FOR IOP

gressive visual-field loss within the previous year, abnormally low or high blood pressure or pulse rate, contraindications or sensitivity to any component of the study treatments, anticipated initiation of, or change in dosage of, other ocular or systemic medications that might have a substantial effect on IOP, and ocular surgery within the past 3 months. Females who were not using a highly effective means of contraception, or those who were pregnant or nursing, were excluded. Continuation of chronic systemic therapy that could have a substantial effect on IOP was allowed, when considered necessary for the patient’s welfare, as long as the dosages remained constant throughout the course of the trial. Artificial tears could also be used, except within 15 minutes of instillation of study medication. Patients wearing rigid gas permeable or hard contact lenses were required to discontinue wearing them at least 1 week prior to the baseline visit.

Treatment At the baseline visit, patients were randomly assigned to one of three treatment groups: brimonidine 0.2%/timolol 0.5% fixed-combination ophthalmic solution BID (fixed brimonidine/timolol, Combigan™, Allergan, Inc.; Irvine, CA), timolol 0.5% BID (timolol maleate, Allergan, Inc.; Irvine, CA), or brimonidine 0.2% TID (Alphagan®, Allergan, Inc.; Irvine, CA), using a 1:1:1 allocation in blocks of 6. The randomization sequence was generated by the study sponsor using the PLAN procedure in SAS version 6.12 (SAS Institute Inc., Cary, NC). In order to maintain masking, patients in the fixed brimonidine/timolol group and the timolol group administered study medication in the morning and evening and a vehicle solution in the afternoon. Patients in the brimonidine group administered study medication in the morning, afternoon, and evening. The afternoon dose in all three groups (vehicle solution or brimonidine) was provided in a separate, smaller bottle to ensure that all drugs were given at the correct time. Patients received their first dose of medication after all evaluations at the baseline visit. Thereafter, patients self-instilled the study medication in the morning between 7 AM and 9 AM, in the afternoon between 1 PM and 3 PM, and in the evening between 7 PM and 9 PM. Follow-up study visits were scheduled at weeks 2 and 6, and month 3.

Outcome measures Efficacy All outcome measures were determined a priori and included in the statistical plan for the study. The primary efficacy measure was mean change from baseline IOP measured at 8 AM (before instillation of study drug), 10 AM, 3 PM (before instillation of study drug), and 5 PM at weeks 2 and 6, and month 3. Two consecutive IOP measurements of each eye were taken with a Goldmann applanation tonometer. If the two measurements differed by more than 2 mmHg, a third measurement was taken. IOP was reported as the mean of two measurements or the median of three measurements. Secondary efficacy measures included mean IOP, the percentage of patients reaching a mean diurnal IOP of less than 18 mmHg at every follow-up visit, the percentage of patients with a mean follow-up IOP (average of all 22 measurements) within specified target pressure ranges (less than 14 mmHg, 14 to 17.5 mmHg, or greater than 17.5 mmHg), and the percentage of patients achieving an average diurnal decrease from baseline IOP of over 20% at every follow-up visit.

Safety The safety evaluation included an assessment of adverse events, as well as biomicroscopy, tests of visual acuity and visual fields, ophthalmoscopy, cup/disc ratio, heart rate, blood pressure, hematology profile, serum chemistry, and urinalysis. Adverse events were assessed for severity and for their probable relationship to the study medication. Investigators rated slit-lamp biomicroscopic findings for the lid, conjunctiva, cornea, anterior chamber, lens, vitreous, and iris/pupil at each visit using a five-point scale (0 none, 0.5 trace, 1 mild, 2 moderate, and 3 severe). The vitreous and optic nerve head were evaluated through a dilated pupil after the 5 PM IOP measurement, and fundus pathology findings were graded using the same five-point scale. Participating investigators could discontinue patients from the study if, in the judgment of the investigators, there were safety concerns or IOP was uncontrolled.

Data analysis and statistics Efficacy analyses were performed for both the intent-to-treat (ITT) population (all patients randomized to treatment) with last observation car-

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CRAVEN ET AL.

ried forward (LOCF) for missing values and the per-protocol population (all patients with no major protocol violations) with no imputation for missing values. Because the per-protocol results were similar to the ITT results, only the ITT analyses are reported in this paper. The safety population consisted of all randomized patients who received at least one dose of study medication and was the same as the ITT population. The experimental unit was the patient. IOP for each patient was calculated as the mean of the IOP values from both eyes. Change from baseline IOP for each patient was determined by first calculating the change for each eye and then taking the average of these values. Mean diurnal IOP for each patient was defined as the mean of all four measurements on a given visit. Achievement of an IOP less than 18 mmHg was evaluated as the percentage of patients achieving a mean diurnal IOP of less than 18 mmHg at all follow-up visits. The percentage of patients reaching specified target pressure ranges was calculated using the mean follow-up IOP (average of all 22 measurements throughout the study) for each patient. Achievement of over 20% IOP lowering was evaluated as the percentage of patients achieving an average diurnal decrease from baseline IOP (average of all four measurements of decrease from baseline on a given visit) of over 20% at every follow-up visit. Nominal categorical variables were analyzed using the Fisher’s exact test or Pearson’s chisquare test. Ordinal categorical variables were analyzed using the Wilcoxon rank-sum test. Withingroup changes from baseline for categorical variables were analyzed using the Wilcoxon signed rank test. Continuous variables were anaTABLE 1.

385 349 36 7 14 6 9 15

(90.6%) (9.4%) (1.8%) (3.6%) (1.6%) (2.3%) (3.9%)

RESULTS Patient disposition In all, 1159 patients were randomized to treatment: 385 in the fixed-combination therapy group, 382 in the brimonidine group and 392 in the timolol group (Table 1). A total of 999 patients (86.2%) completed 3 months of assigned therapy. Of the 160 patients (13.8%) who discontinued participation, 31 (2.7%) did so because of uncontrolled IOP, 81 (7.0%) because of adverse events, and 48 (4.1%) owing to other reasons.

PATIENT DISPOSITION

Fixed Brimonidine/timolol BID Enrolled Completed Discontinued Lack of efficacy Adverse events Oculara Nonoculara Otherb

lyzed using analysis of variance (ANOVA). Within-group changes from baseline for continuous variables were analyzed using paired t tests. A two-way ANOVA model with fixed effects for treatment and investigator was used for the analysis of IOP. Comparisons were made between fixed-combination therapy and each of the two monotherapies in a pairwise fashion using the ANOVA model with the same error term. The significance level was set at 0.05. Point estimates of the mean treatment differences, as well as two-sided 95% confidence intervals (CI) of the differences, were provided at each measurement. A difference between groups of greater than 1.5 mmHg in the mean decrease in IOP from baseline was considered to be clinically significant. A power calculation estimated that a sample size of 150 in each treatment group would provide a power of 98% to detect a 1.5 mmHg difference and a power of 76% to detect a 1.0-mmHg difference in mean change from baseline IOP between groups (using an estimated common standard deviation of 3.2 mmHg).

Brimonidine TID 382 298 84 18 53 35 23 13

(78.0%) (22.0%) (4.7%) (13.9%) (9.2%) (6.0%) (3.4%)

Timolol BID 392 352 40 6 14 7 11 20

(89.8%) (10.2%) (1.5%) (3.6%) (1.8%) (2.8%) (5.1%)

aSome patients discontinued on account of both ocular and nonocular adverse events and were included in both groups. bThis group includes patients who discontinued because of protocol violations, administrative reasons, or other reasons.

341


Patient demographics and baseline characteristics With the exception of gender, baseline demographics were comparable among treatment groups (Table 2). There was a higher percentage of female patients in the brimonidine group (60.5%) than in the fixed brimonidine/timolol group (53.0%) or timolol group (52.6%). The mean age of enrolled patients was 62.6 years (range, 23–89 years). The patient population was primarily Caucasian (76%, 879 of 1159) and Black (16%, 187 of 1159). The primary diagnosis was glaucoma (66%, 762 of 1159), and 69% of patients (795 of 1159) required a washout of IOP-lowering medication prior to study entry. Less than 5% of patients used artificial tears during the study; the among-group difference in artificial tear use was not significant. At the baseline visit, mean IOP in the three treatment groups (Table 2) ranged from 24.7 to 25.0 mmHg at 8 AM, 23.3 to 23.5 mmHg at 10 AM, and 22.1 to 22.5 mmHg at 3 PM. There were no TABLE 2.

Mean Age in Years (Range) Gender Male Female Race Caucasian Black Hispanic Asian Other Iris Color Blue Brown Other Diagnosis Glaucoma Ocular hypertension One eye each Washout Required Yes No Baseline Mean IOP (SEM) 8 AM 10 AM 3 PM 5 PM aBlack

PATIENT DEMOGRAPHICS

statistically significant differences in baseline mean IOP between treatment groups at the 8 AM, 10 AM, or 3 PM measurements. At the 5 PM timepoint, baseline mean IOP was significantly lower in the fixed brimonidine/timolol group (21.8 mmHg) than in the timolol group (22.4 mmHg; P 0.010) but similar to that in the brimonidine group (22.2 mmHg; P 0.058).

IOP-lowering efficacy The mean decrease in IOP from baseline was significantly greater in the fixed brimonidine/timolol group than in the timolol group at all measurements on all follow-up visits throughout the study (P 0.008 at 8 AM, 10 AM, and 3 PM; P 0.026 at 5 PM; Fig. 1). The mean decrease in IOP from baseline was significantly greater in the fixed brimonidine/timolol group than the brimonidine group at all 8 AM, 10 AM, and 3 PM follow-up measurements throughout the study (P 0.001) but not at the 5 PM measurements (Fig-

AND

BASELINE CHARACTERISTICS

Fixed Brimonidine/timolol BID (n 385)

Brimonidine TID (n 382)

Timolol BID (n 392)

62.0 (23–86)

63.8 (28–89)

62.0 (26–89)

181 (47.0%) 204 (53.0%)

151 (39.5%) 231 (60.5%)

186 (47.4%) 206 (52.6%)

290 59 30 4 2

304 55 20 2 1

285 73 28 5 1

0.060 0.046

(75.3%) (15.3%) (7.8%) (1.0%) (0.5%)

(79.6%) (14.4%) (5.2%) (0.5%) (0.3%)

(72.7%) (18.6%) (7.1%) (1.3%) (0.3%)

126 (32.7%) 170 (44.2%) 89 (23.1%)

122 (31.9%) 171 (44.8%) 89 (23.3%)

116 (29.6%) 202 (51.5%) 74 (18.9%)

260 (67.5%) 121 (31.4%) 4 (1.0%)

258 (67.5%) 122 (31.9%) 2 (0.5%)

244 (62.2%) 141 (36.0%) 7 (1.8%)

254 (66.0%) 131 (34.0%)

266 (69.6%) 116 (30.4%)

275 (70.2%) 117 (29.8%)

24.7 23.3 22.1 21.8

24.9 23.5 22.5 22.2

25.0 23.5 22.5 22.4

0.243a

0.061b

0.265

0.394

(0.14) (0.16) (0.17) (0.17)

versus non-Black. versus dark. *Among-group comparison based on Pearson’s Chi-square test.

bLight

P value*

(0.14) (0.17) (0.18) (0.18)

(0.13) (0.16) (0.18) (0.18)

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CRAVEN ET AL.

A

1.5

0.5

0

0

-1

-1

-2 -3 -4 -5 -6 -7 -8

*

*

*

-9

C

3

-2 -3 -4 -5 -6 -7 -8

*

* p < 0.008 vs timolol * p < 0.001 vs brimonidine

*

*

Brimonidine/timolol (n = 385) Brimonidine (n = 382) Timolol (n = 392)

D

Months of treatment 0.5

1.5

0.5

-1

-1

-3 -4 -5

*

*

*

-7 -8 -9 Brimonidine/timolol (n = 385) Brimonidine (n = 382) Timolol (n = 392)


Change from baseline IOP (mm Hg, + SEM)

0

-2


Months of treatment

3

0

-6

1.5

-9 Brimonidine/timolol (n = 385) Brimonidine (n = 382) Timolol (n = 392)


Months of treatment

3



B

Months of treatment 0.5

1.5

3

-2 -3 -4 -5 -6

*

*

*

-7 -8 -9 Brimonidine/timolol (n = 385) Brimonidine (n = 382) Timolol (n = 392)

* p < 0.026 vs timolol

FIG. 1. Mean change from baseline at (A) 8 AM, (B) 10 AM, (C) 3 PM, and (D) 5 PM. Error bars represent standard error of the mean.

ure 1). At 5 PM, the fixed combination had been dosed 9 h previously, while brimonidine had been dosed 2 h previously and was at near peak effect. The mean decrease from baseline IOP (over all measurements at all follow-up visits) ranged from 4.9 to 7.6 mmHg in the fixed brimonidine/timolol group, from 3.1 to 5.5 mmHg in the brimonidine group, and from 4.3 to 6.2 mmHg in the timolol group. The difference in mean change from baseline between the fixed brimonidine/timolol group and the brimonidine group was greater than 1.5 mmHg at all 8 AM, 10 AM, and 3 PM follow-up measurements throughout the study. The difference in mean change from baseline between the fixed brimonidine/timolol group and the timolol group was greater than 1.5 mmHg at all 10 AM follow-up measurements throughout the study. Further, an a priori subgroup analysis by race

showed that the fixed combination reduced IOP more effectively than each component medication in both Black patients and non-Black patients. Mean IOP was significantly lower in the fixed brimonidine/timolol group than in either of the monotherapy groups at all measurements on all follow-up visits except for the 5 PM measurement at week 2 (P 0.001 at 8 AM, 10 AM, and 3 PM; P 0.018 at 5 PM; Fig. 2). At this time point, mean IOP was lower in the fixed brimonidine/timolol group than in the timolol group (P 0.001), while the difference from the brimonidine group tended toward significance (P 0.093). A significantly greater percentage of patients in the fixed brimonidine/timolol group than in either monotherapy group maintained mean diurnal IOP (IOP averaged over all measurements on a given visit) of less than 18 mmHg through-

343

26

Mean IOP (mm Hg, +SEM)

A


24 22 20 18

*

*

16

*

*p < 0.001 vs timolol *p < 0.001 vs brimonidine

B

26



24


*p < 0.001 vs timolol *p < 0.001 vs brimonidine

22 20 18 16

*

*

0

1

2

0

3

1

Months of treatment


26

D


24


22 20 18 16

*

*

*

2

3

Months of treatment

26


24


C

*

14

14

*p < 0.001 vs timolol † p < 0.018 vs brimonidine

22 20 18

*

16

14

*

*

†

†

14 0

1

2

3

0

1

Months of treatment

Mean intraocular pressure (IOP) at (A) 8

out the 3-month study (P 0.001; Fig. 3). Mean diurnal IOP was below this level in 56% of patients in the fixed brimonidine/timolol group, 27% of patients in the brimonidine group, and 37% of patients in the timolol group. The distribution of patients over the target pressure ranges of less than 14 mmHg, 14 to 17.5 mmHg, and greater than 17.5 mmHg favored the fixed brimonidine/timolol group over each of the monotherapy groups (Fig. 4). There was a significant shift toward the lower target pressure range in the fixed brimonidine/timolol group compared with each of the monotherapy groups (P 0.001; Fig. 4). A significantly greater percentage of patients in the fixed brimonidine/timolol group than in either monotherapy group achieved an average diurnal decrease from baseline IOP of over 20% at every follow-up visit (P 0.001 for each comparison; Fig. 5). The average diurnal decrease from baseline was greater than 20% in 57% of patients in the fixed brimonidine/timolol group, 24% of patients in the brimonidine group, and 40% of patients in the timolol group.

3

AM,

(B) 10

AM,

(C) 3

PM,

and (D) 5

PM.

Safety results Of the 1159 patients enrolled in this study, 999 (86%) completed 3 months of dosing (Table 1). Nearly half of the patients who discontinued from the study did so owing to adverse events (81 of 160). The rate of discontinuations resulting

60

* 56

*p < .001 vs timolol *p < .001 vs brimonidine

50

Percentage of patients

FIG. 2.

2

Months of treatment

40

37

30

27

20 10 0 Fixed brimonidine/timolol (n = 385)

Brimonidine (n = 382)

Timolol (n = 392)

FIG. 3. Percentage of patients who had a mean diurnal intraocular pressure (IOP) (average IOP throughout the day) of less than 18 mmHg at all visits.

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CRAVEN ET AL.

60

Fixed brimonidine/timolol (n = 385) 65

Brimonidine (n = 382) Timolol (n = 392)

58


53

50 38

40

37

32

30 20 11

10 3

5

0 < 14 mm Hg

14 to 17.5 mm Hg

> 17.5 mm Hg

IOP range

FIG. 4. Percentage of patients with mean follow-up intraocular pressure (IOP) averaged over all 22 measurements) in specified target pressure ranges. There was a significant shift toward the lower pressure ranges in the fixed brimonidine/timolol group (P 0.001).

from adverse events was similar in the fixed brimonidine/timolol group and the timolol group (3.6% in each group, P 0.961) and higher in the brimonidine 0.2% TID group (13.9%, P 0.001 versus fixed combination). The overall incidence of adverse events in the fixed brimonidine/timolol BID group (211 of 385, 54.8%) was similar to the incidence in the timolol BID group (205 of 392, 52.3%; P 0.483) and lower than the incidence in the brimonidine TID group (245/382, 64.1%; P 0.008). The most common adverse events that showed significant differences between treatment groups were ocular burning and stinging (Table 3). Ocular burning and stinging occurred more often in the fixedcombination group than in the brimonidine group, at rates comparable to those in the timolol group (Table 3). There were fewer serious adverse events among patients in the fixed brimonidine/timolol group (3 of 385, 0.8%) than in the brimonidine group (11 of 382, 2.9%; P 0.030) or the timolol group (11 of 392, 2.8%; P 0.034). Only one serious ocular adverse event occurred in the brimonidine group, a worsening of a previously diagnosed macular degeneration in an 88-year-old woman, but it was determined to be unrelated to study treatment. The only serious treatment-related systemic adverse events were two that occurred in patients treated with timolol. One patient was hospitalized as a result of respiratory distress and the other as a result of tachycardia, sweating, and nausea.

There were no significant between-group differences in changes in visual fields or cup/disc ratio. The percentage of patients with at least a one severity-grade increase from baseline in conjunctival erythema, conjunctival follicles, edema, and macular degeneration was significantly greater for brimonidine than fixed brimonidine/timolol therapy. There were no clinically relevant differences between fixed brimonidine/timolol and either of the individual components in the mean change from baseline at month 3 for any hematology, chemistry, or urinalysis parameter. Small, but statistically significant, mean decreases from baseline in heart rate occurred in the fixed-combination group (2.7 to 4.0 bpm) and timolol group (2.4 to 3.5 bpm) throughout the study (P 0.001). There were also small, but statistically significant, decreases from baseline in diastolic blood pressure at 2 h with fixed-combination therapy (3.4 to 3.7 mmHg) and brimonidine (2.1 to 3.0 mmHg) at all study visits. None of the differences in heart rate and blood pressure between the different treatment groups were considered to be clinically significant.

DISCUSSION In this study, results of the mean change from baseline IOP and mean IOP analyses demonstrated that fixed brimonidine/timolol BID therapy was significantly more effective in lowering IOP than either brimonidine TID or timolol BID alone. Treatment with the fixed combination resulted in an additional 2- to 3-mmHg mean decrease in IOP com70 60


70

*p < .001 vs timolol *p < .001 vs brimonidine

* 57

50 40

40 30

24

20 10 0 Fixed brimonidine/timolol (n = 385)

Brimonidine (n = 382)

Timolol (n = 392)

FIG. 5. Percentage of patients achieving an average diurnal decrease from baseline IOP (average IOP reduction throughout the day) of over 20% at every follow-up visit.

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FIXED-COMBINATION THERAPY FOR IOP TABLE 3.

Adverse event (AE) Ocular burning Ocular stinging Eye pruritus Asthenia Oral dryness Conjunctival folliculitis Allergic conjunctivitis

MOST COMMON ADVERSE EVENTS REGARDLESS

Fixed combination BID (n 385) 38 21 9 9 7 5 4

(9.9%) (5.5%) (2.3%) (2.3%) (1.8%) (1.3%) (1.0%)

Brimonidine TID (n 382) 21 7 25 13 36 16 17

(5.5%) (1.8%) (6.5%) (3.4%) (9.4%) (4.2%) (4.5%)

OF

P value* versus Brimonidine 0.023 0.007 0.005 0.377 0.001 0.014 0.004

CAUSALITYa Timolol BID (n 392) 45 26 9 2 2 2 0

(11.5%) (6.6%) (2.3%) (0.5%) (0.5%) (0.5%) (0.0%)

P value* versus Timolol 0.468 0.491 0.969 0.031 0.105 0.283 0.060

aAll adverse events with an incidence over 2% and a statistically significant between-group difference are listed. *P value for pairwise comparison of brimonidine / timolol versus brimonidine or timolol was based on Pearson’s chi-square test or Fisher’s exact test.

pared with brimonidine monotherapy at 3 of 4 diurnal measurements at each visit and an additional 1- to 2-mmHg mean decrease in IOP compared with timolol monotherapy at all times of the day at each visit. These findings are consistent with earlier studies that suggested that the concomitant use of brimonidine and timolol provided greater IOP lowering that did either drug administered separately.20,21,23,25 A formulation of brimonidine 0.15% preserved with Purite® (Alphagan® P, Allergan, Inc.; Irvine, CA) is available in the United States. This formulation shows equivalent efficacy and improved tolerability compared with brimonidine 0.2% preserved with benzalkonium chloride (BAK).26 The fixed combination used in this study was preserved with BAK and contains brimonidine 0.2%, however, because timolol is not stable in formulations preserved with the gentler preservative Purite. Brimonidine 0.2% preserved with BAK, rather than brimonidine 0.15%-Purite, was used in this study to serve as an appropriate control. The results in the 7th report of the Advanced Glaucoma Intervention Study (AGIS-7)6 showed that patients who consistently reach a low target pressure are at less risk of visual field deterioration. In the AGIS-7 study, patients who achieved the target IOP of less than 18 mmHg at each visit during a 6-year follow-up period had minimal deterioration of visual field over 96 months (the mean change from baseline in visual field defect scores was close to zero), although the visual field of some patients continued to deteriorate despite low IOPs. In comparison, visual fields worsened by an average of 2 to 3 points in patients who did not have IOP less than 18 mmHg at all visits.

The EMGT and AGIS studies showed that for individual patients, the degree and consistency of IOP lowering affects the disease prognosis. Thus, the ability of fixed brimonidine/timolol therapy to lower IOP to clinically relevant target levels is an important measure of its clinical effectiveness. In this study, the fixed combination was significantly more effective than either brimonidine or timolol monotherapy in allowing patients to reach lower target pressures. Fifty-six percent of patients treated with fixed brimonidine/timolol therapy reached and maintained an average diurnal IOP (the average of IOP at 0, 2, 7, and 9h) of less than 18 mmHg at each follow-up visit, versus 27% of patients treated with brimonidine and 37% of patients treated with timolol. The American Academy of Ophthalmology (AAO)27 considers a 20% decrease from baseline IOP to be clinically significant; therefore, the ability of fixed brimonidine/timolol therapy to provide a greater than 20% decrease from baseline IOP was evaluated. Patients were significantly more likely to achieve a greater than 20% IOP lowering with fixed brimonidine/timolol than with either brimonidine or timolol monotherapy. Fifty-seven percent of patients treated with fixed brimonidine/timolol showed a greater than 20% average decrease from baseline IOP at each follow-up visit, compared to 24% of patients treated with brimonidine and 40% of patients treated with timolol. The overall safety profile of fixed brimonidine/timolol therapy in this study was consistent with the results of previous studies of brimonidine and timolol as monotherapies. Significant side-effects associated with brimonidine include allergic conjunctivitis, ocular pruritus, conjuncti-

346

val folliculosis, and dry mouth.28 Significant sideeffects associated with timolol include lowered heart rate, ocular burning and stinging, and occasional serious systemic adverse events.29 There was no evidence of an additive or interactive effect of fixed-combination therapy on side-effects. For every safety parameter evaluated, results for the fixed combination were at least as favorable as those for timolol or brimonidine alone. The incidence of adverse events and discontinuations owing to adverse events was similar with fixed brimonidine/timolol therapy and timolol monotherapy. A higher incidence of adverse events and discontinuations owing to adverse events was associated with brimonidine monotherapy, likely resulting from greater daily drug exposure associated with the TID dosing schedule compared to the fixed-combination BID regimen. Although timolol and the fixed combination were dosed BID in this study, brimonidine was dosed TID to fulfill U.S. Food and Drug Administration regulatory requirements. This difference in dosing schedule meant that at the 5 PM IOP measurements, the fixed combination at near trough effect was compared to brimonidine monotherapy at peak effect. Even so, the fixed combination reduced IOP as effectively as brimonidine monotherapy at 5 PM, and the fixed combination was significantly more efficacious than brimonidine monotherapy at other time points, despite the added dose given to the brimonidine treatment group. As for most studies of medical treatment in glaucoma, a limitation of this study was the possibility that some physicians might have been unmasked with respect to study medication by the presence of particular side-effects. Brimonidine can cause pupillary constriction and is sometimes associated with side-effects related to conjunctival allergy or inflammation.29,30 The observation of either of these effects in a patient may have led some physicians to suspect the presence of brimonidine in the study medication. Analysis of the ITT patient population, as was done in this study, is generally preferred for clinical studies designed to show superiority of one treatment to another.31,32 This type of analysis is more conservative and less sensitive than analysis of the per-protocol patient population for detecting between-group differences but may be a more realistic indicator of treatment efficacy in the clinic.31,32 A main advantage of administering two medications in a single drop is that fixed-combination

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products are convenient to use and may be associated with better patient compliance compared with concomitant use of the component drugs.33 This is important because patient compliance is a significant factor contributing to the success of medical therapy. This study did not assess the concomitant use of brimonidine and timolol. Further studies are needed to determine the relative efficacy of fixedcombination brimonidine/timolol treatment and the concomitant administration of brimonidine and timolol.

CONCLUSIONS Fixed brimonidine/timolol therapy resulted in significantly greater reductions in IOP than either component used as monotherapy. Significantly more fixed-combination therapy patients than monotherapy patients achieved clinically significant endpoints of greater than 20% reductions in IOP and target pressures of less than 18 mmHg. The safety profile of fixed brimonidine/timolol was favorable with no evidence for a potentiation of adverse events.

ACKNOWLEDGMENTS The authors would like to acknowledge the many principal investigators in the Alphagan/ Timolol Study Groups I and II. The principal investigators of the Alphagan/ Timolol (Combigan) Study Groups I and II.

Study Group I Arizona: Noecker, R., M.D., Tucson, AZ. California: Choplin, N., M.D., San Diego, CA; Landholm, W., M.D., Newport Beach, CA; Solish, A., M.D., Pasadena, CA; Weiss, S., M.D., Mission Viejo, CA. Colorado: Kellum, D., M.D., Boulder, CO; Shields, R., M.D., Denver, CO. Connecticut: Rose, A., M.D., New Haven, CT. Florida: Sherwood, M., M.D., Gainesville, FL. Georgia: Pastor, S., M.D., Atlanta, GA. Illinois: Savitt, M., M.D., Gumee, IL. Kentucky: Williams, R., M.D.; Louisville, KY. Lousiana: Wool, B., M.D., Metairie, LA. Massachusetts: Gendelman, D., M.D., Burlington, MA. New York: Gould, H., M.D., New York, NY; Schenker, H., M.D., Rochester, NY; Simmons, S., M.D., Albany, NY; Sturm, R., M.D., Lynbrook, NY. North Carolina: Rotberg, M., M.D., Charlotte, NC. South Carolina: Sharpe, E., M.D., Mount


Pleasant, SC. Texas: Brennan, J., M.D., Sherman, TX; Evans, R., M.D., San Antonio, TX; Whitsett, J., M.D., Houston, TX. Utah: Brodstein, D., M.D., Ogden, UT. Virginia: Caine, R., M.D., Fredericksburg, VA; Sheppard, J., M.D., Norfolk, VA.

Study Group II Arizona: McGarey, D., M.D., Flagstaff, AZ. California: Duzman, E., M.D., Irvine, CA; Lozier, J., M.D., San Diego, CA; Sall, K., M.D., Bellflower, CA; Wirta, D., M.D., Newport Beach, CA. Colorado: Craven, E.R., M.D., Littleton, CO. Connecticut: Sokol, J., M.D., Waterbury, CT. Florida: Levy, N., M.D., Gainesville, FL; McManus, J., M.D., Melbourne, FL. Georgia: Day, D., M.D., Atlanta, GA; DuBiner, H., M.D., Morrow, GA. Kentucky: Koby, M., M.D., Louisville, KY. Louisiana: Stevenson, D., M.D., New Orleans, LA. Massachusetts: Abelson, M., M.D., North Andover, MA. Michigan: Cooke, D., M.D., St. Joseph, MI. New York: Gurevich, L., M.D., West Seneca, NY; Leopold, M., M.D., Fishkill, NY; Prywes, A., M.D., Bethpage, NY. North Carolina: Branch, J., M.D., Winston-Salem, NC; Mundorf, T., M.D., Charlotte, NC. Oregon: Riedel, P., M.D., Bend, OR. Pennsylvania: Spaeth, G., M.D., Philadelphia, PA. South Dakota: Dirks, M., M.D., Rapid City, SD. Texas: Godfrey, D., M.D., Dallas, TX; Walters, T., M.D., Austin, TX; Whiteside, S., M.D., Georgetown, TX. Washington: Bennion, R., M.D., Wenatchee, WA.

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Received: November 2, 2004 Accepted: April 27, 2005

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