timolol combination versus concomitant administration of brimonidine and timolol

Dorzolamide/Timolol Combination versus Concomitant Administration of Brimonidine and Timolol Six-Month Comparison of Efficacy and Tolerability Kenneth N. Sall, MD,1 Linda J. Greff, MD,2 Lisa R. Johnson-Pratt, MD,3 Paul T. DeLucca, PhD,3 Adam B. Polis, MA,3 Andrea H. Kolodny, BS,3 Charlena A. Fletcher, BSN,3 Deborah A. Cassel, RN,3 Denise R. Boyle, BA,3 Franck Skobieranda, MD3 Purpose: To compare the efficacy and tolerability of the 2% dorzolamide/0.5% timolol combination ophthalmic solution twice daily to the concomitant administration of 0.2% brimonidine ophthalmic solution twice daily and 0.5% timolol ophthalmic solution twice daily. Design: Randomized, multicenter, observer-masked, parallel-group study. Participants: Two hundred ninety-three patients with ocular hypertension or primary open-angle glaucoma participated. Intervention: After an open-label 3-week 0.5% timolol run-in period, patients with an hour 2 intraocular pressure (IOP) of ⱖ 22 mmHg were randomly assigned to receive either the dorzolamide/timolol combination twice daily or the concomitant use of brimonidine twice daily and timolol twice daily (brimonidine ⫹ timolol) for 6 months. Main Outcome Measures: The IOP-lowering effects at hour 0 and hour 2 were collected at 1, 3, and 6 months. We hypothesized that both treatment regimens would have comparable hour 2 IOP-lowering effects at month 3. The treatments were considered comparable if the two-sided 95% confidence interval of the treatment difference was within ⫾ 1.5 mmHg. Tolerability data were also collected at 1, 3, and 6 months. Results: The primary efficacy analysis was based on the modified intent-to-treat population. At month 3, hour 2, the dorzolamide/timolol group had an adjusted mean (standard error) change in IOP of ⫺5.04 (0.30) mmHg versus ⫺5.41 (0.30) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.36 (0.40) mmHg (95% confidence interval [CI] of ⫺0.42–1.14 mmHg). At month 3, hour 0, the dorzolamide/timolol group had a change in IOP of ⫺3.66 (0.29) mmHg versus ⫺4.15 (0.28) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.49 (0.39) mmHg (95% CI of ⫺0.27–1.25 mmHg). Likewise, at all other observed time points, the 95% confidence interval of the treatment difference was within ⫾ 1.5 mmHg. Ninety-three patients (64%) in the dorzolamide/timolol group and 88 patients (60%) in the brimonidine ⫹ timolol group had adverse experiences that were deemed drug related by the investigator, for which 7 patients (5%) in the dorzolamide/ timolol group and 8 patients (5%) in the brimonidine ⫹ timolol group were discontinued from the study. Conclusions: The efficacy of the dorzolamide/timolol combination and the concomitant administration of brimonidine and timolol were comparable. The incidence of drug-related adverse experiences and the incidence of discontinuations caused by drug-related adverse experiences were similar between groups. Ophthalmology 2003;110:615– 624 © 2003 by the American Academy of Ophthalmology.

Despite the evolving appreciation of glaucoma as a multifactorial disease, at present, the primary goal of all theraOriginally received: January 3, 2002. Accepted: October 14, 2002. Manuscript no. 220015. 1 Sall Eye Surgery Medical Center Inc., Bellflower, California. 2 Cincinnati Eye Institute, Cincinnati, Ohio. 3 Merck & Co., Inc., West Point, Pennsylvania. Presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting, Fort Lauderdale, Florida, May 2001; at the American Academy of Ophthalmology Annual Meeting, New Orleans, Louisiana, November 2001; at the American Academy of Optometry Annual Meeting, Philadelphia, Pennsylvania, December 2001; and at the © 2003 by the American Academy of Ophthalmology Published by Elsevier Science Inc.

peutic modalities used in the treatment of glaucoma is the reduction of intraocular pressure (IOP). Topical ␤-blockers are the most commonly prescribed initial therapy for the treatment of elevated IOP in patients with glaucoma. However, approximately half of all glaucoma patients eventually require treatment beyond topical ␤-blocker monotherapy. Association for Research in Vision and Ophthalmology Annual Meeting, Fort Lauderdale, Florida, May 2002. Supported by Merck & Co., Inc., Whitehouse Station, NJ. *Reprint requests to Franck Skobieranda, MD, Merck & Co., Inc., HM222, PO Box 4, West Point, PA 19486. ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6320(02)01900-0

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Ophthalmology Volume 110, Number 3, March 2003 Frequently, a second agent is added to a topical ␤-blocker to achieve IOP control. Historically, additional agents were typically administered with ␤-blockers in a concomitant fashion. However, a more recent trend in glaucoma drug development has been toward fixed combinations of 2 agents. Combination solutions may provide several advantages over concomitant dual therapy; commonly cited advantages include increased convenience and improved compliance, increased ease of self-care by the patient, and a greater chance of effective drug administration without the risk of medication washout when one agent is administered closely in time to the other agent.1,2 Dorzolamide (Trusopt, Merck & Co., Inc., Whitehouse Station, NJ), a topical carbonic anhydrase inhibitor, was initially developed for use as a monotherapy. More recently, dorzolamide was combined with timolol, a nonselective ␤-blocker, in a fixed combination ophthalmic solution (Cosopt, Merck & Co., Inc., Whitehouse Station, NJ). In clinical studies, the efficacy of this combination preparation is comparable to the concomitant administration of dorzolamide and timolol and greater than either of its components used alone.3–5 Brimonidine (Alphagan, Allergan Inc., Irvine, CA), an ␣2-adrenoreceptor agonist, is another adjunctive agent developed as a single-agent ophthalmic solution for use in patients with open-angle glaucoma and ocular hypertension. In current practice, brimonidine is commonly used as monotherapy or administered concomitantly with other glaucoma medications, including ophthalmic ␤-blockers and prostaglandins. When administered with other medications, brimonidine is frequently dosed twice daily, despite threetimes-daily labeling. The dorzolamide/timolol fixed combination ophthalmic solution and the concomitant use of brimonidine and timolol represent 2 tenable options in the care of glaucoma patients who require treatment beyond ␤-blocker monotherapy. A previous comparison between dorzolamide monotherapy and brimonidine monotherapy demonstrated comparable efficacy between dorzolamide and brimonidine by Molfino et al (Invest Ophthalmol Vis Sci 39 [Suppl]:481,1998). Previous studies have compared dorzolamide and brimonidine as adjunctive therapy to ophthalmic ␤-blockers, but these studies did not use the twice-daily dosing of dorzolamide, as it is used in the dorzolamide/timolol fixed combination, and did not use the twice-daily dosing of brimonidine, as it is often used in current practice, whether as monotherapy or as adjunctive therapy.6 – 8 The purpose of this study was to compare these dual therapy regimens as they are commonly used in current ophthalmologic practice with respect to several efficacy and tolerability parameters.

Material and Methods Study Design This was a prospective, randomized, observer-masked, parallel, active-controlled, multicenter study conducted at 31 US sites. It was anticipated that approximately 300 patients would be randomly assigned. This study size ensured 90% power that the 95% confidence interval (CI) for the treatment difference in mean

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change in hour 2 IOP at month 3 fell within the comparability interval of ⫾ 1.5 mmHg, assuming the within-group standard deviation of 4 mmHg. The study consisted of a 3-week run-in period of 0.5% timolol maleate ophthalmic solution twice daily followed by a 6-month, observer-masked, active treatment period. At the end of the run-in period, subjects with an hour 2 IOP of ⱖ 22 mmHg in at least one eye while receiving timolol monotherapy were randomly assigned to receive either 2% dorzolamide hydrochloride/0.5% timolol maleate combination ophthalmic solution twice daily (dorzolamide/ timolol) or the concomitant administration of 0.2% brimonidine tartrate ophthalmic solution twice daily and 0.5% timolol maleate ophthalmic solution twice daily (brimonidine ⫹ timolol) for 6 months. Branded product supplies were used for combination dorzolamide/timolol and brimonidine, whereas generic product supplies were permitted for timolol.

Study Population We studied patients aged 18 years or older with ocular hypertension or primary open-angle glaucoma in both eyes. Patients with a history of ocular inflammation, trauma, or ocular surgical procedures occurring in the 3 months before the study were excluded from participation. Patients with conditions contraindicated in the product labels for dorzolamide, brimonidine, or timolol were also excluded from the study. Patients using systemic antihypertensive medications were permitted to participate if the antihypertensive treatment regimen remained stable throughout the study. All patients were entered into the study with consent processes approved by institutional review boards. The study was conducted under good clinical practice guidelines.

Procedures Patients were screened with an ophthalmologic history and dilated ophthalmologic examination. Automated perimetry was performed with one of the following software packages: Humphrey FastPack, SITA Standard, SITA Fast, or SITA 24 –2 (Zeiss Ophthalmic Systems, Dublin, CA). Gonioscopy was performed if the angle was not visualized in the 6 months before the start of the study. Patients were instructed to treat both eyes with open-labeled timolol at 9:00 AM and 9:00 PM daily, beginning with the first dose later that evening and continuing for the 3-week run-in period. Patients returned on the morning of randomization without administering the morning dose of timolol so that accurate hour-0 and hour-2 IOP measurements would be obtained. On the day of randomization, hour-0 IOP measurements were performed, followed by administration of the morning dose of timolol at approximately 9:00 AM. Hour-2 IOP measurements were obtained precisely 2 hours later. Patients with an hour-2 IOP of ⱖ 22 mmHg in at least one eye were randomly assigned to receive treatment in both eyes with either dorzolamide/timolol or brimonidine ⫹ timolol. The first dose of active treatment period medication occurred later that evening. Patients randomly assigned to dorzolamide/timolol were instructed to administer 1 drop of drug at 9:00 AM and 9:00 PM daily. Patients randomly assigned to brimonidine ⫹ timolol were instructed to administer 1 drop of timolol at 8:50 AM and 8:50 PM and 1 drop of brimonidine at 9:00 AM and 9:00 PM daily. At each visit, compliance was assessed by direct patient inquiry, and missed doses were noted. For each study site, an unmasked person allocated and managed the active treatment period medication(s) but remained isolated from the rest of the study. All efficacy and tolerability evaluations were performed by masked investigators. Throughout the study, patients were cautioned to avoid disclosure of their treatment regimen to any masked study personnel.

Sall et al 䡠 Dorzolamide/Timolol Combination vs. Brimonidine and Timolol Table 1. Patient Accounting

The subjects returned for follow-up efficacy and tolerability evaluations at 1, 3, and 6 months after randomization.

Dorzolamide/Timolol Brimonidine ⴙ Timolol N ⴝ 144 N ⴝ 149 n (%) n (%)

Main Outcome Measures Trough and peak IOP (hour 0 and hour 2, respectively) were established at randomization and measured after 1, 3, and 6 months of therapy. For the statistical analysis of efficacy, the eye with the greater hour-0 IOP measurement at randomization was declared to be the study eye. If the hour-0 IOP measurement was the same in both eyes, the hour-2 IOP measurements were compared, and the eye with the greater hour-2 IOP measurement was declared to be the study eye. If the hour-2 IOP measurement was also the same in both eyes, the right eye was declared to be the study eye. The primary efficacy end point was the change in hour-2 IOP between randomization and the month-3 treatment interval and will be described as the change in IOP at month 3. The month-3, hour-2 IOP was chosen as the primary efficacy end point, because it reflected a typical time at which the efficacy of an antiglaucoma medication is judged in a clinical setting; that is, after several months of therapy and after the morning dose of medication on a particular day. The change in hour-0 IOP between randomization and month 3 was also calculated and represented the nadir of efficacy of a therapy. Similar calculations of the changes in hour-0 and hour-2 IOP were made at month 1 and month 6. For this study, comparability between treatments was defined as a treatment difference of ⬍ 1.5 mmHg between groups; that is, the treatment regimens were comparable if the 95% CI for the treatment difference in mean change from baseline IOP was within ⫾ 1.5 mmHg. We hypothesized that the treatment regimens would have comparable hour-2 IOP-lowering effects at month 3. In addition, we hypothesized that the treatment regimens will have comparable hour-0 IOP-lowering effects at month 3. Efficacy after 1 and 6 months of therapy was also compared. This analysis was based on randomized treatment groups and included all patients who took at least one dose of study medication and had IOP data at baseline and at least one value after randomization (Modified Intent-to-Treat analysis, expressed as MITT). The last observation carried forward approach was used, whereby missing data from a treatment evaluation were imputed by carrying data forward from the most recent nonmissing evaluation occurring subsequent to the randomization visit. A supportive analysis of efficacy was conducted using a perprotocol approach. For example, this analysis excluded observations made outside of the prespecified study visit intervals and observations made when patients took concomitant medications not permitted during the study. Data were not carried forward for the per-protocol analysis. The efficacy analysis was based on an analysis of covariance model including terms for treatment group, study site, and randomization IOP. The comparison of changes in IOP between the dorzolamide/timolol group and the brimonidine ⫹ timolol group were calculated as the adjusted mean treatment difference (standard error) and are expressed as the treatment difference (standard error) between the 2 treatment groups. Ninety-five percent confidence intervals on the within-group and between-group differences were computed on the basis of adjusted means and standard errors. All treatment comparisons were based on two-sided tests with an ␣-level of 0.05. A treatment comparison of randomization IOP data was performed using a one-way analysis of variance. Demographic characteristics were summarized using the Fisher exact test for categorical data and a one-way analysis of variance for continuous data. Lack of test drug efficacy that necessitated withdrawal from the study was determined by the investigator at each follow-up visit

Completed Discontinued Lack of efficacy Adverse experiences Other

117 (81) 27 (19) 10 (7) 8 (6) 9 (6)

113 (76) 36 (24) 9 (6) 10 (7) 17 (11)

after randomization. The cumulative percentage of patients who discontinued because of lack of test drug efficacy during this 6-month trial was analyzed using Kaplan-Meier estimates and the log rank test. For each patient, the automated perimetry examination at the discontinuation visit was compared with the examination obtained at the screening visit, and degradation of visual field performance was noted by the investigator as an adverse experience. Tolerability data were gathered at randomization and after months 1, 3, and 6 of treatment. Tolerability data were obtained from both the study eye and the nonstudy eye. The tolerability analysis compared the relative frequency of any adverse experiences, drug-related adverse experiences, drug-related adverse experiences to discontinuation, serious adverse experiences, drugrelated serious adverse experiences, and ocular allergies during the course of the study. For the purpose of this study, the broad term of ocular allergy encompassed the diagnoses of blepharitis, allergic conjunctivitis, and hypersensitivity reaction. We hypothesized that the incidence of ocular allergy was less for dorzolamide/ timolol compared with brimonidine ⫹ timolol. For the tolerability analysis, subjects were grouped by the actual treatment regimen they received (as-treated approach). The Cochran-Mantel-Haenszel test with an ␣-level of 0.05 was used to compare tolerability data. Compliance with treatment was calculated for each randomly assigned patient who took at least one dose of study medication. Patients reported missed doses at study visits. The percentage of compliance was equal to the number of drops that were taken divided by the number of drops that were prescribed, multiplied by 100. Descriptive statistics were used to analyze compliance.

Results Population A total of 293 patients with ocular hypertension or primary openangle glaucoma were randomly assigned at 29 sites. One site did not screen any patients for the study, and another site screened but did not randomly assign any patients. Two hundred thirty patients completed the study: 117 patients in the dorzolamide/timolol group and 113 patients in the brimonidine ⫹ timolol group (Table 1). The treatment groups were similar with respect to gender, age, qualifying disease condition, and hour-2 IOP at randomization (Table 2). The distribution of race was different between treatment groups (P ⫽ 0.047). More black patients were enrolled in the dorzolamide/timolol group (27.8%) than in the brimonidine ⫹ timolol group (16.1%). A total of 144 patients were randomly assigned to the dorzolamide/timolol group, and 149 patients were randomly assigned to the brimonidine ⫹ timolol group; however, 2 of the patients randomly assigned to receive dorzolamide/timolol and 3 of the patients randomly assigned to receive brimonidine ⫹ timolol were

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Ophthalmology Volume 110, Number 3, March 2003 Table 2. Patient Characteristics Dorzolamide/Timolol N ⴝ 144

Brimonidine ⴙ Timolol N ⴝ 149

Total N ⴝ 293

77 (53.5%) 67 (46.5%)

73 (49.0%) 76 (51.0%)

150 (51.2%) 143 (48.8%)

64.9 10.7 36–89

63.7 12.0 33–93

64.3 11.4 33–93

92 (63.9%) 40 (27.8%) 12 (8.3%) 0 24.4

108 (72.5%) 24 (16.1%) 15 (10.1%) 2 (1.3%) 24.3

200 (68.3%) 64 (21.8%) 27 (9.2%) 2 (0.7%)

110 (76.4%)† 36 (25.0%)†

115 (77.2%)† 37 (24.8%)†

225 (76.8%) 73 (24.9%)

Gender Female Male Age (yrs) Mean Standard deviation Range Race* White Black Hispanic American Native American Mean hour-2 intraocular pressure at randomization (mmHg) Presenting condition Primary open-angle glaucoma Ocular hypertension

*P ⫽ 0.047 Five patients presented with ocular hypertension in one eye and primary open-angle glaucoma in the fellow eye.

†

inadvertently administered the other treatment regimen through the study. Thus, the MITT efficacy analysis grouped subjects according to their randomized treatment allocation (i.e., subjects were analyzed according to their assigned treatment and not their received treatment). These 5 subjects who received the incorrect treatment were excluded from the per-protocol efficacy analysis. Also, an additional 12 subjects took an incorrect regimen (for example, concomitant dorzolamide/timolol and timolol solutions) at some time during the study. As previously, these subjects were grouped according to their randomized treatment allocation for the MITT efficacy analysis and were excluded from the per-protocol efficacy analysis for those time points impacted by the incorrect regimen. For the tolerability analysis, all subjects were grouped according to the actual treatment received; for example, the 2 subjects who were randomly assigned to dorzolamide/timolol but actually received brimonidine ⫹ timolol were considered as brimonidine ⫹

timolol patients for the tolerability analysis. Eight subjects received an incorrect regimen at some time during the study that involved both dorzolamide and brimonidine, and these subjects were grouped according to their randomized treatment allocation for the tolerability analysis.

Efficacy MITT Analysis Hour 2 IOP data are seen in Table 3 and Figure 1. At month 1, the dorzolamide/timolol group had a change in hour-2 IOP of ⫺4.82 (0.27) mmHg versus ⫺5.49 (0.27) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.67 (0.36) mmHg (95% CI of ⫺0.04 –1.38 mmHg). At month 3, the dorzolamide/ timolol group had a change in hour-2 IOP of ⫺5.04 (0.30) mmHg versus ⫺5.41 (0.30) mmHg in the brimonidine ⫹ timolol group,

Table 3. Hour 2 Intraocular Pressure (Modified Intent-to-Treat Analysis)

Month 1 Randomization IOP ⫾ SD (mmHg) Month 1 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 3 Randomization IOP ⫾ SD (mmHg) Month 3 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 6 Randomization IOP ⫾ SD (mmHg) Month 6 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI

Dorzolamide/Timolol

Brimonidine ⴙ Timolol

n ⫽ 138 24.44 ⫾ 2.78 19.65 ⫾ 3.39 ⫺4.82 ⫾ 0.27 (⫺5.34, ⫺4.29) n ⫽ 140 24.42 ⫾ 2.76 19.49 ⫾ 4.03 ⫺5.04 ⫾ 0.30 (⫺5.63, ⫺4.46) n ⫽ 140 24.42 ⫾ 2.76 20.00 ⫾ 3.90 ⫺4.59 ⫾ 0.29 (⫺5.16, ⫺4.02)

n ⫽ 136 24.29 ⫾ 2.79 18.87 ⫾ 3.82 ⫺5.49 ⫾ 0.27 (⫺6.02, ⫺4.96) n ⫽ 139 24.33 ⫾ 2.79 19.04 ⫾ 3.89 ⫺5.41 ⫾ 0.30 (⫺5.99, ⫺4.82) n ⫽ 139 24.33 ⫾ 2.79 19.44 ⫾ 3.94 ⫺5.07 ⫾ 0.29 (⫺5.65, ⫺4.49)

Treatment Difference

P Value 0.659

0.67 ⫾ 0.36 (⫺0.04, 1.38)

0.062 0.784

0.36 ⫾ 0.40 (⫺0.42, 1.14)

0.360 0.784

0.48 ⫾ 0.39 (⫺0.29, 1.25)

0.219

P values for randomization intraocular pressure between-treatment comparison are based on two-sample t tests. Adjusted means and standard errors and between- and within-treatment comparisons are based on analysis of covariance models with terms for treatment group, study site, and randomization intraocular pressure. CI ⫽ confidence interval; IOP ⫽ intraocular pressure; SD ⫽ standard deviation; SE ⫽ standard error.

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Sall et al 䡠 Dorzolamide/Timolol Combination vs. Brimonidine and Timolol

Figure 1. Mean change from baseline in hour-2 intraocular pressure. SE ⫽ standard error.

with a treatment difference of 0.36 (0.40) mmHg (95% CI of ⫺0.42–1.14 mmHg). At month 6, the dorzolamide/timolol group had a change in hour-2 IOP of ⫺4.59 (0.29) mmHg versus ⫺5.07 (0.29) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.48 (0.39) mmHg (95% CI of ⫺0.29 –1.25 mmHg). Hour-0 IOP data are seen in Table 4 and Figure 2. At month 1, the dorzolamide/timolol group had a change in hour-0 IOP of ⫺3.32 (0.26) mmHg versus ⫺3.69 (0.25) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.37 (0.35) mmHg (95%CI of ⫺0.31–1.05 mmHg). At month 3, the dorzolamide/timolol group had a change in hour-0 IOP of ⫺3.66 (0.29) mmHg versus ⫺4.15 (0.28) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.49 (0.39) mmHg (95% CI of ⫺0.27–1.25 mmHg). At month 6, the dorzolamide/

timolol group had a change in hour-0 IOP of ⫺3.12 (0.28) mmHg versus ⫺3.82 (0.27) mmHg in the brimonidine ⫹ timolol group, with a treatment difference of 0.70 (0.37) mmHg (95% CI of ⫺0.04 –1.43 mmHg).

Per-Protocol Analysis At each time point, subjects could be excluded from the perprotocol analyses for one or more reasons. For example, the most common events that excluded 80 subjects from the month-3, hour-2 per-protocol analysis were the occurrence of exclusionary conditions, medications, or procedures during the study; subject discontinuation from the study before the month-3 visit interval; poor compliance during the study; and administration of the in-

Table 4. Hour 0 Intraocular Pressure (Modified Intent-to-Treat Analysis)

Month 1 Randomization IOP ⫾ SD (mmHg) Month 1 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 3 Randomization IOP ⫾ SD (mmHg) Month 3 IOP ⫾ SD (mmHg) Change in IOP, (adjusted mean ⫾ SE (mmHg) 95% CI Month 6 Randomization IOP ⫾ SD (mmHg) Month 6 IOP ⫾ SD (mmHg) Change in IOP, (adjusted mean ⫾ SE (mmHg) 95% CI

Dorzolamide/Timolol

Brimonidine ⴙ Timolol

n ⫽ 141 25.14 ⫾ 3.31 22.00 ⫾ 3.89 ⫺3.32 ⫾ 0.26 (⫺3.84, ⫺2.80) n ⫽ 143 25.16 ⫾ 3.28 21.75 ⫾ 4.18 ⫺3.66 ⫾ 0.29 (⫺4.24, ⫺3.08) n ⫽ 143 25.16 ⫾ 3.28 22.22 ⫾ 3.93 ⫺3.12 ⫾ 0.28 (⫺3.68, ⫺2.56)

n ⫽ 145 25.05 ⫾ 3.51 21.56 ⫾ 3.98 ⫺3.69 ⫾ 0.25 (⫺4.19, ⫺3.19) n ⫽ 147 25.03 ⫾ 3.50 21.13 ⫾ 3.99 ⫺4.15 ⫾ 0.28 (⫺4.71, ⫺3.59) n ⫽ 147 25.03 ⫾ 3.50 21.44 ⫾ 4.06 ⫺3.82 ⫾ 0.27 (⫺4.36, ⫺3.28)

Treatment Difference

P Value 0.811

0.37 ⫾ 0.35 (⫺0.31, 1.05)

0.289 0.759

0.49 ⫾ 0.39 (⫺0.27, 1.25)

0.208 0.759

0.70 ⫾ 0.37 (⫺0.04, 1.43)

0.063

P values for randomization intraocular pressure between-treatment comparison are based on two-sample t tests. Adjusted means and standard errors and between- and within-treatment comparisons are based on analysis of covariance models with terms for treatment group, study site, and randomization intraocular pressure. CI ⫽ confidence interval; IOP ⫽ intraocular pressure; SD ⫽ standard deviation; SE ⫽ standard error.

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Figure 2. Mean change from baseline in hour-0 intraocular pressure. SE ⫽ standard error.

correct treatment at some time during the study. The per-protocol efficacy analysis appears in Tables 5 (hour-2) and 6 (hour-0). Of note are the month-3, hour-2 treatment difference of 0.90 (0.45) mmHg (95% CI of 0.02–1.78 mmHg) favoring brimonidine ⫹ timolol, and the month-1, hour-0 treatment difference of ⫺0.04 (0.36) mmHg (95% CI of ⫺0.76 – 0.67 mmHg) favoring dorzolamide/timolol, because these results differ from the corresponding time points of the MITT analysis.

group and 9 subjects in the brimonidine ⫹ timolol group. At month 1, the Kaplan-Meier estimates were 0% for the dorzolamide/timolol group and 1% for the brimonidine ⫹ timolol group. At month 3, the estimates were 2.9% for the dorzolamide/timolol group and 3.5% for the brimonidine ⫹ timolol group, and at month 6, the estimates were 7.6% for the dorzolamide/timolol group and 6.7% for the brimonidine ⫹ timolol group. The Kaplan-Meier curves were not statistically different (P ⬎ 0.50) and are displayed in Figure 3.

Discontinuations Because of Lack of Test Drug Efficacy

Visual Field Examinations

Nineteen subjects were discontinued from the study because of lack of test drug efficacy: 10 subjects in the dorzolamide/timolol

Three subjects had visual field examinations that worsened since their baseline examination. All three subjects were randomly assigned to the brimonidine ⫹ timolol treatment group.

Table 5. Hour 2 Intraocular Pressure (Per-Protocol Analysis)

Month 1 Randomization IOP ⫾ SD (mmHg) Month 1 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 3 Randomization IOP ⫾ SD (mmHg) Month 3 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 6 Randomization IOP ⫾ SD (mmHg) Month 6 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI

Dorzolamide/Timolol

Brimonidine ⴙ Timolol

n ⫽ 103 24.48 ⫾ 2.85 19.60 ⫾ 3.27 ⫺4.88 ⫾ 0.30 (⫺5.48, ⫺4.29) n ⫽ 98 24.41 ⫾ 2.62 19.62 ⫾ 3.96 ⫺4.87 ⫾ 0.34 (⫺5.54, ⫺4.20) n ⫽ 85 24.37 ⫾ 2.55 19.93 ⫾ 3.24 ⫺4.54 ⫾ 0.35 (⫺5.22, ⫺3.86)

n ⫽ 107 24.43 ⫾ 2.91 19.19 ⫾ 3.69 ⫺5.23 ⫾ 0.29 (⫺5.81, ⫺4.66) n ⫽ 101 24.34 ⫾ 2.85 18.76 ⫾ 3.45 ⫺5.77 ⫾ 0.33 (⫺6.42, ⫺5.12) n ⫽ 88 24.23 ⫾ 2.86 19.23 ⫾ 3.49 ⫺4.96 ⫾ 0.34 (⫺5.62, ⫺4.30)

Treatment Difference

P Value 0.906

0.35 ⫾ 0.40 (⫺0.44, 1.14)

0.384 0.862

0.90 ⫾ 0.45 (0.02, 1.78)

0.046 0.732

0.42 ⫾ 0.46 (⫺0.48, 1.33)

0.358

P values for randomization intraocular pressure between-treatment comparison are based on two-sample t tests. Adjusted means and standard errors and between- and within-treatment comparisons are based on analysis of covariance models with terms for treatment group, study site, and randomization intraocular pressure. CI ⫽ confidence interval; IOP ⫽ intraocular pressure; SD ⫽ standard deviation; SE ⫽ standard error.

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Sall et al 䡠 Dorzolamide/Timolol Combination vs. Brimonidine and Timolol

Figure 3. Discontinuations because of lack of test drug efficacy.

Tolerability During the 3-week timolol run-in period, 28 subjects (10%) reported an adverse experience. Seven subjects reported adverse experiences that were deemed drug-related by the investigator, but no drug-related adverse experiences resulted in discontinuation. The most common drug-related adverse experiences observed during the timolol run-in period were ophthalmic itching (2 subjects) and superficial punctate keratitis (2 subjects). No subjects reported adverse experiences that were deemed serious in nature during the run-in period. No diagnoses consistent with ocular allergy were made during the run-in period. Active treatment period adverse experiences are summarized in Table 7. During the 6-month active treatment period, 111 patients (77%) in the dorzolamide/timolol group and 105 patients (71%) in the brimonidine ⫹ timolol group reported an adverse experience. Ninety-three subjects (64%) in the dorzolamide/timolol group and 88 subjects (60%) in the brimonidine ⫹ timolol group reported adverse experiences that were deemed drug related by the inves-

tigator. Discontinuation because of a drug-related adverse event occurred in 7 subjects (5%) and 8 subjects (5%) in the dorzolamide/timolol group and brimonidine ⫹ timolol group, respectively. These differences were not statistically significant. The most common drug-related adverse experiences reported during the active treatment period are listed in Table 8. Five subjects in each treatment group (3%) reported a total of 15 adverse experiences that were deemed serious in nature by the investigators. The specific conditions are listed in Table 7. Of these, two of the serious adverse experiences in the brimonidine ⫹ timolol group were judged by the investigator to be drug related (congestive heart failure in a 59-year-old female and atrial fibrillation in an 85-year-old female). No serious adverse experiences in the dorzolamide/timolol group were deemed drug related. These differences were not statistically significant. Seven subjects (5%) in the dorzolamide/timolol treatment group and 11 subjects (7%) in the brimonidine ⫹ timolol treatment group received a diagnosis consistent with ocular allergy during

Table 6. Hour 0 Intraocular Pressure (Per-Protocol Analysis)

Month 1 Randomization IOP ⫾ SD (mmHg) Month 1 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 3 Randomization IOP ⫾ SD (mmHg) Month 3 IOP ⫾ SD (mmHg) Change in IOP, adjusted mean ⫾ SE (mmHg) 95% CI Month 6 Randomization IOP ⫾ SD (mmHg) Month 6 IOP ⫾ SD (mmHg) Change in IOP, (adjusted mean ⫾ SE (mmHg) 95% CI

Dorzolamide/Timolol

Brimonidine ⴙ Timolol

n ⫽ 103 25.31 ⫾ 3.54 21.93 ⫾ 3.59 ⫺3.33 ⫾ 0.27 (⫺3.87, ⫺2.79) n ⫽ 98 25.23 ⫾ 3.32 21.74 ⫾ 3.96 ⫺3.60 ⫾ 0.33 (⫺4.25, ⫺2.96) n ⫽ 85 25.15 ⫾ 3.30 22.11 ⫾ 3.30 ⫺2.98 ⫾ 0.33 (⫺3.62, ⫺2.33)

n ⫽ 109 25.06 ⫾ 3.42 21.81 ⫾ 3.76 ⫺3.29 ⫾ 0.26 (⫺3.81, ⫺2.77) n ⫽ 103 24.99 ⫾ 3.43 21.35 ⫾ 3.87 ⫺3.93 ⫾ 0.32 (⫺4.55, ⫺3.31) n ⫽ 88 25.05 ⫾ 3.55 21.58 ⫾ 3.89 ⫺3.47 ⫾ 0.32 (⫺4.10, ⫺2.84)

Treatment Difference

P Value 0.597

⫺0.04 ⫾ 0.36 (⫺0.76, 0.67)

0.909 0.606

0.33 ⫾ 0.43 (0.52, 1.17)

0.444 0.851

0.49 ⫾ 0.43 (⫺0.37, 1.34)

0.259

P values for randomization intraocular pressure between-treatment comparison are based on two-sample t tests. Adjusted means and standard errors and between- and within-treatment comparisons are based on analysis of covariance models with terms for treatment group, study site, and randomization intraocular pressure. CI ⫽ confidence interval; IOP ⫽ intraocular pressure; SD ⫽ standard deviation; SE ⫽ standard error.

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Ophthalmology Volume 110, Number 3, March 2003 Table 7. Adverse Experiences Patients with One or More. . . AE Drug-related* AE Discontinued due to drug-related* AE Serious AE† Drug-related* serious AE Ocular allergy

Dorzolamide/Timolol N ⴝ 145 (%)

Brimonidine ⴙ Timolol N ⴝ 148 (%)

111 (77) 93 (64) 7 (5)

105 (71) 88 (60) 8 (5)

5 (3) 0

5 (3) 2 (1)

7 (5)

11 (7)

*Determined by the investigator to be possibly, probably, or definitely drug-related. † Serious adverse experiences: Dorzolamide/timolol (5 patients): allergic reaction to iodine, benign atrial myxoma, parathyroid hyperplasia, pneumonia, traumatic amputation of finger and thumb. Brimonidine ⫹ timolol (5 patients): atrial fibrillation ⫹ stroke, myocardial infarction ⫹ congestive heart failure ⫹ mediastinitis, congestive heart failure, coronary artery disease, cystoid macular edema ⫹ venous stasis retinopathy ⫹ neovascular rubeotic glaucoma. The differences between treatment groups were not statistically significant. AE ⫽ adverse experiences.

the active treatment period of the study. This difference was not statistically significant.

Compliance Compliance was similar between treatment groups (mean compliance was 95% and 93% in the dorzolamide/timolol and brimonidine ⫹ timolol groups, respectively). In the dorzolamide/ timolol group, 6% of subjects were less than 80% compliant compared with 11% in the brimonidine ⫹ timolol group.

Discussion The dorzolamide/timolol fixed combination ophthalmic solution and the concomitant use of brimonidine and timolol ophthalmic solutions represent two frequently used options in the care of glaucoma patients who require treatment beyond topical ␤-blocker monotherapy. To date, however, there had been no previous comparisons of efficacy and tolerability between these regimens as frequently used in current ophthalmologic practice. The purpose of this study was to compare these commonly used regimens with respect to several efficacy and tolerability parameters. Because of the complexity of chemical stability, sterility, and container testing if medications were transferred to another container or if a masking label was applied to the medication bottles, an observer-masked design was selected. Subjects were aware of their assigned therapy. Although not a double-masked design, subjects were continually reminded to not reveal their assigned therapy to the investigator. For each study site, an unmasked person allocated and managed the active treatment period medication(s) but remained isolated from the rest of the study, and all efficacy and tolerability evaluations were performed by masked investigators. This study enrolled patients with primary open-angle

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Table 8. Number of Patients with Drug-Related Adverse Experiences (Incidence ⬎ 3% in Any Treatment Group) Dorzolamide/Timolol Brimonidine ⴙ Timolol N ⴝ 145 N ⴝ 148 Ocular burning* Taste perversion* Ocular stinging† Conjunctival injection Oral dryness Ophthalmic itching Asthenia/fatigue Blurred vision Blepharitis Follicular conjunctivitis

59 (41%) 37 (26%) 32 (22%) 23 (16%) 21 (15%) 21 (15%) 14 (10%) 7 (5%) 5 (3%) 3 (2%)

29 (20%) 14 (10%) 18 (12%) 24 (16%) 30 (20%) 21 (14%) 20 (14%) 5 (3%) 3 (2%) 10 (7%)

*P value ⬍ 0.001. † P value ⫽ 0.024. Unless noted, any difference in relative frequency of a specific adverse experience was not significantly different. Patients were permitted to describe several ocular symptoms at any given time (e.g. ocular burning, stinging, and itching).

glaucoma or ocular hypertension. For this study, the treatment groups were well matched, with similar age and gender distributions. Hour-2 IOP levels at randomization were also similar, as were the proportions of patients with primary open-angle glaucoma and ocular hypertension. The brimonidine ⫹ timolol group contained a smaller proportion of black subjects than did the dorzolamide/timolol group. However, there are no existing reports in the literature of differential efficacy of brimonidine, dorzolamide, or timolol according to race. The efficacy of these regimens was compared at 2 diurnal time points: at trough, just before the morning dose of study medications (hour-0), and at peak, 2 hours after the morning dose of the study medications (hour-2). These time points capture the full range of efficacy with a relatively short study visit. We compared these time points at 3 intervals: after 1, 3, and 6 months of treatment, to reflect current ophthalmologic practice. The month-3, hour-2 IOP was chosen as the primary efficacy end point, because it reflected a typical time at which the efficacy of an antiglaucoma medication is observed in a clinical setting; that is, after several months of therapy and after the morning dose of medication on that particular day. In this study, the 2 treatment regimens had comparable efficacy at all observed time points. Comparability was demonstrated at month 3, hour-2 to satisfy the primary hypothesis of this study. In addition, comparability was also demonstrated at month 3, hour-0, and at all other hour-2 measurements (months 1 and 6) and hour-0 measurements (months 1 and 6). The per-protocol efficacy analysis was conducted to compare the results of the study population at large against the results of those subjects who rigidly adhered to the protocol. Although the factors that excluded subjects from the per-protocol analysis were examined, it is believed that the results were generally consistent with those of the MITT analysis, with treatment differences consistent at 4 of the 6 time points in the study. The month-3, hour-2 treatment difference of 0.90 mmHg favoring brimonidine ⫹ timolol

Sall et al 䡠 Dorzolamide/Timolol Combination vs. Brimonidine and Timolol was greater than the corresponding MITT value of 0.36 mmHg, and the month-1, hour-0 treatment difference of 0.04 mmHg favoring dorzolamide/timolol was different than the corresponding MITT value of 0.3 mmHg favoring brimonidine ⫹ timolol. The most common reason that subjects were excluded from the per-protocol analysis was an encroachment on entry criteria after randomization. Subjects who developed or recalled exclusionary conditions after randomization, patients whose medication regimen changed in a manner that could potentially confound subsequent efficacy or tolerability evaluations, or subjects who underwent exclusionary ocular procedures after randomization were excluded from the per-protocol analysis. A second portion of subjects were excluded from this analysis because they discontinued from the study before the month-3 visit interval. Their previous observations were carried forward for the MITT analysis but were considered to be exclusionary from the per-protocol analysis. A third portion of subjects was excluded because of poor compliance. Subjects who took less than 14 days of timolol during the 3-week run-in period or who reported compliance of ⱕ80% or ⱖ120% during the active treatment phase were excluded. Twelve additional subjects were excluded because they were randomly assigned to one treatment group but actually received the other treatment, or were administered an incorrect regimen (for example, concomitant dorzolamide/ timolol and timolol solutions) at some time during the study. This study was used to pilot a study drug distribution system through a third-party retail pharmacy distributor, and, in these cases, the drug allocation schedules were not accurately followed. However, the MITT efficacy analysis, which grouped subjects according to the assigned treatment arm, and the per-protocol analysis, which excluded subjects who received the incorrect treatment regimen, were generally consistent. The rate of discontinuation because of lack of test drug efficacy was similar in both treatment groups at all follow-up intervals; this finding was consistent with comparable efficacy profiles. The incidence of reported adverse experiences was relatively high in both treatment groups. As expected, most adverse experiences for both treatment groups were drug related and ocular in nature. The most common drug-related adverse experiences for dorzolamide/timolol observed in this study (burning, stinging, and dysgeusia) were consistent with previous observations.3–5 Similarly, the most common drug-related adverse experiences for brimonidine ⫹ timolol observed in this study (dry mouth, conjunctival injection, and ophthalmic burning) had previously been noted.9 Despite similar overall rates, the distribution of drug-related adverse-experience symptoms is different, with a relatively narrow distribution of adverse symptoms for the dorzolamide/timolol combination and a relatively broad distribution for concomitant brimonidine ⫹ timolol. The relatively narrow distribution of adverse symptoms for the dorzolamide/timolol combination generated statistically more burning, stinging, and dysgeusia compared with the brimonidine ⫹ timolol regimen. Despite the prominence of

drug-related adverse experiences, very few subjects in either treatment group actually discontinued participation in the study because of adverse experiences. The hypothesis that dorzolamide/timolol would have a lower incidence of ocular allergy compared with brimonidine ⫹ timolol was not satisfied; in this study, the relative incidence of ocular allergy was similar between the treatment groups. However, this study was not powered to detect a difference in the incidence of ocular allergy but was powered to address the efficacy hypothesis. Subject-reported compliance with both treatment regimens in this study was very high. A high level of compliance is anticipated in the relatively controlled environment of a clinical drug trial.10,11 However, compliance in this study was measured only from subject reporting at follow-up study visits. This method of compliance assessment may have been confounded by factors such as subject recall of missed doses and overestimation of compliance in an attempt to satisfy the perceived expectations of study investigators. The purpose of this study was to compare the dorzolamide/timolol fixed combination ophthalmic solution and the concomitant use of brimonidine and timolol ophthalmic solutions with respect to several efficacy and tolerability parameters. The results of this study were consistent with earlier reports of comparable efficacy and tolerability observed when dorzolamide and brimonidine were compared as monotherapies. One would expect that the addition of the same agent —timolol—to dorzolamide and brimonidine would preserve comparable efficacy and tolerability profiles. This study, indeed, demonstrated comparable efficacy and tolerability profiles for these dual-therapy regimens as they are typically administered in current ophthalmologic practice. These results provide the practitioner 2 comparable options when therapy beyond topical ␤-blockers is required. Acknowledgments. Participating Investigators: Frank Ashburn, MD, Arthur Barlis, MD, Louis Cantor, MD, Douglas Day, MD, Monte Dirks, MD, Harvey Dubiner, MD, Richard Evans, MD, William Flynn, MD, Brennan Greene, MD, Linda Greff, MD, David Karp, MD, Theodore Krupin, MD, Charles Lederer, MD, Norman Levy, MD, Richard Lewis, MD, Jeffrey Liebmann, MD, Jacqueline Lustgarten, MD, Thomas Mundorf, MD, Robert Noecker, MD, Jonathan Nussdorf, MD, Edward Rockwood, MD, Kenneth Sall, MD, Howard Schenker, MD, Janet Serle, MD, Elizabeth Sharpe, MD, Les Siegel, MD, George Spaeth, MD, William Stewart, MD, Lloyd Suter, MD, Tom Walters, MD, Robert Williams, MD.

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