Journal of Glaucoma 11:119–126
`© 2002 Lippincott Williams & Wilkins, Inc.
`
`Twelve-Month Evaluation of Brimonidine-Purite Versus
`Brimonidine in Patients With Glaucoma or Ocular Hypertension
`
`L. Jay Katz, MD
`
`Brimonidine-Purite Study Groups 1 and 2, Wills Eye Hospital, Philadelphia, Pennsylvania
`
`Purpose: To compare the efficacy and safety of brimonidine-Purite (Alphagan;
`Allergan, Irvine, CA) 0.15% and 0.2% three times daily with brimonidine (Alphagan)
`0.2% three times daily in patients with glaucoma or ocular hypertension.
`Patients and Methods: In this 12-month, randomized, multicenter, double-
`masked, parallel-group study, patients were randomly assigned to receive brimonidine-
`Purite 0.15% (n ⳱ 381), brimonidine-Purite 0.2% (n ⳱ 383), or brimonidine 0.2% (n
`⳱ 383) three times daily. Visits were conducted before the study, at baseline, at weeks
`2 and 6, and at months 3, 6, 9, and 12. Diurnal intraocular pressure was measured at
`8 AM, 10 AM, 3 PM, and 5 PM at baseline, week 6, and at months 3, 6, and 12. Intraocular
`pressure was also measured at 8 and 10 AM at week 2 and month 9. Safety was
`evaluated by adverse events and other ocular and systemic measures.
`Results: At baseline, mean intraocular pressure was similar in the three treatment
`groups. During follow-up, there were no statistically significant among-group differ-
`ences in mean intraocular pressure or mean changes from baseline intraocular pressure
`(at peak or trough). The difference in mean intraocular pressure between the bri-
`monidine-Purite-0.15% and brimonidine-0.2% treatment group was less than 1 mm Hg
`at all time points. The relative percent difference in allergic conjunctivitis was 41%
`lower in the brimonidine-Purite 0.15% group compared with the brimonidine 0.2%
`group. The comfort and satisfaction rating significantly favored brimonidine-Purite
`0.15%.
`Conclusions: Over 12-months, brimonidine-Purite 0.15% and 0.2% provided in-
`traocular pressure lowering comparable with brimonidine 0.2% in patients with glau-
`coma or ocular hypertension. Brimonidine-Purite 0.15% showed the most favorable
`safety and tolerability profile with a reduced incidence of allergic conjunctivitis and
`better satisfaction and comfort rating.
`Key Words: Benzalkonium chloride—Brimonidine—Glaucoma—Ocular hyper-
`tension—Purite.
`
`Since the introduction of brimonidine 0.2% ophthal-
`mic solution (Alphagan; Allergan, Irvine, CA) in 1996,
`this highly selective ␣
`2-adrenergic agonist has proven to
`be an effective and safe agent for the long-term manage-
`ment of glaucoma and ocular hypertension.1 In a ran-
`
`Received May 9, 2001; accepted August 7, 2001.
`Members of the Brimonidine-Purite Study Groups 1 and 2 are listed
`in the Appendix at the end of this article.
`Supported by Allergan (Irvine, CA).
`Address correspondence and reprint requests to L. Jay Katz, MD,
`Wills Eye Hospital, 900 and Walnut Street, Philadelphia, PA 19107-
`5599. E-mail: ljk22222@aol.com
`
`domized, continuous clinical trial, the efficacy of bri-
`monidine 0.2% twice daily was sustained over 4 years
`and was comparable with the efficacy of timolol
`0.5%.2–6 Additional studies have shown the flexibility of
`brimonidine 0.2% twice daily as an effective mono-
`therapy, adjunctive, and replacement therapy.7–9 Bri-
`monidine 0.2% twice daily has become a widely ac-
`cepted first- and second-line therapy for the long-term
`management of glaucoma and ocular hypertension.
`Studies show that brimonidine 0.2% has a lower risk
`of systemic adverse events than topical ␤-block-
`ers.2,3,7,10,11 In addition, brimonidine 0.2% has a lower
`
`119
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`120
`
`L. J. KATZ
`
`incidence of ocular allergy and shows no cross toxicity
`compared with apraclonidine (Iopidine; Alcon, Fort
`Worth, TX).12 Reports of ocular allergy associated with
`chronic brimonidine therapy range from 4.2% to 12.7%
`of patients, depending on the diagnostic criteria and du-
`ration of therapy.1,4,13
`A new formulation of brimonidine ophthalmic solu-
`tion has been developed to enhance safety and tolerabil-
`ity while maintaining effective intraocular pressure
`(IOP) reduction. Brimonidine-Purite (Alphagan, Aller-
`gan, Irvine, CA) has a different preservative and a lower
`concentration of active drug than the original bri-
`monidine 0.2% (Alphagan). In the reformulation, the
`preservative has been changed from benzalkonium chlo-
`ride (BAK) to Purite. Benzalkonium chloride is the most
`common antimicrobial preservative used in topical mul-
`tiuse ophthalmic preparations, including most glaucoma
`medications.14,15 It works by denaturing proteins, lysing
`cytoplasmic membranes, and oxidizing enzymes. At high
`concentrations, BAK may be more toxic than other pre-
`servatives. It can accumulate and remain in ocular tissue
`for relatively lengthy periods, and may induce cell death
`in a dose-dependent manner.16,17 Because glaucoma is a
`chronic disease and patients may be taking multiple glau-
`coma medications, these patients may be exposed to high
`concentrations of BAK with potentially detrimental ocu-
`lar effects. In contrast, Purite is a stabilized oxychloro
`complex and oxidative preservative used in Refresh
`Tears (Allergan, Irvine, CA) artificial eye lubricant and
`Lens Plus Purite (Allergan, Irvine, CA) Saline.18–20
`When Purite is exposed to light, it is converted to natural
`tear components (i.e., sodium and chloride ions, oxygen,
`and water).21 Purite is a microbicide with a wide spec-
`trum of antimicrobial activity and a very low level of
`toxicity in mammalian cells.22
`In addition to the change in preservative, brimonidine-
`Purite 0.15% contains 25% less active drug than original
`brimonidine 0.2%. Animal studies suggest that bri-
`monidine tartrate has enhanced ocular bioavailability
`when formulated as brimonidine-Purite.23 In addition,
`0.15% is the lowest effective concentration tested, which
`attains the desired therapeutic effect.24 Therefore, the
`new formulation of brimonidine may provide an im-
`proved safety and tolerability profile with comparable
`efficacy.
`The objective of this study was to evaluate the safety
`and efficacy of brimonidine-Purite 0.15% and 0.2%
`compared with brimonidine 0.2%. The results represent
`the pooled analyses of two identically designed clinical
`trials. All three study medications were administered
`three times daily for 1 year in patients with glaucoma or
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
`ocular hypertension. Although brimonidine twice daily
`has been shown to be as effective as three-times-daily
`brimonidine,24,25 the three-times-a-day dosage was se-
`lected for this study to satisfy US regulatory require-
`ments.
`
`PATIENTS AND METHODS
`
`Study Design
`
`Two identically designed, 12-month, double-masked,
`randomized, parallel-group studies were conducted at 44
`sites across the United States. The results presented here
`are from the analyses of pooled data from these two
`clinical trials. The studies were conducted in accordance
`with Institutional Review Board and Informed Consent
`Regulations. Each investigator obtained appropriate re-
`view board approval before study initiation. All patients
`gave their written consent before participating in any
`study-related activities. Patients who were treated with
`ocular hypotensive medications before study entry were
`required to undergo a washout period ranging from 4 to
`28 days, depending on the medication taken. This wash-
`out eliminated any potential residual effects of previous
`therapy.
`Patients were randomly assigned to receive bri-
`monidine-Purite 0.15% (n ⳱ 381), brimonidine-Purite
`0.2% (n ⳱ 383), brimonidine 0.2% (n ⳱ 383) three
`times daily in the morning (7:30–8:30 AM), in the mid-
`afternoon (2:30–3:30 PM), and in the evening (9:30–
`10:30 PM). Scheduled visits occurred before study, at
`baseline, at weeks 2 and 6, and at months 3, 6, 9, and 12.
`
`Criteria
`
`Key inclusion criteria included an age of 18 years or
`older with a diagnosis of glaucoma (primary open angle,
`pseudoexfoliative, pigment dispersion, chronic angle
`closure with a patent peripheral iridectomy/iridotomy for
`at least 3 months) or ocular hypertension (IOP ⱖ 22 mm
`Hg, ⱕ 34 mm Hg in each eye after washout, with be-
`tween-eye IOP asymmetry ⱕ 5 mm Hg), likelihood to be
`controlled on monotherapy, negative pregnancy test for
`women of childbearing potential, and best corrected vi-
`sual acuity of 20/100 or better.
`Key exclusion criteria included uncontrolled systemic
`disease, other active ocular disease, abnormally low or
`high blood pressure or heart rate, anticipated alteration of
`existing chronic therapy with agents that could substan-
`tially affect IOP, use of ocular medication other than
`periodic use of artificial tears, and functionally signifi-
`cant visual field loss.
`
`PAGE 2 OF 8
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`

`
`NEW FORMULATION OF BRIMONIDINE
`
`121
`
`Efficacy Variables
`
`The primary efficacy variable was IOP. Diurnal IOP
`was measured at approximately 8 AM (before the morn-
`ing drop), 10 AM, 3 PM (before the afternoon drop), and
`5 PM at baseline, week 6, and at months 3, 6, and 12. The
`IOP was also measured at approximately 8 AM (before
`the morning drop) and 10 AM at week 2 and month 9.
`Other efficacy variables included clinical success as
`evaluated by the investigator (regardless of whether a
`physician recommended continuation of study medica-
`tion for the patient), subject satisfaction evaluation, and
`subject comfort evaluation using standardized scales.
`Other measures that were evaluated included adverse
`events, visual acuity, cup/disc ratio, biomicroscopy, oph-
`thalmoscopy, visual fields, heart rate, and systolic and
`diastolic blood pressure. The severity of adverse events
`was assessed based on the following guidelines: mild
`(awareness of sign or symptom, but easily tolerated),
`moderate (discomfort enough to cause interference with
`usual activity) and severe (incapacitating or unable to
`work or perform usual activities).
`
`Statistical Analysis
`
`The primary variables of analysis for efficacy were
`mean IOP and the mean change in IOP from baseline.
`These IOP data were analyzed using both the intent-to-
`treat with last observation carried forward and per-
`protocol populations. The per-protocol population con-
`sisted of observed cases. Only patients who met the pro-
`tocol entry criteria, had no major protocol violations,
`received study medication, and had at least one follow-
`up visit were included in the per-protocol analysis, and
`only data from visits within specified time windows were
`included. Decisions for per-protocol exclusions were
`made before unmasking of the treatment groups for
`analysis. Safety data were analyzed using the intent-to-
`treat population. For comparison of treatment efficacy,
`both noninferiority and a two-sided paired t test for su-
`periority were performed. Noninferiority criteria were set
`by the US Food and Drug Administration. Criteria were
`tested by constructing a two-sided 95% confidence in-
`terval for the between-group difference between experi-
`mental drug and brimonidine in mean IOP. If the upper
`limit of 95% confidence interval at all time points did not
`exceed 1.5 mm Hg, brimonidine-Purite was considered
`at least as effective as brimonidine.
`Nominal categorical data such as sex and race were
`analyzed by the Cochran-Mantel-Haenszel method and
`continuous variables such as age and blood pressure
`were analyzed using a two-way analysis of variance with
`
`factors of treatment group and investigator site. Adverse
`events were analyzed using the Pearson ␹2 test or Fisher
`exact test. Ordinal categorical variables such as comfort
`and safety data were analyzed using the stratum (inves-
`tigator site) adjusted Kruskal-Wallis and Wilcoxon rank-
`sum test.
`
`RESULTS
`
`Subject Demographics
`
`The demographics and clinical characteristics of pa-
`tients taking brimonidine-Purite 0.15% three times daily,
`brimonidine-Purite 0.2% three times daily, and bri-
`monidine 0.2% three times daily are summarized in
`Table 1. No significant between-group differences were
`noted in baseline demographics, which included mean
`patient age, gender, race, and iris color.
`
`Efficacy
`
`Criteria for the per-protocol analysis were met by
`97.9% (1,123 of 1,147) of patients (brimonidine-Purite
`0.15%, 97.6% [372 of 381 patients]; brimonidine-Purite
`0.2%, 97.9% [375 of 383 patients]; brimonidine 0.2%,
`98.2% [376 of 383 patients]) and 92% of all data points
`were included with a similar distribution across the treat-
`ments. Twenty-four patients did not meet the entry cri-
`teria as defined in the study protocol and were excluded
`from the efficacy analysis. Other key reasons for patient
`data exclusions from the per-protocol analysis included
`use of excluded medications during the study, inappro-
`priate instillation of study medications, and visits occur-
`ring outside of visit windows. There was no significant
`difference in the IOP results between the intent-to-treat
`and per-protocol analyses, and the per-protocol results
`are presented. The conclusions drawn from either intent-
`to-treat or per-protocol populations were the same.
`
`Overall IOP Efficacy
`
`At baseline, mean IOP was similar across the three
`treatment groups at each time point. Baseline mean IOP
`at 10 AM was 23.6 mm Hg (with an approximate SD of
`3.2 mm Hg). Baseline mean IOP at 8 AM was 24.9 mm
`Hg (with an approximate SD of 2.7 mm Hg) (Fig. 1 and
`2). Over the next 12 months, the difference in mean IOP
`at 10 AM (morning peak) (Fig. 1) and 8 AM (morning
`trough) (Fig. 2) between brimonidine-Purite 0.15% and
`brimonidine 0.2% was less than or equal to 0.4 mm Hg.
`The mean IOP for each group was within 1 mm Hg of
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
`PAGE 3 OF 8
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`

`
`122
`
`L. J. KATZ
`
`TABLE 1. Demographics and clinical characteristics of patients on brimonidine-Purite 0.15%, brimonidine-Purite 0.2%, and
`brimonidine 0.2%
`
`Brimonidine-Purite 0.15%
`(n ⳱ 381)
`
`Brimonidine-Purite 0.2%
`(n ⳱ 383)
`
`Brimonidine 0.2%
`(n ⳱ 383)
`
`Total (n ⳱ 1147)
`
`Variable
`
`Age (years)
`Mean
`SD
`Min
`Max
`Median
`Sex
`Male
`Female
`Race
`Caucasian
`Black
`Asian
`Hispanic
`Other
`Iris color
`Blue
`Brown
`Green
`Hazel
`Other
`
`No.
`
`63.4
`12.8
`22.4
`88.8
`64.7
`
`169
`212
`
`303
`48
`2
`28
`0
`
`113
`179
`23
`59
`7
`
`(%)
`
`44.4%
`55.6%
`
`79.5%
`12.6%
`0.5%
`7.3%
`0.0%
`
`29.7%
`47.0%
`6.0%
`15.5%
`1.8%
`
`No.
`
`63.8
`12.1
`25.4
`90.4
`65.8
`
`162
`221
`
`298
`59
`1
`23
`2
`
`108
`196
`18
`58
`3
`
`(%)
`
`42.3%
`57.7%
`
`77.8%
`15.4%
`0.3%
`6.0%
`0.5%
`
`28.2%
`51.2%
`4.7%
`15.1%
`0.8%
`
`No.
`
`62.7
`12.6
`25.2
`93.4
`64.2
`
`167
`236
`
`305
`47
`3
`26
`2
`
`111
`183
`18
`68
`3
`
`(%)
`
`No.
`
`(%)
`
`63.3
`12.5
`22.4
`93.4
`64.7
`
`498
`649
`
`906
`154
`6
`77
`4
`
`332
`558
`59
`185
`13
`
`43.4%
`56.6%
`
`79.0%
`13.4%
`0.5%
`6.7%
`0.3%
`
`28.9%
`48.6%
`5.1%
`16.1%
`1.1%
`
`43.6%
`56.4%
`
`79.6%
`12.3%
`0.8%
`6.8%
`0.5%
`
`29.0%
`47.8%
`4.7%
`17.8%
`0.8%
`
`P
`
`0.460
`
`0.845
`
`0.377
`
`0.468
`
`the mean IOP in the other groups at all visits and all time
`points, showing comparable IOP-lowering capabilities.
`
`Brimonidine-Purite 0.15% Versus
`Brimonidine 0.2%
`
`There were no statistically significant differences in
`diurnal mean IOP measurements between brimonidine-
`
`Purite 0.15% and brimonidine 0.2%, except at the 5-PM
`time point at month 3 (P ⳱ 0.046) where the mean IOP
`difference was 0.5 mm Hg in favor of brimonidine 0.2%.
`There were no statistically significant differences in the
`mean changes from baseline in diurnal IOP measure-
`ments, except for the 10-AM time point at week 2 (P ⳱
`0.015), the 5-PM time point at month 3 (P ⳱ 0.010), and
`the 5-PM time point at month 6 (P ⳱ 0.004). The mean
`
`FIG. 1. Efficacy graph at 10 AM (peak) showing mean intraocular pressure of patients with glaucoma or ocular hypertension during
`12-month treatment with brimonidine-Purite 0.15% and brimonidine 0.2% (Alphagan). The difference in mean intraocular pressure
`between the treatment groups was less than or equal to 0.4 mm Hg at all time points. All standard errors were less than 0.180.
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
`PAGE 4 OF 8
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`

`
`NEW FORMULATION OF BRIMONIDINE
`
`123
`
`FIG. 2. Efficacy graph at 8 AM (trough) showing mean intraocular pressure of patients with glaucoma or ocular hypertension during
`12-month treatment with brimonidine-Purite 0.15% and brimonidine 0.2% (Alphagan). All standard errors were less than 0.211.
`
`change from baseline IOP difference was 0.6, 0.7, and
`0.9 mm Hg, respectively favoring brimonidine 0.2%.
`The noninferiority criteria were satisfied because 40/40
`of the upper limits of 95% confidence intervals were less
`than or equal to 1.5 mm Hg, with 36/40 less than or equal
`to 1.0 mm Hg (mean IOP and mean change from baseline
`IOP), showing that brimonidine-Purite 0.15% was com-
`parable in efficacy with brimonidine 0.2%.
`
`Brimonidine-Purite 0.15% Versus
`Brimonidine-Purite 0.2%
`
`There were no statistically significant differences ob-
`served in mean IOP or mean changes from baseline in
`diurnal IOP measurements between brimonidine-Purite
`0.15% and brimonidine-Purite 0.2%, except at the 5-PM
`time point at month 3 (P ⳱ 0.027, mean IOP), the 10-AM
`time point at month 9 (P ⳱ 0.009, mean IOP), and the
`10-AM time point at month 12 (P ⳱ 0.011, mean IOP).
`The mean IOP difference was 0.6, 0.8, and 0.8 mm Hg,
`respectively, favoring brimonidine-Purite 0.2%. The
`noninferiority criteria were satisfied because 40/40 of the
`upper limits of 95% confidence intervals were less than
`or equal to 1.5 mm Hg, with 35/40 less than or equal to
`1.0 mm Hg (mean IOP and mean changes from baseline
`IOP), showing that brimonidine-Purite 0.15% was com-
`parable in efficacy with brimonidine-Purite 0.2%.
`
`Brimonidine-Purite 0.2% Versus Brimonidine 0.2%
`
`In the comparison of brimonidine-Purite 0.2% and bri-
`monidine 0.2%, there were no statistically significant
`
`differences observed in mean IOP or mean changes from
`baseline in diurnal IOP measurements except for the 10-
`AM time point at month 9 (P ⳱ 0.045, mean IOP), the
`10-AM time point at month 12 (P ⳱ 0.018, mean IOP),
`and the 5-PM time point at month 12 (P ⳱ 0.041, mean
`IOP). The average difference in mean IOP and mean
`changes from baseline in IOP difference was −0.6, −0.8,
`and −0.7 mm Hg, respectively, favoring brimonidine-
`Purite 0.2%. The only measurement favoring bri-
`monidine 0.2% was at the 10-AM time point at month 6
`(mean change from baseline IOP difference of 0.7 mm
`Hg, P ⳱ 0.019). The noninferiority criteria were satis-
`fied because 40/40 of the upper limits of the 95% con-
`fidence intervals were less than or equal to 1.5 mm Hg,
`with 37/40 less than or equal to 1.0 mm Hg (mean IOP
`and mean changes from baseline IOP), showing that bri-
`monidine-Purite 0.2% was comparable in efficacy with
`brimonidine 0.2%.
`
`Safety
`
`The following results were analyzed as intent-to-treat,
`and all data points were considered. Throughout the
`study, patients were monitored for signs and symptoms
`of adverse events (Table 2). Investigators rated the ma-
`jority of adverse events as mild or moderate in severity.
`The overall frequency of treatment-related adverse
`events reported was fewer in the brimonidine-Purite
`0.15% than with brimonidine-Purite 0.2% or bri-
`monidine 0.2%. There was a lower incidence rate of
`allergic conjunctivitis, conjunctival hyperemia, and oral
`dryness favoring brimonidine-Purite 0.15% compared
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
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`

`
`124
`
`L. J. KATZ
`
`TABLE 2. Summary of treatment-related adverse events of patients with glaucoma or ocular hypertension during twelve-month
`treatment with brimonidine-Purite 0.15%, brimonidine-Purite 0.2%, and brimonidine 0.2% (among group P-values). The second
`P-value is a summary of possible, probable, and definite treatment-related adverse events in pairwise comparison of patients
`with glaucoma or ocular hypertension during twelve-month treatment with brimonidine-Purite 0.15 and brimonidine 0.2%
`
`Adverse event
`
`Allergic conjunctivitis
`Oral dryness
`Conjunctival hyperemia
`Eye discharge
`
`Brimonidine-Purite
`0.15% (n ⳱ 381)
`No. (%)
`
`Brimonidine-Purite
`0.2% (n ⳱ 383)
`No. (%)
`
`Brimonidine 0.2%
`(n ⳱ 383)
`No. (%)
`
`Amongst
`group P
`
`Brimonidine-Purite 0.15
`vs. brimonidine 0.2% P
`
`35 (9.2%)
`20 (5.3%)
`69 (18.2%)
`5 (1.3%)
`
`56 (14.6%)
`36 (9.4%)
`81 (21.1%)
`7 (1.8%)
`
`60 (15.7%)
`40 (10.4%)
`98 (25.6%)
`15 (3.9%)
`
`0.018
`0.024
`0.043
`0.043
`
`0.007
`0.008
`0.013
`0.025
`
`with the treatment groups. There was only a 0.8% inci-
`dence of somnolence with brimonidine-Purite 0.15%
`compared with 2.6% in brimonidine-Purite 0.2% and bri-
`monidine 0.2%. Although this difference did not meet
`statistical significance, because it is a rare adverse event
`it could be clinically relevant.
`Table 2 also shows a direct comparison of the adverse
`events between the subjects on brimonidine-Purite
`0.15% and brimonidine 0.2%. This pairwise comparison
`showed a statistically significant difference favoring bri-
`monidine-Purite 0.15% (P < 0.001) in overall incidence
`of adverse events. Statistically significant lower inci-
`dences of conjunctival hyperemia, allergic conjunctivitis,
`and oral dryness were shown in the brimonidine-Purite
`0.15% group (P ⱕ 0.013).
`There were no statistical differences in the visual acu-
`ity, cup/disc ratio, visual fields, heart rate, and systolic
`and diastolic blood pressure.
`
`Quality of Life
`
`There were no statistical differences in the investiga-
`tors’ response to the clinical success of the medications.
`However, there were significant differences in how pa-
`tients rated their satisfaction with their study medication
`at the time of exit from the study. The level of satisfac-
`tion was greater for patients using brimonidine-Purite
`0.15% than those using brimonidine 0.2% (P ⳱ 0.005)
`(Fig. 2). Although less statistically significant, the level
`of satisfaction was greater for patients using bri-
`monidine-Purite 0.2% than those using brimonidine
`0.2% (P ⳱ 0.020). There was no statistical difference
`between the level of satisfaction of patients using bri-
`monidine-Purite 0.15% compared with those using bri-
`monidine-Purite 0.2%.
`Throughout the year, more than 90% of all the treat-
`ment groups rated their study medications as comfort-
`able, very comfortable, or soothing (Fig. 3). However,
`there were significant differences in how patients rated
`the comfort of their study medication at the time of exit
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
`from the study. Significantly more patients reported that
`brimonidine-Purite 0.15% was more comfortable than
`brimonidine 0.2% (P ⳱ 0.042). Furthermore, patients
`reported that brimonidine-Purite 0.2% was more com-
`fortable than brimonidine 0.2% (P ⳱ 0.027). There was
`no statistical significance between the level of comfort of
`patients using brimonidine-Purite 0.15% compared with
`those using brimonidine-Purite 0.2%.
`
`Patient Discontinuations
`
`The most frequent reasons cited for discontinuation (in
`descending order) were adverse events, lack of efficacy,
`administrative issues, and protocol violations. Lack of
`efficacy was cited as the reason for discontinuation in
`only 5.3% of these patients in all 3 groups.
`There were no statistical differences among the groups
`regarding adverse events that led to discontinuation from
`the study (P ⳱ 0.203). A smaller percentage of patients,
`however, discontinued therapy in the brimonidine-Purite
`
`FIG. 3. Patient satisfaction evaluation summary for patients with
`glaucoma or ocular hypertension during 12-month treatment with
`brimonidine-Purite 0.15%, brimonidine-Purite 0.2%, and bri-
`monidine 0.2%. The among-group P of 0.010 is a comparison of
`the seven-category response distributions for the three treatment
`groups. Patients rated the level of satisfaction with their study
`medication at the time of exit from the study. The pairwise com-
`parison of brimonidine-Purite 0.15% versus brimonidine 0.2%
`yielded a P of 0.005, favoring brimonidine-Purite 0.15%.
`
`PAGE 6 OF 8
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`

`
`NEW FORMULATION OF BRIMONIDINE
`
`125
`
`0.15% (21.8%) group than in the brimonidine-Purite-
`0.2% (24.8%) or brimonidine-0.2% (27.4%) groups. The
`most common adverse events leading to discontinuation
`were conjunctival hyperemia, allergic conjunctivitis, and
`eye pruritus. Indeed, 5.1% fewer patients in brimonidine-
`Purite 0.15% cited allergic conjunctivitis as reason for
`discontinuation compared to brimonidine 0.2% (P ⳱
`0.017).
`
`DISCUSSION
`
`In this pooled analysis of two identically designed,
`12-month, randomized, multisite, double-masked, paral-
`lel-group studies, brimonidine-Purite 0.15% and 0.2%
`provided IOP lowering comparable with brimonidine
`0.2% in patients with glaucoma or ocular hypertension.
`Overall,
`the new 0.15% concentration of the bri-
`monidine-Purite formulation showed IOP efficacy clini-
`cally comparable with brimonidine 0.2% throughout this
`1-year study.
`The formulations were applied three times daily in this
`study. The mean IOP at trough (8-AM measurement, be-
`fore morning drop) of all 3 groups was comparable to the
`mean IOP at trough in previous studies where bri-
`monidine 0.2% was administered twice daily2–4 In an
`earlier study, application of brimonidine 0.2% three
`times daily and twice daily provided comparable IOP
`lowering at morning trough.24 This finding suggests that
`brimonidine-Purite 0.15% would have comparable effi-
`cacy on morning IOP whether applied twice daily or
`three times daily; this hypothesis is being tested in an
`ongoing clinical trial.
`Brimonidine 0.2%, which has been marketed since
`1996, has shown a favorable adverse event profile, ex-
`cept for allergic conjunctivitis. The incidence of allergic
`conjunctivitis with brimonidine 0.2% has been reported
`to be 12.7% with twice-daily dosing.4 In this present
`study, the incidence of allergic conjunctivitis was 15.7%
`for patients taking brimonidine 0.2% three times daily
`The higher incidence of allergic conjunctivitis is likely
`related to the increased frequency of dosing. It is inter-
`esting that the incidence of allergic conjunctivitis with
`patients on brimonidine-Purite 0.15% three times daily,
`which contains 25% less active ingredient of bri-
`monidine, was only 9.2%. This incidence rate is less than
`the 12.7% incidence rate previously reported. This find-
`ing strongly suggests that with a twice-daily dosing of
`brimonidine-Purite 0.15%, the incidence of allergic con-
`junctivitis may be even lower than the 9.2% incidence
`with three-times-daily dosage regimen. Furthermore, it
`appears that the decreased concentration of brimonidine
`is primarily responsible for the decreased incidence of
`
`allergic conjunctivitis. The relative percent difference in
`allergic conjunctivitis during this current 1-year study
`was at least 41% less with brimonidine-Purite 0.15%
`than with brimonidine-Purite 0.2% or brimonidine 0.2%.
`Brimonidine-Purite 0.15% also had a significantly lower
`incidence of oral dryness than brimonidine 0.2%. Al-
`though not statistically significant, the lower incidence of
`somnolence with brimonidine-Purite 0.15% could prove
`to be beneficial. These findings suggest
`that bri-
`monidine-Purite 0.15% has a superior adverse-events
`profile compared with brimonidine 0.2%.
`In addition to having a comparable IOP-lowering ef-
`fect to brimonidine 0.2% solution and a superior adverse
`event profile, reformulated brimonidine-Purite 0.15%
`appears to be better tolerated than brimonidine 0.2%.
`Brimonidine-Purite 0.15% had a significantly higher rate
`of satisfaction (P ⳱ 0.005) and comfort (P ⳱ 0.042)
`than the original formulation (Figs. 2 and 3). At the
`patients’ last visit, more than 80% were satisfied with the
`reformulated brimonidine-Purite 0.15%, and 84.6% (P
`⳱ 0.042) found it to be comfortable. The higher comfort
`experienced by those in the brimonidine-Purite groups
`should lead to improved compliance with the antiglau-
`coma regimen. The potentially enhanced ocular bioavail-
`ability associated with the reformulation may also ex-
`plain why brimonidine-Purite 0.15% shows efficacy
`comparable with brimonidine 0.2% with a lower concen-
`tration of active drug (Fig. 4).
`
`FIG. 4. Patient comfort evaluation summary for patients with
`glaucoma or ocular hypertension during 12-month treatment with
`brimonidine-Purite 0.15%, brimonidine-Purite 0.2%, and bri-
`monidine 0.2%. The among-group P of 0.049 is a comparison of
`the six-category response distributions for the three treatment
`groups. Patients rated the level of satisfaction with their study
`medication at the time of exit from the study. The pairwise com-
`parison of brimonidine-Purite 0.15% versus brimonidine 0.2%
`yielded a P of 0.042, favoring brimonidine-Purite 0.15%.
`
`J Glaucoma, Vol. 11, No. 2, 2002
`
`PAGE 7 OF 8
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`

`
`126
`
`L. J. KATZ
`
`CONCLUSIONS
`
`Brimonidine-Purite at concentrations of 0.15% or
`0.2% effectively lowers IOP in patients with glaucoma or
`ocular hypertension. Brimonidine-Purite 0.15% also
`shows comparable efficacy with brimonidine 0.2% with
`less than a 1-mm Hg difference between study drugs at
`all time points throughout this study. The brimonidine-
`Purite 0.15% concentration showed a more favorable
`safety and tolerability profile with a 41% relative percent
`reduction in ocular allergy when compared with bri-
`monidine 0.2%. The brimonidine-Purite 0.15% formula-
`tion received superior satisfaction and comfort ratings.
`Based on these clinical findings, it can be concluded that
`brimonidine-Purite 0.15% is an effective, safe, and well-
`tolerated therapy for the long-term treatment of high
`IOP.
`
`APPENDIX
`
`Members of the Brimonidine-Purite Study Groups 1
`and 2 investigators include (in alphabetical order) Mark
`Abelson, MD, Edward Andersen, MD, Amy Batoosingh
`BA, Richard S. Bennion, MD, E. Randy Craven, MD,
`Harvey DuBiner, MD, Richard Evans, MD, Carlos Felix,
`MS, William C. Flynn, MD, Daniel Foreman, MD, Gary
`N. Foulks, MD, Stephen Gee, MD, L. Jay Katz, MD,
`Alex Kent, MD, Jeff Lozier, MD, Jeffrey Morris, MD,
`Thomas Mundorf, MD, Charles S. Ostrov, MD, Matthew
`Parsons, MD, Jay Perlman, MD, PhD, Michael J. Price,
`MD, Arnold Prywes, MD, Edward R. Rashid, MD, Pat-
`rick Riedel, MD, Elenora Safyan, BS, Kenneth Sall, MD,
`John Samples, MD, Thomas Samuelson, MD, Howard I.
`Schenker, MD, Gail Schwartz, MD, PA, John D. Shep-
`pard, MD, Dong H. Shin, MD, PhD, Steven Simmons,
`MD, Dara Stevenson, MD, William C. Stewart, MD,
`Richard T. Sturm, MD, Lloyd Suter, MD, Stuart A.
`Terry, MD, Christopher M. Tortora, MD, Thomas R.
`Walters, MD, Mark Weiss, MD, Sidney Weiss, MD,
`Robert D. Williams, MD, Lisa Wohl, MD, SC, Eugene
`Barry Wolchok, MD, and Brandon Wool, MD.
`
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