Download Brimonidine P 0.1%

The Additive IOP-Lowering Effect
of Brimonidine 0.1% vs
Brinzolamide 1.0% Adjunctive to
Latanoprost 0.005%
Douglas Day1 and David Hollander2
1. Omni Eye Services, Atlanta, GA; 2. Allergan, Inc., Irvine, CA
Financial Disclosure
This study was sponsored by Allergan, Inc.
D. Day has no proprietary interest in any of the study drugs or their manufacturers.
D. Hollander is an employee of Allergan, Inc.
Abstract
 Purpose: Evaluate efficacy/safety of brimonidine 0.1% vs brinzolamide
adjunctive to latanoprost.
 Methods: Investigator-masked, randomized, parallel-group study of
40 patients randomized to brimonidine 0.1% or brinzolamide 1.0% TID
adjunctive to latanoprost. Subjects administered latanoprost once daily in
the evening and the study medication 3 times daily for 3 months. Mean
diurnal intraocular pressure (IOP) was calculated based on IOP
measurements at 8 AM, 10 AM, and 4 PM at each study visit (baseline,
1 month, and 3 months).
 Results: Equivalent mean diurnal baseline IOPs on latanoprost (19.6,
19.8 mm Hg; P = .846). At 3 months, the additional mean reduction from
latanoprost baseline for brimonidine and brinzolamide, respectively, was 3.3
and 2.1 mm Hg (P = .028). Blurred vision (P = .011) at 1 month and unusual
taste at 1 and 3 months were more common with brinzolamide
(P = .002, P = .031, respectively).
 Conclusion: Brimonidine 0.1% provided greater or equivalent IOP lowering
compared with brinzolamide adjunctive to latanoprost.
Introduction
 The once-daily prostaglandin analogs (PGAs) (bimatoprost, latanoprost, and travoprost)
effectively reduce intraocular pressure (IOP) and are often used as monotherapy to treat
glaucoma and ocular hypertension (OHT). Many patients, however, do not achieve
sufficiently low IOP with a single medication.1 Over 20% of patients who are initiated on
monotherapy with a once-daily PGA may be expected to require adjunctive therapy within
the next year.2
 A primary consideration in choosing adjunctive medication is IOP-lowering efficacy. An
adjunctive therapy ideally provides at least an additional 15% reduction in IOP from baseline
on the initial therapy.3 Several classes of IOP-lowering medications have been evaluated as
adjunctive therapies to PGAs. Brinzolamide is an ophthalmic suspension of a carbonic
anhydrase inhibitor (CAI). When used as adjunctive therapy to latanoprost, brinzolamide
has been demonstrated to reduce IOP as effectively as dorzolamide, the first topical CAI
introduced for IOP lowering, and to be associated with less ocular discomfort.4 Brimonidine,
a highly selective alpha-adrenergic agonist, has similarly been shown to effectively reduce
IOP when used in combination with PGAs including latanoprost.5-7
 The purpose of the present study was to evaluate the IOP-lowering efficacy and tolerability
of brimonidine Purite® 0.1% compared with brinzolamide 1% when used as adjunctive
therapy to latanoprost in patients with glaucoma or OHT.
References: 1. Kass et al. Arch Ophthalmol. 2002;120:701-713; 2. Covert and Robin. Curr Med Res Opin. 2006;22:971-976; 3. Glaucoma Disease
Management Guide. PDR 2004; 4. Tsukamoto et al. J Ocul Pharmacol Ther. 2005;21:395-399; 5. Lee and Gornbein. J Glaucoma. 2001;10:220-226;
6. Konstas et al. Ophthalmology. 2005;112:603-608; 7. Netland et al. Adv Ther. 2003;20:20-30.
Methods: Study Design and Patients
 This was a randomized, single-center, investigator-masked, parallel-group study.
 Patients diagnosed with glaucoma or OHT who were currently on latanoprost
monotherapy and in need of additional IOP lowering were enrolled.
 Patients were required to have been on latanoprost monotherapy for at least 30
days prior to study enrollment and to have a screening IOP of 18 mm Hg or higher
in at least 1 eye.
 Eligible patients were randomized to 1 of 2 adjunctive treatment groups:
– Brimonidine P 0.1% TID (Alphagan® P 0.1%; Allergan, Inc.; Irvine, CA)
– Brinzolamide 1% TID (Azopt®; Alcon Laboratories, Inc.; Fort Worth, TX)
 Study drugs were dosed at 8 AM, 4 PM, and 10 PM (± 1 hour) for 3 months.
 Marketed bottles of brimonidine P and brinzolamide were provided to patients
in identically appearing masked cartons labeled with the patient randomization
number.
 Latanoprost was provided in its marketed bottle and was dosed in the evening
10 minutes apart from the instillation of study medication.
 Study visits were at baseline, month 1, and month 3.
Methods: Outcome Measures and
Analysis
 IOP was measured at each visit at 8 AM (morning trough, just before study drug
instillation), 10 AM (peak effect) and 4 PM (before second dose of study drug).
 Efficacy outcome measures included mean diurnal IOP at each visit and mean IOP
at each timepoint and visit.
 Safety measures included comfort/tolerability, ocular signs and symptoms, adverse
events, and visual acuity.
 A written questionnaire was administered at each follow-up visit to evaluate the
comfort and tolerability of study drug instillation.
 Analyses of IOP were based on the worse eye (the eye with the higher IOP at 8 AM
on baseline) for the intent-to-treat patient population with imputation for missing
values using the last observation carried forward.
 Diurnal IOP for a patient was defined as the mean of the 8 AM, 10 AM, and 4 PM
measurements taken at a particular visit.
 Baseline differences in IOP between treatment groups were evaluated using analysis
of variance (ANOVA).
 An analysis of covariance (ANCOVA) model with baseline IOP as the covariate was
used to evaluate differences between treatment groups at follow-up visits.
Results: Patient Characteristics and
Disposition
Brimonidine P 0.1%
(N = 20)
Brinzolamide 1%
(N = 20)
Mean age (years)
60.0
57.5
Sex (male/female)
45%/55%
65%/35%
Black
55%
45%
White
45%
45%
Hispanic
0%
5%
Asian
0%
5%
5%
10%
Chronic open-angle glaucoma
85%
75%
Chronic angle-closure glaucoma
10%
10%
0%
5%
Race
Diagnosis
OHT
Mixed
 There were no significant differences between treatment groups in patient demographics.
– Half of the patients were black, and most were diagnosed with chronic open-angle glaucoma.
 Thirty-four patients (85%) completed the study as planned.
– In the brinzolamide group, 3 patients exited the study early because of adverse events (eye pain, pruritus, and brain
tumor) and 1 was lost to follow-up.
– In the brimonidine P group, 1 patient discontinued due to an adverse event (hypertension) and 1 due to lack of efficacy.
Mixed diagnosis = one eye with OHT and the other with chronic open-angle glaucoma.
Results: Mean Diurnal IOP
Mean (± SEM) diurnal IOP
(mm Hg)
Brinzolamide 1% (N = 20)
20
Brimonidine Purite® 0.1% (N = 20)
19.8
*P ≤ .028 vs brinzolamide
19.6
17.9
18
17.8
16.4
16.3
16
*
*
14
0
1
2
3
Month
 Baseline mean diurnal IOPs on latanoprost were similar in the 2 treatment groups
(bimatoprost: 19.6 mm Hg, travoprost: 19.8 mm Hg; P = .846).
 Both brimonidine P 0.1% and brinzolamide reduced diurnal IOP substantially when
added to ongoing latanoprost therapy.
 Adjunctive brimonidine P provided significantly lower mean diurnal IOP than adjunctive
brinzolamide at both follow-up visits (P ≤ .028).
 At month 3, the additional mean reduction from latanoprost baseline was
3.3 mm Hg with brimonidine P vs 2.1 mm Hg with brinzolamide (P = .028).
Mean IOP (SEM) at Each Hour (mm Hg)
Month 1
Brim P 0.1%
(N = 20)
Brinz 1.0%
(N = 20)
8 AM (trough)
17.8 (0.68)
18.1 (0.60)
10 AM (peak)
15.1 (0.65)
4 PM
16.2 (0.67)
Month 3
Brim P 0.1%
(N = 20)
Brinz 1.0%
(N = 20)
.896
18.2 (0.76)
18.2 (0.71)
.716
17.6 (0.76)
.002
14.6 (0.63)
17.4 (0.51)
<.001
18.1 (0.78)
.035
16.3 (0.61)
17.8 (0.49)
.050
P Value
P Value
 Baseline mean IOPs on latanoprost were similar in the 2 treatment groups at each hour.
 Brimonidine P provided significantly lower IOP compared with brinzolamide at the
10 AM (peak effect) and 4 PM time points at both 1 and 3 months (P ≤ .050).
 At 8 AM (trough effect) mean IOP was similar in the 2 treatment groups.
 The reduction from baseline IOP on latanoprost at individual time points during follow-up
ranged from 2.2 to 4.8 mm Hg with brimonidine P and from 1.4 to 2.9 mm Hg with
brinzolamide.
Comfort and Tolerability of Eye Drop
Instillation: Survey Results
Number of Patients Responding “Yes”
(% of Total Responses)
Month 1
Month 3
Brim P 0.1%
Brinz 1.0%
P Value
Brim P 0.1% Brinz 1.0%
P Value
Unusual taste
1 (5.0%)
9 (50.0%)
.002
2 (11.1%)
7 (43.8%)
.031
Unusual
sensation in eye
1 (5.0%)
1 (5.6%)
.939
1 (5.6%)
1 (6.3%)
.932
Ocular
discomfort
3 (15.0%)
5 (29.4%)
.289
3 (16.7%)
2 (12.5%)
.732
Change in vision
2 (10.0%)
8 (47.1%)
.011
1 (5.6%)
2 (12.5%)
.476
Patients were asked whether they experienced an unusual taste, an unusual ocular sensation, ocular
discomfort, or any change in vision after instilling their eye drop medications. All patient responses
were “yes” or “no”; there were no responses of “not sure.”
 Brinzolamide-treated patients were significantly more likely than brimonidine P-treated patients
to report an unusual taste associated with eye drop instillation at both months 1 and 3.
 Patients in the brinzolamide group were also more likely than those in the brimonidine P group
to report changes in vision (usually described as blurred vision) at month 1.
 One patient in the brinzolamide group reported that the bitter taste associated with eye drop
instillation caused him to want to discontinue his study medication.
Other Safety Parameters
 There were no significant differences between treatment
groups in biomicroscopic findings or changes from
baseline visual acuity.
 Treatment-related adverse events were reported for
4 patients (20%) in the brimonidine P group and 3
patients (15%) in the brinzolamide group.
 There was no significant between-group difference in the
overall incidence of treatment-related adverse events or
in the incidence of any individual treatment-related
adverse event.
Discussion
 In patients with inadequate IOP control on latanoprost, mean IOP at 10 AM and 4 PM and
mean diurnal IOP were significantly lower with adjunctive brimonidine P than with
brinzolamide. Mean IOP at 8 AM was similar in the 2 treatment groups.
 The difference between treatment groups in mean diurnal IOP at months 1 and 3 is likely to
be clinically significant, because in the Early Manifest Glaucoma Trial, each 1 mm Hg
decrease in IOP was associated with a 10% decrease in the risk of glaucoma progression.1
 Although brimonidine P and brinzolamide are often dosed twice daily in clinical practice, they
were dosed thrice daily in this study as recommended in their prescribing information.
 It is unlikely that the additional afternoon dose of drugs affected the efficacy results, because
all of the IOP measurements were taken prior to the second daily dose of medication given
in the afternoon.
 Transient side effects associated with eye drop instillation may cause patient discomfort and
decrease patients’ compliance with treatment.
 At month 1, more brinzolamide-treated patients than brimonidine P–treated patients reported
blurred vision and bitter taste associated with eye drop instillation.
 By month 3, the number of brinzolamide-treated patients who reported blurred vision had
decreased, but bitter taste remained more common in patients treated with brinzolamide.
 Both brimonidine P and brinzolamide were well tolerated.
Reference: 1. Leske et al. Arch Ophthalmol. 2003;121:48-56.
Conclusions
 Brimonidine P provided significantly lower diurnal IOP
than brinzolamide when added to latanoprost therapy.
 Bitter taste after eye drop instillation was significantly less
common with brimonidine P than with brinzolamide
adjunctive therapy.