The Additive IOPLowering Effect of Brimonidine 0'1% vs Brinzolamide 1'0% Adjunctive to Latanoprost 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.
2
Abstract

• Purpose Evaluate efficacy/safety of brimonidine
  0.1 vs brinzolamide adjunctive to latanoprost.
• Methods Investigator-masked, randomized,
  parallel-group study of40 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.

3
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.
2002120701-713 2. Covert and Robin. Curr Med
Res Opin. 200622971-976 3. Glaucoma Disease
Management Guide. PDR 2004 4. Tsukamoto et al. J
Ocul Pharmacol Ther. 200521395-399 5. Lee and
Gornbein. J Glaucoma. 200110220-2266. Konstas
et al. Ophthalmology. 2005112603-608 7.
Netland et al. Adv Ther. 20032020-30.
4
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 patientsin
  identically appearing masked cartons labeled with
  the patient randomization number.
• Latanoprost was provided in its marketed bottle
  and was dosed in the evening10 minutes apart
  from the instillation of study medication.
• Study visits were at baseline, month 1, and month
  3.

5
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.

6
Results Patient Characteristics and Disposition

• 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.
7
Results Mean Diurnal IOP
P .028 vs brinzolamide
Mean ( SEM) diurnal IOP (mm Hg)


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 was3.3 mm Hg with
  brimonidine P vs 2.1 mm Hg with brinzolamide (P
  .028).

8
Mean IOP (SEM) at Each Hour (mm Hg)

• 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.

9
Comfort and Tolerability of Eye Drop
Instillation Survey Results
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.

10
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
  for4 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.

11
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 Ptreated 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.
200312148-56.
12
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.