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One-Year, Randomized Study Comparing Bimatoprost and Timolol in Glaucoma and Ocular Hypertension
Eve J. Higginbotham, MD;
Joel S. Schuman, MD;
Ivan Goldberg, MBBS, FRANZCO;
Ronald L. Gross, MD;
Amanda M. VanDenburgh, PhD;
Kuankuan Chen, MS;
Scott M. Whitcup, MD;
for the Bimatoprost Study Groups 1 and 2
Arch Ophthalmol. 2002;120:1286-1293.
ABSTRACT
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Objective To compare bimatoprost with timolol maleate in patients with glaucoma
or ocular hypertension.
Methods In 2 identical, multicenter, randomized, double-masked, 1-year clinical
trials, patients were treated with 0.03% bimatoprost once daily (QD) (n =
474), 0.03% bimatoprost twice daily (BID) (n = 483), or 0.5% timolol maleate
BID (n = 241).
Main Outcome Measures Diurnal intraocular pressure (IOP) at 8 AM, 10 AM, and 4 PM and safety
variables (IOP was also measured at 8 PM at selected sites).
Results Bimatoprost QD provided significantly lower mean IOP than timolol at
every time of the day at each study visit (P<.001).
This was also true for bimatoprost BID at most time points, but the efficacy
was not as good as that of the QD regimen. At 10 AM (peak timolol effect)
at month 12, the mean reduction in IOP from baseline was 7.6 mm Hg (30%) with
bimatoprost and 5.3 mm Hg (21%) with timolol (P<.001).
A significantly higher percentage of patients receiving bimatoprost QD (58%)
than timolol (37%) achieved IOPs at or below 17 mm Hg (10 AM, month 12; P<.001). The most common adverse effect with bimatoprost
was hyperemia (significantly higher with bimatoprost QD than timolol; P<.001).
Conclusions Bimatoprost QD provides sustained IOP lowering superior to timolol or
bimatoprost BID and achieves low target IOPs in significantly more patients.
INTRODUCTION
BIMATOPROST IS a synthetic prostamide analogue that potently lowers
intraocular pressure (IOP).1-2 Bimatoprost
has been shown to help a substantially greater percentage of patients to achieve
low IOPs ( 17 mm Hg) than does timolol maleate.3-4
Two large-scale, double-masked, phase 3 clinical (pivotal) trials were
undertaken to evaluate the safety and efficacy of once- (QD) or twice-daily
(BID) regimens of 0.03% bimatoprost ophthalmic solution (Lumigan; Allergan
Inc, Irvine, Calif) compared with timolol maleate BID in patients with glaucoma
or ocular hypertension. Interim safety and efficacy results were evaluated
at 3 and 6 months without breaking study masking for the patients or the study
investigators.3-4 These analyses
demonstrated that bimatoprost QD was more effective in lowering IOP than was
timolol throughout the day at all study visits through 6 months (P.001). Moreover, a significantly higher percentage of patients
treated with bimatoprost QD achieved low pressures (17 mm Hg) than did
patients treated with timolol (the highest P value
for the comparison to timolol was .007). Bimatoprost BID was also more effective
than timolol at most time points, but was slightly less effective than the
QD regimen.
Because glaucoma is a chronic disease, it is important to evaluate the
long-term efficacy and safety of new glaucoma medications. The present report
describes the pooled 12-month results from the 2 pivotal clinical trials comparing
bimatoprost with timolol.
METHODS
STUDY DESIGN
Two multicenter, randomized, double-masked, parallel-group, active-controlled
trials were conducted to compare the safety and efficacy of bimatoprost QD,
bimatoprost BID, and timolol maleate BID. The study protocols were identical,
and the data were pooled for analysis.
Both studies were conducted in accordance with the Declaration of Helsinki
and the guidelines set forth by the International Council on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for Human Use
and the United States Code of Federal Regulations CFR21. All investigators
obtained appropriate institutional review board or ethics committee approval
before initiating the study, and all patients provided written informed consent
before any study-related procedures or changes in treatment.
PATIENTS
Key inclusion criteria included a diagnosis of primary open-angle glaucoma,
chronic angle-closure glaucoma with patent iridotomy, pseudoexfoliative glaucoma,
pigmentary glaucoma, or ocular hypertension. Washout of ocular hypotensive
medications occurred before the baseline visit, and patients were required
to have a postwashout IOP of at least 22 mm Hg and no greater than 34 mm Hg
and a best-corrected visual acuity of 20/100 or better in each eye. Washout
periods ranged from 4 days to 4 weeks, depending on the medication. Parasympathomimetics
and carbonic anhydrase inhibitors were washed out for 4 days, sympathomimetics
and topical  -agonists were washed out for 2 weeks, and topical  -blockers
(alone or in combination) and topical prostaglandins were washed out for 4
weeks. Key exclusion criteria included any contraindication to topical -blocker
therapy, functionally significant visual field loss within the past year,
filtering surgery within the past 6 months, or other intraocular surgery within
the past 3 months. Women who were pregnant, nursing, planning a pregnancy,
or of childbearing potential and not using a reliable form of contraception
were also excluded.
TREATMENT ASSIGNMENT AND DRUG ADMINISTRATION
At baseline, patients were randomly assigned in a 2:2:1 ratio to receive
0.03% bimatoprost QD, 0.03% bimatoprost BID, or 0.5% timolol maleate BID.
The study sponsor generated the allocation sequence. The bimatoprost QD group
received bimatoprost in the evening and a vehicle control solution in the
morning to maintain the study mask. Medications were supplied in identical-appearing
bottles that were color coded for use in the morning or the evening. Patients
were instructed to self-instill their medication into both eyes at approximately
8 AM and 8 PM. On study visits, the morning dose was administered by the study
investigator immediately after the first examination (at approximately 8 AM).
Scheduled visits occurred before the study, at baseline (day 0), weeks 2 and
6, and months 3, 6, 9, and 12.
EFFICACY AND SAFETY VARIABLES
The primary outcome measure was diurnal IOP. Measurements were performed
at 8 AM, immediately preceding the instillation of the morning dose of the
study medication, and at 10 AM and 4 PM. Patients at selected sites (approximately
25% of all enrolled) also had IOP recorded at 8 PM (bimatoprost QD group,
n = 124; bimatoprost BID group, n = 123; and timolol group, n = 65). At month
9, IOP was recorded only at 8 AM and (at selected sites) 8 PM.
Safety measures included adverse events, visual acuity, visual fields,
blood pressure, heart rate, blood chemistry, iris pigmentation, and results
of hematology, urinalysis, laser flare photometry, biomicroscopy, and ophthalmoscopy
readings. The severity of adverse events was assessed using the following
definitions as guidelines: mild indicates awareness of a sign or a symptom,
but easily tolerated; moderate, enough discomfort to cause interference with
usual activities; and severe, incapacitating, with the inability to work or
to perform usual activities. Hyperemia was evaluated on the following scale:
none, 0; trace, 0.5; mild, 1.0; moderate, 2.0; and severe, 3.0. To evaluate
changes in iris pigmentation, investigator(s) at each site compared Polaroid
photographs (Polaroid Corporation, Cambridge, Mass) of each patient's eyes
from the baseline and follow-up visits. A color-calibration strip was photographed
beside the eye to verify consistent photographic color processing. A reading
center at the sponsor site (consisting of 2 evaluators) also evaluated all
photographs in a masked fashion and obtained slightly lower but generally
comparable results. At selected sites, laser-flare photometry readings (using
a Kowa FM-500 photometer; Kowa Company, Ltd, Chuo-ku, Tokyo, Japan) were recorded
before fluorescein instillation or pupil dilation.
ANALYSES
All randomized patients were included in the efficacy analysis (intent-to-treat
population), and for patients who discontinued before the month 12 visit,
the last observed data were carried forward in the analysis for all subsequent
time points. An intent-to-treat analysis with the last observation carried
forward is the standard analysis for clinical studies of this type and is
considered the most conservative analysis. It is much more difficult for a
drug to appear to perform well in an intent-to-treat analysis with the last
observation carried forward than in a per-protocol analysis because data from
patients who did not receive study medications or who left the study early
for any reason (including lack of efficacy) were kept in the efficacy analysis.
Similar results (not shown) were obtained when the analysis used the per-protocol
patient population without the last observations carried forward. Analysis
of IOP used only data from the eye with the higher IOP at 8 AM at baseline
(worse eye). If both eyes had the same IOP at baseline, the protocol required
that the right eye be used. All patients who received at least 1 dose of study
medication were included in the safety analyses.
Nominal categorical variables were analyzed using the Fisher exact test,
the Pearson  2 test, or Cochran-Mantel-Haenszel methods.5 Ordinal categorical variables were analyzed by means
of the Wilcoxon rank sum test.6 Continuous
variables were analyzed using analysis of variance (ANOVA). We compared the
frequency distributions of patients who had achieved desirable target IOP
levels between groups. We performed the analysis for each target IOP at a
given time point using the Pearson 2 test.
Tests of noninferiority and superiority were performed for the pairwise
between-group comparisons of IOP at each time point. The level for
statistical significance was .05. Noninferiority of bimatoprost was claimed
when the upper limit of the 95% confidence interval of the difference (bimatoprost
minus timolol) was no greater than 1 mm Hg. Superiority was claimed when the
upper limit of the confidence interval was less than 0 mm Hg. The power of
each study was at least 0.85 to claim noninferiority of bimatoprost to timolol,
based on a maximum difference of 1.5 mm Hg and using an estimate of variability
(SD = 4.052) from a prior study.7 To test for
an interaction of drug effect with patient race, the ANOVA was performed with
the main effects of treatment group, race (black vs nonblack), and treatment-by-race
interaction. The level of significance for the interaction was set
at .10 to accommodate a possible low power for this test.
We used the SAS computer program package (version 6.12 and version 7
on Unix; SAS Institute Inc, Cary, NC) for computation and analysis. All the
variables were analyzed using SAS procedures (version 6.12 on Unix; SAS Institute
Inc) with the exception of variables of adverse events, which were analyzed
using version 8.
The sample-size estimate was based on the mean change in IOP from baseline.
With 200 patients in each of the bimatoprost treatment groups and 100 patients
in the timolol group, the power was 0.85 to claim that the mean IOP change
from baseline with bimatoprost QD or BID was more than 1.5 mm Hg greater than
that with timolol.
RESULTS
PATIENT POPULATION
A total of 1198 patients were enrolled in the 2 studies. Of these, 474
patients received bimatoprost QD, 483 received bimatoprost BID, and 241 received
timolol at 61 study sites. Fifty sites were located in the United States,
4 in Canada, 5 in Australia, and 2 in New Zealand. The first patient was enrolled
on November 3, 1998, and the last patient completed the 12 months of treatment
on August 4, 2000. One thousand nine patients (84% of all enrolled) completed
the study. Of the 189 patients who exited the study early, 123 discontinued
owing to (mostly local) adverse events; 26, owing to lack of efficacy; 34,
for administrative reasons; and 6, for other reasons. Patients were queried
at each follow-up visit regarding use of study medication, and any changes
in the study regimen were recorded. Patients or study visits could be excluded
from the per-protocol analysis if significant changes in the study medication
regimen were present. However, the present report is based on an analysis
of the intent-to-treat population and includes all patients. Full details
of patient flow through the study and exit status are given in Figure 1 and Table 1.
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Figure 1. Trial profile. QD indicates once
daily; BID, twice daily.
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Table 1. Patient Disposition*
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We found no statistically significant among-group differences in demographic
characteristics, clinical diagnosis, or baseline IOP (Table 2). We also found no among-group difference in medical history
or the use of concomitant medication that could affect IOP (eg, -blockers).
Medical histories did not designate any patients as low responders to -blockers
or prostaglandin agonists. Most patients were white, with brown or blue irides
and a diagnosis of glaucoma. Approximately 18% of the study population was
black. None of the black patients were from the Australian or New Zealand
sites, and it is consequently unlikely that any Australian aborigines (who
have a very low incidence of glaucoma) were included in the black subpopulation.
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Table 2. Patient Characteristics*
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IOP-LOWERING EFFICACY
Baseline IOP was similar among the treatment groups throughout the day
(Table 2). Bimatoprost QD provided
IOP control that was superior to that of timolol at all time points and all
follow-up visits throughout the 12-month study. During all times of the day
at which posttreatment measurements were obtained, mean IOP ranged from 16.2
to 18.0 mm Hg with bimatoprost QD and from 18.2 to 20.0 mm Hg with timolol.
As has been reported previously, bimatoprost BID did not perform as well as
bimatoprost QD.3-4 The presentation
of the efficacy results will focus on the data from the bimatoprost QD group,
because this was the study regimen approved by regulatory authorities.
The peak effect for timolol typically occurs 2 hours after dosing. Therefore,
in this report, the comparative response at each study visit will focus on
the 10 AM IOP measurement on each follow-up visit (dosing occurred after the
8 AM examination at each visit). At 10 AM, mean ± SEM IOP ranged from
16.4 ± 0.2 to 17.0 ± 0.2 mm Hg with bimatoprost QD and from
18.2 ± 0.2 to 19.0 ± 0.2 mm Hg with timolol (Figure 2). The difference between the bimatoprost QD and timolol
groups was statistically significant at every follow-up visit (P<.001). Mean IOP reductions from baseline were also significantly
greater with bimatoprost QD than with timolol at this morning peak throughout
the 12-month treatment period (P<.001). Mean IOP
reductions ranged from 7.6 to 8.3 mm Hg (30.2%-32.9%) in the bimatoprost QD
group and from 5.1 to 5.8 mm Hg (20.4%-23.3%) in the timolol group. The mean
IOP reduction from baseline consistently ranged from 1.8 to 2.1 mm Hg greater
in the bimatoprost QD group than in the timolol group at the 10 AM measurement.
The decrease from baseline IOP was up to 8.8 mm Hg in the bimatoprost QD group
compared with 6.5 mm Hg in the timolol group (across all times of day and
all study visits).
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Figure 2. Mean ± SEM intraocular
pressure (IOP) at 10 AM (peak timolol effect) at each study visit. Asterisk
indicates P<.001 vs timolol and bimatoprost twice
daily (BID); dagger, P = .001 vs timolol. QD indicates
once daily.
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Significantly higher percentages of patients achieved low IOP levels
with bimatoprost QD than with timolol (Figure
3). The 10 AM measurement at month 12 revealed that target IOPs
at or below 17 mm Hg were achieved by 57.6% of the bimatoprost QD group compared
with 36.5% of the timolol group (P<.001). Pressures
at or below 15 mm Hg were achieved by 30.6% of the bimatoprost QD group and
15.8% of the timolol group (P<.001). Patients
in the bimatoprost QD group were up to 2 times more likely than those
in the timolol group to achieve low pressures that were at or below 12, 13,
14, 15, 16, or 17 mm Hg.
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Figure 3. The percentage of patients achieving
specific low intraocular pressures (IOPs) at 10 AM (peak timolol effect) after
12 months of therapy. Asterisk indicates P.001
vs timolol. QD indicates once daily; BID, twice daily.
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Bimatoprost QD was also superior to timolol in maintaining a low IOP
throughout the day. As mentioned in the two preceding paragraphs, bimatoprost
QD produced significantly lower mean IOPs than did timolol at every time of
the day at each follow-up visit throughout the 12-month treatment period (P.001). The overall diurnal mean IOP (average of all
measurements at a given time from all follow-up visits) was significantly
lower in the bimatoprost QD group than the timolol group at each time of day.
Throughout the day, overall mean IOP in the bimatoprost QD group was approximately
2 mm lower than the overall mean IOP in the timolol group (P<.001; Figure 4). The
IOP-lowering efficacy of the single evening dose of bimatoprost was still
profound 24 hours after dosing. At the 8 PM measurements, mean ± SEM
IOP ranged from 16.2 ± 0.3 to 17.2 ± 0.3 mm Hg with bimatoprost
QD (n = 124) compared with 18.2 ± 0.5 to 20.0 ± 0.6 mm Hg with
timolol BID (n = 65).
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Figure 4. Overall diurnal mean intraocular
pressure (IOP). The overall mean diurnal IOP is the average of all measurements
at a given time from all follow-up visits. Asterisk indicates P<.001 vs timolol. QD indicates once daily; BID, twice daily.
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A subgroup analysis by race demonstrated that bimatoprost was significantly
more effective than timolol in lowering IOP in both black and nonblack patients.
Bimatoprost lowered IOP to the same extent in both black and nonblack patients,
while timolol was notably less effective in blacks than in nonblacks (by up
to approximately 2 mm). The statistical validity of this was identified from
the significant treatment-by-race interaction based on the analysis of variance
model for repeated measures with the fixed effects of treatment, time, race
(black and nonblack), and treatment-by-race interaction. When either mean
IOP or mean change from baseline IOP was analyzed for each time of day across
all study visits the difference between blacks and nonblacks was statistically
significant at P = .01.
For each analysis of pooled data from both phase 3 trials, similar results
were obtained when data from the individual trials were evaluated separately.
For example, in each trial and in the pooled data, diurnal mean IOP at month
12 was consistently 2 to 3 mm Hg lower with bimatoprost QD than with timolol
throughout the day (Figure 5).
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Figure 5. Diurnal mean intraocular pressure
(IOP) at month 12 for trials 1 (A) and 2 (B) separately. There was inadequate
power for pairwise comparisons at 8 PM because the sample sizes were too small
at this time. Asterisk indicates P.001 vs timolol.
BID indicates twice daily; QD, once daily.
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SAFETY AND TOLERABILITY
We found a low rate of discontinuations due to adverse events. All 3
treatment regimens were safe and well tolerated. The most common adverse effects
associated with bimatoprost were conjunctival hyperemia and eyelash growth.
Other potentially treatment-related adverse events that occurred in
more than 5% of the bimatoprost QD group are listed in Table 3 and included eye pruritus, eye dryness, eye burning, eyelid
pigmentation, foreign-body sensation, eye pain, and visual disturbance. For
some of these adverse events, we found a significantly higher incidence in
the bimatoprost QD group than in the timolol group. However, no statistically
significant difference was found between the bimatoprost QD and timolol groups
in the number of reports of eye pain, visual disturbance, and burning sensation
in the eye. Patients in the bimatoprost BID group had a higher incidence of
hyperemia, eyelash growth, eyelid pigmentation, and eye pain than did patients
in the bimatoprost QD group (P<.01). Most treatment-related
adverse events were mild in severity.
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Table 3. Treatment-Related Adverse Events*
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Assessment of the hyperemia findings were confounded by the fact that
trace or greater conjunctival hyperemia was present at baseline (before the
initial administration of the study medication) in 25.1% of the patients in
the bimatoprost QD group and in 17.8% of the patients in the timolol group.
Mean scores of conjunctival hyperemia (worse severity of the eyes) were low
(in the trace range) in the bimatoprost QD treatment group and remained low
throughout the study (Figure 6).
Only 5.3% of patients experienced greater than a 1-U (mild) increase in hyperemia
during this 12-month study. Only 3.4% of the patients in the bimatoprost QD
group, 5.6% of those in the bimatoprost BID group, and 0.4% of those in the
timolol group discontinued from the study owing to hyperemia (P = .01; bimatoprost QD vs timolol). The median time to onset of hyperemia
was 14 days after the initiation of therapy, and in most cases it began within
the first 6 weeks. No patients receiving bimatoprost QD discontinued the study
because of conjunctival hyperemia after month 6.
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Figure 6. Mean conjunctival hyperemia scores
(obtained in the worse eyes). The scale for evaluating hyperemia is explained
in the "Efficacy and Safety Variables" subsection of the "Methods" section.
QD indicates once daily; BID, twice daily.
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Laser-flare photometry measurements (a common measure of ocular inflammation)
of a subset of 310 patients (124 in the bimatoprost QD group, 123 in the bimatoprost
BID group, and 63 in the timolol group) demonstrated that there were no significant
differences among the treatment groups in mean laser-flare photometry readings
or in mean changes from baseline. In addition, we found no increase in flare
readings in those patients in whom conjunctival hyperemia developed. In fact,
after 12 months of bimatoprost QD treatment, mean laser-flare photometry readings
were lower in patients who had a mild or greater increase in conjunctival
hyperemia (7.67 photon counts/ms) compared with those in patients who had
no change, a trace increase, or a decrease in hyperemia (9.26 photon counts/ms)
(Figure 7); however, this difference
was not statistically significant (P = .37).
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Figure 7. Mean laser-flare photometer readings
in patients with greater or lesser changes in hyperemia. Readings are given
in photon counts per millisecond.
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Changes in iris pigmentation, determined by the results of the masked
investigators' evaluation of the photographs, were reported in 7 (1.5%) of
the 474 patients in the bimatoprost QD group, 9 (1.9%) of the 483 patients
in the bimatoprost BID group, and no patients in the timolol group. Generally
comparable findings were obtained by the sponsor's reading center.
The incidence of adverse events leading to discontinuation was comparably
low in the bimatoprost QD and timolol groups. In the bimatoprost QD treatment
group, 8.4% of patients discontinued owing to adverse events, compared with
5.0% in the timolol group (P = .09). The discontinuation
rate due to ocular adverse events was 5.3% in the bimatoprost QD group and
1.7% in the timolol group. This difference was statistically significant (P = .02), exclusively because of the statistically significant
difference in the number of patients who discontinued owing to hyperemia (3.4%
in the bimatoprost QD group and 0.4% in the timolol group; P = .01). We found no between-group difference in the number of patients
who discontinued because of any other adverse event. In the bimatoprost BID
treatment group, 14.7% of patients discontinued because of adverse events
(P = .003 compared with bimatoprost QD).
No clinically significant changes in results of ophthalmoscopy, laser-flare
photometry readings, visual acuity, visual fields, or systemic safety variables
were found with any treatment regimen.
COMMENT
The pooled 1-year results of the 2 pivotal phase 3 trials clearly demonstrated
that bimatoprost QD was superior to timolol in long-term IOP reduction. Significantly
higher percentages of patients achieved low pressures with bimatoprost QD,
and IOP was controlled throughout the day. The efficacy of bimatoprost QD
was sustained throughout the 1-year study. The mean reduction from baseline
IOP in the bimatoprost QD group was very consistent (range, 30%-33%) at follow-up
visits through 1 year of treatment.
Controlling IOP is critical to slowing the progression of glaucomatous
damage in patients with glaucoma or ocular hypertension. Elevated IOP is the
single most important risk factor for open-angle glaucoma, and numerous studies8-12 have
found that reducing IOP decreases the risk for visual field loss in patients
with glaucoma. A recent analysis by the Advanced Glaucoma Intervention Study
group demonstrated that after surgery to reduce IOP, patients who consistently
had IOPs less than 18 mm Hg at every clinic visit during the 6-year follow-up
showed mean changes in visual fields close to 0.12 In
these patients, the mean IOP was very low (12.3 mm Hg), suggesting that lower
IOPs result in greater patient benefit. Reductions in IOP of 30% or greater
have also been shown to significantly reduce the rate of glaucomatous progression
in patients with normal-tension glaucoma.8 Even
in patients without evidence of optic disc cupping, reduction of an elevated
IOP can be beneficial in delaying the onset of early glaucomatous damage.9-10 Therefore, a goal of glaucoma therapy
should be the achievement and maintenance of target IOPs that are low enough
to minimize glaucomatous progression.13 On
the basis of the superior IOP-lowering efficacy of bimatoprost QD demonstrated
in the present study, long-term bimatoprost QD treatment may reasonably be
assumed to provide greater protection for the visual field than does timolol
in patients with glaucoma or ocular hypertension. The greater ability of bimatoprost
to help patients reach IOP levels more consistently below 18 mm Hg should
prove particularly beneficial.8, 12
A recent study by Asrani and colleagues14 reported
that large fluctuations in diurnal IOP are an independent risk factor for
the progression of glaucomatous damage. The results of the present study show
that bimatoprost QD effectively controls IOP fluctuations throughout the day
that could otherwise increase the risk for further optic nerve damage.15-16
Numerous studies have reported significant differences between black
and nonblack populations in the prevalence of glaucoma17-18 and
the response to treatment.18 Population-based
studies have reported that glaucoma is 4 to 6 times more prevalent in black
than in nonblack populations and that glaucoma is 6 to 8 times more likely
to lead to blindness in black than in nonblack populations.17 The
reasons for the greater prevalence and visual field loss in black populations
are not yet known. The results of the present study demonstrated that bimatoprost
QD reduces IOP as effectively in black as in nonblack patients, and that bimatoprost
QD provides IOP lowering superior to that of timolol across both of these
patient populations.
Throughout 1 year of treatment, bimatoprost QD was safe and well tolerated.
The most common adverse effect, conjunctival hyperemia, was generally well
tolerated and mild in severity. In our experience, hyperemia can resolve after
2 to 4 weeks of treatment. The lack of any correlation between hyperemia and
laser-flare photometry readings indicates that there was no association with
intraocular inflammation and confirms the general finding that this adverse
effect does not represent a significant clinical safety concern. The investigating
physicians reported an increase in iris pigmentation in only 1.5% of the patients
in the bimatoprost group treated for 12 months. By comparison, in the phase
3 clinical trials of latanoprost in which iris pigmentation changes were evaluated
at a reading center, the incidence of increased iris pigmentation ranged from
10.9% to 22.9% of patients treated with latanoprost QD for 12 months.19 These results suggest that iris pigmentation changes
may occur less frequently with bimatoprost than with latanoprost. However,
given the different techniques used in the studies of these 2 drugs and the
variation in the ability of investigators to detect iris pigment changes,
a long-term comparison of bimatoprost with latanoprost using a single method
will be needed to evaluate this issue more thoroughly.
Bimatoprost BID was associated with a significantly higher incidence
of certain adverse events than was bimatoprost QD. This, along with the greater
efficacy of the QD regimen, supports the once-daily use of this drug.
CONCLUSIONS
We found 0.03% bimatoprost QD to be clinically and statistically superior
to 0.5% timolol maleate BID in lowering IOPs in patients with glaucoma or
ocular hypertension. Significantly more patients achieve very low target pressures
with bimatoprost QD than with timolol maleate BID. Bimatoprost QD provides
potent IOP control throughout the day and is safe and well tolerated. The
efficacy of bimatoprost QD is sustained through at least 1 year of treatment.
AUTHOR INFORMATION
Submitted for publication January 31, 2002; final revision received
May 15, 2002; accepted July 5, 2002.
This study was sponsored by Allergan Inc, Irvine, Calif.
This study was presented at the Annual Meeting of the American Academy
of Ophthalmology, New Orleans, La, November 13, 2001.
| Study Group Investigators
Bimatoprost Study Group 1
Mark B. Abelson, MD (North Andover, Mass); George
Baerveldt, MD (Cleveland, Ohio); Stephen Best, MD (Auckland, New Zealand); James D. Branch, MD (Winston-Salem, NC); James D. Brandt, MD (Sacramento,
Calif); John Brennan, MD (Sherman, Tex); Anne
M. V. Brooks, MD (East Melbourne, Victoria); Salim
Butrus, MD (Washington, DC); Leonard R. Cacioppo,
MD (Brooksville, Fla); Guy D'Mellow, MD (Brisbane, Queensland); Harvey B. DuBiner, MD (Morrow, Ga); Efraim Duzman, MD (Irvine, Calif); Robert
J. Foerster, MD (Colorado Springs, Colo); Jonathan
Frantz, MD (Fort Myers, Fla); Walter I. Fried, MD,
PhD (Gurnee, Ill); David K. Gieser, MD (Wheaton, Ill); Richard A. Lewis, MD (Sacramento,
Calif); Andrew Logan, MD (Wellington, New Zealand); Richard McGovern, MD (Adelaide, South Australia); Thomas Mundorf, MD (Charlotte, NC); George
F. Nardin, MD (Kailua, Hawaii); Jonathan Nussdorf,
MD (Louisville, Ky); Julian Rait, MD (East Melbourne); Robert L. Shields, MD (Denver,
Colo); Thomas R. Walters, MD (Austin, Tex); Jeffrey
C. Whitsett, MD (Houston, Tex); Jacob T. Wilensky,
MD (Chicago, Ill); Robert Williams, MD (Louisville).
Bimatoprost Study Group 2
Allen Beck, MD (Atlanta, Ga); Louis Cantor,
MD (Indianapolis, Ind); George Cioffi, MD (Portland, Ore); John S. Cohen, MD (Cincinnati, Ohio); David Cooke, MD (St Joseph, Mich); Andrew
Crichton, MD (Calgary, Alberta); Denise F. Dudley,
MD (Bellingham, Wash); Richard Evans, MD (San Antonio, Tex); Stephen Greenberg, MD (Holbrook,
NY); Neeru Gupta, MD, PhD (Toronto, Ontario); Leonard
Gurevich, MD (West Seneca, NY); Oscar Kasner, MD (Montreal, Quebec); Donald Kellum, MD (Boulder, Colo); Melvyn Koby, MD (Louisville); John
Kwedar, MD (Springfield, Ill); David McGarey, MD (Flagstaff, Ariz); Frederick Mikelberg, MD (Vancouver, British Columbia); Robert Noecker, MD (Tucson, Ariz); Leon L. Remis, MD (Marblehead, Mass); Robert Ritch, MD (New York, NY); Michael
Rotberg, MD (Charlotte); Howard I. Schenker, MD (Rochester, NY); Elizabeth Sharpe, MD (Mt Pleasant, SC); Mark B. Sherwood, MD (Gainesville,
Fla); Joseph Sokol, MD (Waterbury, Conn); Alfred
Solish, MD (Pasadena, Calif); Julia Whiteside-Michel,
MD (Little Rock, Ark); and Barbara Wirostko, MD (Huntington Station, NY).
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Corresponding author and reprints: Eve J. Higginbotham, MD, Department
of Ophthalmology, University of Maryland at Baltimore, 419 W Redwood St, Suite
580, Baltimore, MD 21201-1595 (e-mail: fcwejh6786{at}aol.com).
From the Department of Ophthalmology, University of Maryland at Baltimore
(Dr Higginbotham); the New England Eye Center, New England Medical Center,
Tufts University School of Medicine, Boston, Mass (Dr Schuman); the Eye Associates
and Sydney Eye Hospital, Sydney, New South Wales (Dr Goldberg); the Department
of Ophthalmology, Baylor College of Medicine, Houston, Tex (Dr Gross); and
Allergan Inc, Irvine, Calif (Drs VanDenburgh and Whitcup and Mr Chen). Drs
Higginbotham, Schuman, Goldberg, Gross and the members of the study groups
were paid evaluators and do not have any financial or proprietary interest
in any of the drugs used in the study or in the study sponsor.
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