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Comparison of the Ocular Hypotensive Lipid AGN 192024 With Timolol
Dosing, Efficacy, and Safety Evaluation of a Novel Compound for Glaucoma Management
Robert A. Laibovitz, MD;
Amanda M. VanDenburgh, PhD, MBA;
Carlos Felix, MS;
Robert David, MD;
Amy Batoosingh, BA;
Allan Rosenthal, PhD;
Janet Cheetham, PharmD
Arch Ophthalmol. 2001;119:994-1000.
ABSTRACT
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Objective To compare the safety and efficacy of the ocular hypotensive lipid AGN
192024 (Lumigan) with those of timolol.
Methods A 30-day, randomized, investigator-masked, clinical trial involving
100 patients with elevated intraocular pressure (IOP). Study medications were
instilled topically. Doses of 0.003%, 0.01%, or 0.03% AGN 192024 were given
once daily for 3 weeks then twice daily for 1 week, and vehicle control or
0.5% timolol was given twice daily for 4 weeks. Mean change in IOP from baseline
was the primary efficacy variable. Safety parameters included adverse events,
hyperemia grading, laser flare meter analysis, heart rate, and blood pressure.
Results Timolol and all 3 concentrations of AGN 192024 lowered IOP from baseline
(P<.001). A dosage of 0.03% AGN 192024 once daily
lowered IOP significantly more than timolol (P .02)
at every study visit except day 21 (P = .053) and
provided better diurnal IOP control. Twice-daily dosing of AGN 192024 provided
no clinically significant benefit over once-daily dosing. All treatment regimens
were safe and well tolerated, with no clinically significant effects on heart
rate or blood pressure and no between-group differences in the incidence of
adverse events. The only significant ocular safety finding with AGN 192024
was a dose-related mild increase in conjunctival hyperemia.
Conclusions Of the 3 concentrations tested, 0.03% AGN 192024 once daily had the
best therapeutic profile. AGN 192024 was safe and well tolerated, and it provided
superior ocular hypotensive efficacy and diurnal IOP control compared with
timolol in patients with ocular hypertension and glaucoma.
INTRODUCTION
ELEVATED intraocular pressure (IOP) associated with glaucoma and ocular
hypertension is primarily managed with topical ocular hypotensive agents.1 Nonselective  -adrenergic blocking agents such
as timolol have been the most commonly prescribed therapeutic option. However,
a propensity for long-term drift2 and an association
with systemic adverse effects3-4
have prompted the search for safer and more efficacious ocular hypotensive
agents. Accordingly, several new agents from a diverse array of pharmacological
classes have been introduced for the management of ocular hypertension and
glaucoma. Among these are the topical carbonic anhydrase inhibitors, selective  2-adrenergic agonists, and ester prodrugs of prostaglandin F2(PGF2) analogs such as latanoprost and unoprostone
isopropyl ophthalmic solution.5-10
In this report, we introduce our early clinical findings with AGN 192024
(Lumigan; Allergan Inc, Irvine, Calif), formerly identified as an ocular hypotensive
lipid.11-17
These compounds are pharmacologically unique. They are inactive at the human
PGF2-sensitive (FP) receptor and at all other known prostanoid
receptors and are devoid of several PGF2-associated activities.11, 18-20 Yet
in preclinical evaluation it was found that they possess substantial IOP-lowering
efficacy.12 Recent studies have elucidated
the pharmacological basis of AGN 192024 to be related to the prostamides,
which were recently discovered as biosynthetic products of anandamide.17
To evaluate the relative therapeutic potential of AGN 192024 for glaucoma
management, we conducted a 30-day, randomized, investigator-masked, parallel-group,
graduated-dosing frequency clinical trial involving patients with ocular hypertension
or glaucoma. The safety, tolerability, and ocular hypotensive efficacy of
topically applied 0.003%, 0.01% and 0.03% concentrations of AGN 192024 were
compared with those of AGN 192024 vehicle and 0.5% timolol. Doses of 0.003%,
0.01%, and 0.03% AGN 192024 were administered once in the evening for 3 weeks,
then twice daily for an additional week. The AGN 192024 vehicle and 0.5% timolol
were administered twice daily throughout the study.
SUBJECTS AND METHODS
STUDY POPULATION
This 30-day comparison trial was conducted from October 1996 through
February 1997 by Eye Research Associates, Austin, Tex. The protocol was reviewed
and approved by a governing institutional review board. The study was conducted
according to the Declaration of Helsinki, Good Clinical Practices, and applicable
Code of Federal Regulations.
Men or women (not of child-bearing potential) 21 years or older with
a diagnosis of ocular hypertension (elevated IOP without evidence of visual
field loss) or primary open-angle glaucoma were eligible for the study. Other
primary eligibility criteria included uncontrolled (postwashout) IOP between
23 and 34 mm Hg in both eyes, between-eye asymmetry in IOP of no more than
5 mm Hg, and corrected visual acuity of at least 20/100 in each eye.
Key exclusion criteria included uncontrolled systemic disease, known
allergy or sensitivity to the study medications, contraindications to -adrenergic
blocker therapy, anticipated alteration during the study of existing long-term
therapy with agents that could affect IOP, anticipated use of topical or systemic
steroids during the study, and history of refractive surgery within 1 year
or laser surgery within 3 months before the study.
All patients had newly diagnosed conditions and were free of medication
at the time of enrollment or were taking only 1 medication, which was washed
out before the study. Washout periods ranged from 4 to 30 days as follows:
4 days for parasympathomimetics and carbonic anhydrase inhibitors, 2 weeks
for nonselective adrenergic agonists and topical -agonists, and 4 weeks
for -adrenergic blocking agents and prostaglandins.
One hundred qualified patients were enrolled after obtaining written
informed consent. Patients were distributed by random assignment to 1 of 5
treatment groups with 20 patients in each group. Enrolled patients could voluntarily
withdraw at any time. Any patient who had an unacceptable response to treatment
that affected his or her welfare, including an inappropriate IOP response
(eg, an increase of 3 mm Hg or more in IOP from pretreatment baseline) was
eliminated from the study.
MASKING, INTERVENTION, AND TIMING
Treatment groups received a 0.03%, 0.01%, or 0.003% concentration of
AGN 192024; 0.5% timolol; or AGN 192024 vehicle control. Study medications
were dispensed in identical-appearing, coded bottles supplied by Allergan
Inc. The study was investigator masked. Because there were differences in
dosing frequencies, the study coordinator was responsible for dispensing and
administering the medications, and the patients were instructed to refrain
from showing the study medications to the investigator.
Dosing (1 drop in each eye) commenced on day 0 following the last baseline
diurnal IOP measurement. For the AGN 192024 active treatment groups, study
medication was administered at 24-hour intervals (between 7:30 PM and 9:30
PM) every day for 21 days, then at 12-hour intervals (between 7:30 AM and
9:30 AM and between 7:30 PM and 9:30 PM) every day for an additional 7 days.
For the timolol and vehicle groups, study medication was administered at 12-hour
intervals (between 7:30 AM and 9:30 AM and between 7:30 PM and 9:30 PM) every
day for 28 days.
Scheduled visits included a prestudy visit followed by study visits
on day 0 (baseline); days 3, 7, 14, and 21 (end once-daily dosing phase);
days 23 and 28 (end twice-daily dosing phase); and day 30 (2 days following
last dose). Patients came to the clinic for the evening dosing on the days
before study visits (ie, on days 2, 6, 13, 20, 22, and 27), and the study
coordinator administered the study medication. Patients instilled their own
medication at all other time points. Patients using medication twice daily
were instructed not to use their drops on the morning of a scheduled visit;
the study medications were instilled by the study coordinator following the
hour 12 ophthalmic examination.
Because the medications were nonpreserved (no preserved formulations
were available at the time the study was conducted), a new bottle was used
each day. One bottle was used for both eyes. Patients and the investigator
were asked to store study medications at room temperature.
PRIMARY EFFICACY VARIABLE: MEAN CHANGE IN IOP
The primary efficacy variable was mean reduction of IOP from baseline
as measured in millimeters of mercury using Goldmann applanation tonometry
attached to a slitlamp. Baseline IOP was established after washout and before
administration of medications on day 0. The IOP of both eyes was measured
and the values averaged for analyses. The IOP at 8 AM was measured at each
study visit. Diurnal IOP measurements were taken at 8 AM, 12 noon, 4 PM, 8
PM, and 10 PM on days 0, 14, 21, and 28.
PRIMARY SAFETY VARIABLES
Adverse Events
The occurrence of ocular and systemic adverse events was monitored throughout
the study, and each event was recorded by the investigator, with the severity
(mild, moderate, or severe) and the causality of the event relative to the
study medication (ie, definite, probable, possible, unlikely, unknown, or
none) noted.
Ocular Safety
Biomicroscopy and ophthalmoscopy were performed at all study visits,
and visual acuity and anterior chamber flare were evaluated. Biomicroscopy
was performed using slitlamp examination without pupil dilation and included
inspection of the lids, conjunctiva, cornea, anterior chamber, lens, and vitreous.
Observations were reported on a 4-point grading scale (0 = none, 1 = mild,
2 = moderate, and 3 = severe). Biomicroscopic observations of conjunctival
hyperemia were reported on a 5-point scale (0 = none, 0.5 = trace, 1 = mild,
2 = moderate, and 3 = severe).
Best-corrected visual acuity at distance was measured using a Snellen
chart. Laser flare meter readings were collected using a KOWA FM-500 Laser
Flare Meter (Kowa Company Ltd, Chuo-Ku, Tokyo, Japan). The results were recorded
in photon counts per millisecond. Readings were taken before the morning instillation
of study medication (for the twice-daily dosing groups) and no later than
7:30 AM.
At the prestudy visit and on study day 30, cup-disc ratio and fundus
pathology were assessed using direct and indirect ophthalmoscopy. Cup-disc
ratio was recorded on a scale from 0.0 to 0.9 based on the Allergan Armaly
Chart. Fundus examinations were done through a dilated pupil, and observations
were recorded using a 4-point grading scale as above.
Heart Rate and Blood Pressure
Heart rate and blood pressure were measured at all study visits. Heart
rate, recorded as beats per minute, was measured with the patient in a resting
position for at least 5 minutes. Resting systolic and diastolic blood pressure
was measured and recorded in millimeters of mercury.
ANALYSIS
Data were summarized with descriptive statistics (mean and SE) for continuous
variables and with frequency distributions for categorical variables. Our
a priori hypothesis was that a sample size of 19 per group would give us a
power of 0.88 to detect a mean change of 4 mm Hg or more from baseline mean
IOP.
For continuous variables, analysis of variance and the t test on rank scores were used for overall and pairwise comparisons.21 The Wilcoxon signed rank test was used to test for
changes from baseline. For ordinal variables, the Kruskal-Wallis test and
the Wilcoxon rank sum test were used for overall and pairwise comparisons.22 For nominal variables, the Pearson  2
test or the Fisher exact test was used for the comparisons.23
All pairwise comparisons were evaluated whenever the overall comparison was
statistically significant.24 P.05 was considered statistically significant. Statistical analysis
was performed using the SAS computer package (version 6.12; SAS Institute,
Cary, NC).
RESULTS
DEMOGRAPHICS
The demographics of the 100 patients who were enrolled in the study
are presented in Table 1. There
were no significant differences in age, height, weight, sex, race, iris color,
diagnosis, or medical and ophthalmic profiles among the treatment groups.
All enrolled patients completed the 30-day study. Therefore, analysis of efficacy
and safety was based on the results for all 100 patients.
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Table 1. Patient Demographics*
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OCULAR HYPOTENSIVE EFFICACY AT 8 AM AND 8 PM
In a dose-dependent manner, all 3 concentrations of AGN 192024 and 0.5%
timolol caused a significant (P.001) and sustained
reduction in IOP from baseline at the 8 AM time point (Figure 1). Changing the dosing regimen to twice daily from once
daily had little effect on the efficacy of 0.01% or 0.03% AGN 192024 solutions
(Table 2). For the 0.03% AGN 192024
treatment group, the mean change from baseline IOP ranged from -7.2
to -8.2 mm Hg during once-daily dosing and from -7.7 to -8.7
mm Hg during twice-daily dosing. Twice-daily timolol produced a mean reduction
from baseline IOP at 8 AM of -3.4 to -3.9 mm Hg throughout the
study.
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Table 2. Mean Change and Mean Percent Change From Baseline Intraocular
Pressure (IOP) at 8 AM During Once-Daily (Days 0-21) and Twice-Daily (Days
23-28) Study Phases
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The ocular hypotensive efficacy of the 0.01% and 0.03% concentrations
of AGN 192024, instilled once daily or twice daily, was significantly greater
than that of timolol taken twice daily. The 0.03% concentration of AGN 192024
lowered IOP from the 8 AM baseline significantly more than timolol (P.02) at every study visit except day 21 (P = .053). The 0.01% AGN 192024 dose reduced IOP from baseline significantly
more than timolol at every visit (P.04) except
day 3 (P = .11). The IOP-lowering efficacy of 0.003%
AGN 192024 taken once daily and twice daily was comparable to that of 0.5%
timolol taken twice daily.
On day 30 (48 hours following the last instillation), AGN 192024 demonstrated
a prolonged IOP-lowering effect at 8 AM, with a mean change from baseline
IOP of -5.6 mm Hg in the 0.03% group compared with -2.1 mm Hg
in the timolol group (P = .02).
The superior efficacy of AGN 192024 was also evident when considering
mean percent reduction from baseline IOP at 8 AM. The mean percent IOP reduction
in the 0.03% group ranged from 25.7% (on day 21) to 31.5% (on day 23), compared
with a range of 12.9% (on day 14) to 15.0% (on day 3) in the timolol group.
On day 14 at the 8 AM time point, the 0.03% and 0.01% AGN 192024 twice-daily
groups had significantly higher mean percent reductions from baseline IOP
than did timolol (Figure 2).
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Figure 2. Mean (SE) percent change from
baseline intraocular pressure (IOP) at 8 AM on day 14. The mean percent decrease
from baseline IOP was significantly greater in the 0.01% AGN 192024 once-daily
(P= .04) and 0.03% once-daily (P= .003) groups than in the 0.5% timolol twice-daily group.
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Because the IOP-lowering effect of topical AGN 192024 approaches maximal
levels (peak) approximately 12 hours following instillation,24
the IOP-lowering effect on days 14 and 21 at 8 PM (24 hours following instillation
of AGN 192024) was also examined. As shown in Table 3, 0.03% AGN 192024 taken once daily produced significantly
greater mean reductions of IOP than timolol taken twice daily (P.03) at 8 PM on days 14 and 21.
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Table 3. Mean Change and Mean Percent Change From Baseline Intraocular
Pressure (IOP) at 8 PM on Days 14 and 21
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DIURNAL IOP CONTROL
The 0.01% and 0.03% concentrations of AGN 192024 given once or twice
daily produced a significant mean reduction in IOP from baseline throughout
the day (P.001) and provided better diurnal IOP
control than timolol taken twice daily. On day 21 the mean reduction of IOP
with 0.03% AGN 192024 taken once daily was significantly greater than that
with timolol taken at noon, 4 PM, 8 PM, and 10 PM (P.03; Figure 3). The 0.01% concentration of AGN
192024 administered once daily produced a significantly greater mean change
in IOP than did timolol at the 8 AM and 8 PM time points (P.02). Similar observations were made on day 14 (once-daily phase)
of the study, with better diurnal IOP control seen with 0.01% and 0.03% AGN
192024 than with timolol.
Twice-daily dosing of the 0.01% and 0.03% concentrations of AGN 192024
provided little benefit over once-daily dosing in the level of diurnal IOP
control achieved (Figure 4). Although
IOP lowering may have been slightly enhanced with twice-daily dosing of the
0.003% concentration, twice-daily dosing of 0.01% and 0.03% AGN 192024 provided
roughly the same mean reduction in IOP from baseline throughout the day as
did once-daily dosing (compare Figure 3
and Figure 4). Again on day 28,
the 0.03% and 0.01% concentrations of AGN 192024 provided a significantly
greater mean decrease in IOP from baseline than did timolol at most time points
(P.04).
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Figure 4. Mean (SE) changes from baseline
diurnal intraocular pressure (IOP) on day 28 (end twice-daily phase). The
0.01% and 0.03% AGN 192024 twice-daily regimens provided better diurnal IOP
control than did 0.5% timolol given twice daily. The mean reduction from baseline
IOP in the 0.03% AGN 192024 group was significantly greater (P.04) than that in the timolol group at every time point except
noon. The mean reduction from baseline IOP in the 0.01% AGN 192024 group was
significantly greater than that with timolol taken at 8 AM (P= .004) and 4 PM (P= .008) and tended toward
superiority at 8 PM (P= .056).
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ADVERSE EVENTS
All 3 concentrations of AGN 192024 and timolol had favorable safety
profiles and were well tolerated. All patients completed the study. The overall
incidence of adverse events was minimal in all treatment groups (Table 4).
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Table 4. The Number of Patients Experiencing Adverse Events of Any
Causality*
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There were no significant differences between active treatment groups
in the incidence of any particular adverse event. The most frequent adverse
event was conjunctival hyperemia, reported in 1 (5%), 3 (15%), and 1 (5%)
of the 20 patients in the 0.003%, 0.01%, and 0.03% AGN 192024 groups, respectively.
There were no reports of hyperemia in the AGN 192024 vehicle or timolol treatment
groups. The incidence of hyperemia in the AGN 192024 groups during the once-daily
and twice-daily phases combined was not significantly different from that
in the timolol group (P .23). Other adverse events
reported in 2 or more patients treated with AGN 192024 included ocular dryness
(5/60), foreign body sensation (2/60), ocular pruritus (2/60), diarrhea (3/60),
headache (2/60), and dyspnea (2/60). None of these events was considered serious.
OCULAR SAFETY
Ocular safety parameters were unaffected, other than a minor dose-related
increase in the degree of conjunctival hyperemia (generally a trace to mild
increase during the once-daily phase) in the AGN 192024 groups and increased
laser flare meter readings in the timolol group. Although conjunctival hyperemia
was observed in all treatment groups, mean grading scores of hyperemia in
the 0.01% and 0.03% AGN 192024 groups were significantly higher than those
in the timolol group at most study visits (P.03).
During the once-daily phase of the study, mean hyperemia scores (ranges) were
as follows: timolol group, 0.35 to 0.50; vehicle group, 0.50 to 0.63; 0.003%
AGN 192024 group, 0.65 to 0.78; 0.01% AGN 192024 group, 0.85-0.95; and 0.03%
AGN 192024 group, 0.80 to 0.98. When the dosing schedule was changed from
once to twice daily, a slight increase in mean hyperemia scores was found
with the 2 highest concentrations of AGN 192024 (mean score ranges of 0.93
to 1.00 in the 0.01% AGN 192024 group and 1.03 to 1.08 in the 0.03% AGN 192024
group). There were no other significant findings with biomicroscopy.
Baseline laser flare meter readings were comparable among treatment
groups (P = .12). The aqueous humor protein concentration
was significantly increased from baseline at each study visit during treatment
with timolol (P.001). The mean increase in laser
flare readings from the baseline of 7.52 ranged from 1.58 to 2.36 in the timolol
group. The changes in laser flare readings in the timolol group were significantly
different from those in all other treatment groups (P.04).
No clinically significant changes in cup-disc ratio were seen, and visual
acuity remained relatively unchanged throughout the study.
CARDIOVASCULAR SAFETY
All 3 concentrations of AGN 192024, whether given once or twice daily,
were safe and produced no clinically significant mean changes in heart rate
or blood pressure from baseline (Table 5).
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Table 5. Mean Changes in Heart Rate and Blood Pressure (BP) From Baseline*
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COMMENT
In this randomized, investigator-masked clinical trial, both once- and
twice-daily instillations of 0.003%, 0.01%, or 0.03% AGN 192024 were safe,
well tolerated, and effective. Moreover, AGN 192024 provided superior ocular
hypotensive efficacy and better diurnal IOP control than timolol.
In a sustained, dose-dependent manner, all 3 concentrations of AGN 192024,
given once or twice daily, as well as timolol given twice daily produced significant
mean reductions from baseline IOP at 8 AM (P.001).
A 31.5% maximum reduction in IOP was observed in the 0.03% AGN 192024 group
compared with a 15.0% maximum reduction in the timolol group. Moreover, once-and
twice-daily 0.03% AGN 192024 provided better IOP control than timolol given
twice throughout the day. The IOP lowering with 0.03% AGN 192024 was substantial
even at 24 hours following evening instillation, with a mean IOP reduction
of approximately 5.0 mm Hg (P.03) from baseline
at the 8 PM measurement. The mean reductions from baseline IOP achieved with
timolol treatment in this clinical trial were less than anticipated, possibly
because patients were not excluded for previous use of timolol. However, the
mean reductions of IOP in the 0.03% AGN 192024 group were greater than the
reductions typically reported with timolol (approximately 20% to 25% from
baseline6-9,17, 25-26),
confirming the outstanding ocular hypotensive efficacy of AGN 192024 in this
clinical trial.
The only significant between-group difference in ocular side effects
was trace to mild conjunctival hyperemia in the AGN 192024 group. The degree
of conjunctival hyperemia in the AGN 192024 groups was dosing frequency related,
with lower mean grading scores seen in the 0.03% once-daily vs twice-daily
regimens.
There were no biomicroscopic findings of flare in this study. Although
the slitlamp can be used to detect clinically significant flare and cells
in the anterior chamber, it may not be sensitive enough for evaluation of
subtle disruption of the blood aqueous barrier. The most sensitive equipment
available to evaluate blood aqueous barrier integrity is the laser flare meter.
In this study, the KOWA FM-500 was used to quantify any effect of AGN 192024
on the blood aqueous barrier. There were no significant changes in laser flare
meter readings in any of the AGN 192024 treatment groups. In the timolol treatment
group, the laser flare measurements demonstrated a statistically significant
increase in photon counts in the aqueous humor. This is consistent with the
results of studies by Araie et al27 and Stur
et al28 in which timolol caused an increase
in total protein concentration in the aqueous humor. The results of these
previous studies were consistent with timolol-associated reduction of aqueous
humor production, without any sign of breakdown of the blood aqueous barrier.
The nonselective -adrenergic blocking agents, although generally
effective ocular hypotensive agents, can be systemically absorbed29 and cause untoward central nervous system and cardiopulmonary
adverse effects.30-32
Thus, the nonselective -adrenergic blocking agents are contraindicated
in patients with, or at high risk for, cardiopulmonary disease. In this study,
AGN 192024 had no consistent effects on heart rate or blood pressure, suggesting
that the systemic safety profile of AGN 192024 is likely to be favorable.
Our observations in this clinical study, taken together with the unique
preclinical pharmacological profile of AGN 192024, suggest that AGN 192024
has great potential as an agent for the management of glaucoma and ocular
hypertension. In this short-term trial, AGN 192024 appeared to be highly efficacious,
well tolerated, and systemically safe. The robust IOP lowering efficacy of
AGN 192024 observed in this study suggests that future studies should be carried
out to elucidate the molecular activity and aqueous flow and outflow effects
of AGN 192024.
In conclusion, although all 3 concentrations and both dosing regimens
tested were effective and had an acceptable safety profile, the 0.03% concentration
of AGN 192024 instilled topically once in the evening had the most advantageous
overall therapeutic profile. In this short-term study, 0.03% AGN 192024 given
once daily provided superior ocular hypotensive efficacy and better diurnal
IOP control than 0.5% timolol given twice daily and was well tolerated in
patients with elevated IOP. Further clinical evaluation of 0.03% AGN 192024
given once daily for long-term management of glaucoma and ocular hypertension
is warranted.
AUTHOR INFORMATION
Accepted for publication December 1, 2000.
This study was supported by Allergan Inc.
Reprints and corresponding author: Amanda M. VanDenburgh, PhD, MBA,
Allergan Inc, 2525 Dupont Dr, Mail Stop T2-4D, Irvine, CA 92623-9534.
From Eye Research Associates, Austin, Tex (Dr Laibovitz); and Allergan
Inc, Ophthalmology Clinical Research, Irvine, Calif (Drs VanDenburgh, David,
Rosenthal, and Cheetham, Mr Felix, and Ms Batoosingh). Dr Laibovitz was a
paid evaluator and does not have any financial or proprietary interest in
AGN 192024 or the study sponsor, Allergan Inc. Drs VanDenburgh, David, Rosenthal,
and Cheetham, Mr Felix, and Ms Batoosingh are employees of Allergan Inc.
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