Efficacy and Safety of Bimatoprost in Patients with Elevated Intraocular Pressure

SURVEY OF OPHTHALMOLOGY VOLUME 45 • SUPPLEMENT 4 • MAY 2001

Efficacy and Safety of Bimatoprost in Patients with Elevated Intraocular Pressure: A 30-Day Comparison with Latanoprost Harvey DuBiner, MD,1 David Cooke, MD,2 Monte Dirks, MD,3 William C. Stewart, MD,4 Amanda M. VanDenburgh, PhD,5 and Carlos Felix, MS5 1

Clayton Eye Center, Morrow, Georgia; 2Great Lakes Eye Care, St. Joseph, Michigan; 3Ophthalmology Service, Brooke Army Medical Center, San Antonio, Texas; 4Pharmaceutical Research Corporation, Charleston, South Carolina; 5Allergan, Inc., Clinical Ophthalmology, Irvine, California, USA Abstract. Purpose: To compare the safety and efficacy of bimatoprost and latanoprost in patients with primary open-angle glaucoma or ocular hypertension. Methods: This was a 30-day, multicenter, doublemasked, randomized, clinical trial. Patients (n  64) diagnosed with primary open-angle glaucoma or ocular hypertension were randomly assigned to receive bimatoprost 0.03%, latanoprost 0.005%, or vehicle topically in both eyes once daily, in the evening, for 29 days. The primary endpoint was the reduction in IOP from baseline on day 14 and day 29. Secondary outcome measures included eye examinations and safety parameters. Results: Bimatoprost and latanoprost significantly lowered IOP from baseline (p  .001). Bimatoprost lowered IOP more than latanoprost at every timepoint measured (bimatoprost: 25–34% reduction, 5.9–8.9 mm Hg; latanoprost: 20–31% reduction, 4.4–7.9 mm Hg), although the between-group differences did not reach statistical significance. Over the 12-hour course of IOP measurements on day 29, bimatoprost provided better diurnal IOP control than latanoprost (p  .0378, area under the curve of diurnal IOP reductions, 1-way ANOVA with pairwise t-test). Both treatment regimens were safe and well tolerated, with no significant between-group differences in reports of specific adverse events. The most common side effect was conjunctival hyperemia, which was similarly apparent in the bimatoprost and latanoprost treatment groups. Conclusions: At the end of this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal IOP control than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma. (Surv Ophthalmol 45(Suppl 4):S353–S360. © 2001 by Elsevier Science Inc. All rights reserved.) Key words. glaucoma • ocular hypertension • bimatoprost • AGN 192024 • latanoprost • prostamide • Lumigan™

Bimatoprost is a member of a new class of pharmacologically unique ocular hypotensive agents called prostamides.17,18 Prostamides were originally described as biosynthetic products derived from anandamide, an endogenous membrane lipid19 (Woodward et al, 11th International Conference on Advances in Prostaglandin and Leukotriene Re-

search, 2000 [abstract]). Recently, naturally occurring prostamides that are potent and highly efficacious ocular hypotensive agents were discovered in ocular tissue, suggesting that prostamides normally regulate IOP (Chen J, Krauss AH-P, Protzman CE, et al: Presentation at the meeting of the British Pharmacological Society, 2000 [abstract]; Krauss AH-P,

S353 © 2001 by Elsevier Science Inc. All rights reserved.

0039-6257/01/$–see front matter PII S0039-6257(01)00212-0

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Surv Ophthalmol 45 (Suppl 4) May 2001

Chen J, Protzman C, et al: Pharmacology, biosynthesis and ocular hypotensive activity of prostamide F2 [prostaglandin F2 1-ethanoloamide], a novel naturally occurring substance [abstract]. Association for Ocular Pharmacology and Therapeutics, 2000 [abstract]). Bimatoprost is a synthetic analog of these naturally occurring prostamides, and it mimics the prostamides by demonstrating strong intraocular pressure (IOP)-lowering activity.14,15 In an earlier 30day clinical trial, bimatoprost 0.03% once daily demonstrated ocular hypotensive efficacy superior to timolol 0.5% twice daily in patients with ocular hypertension or glaucoma.14 No systemic adverse effects of bimatoprost were observed, and bimatoprost had a favorable tolerability profile. The prostaglandin F2 (PGF2) analog prodrug latanoprost is an ocular hypotensive agent used in the management of glaucoma and ocular hypertension. Latanoprost is widely available and has displayed ocular hypotensive efficacy similar to or greater than that exhibited by timolol in controlled comparative clinical studies.2,3,16 To further evaluate the therapeutic potential of bimatoprost, we conducted a 30day, randomized, double-masked, parallel group, clinical trial involving patients with open-angle glaucoma or ocular hypertension. The safety, tolerability and ocular hypotensive efficacy of once-daily topically-applied bimatoprost 0.03% and latanoprost 0.005% were compared.

Methods STUDY POPULATION

This 30-day clinical trial was conducted at four investigational sites. All aspects of the study were in compliance with the Declaration of Helsinki and the applicable Code of Federal Regulations, and all patients provided written informed consent. The study population consisted of men and women,  21 years of age, diagnosed with primary open-angle glaucoma or ocular hypertension, based on the determination of the principal investigators. Other key inclusion criteria included: IOP likely to be controlled on monotherapy; uncontrolled (postwashout) 8 am day 0 (baseline) IOP  23 mm Hg and  34 mm Hg in each eye; IOP asymmetry between the eyes  5 mm Hg; and corrected visual acuity of at least 20/100 in each eye. Key exclusion criteria were any uncontrolled systemic disease or severe cardiovascular disease; females of child-bearing potential who were pregnant, nursing, or not using reliable birth control; functionally significant abnormal blood parameters; any previous use of latanoprost; clinically relevant low or high heart rate or blood pressure; known allergy or hypersensitivity to either of the study medication(s)

DUBINER ET AL

or their components; anticipated use of topical or systemic steroids; anticipated alteration of existing chronic therapy with agents that can have a substantial effect on IOP; anticipated wearing of contact lenses during the study; and a history of laser or other intraocular surgery within the 3 months prior to the study. All patients were either newly diagnosed and free of ocular medication at the time of enrollment, or were on medication that was to be washed out prior to baseline. Washout periods were 4 days for parasympathomimetics and carbonic anhydrase inhibitors, 2 weeks for adrenergic agonists, and 4 weeks for topical beta-blockers. INTERVENTION

A total of 106 patients were enrolled and distributed by random assignment to one of five treatment groups. In three arms of the study, treatment groups were administered bimatoprost 0.03% (n  21), latanoprost 0.005% (n  22), or vehicle (inactive control solution) once daily at 8 pm ( 1 hour). Treatment groups in the other two arms of the study received another compound or a formulation of bimatoprost that is not being pursued for further development; results from these study arms are not reported here. Bottles of bimatoprost were supplied by the manufacturer, Allergan, Inc. Bottles of latanoprost (manufactured for Pharmacia and Upjohn by Automatic Liquid Packaging, Inc.) were stripped of the manufacturer’s labels. All bottles of medications used in the study were masked with coded labels. Because the bottles had different shapes, a study coordinator not otherwise involved with the study dispensed the medications at each site, and patients were instructed to refrain from showing the study medications to the investigators or to any site personnel involved with the study. The study design included a prestudy visit at least 2 days before the baseline visit (depending on the required washout period), and study visits on day 0 (baseline), day 14, and day 29. Patients were instructed to instill one drop of study medication in each eye once daily, in the evening at 8 pm for 29 days, beginning on day 0 of the study. Patients were to use a new bottle of medication each day. IOP MEASUREMENTS

Efficacy was evaluated by the reduction in IOP from baseline. IOP was measured in mm Hg with an applanation tonometer affixed to a slit lamp. At least one IOP measurement was taken for each eye at each timepoint. The focus was on the outcomes of patients, not individual eyes. Thus, mean IOP values from both eyes were used for analyses. To avoid bias, patients with asymmetry of IOP between eyes  5 mm Hg at

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EFFICACY AND SAFETY OF BIMATOPROST

baseline were excluded from the study. Baseline IOP measurements were obtained at 8 am, 12 noon, 4 pm, and 8 pm on day 0. Follow-up IOP measurements were obtained at 8 am on day 14 and at 8 am, 12 noon, 4 pm, and 8 pm on day 29 of the study. ADVERSE EVENTS

Adverse events that occurred during the study were documented, with the severity of the event (mild, moderate, or severe) and its relationship to the study treatment (none, unlikely, possible, probable, or definite) noted. OCULAR SAFETY

Biomicroscopy and visual acuity measurements were carried out at each study visit. Biomicroscopy was performed with use of slit-lamp examination without pupil dilation. The examination included evaluation of the condition of the lids, conjunctiva, cornea, anterior chamber, lens, and anterior vitreous. General observations were recorded using a 4-point scale in which 0  none, 1  mild, 2  moderate, and 3  severe. Observations of conjunctival hyperemia were recorded using a 5-point scale in which 0  none, 0.5  trace, 1  mild, 2  moderate, and 3  severe. Ophthalmoscopy was performed through a dilated pupil at the prestudy and day 29 visits. The cup:disk ratio was assessed and reported on a scale of 0.0–0.9 based on the Allergan Armaly Chart. Fundus pathology was recorded using the 4-point scale described above. SYSTEMIC SAFETY

At all study visits, heart rate (bpm) and blood pressure (mm Hg) were measured with the patient seated after a 5-min resting period. Blood pressure was measured with a sphygmomanometer. Neither arm was specified for measurement. At the prestudy visit and on days 0 and 29, blood samples were drawn for fasting blood chemistry and hematology. The blood chemistry panel included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, cholesterol (total, HDL, LDL), creatinine, gamma glutamyl transpeptidase, glucose, lactic dehydrogenase, protein (total, albumin, globulin), triglycerides, and electrolytes (calcium, potassium, and sodium). Hematology parameters included hematocrit, hemoglobin, platelet count, total white blood cells, and a white blood cell differential (5-part, including neutrophils, lymphocytes, monocytes, basophils, and eosinophils). DATA ANALYSIS

A priori calculations were used to estimate the sample size needed for statistical power. For the

change from baseline IOP, sample sizes of 20 subjects per group would give a power of 0.85 to detect a change of 4 mm Hg. IOP was analyzed according to protocol. The Pearson chi-square test or the Fisher exact test was used for analysis of nominal variables.6 For ordinal variables, the Kruskal-Wallis test and the Wilcoxon rank-sum test were used for overall and pairwise comparisons7 and the Wilcoxon signed-rank test7 was used to test for changes from baseline. A worse-eye analysis was performed for biomicroscopic findings, using values from the eye with the worse outcome at the particular visit. ANOVA and the students t-test were used for overall and pairwise comparisons of continuous variables.4 Because there were significant among-group differences in baseline IOP, ANCOVA was used to test for differences among groups in mean IOP reductions from baseline, using baseline IOP as the covariate to remove any confounding influence of baseline IOP. Comparisons of overall mean IOP reductions among groups were performed using 1-way ANOVA for repeated measures. AUC (area under the curve) analysis can be used to examine outcomes over time. The AUC of IOP reductions measured over the diurnal timepoints (8 am, 12 noon, 4 pm, 8 pm on day 29) was calculated for each patient. Mean AUC of diurnal IOP reductions was compared among and between groups using 1-way ANOVA and paired t-tests. Confidence intervals were calculated to determine the similarity in IOP-lowering efficacy of bimatoprost and latanoprost. The power was  0.4 to detect that bimatoprost was at least as efficacious as latanoprost; bimatoprost was determined to be at least as efficacious as latanoprost when the upper limit of the 95% confidence interval of the between-group difference in IOP reduction (bimatoprost minus latanoprost) was no more than 2 mm Hg. In each analysis, a two-sided p  0.05 was considered to be statistically significant.

Results PATIENT CHARACTERISTICS AND DISPOSITION

A total of 64 patients were enrolled in the three treatment groups. There were no statistically significant differences among the groups in ophthalmic diagnosis, medical or ophthalmic history, or demographic variables (Table 1). Diurnal baseline IOP values were comparable among treatment groups at 8 am, 12 noon, and 8 pm (Table 1). At 4 pm, the bimatoprost versus latanoprost and vehicle betweengroup differences in baseline IOP were significant (p  .026; 1-way ANOVA with pairwise t-tests); therefore, analyses of IOP reductions used baseline IOP as a covariate.

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DUBINER ET AL TABLE 1

Patient Characteristics Bimatoprost (n  21)

Latanoprost (n  22)

Vehicle (n  21)

68.8  1.6 53–79

64.3  2.1 43–77

66.4  2.2 47–82

11/10

10/12

8/13

16 (76%) 5 (24%)

18 (82%) 4 (18%)

18 (86%) 3 (14%)

7 (33%) 14 (66%)

11 (50%) 11 (50%)

8 (38%) 13 (62%)

9 (43%) 12 (57%)

10 (46%) 12 (54%)

10 (48%) 11 (52%)

25.6  0.5 24.8  0.5 24.1  0.7 22.7  0.9

25.2  0.6 22.9  0.8 22.0  0.6 21.4  0.7

25.8  0.6 23.4  0.7 22.0  0.6 22.3  0.7

Age (years) (mean  SEM) range Sex Male/Female Race Caucasian Non-Caucasian Iris Colora Dark Light Diagnosis POAGb OHTc Baseline IOP (mean  SEM) (mm Hg) 8 am 12 noon 4 pm 8 pm a

Dark: brown or black; Light: any other color. POAG: primary open-angle glaucoma. c OHT: ocular hypertension. b

All 64 subjects were included in the safety analyses. Five patients did not complete the 30-day study. One patient discontinued from the latanoprost group because of body aches and stomach cramping. Two patients discontinued from the bimatoprost group because of ocular symptoms (eyelid edema, conjunctival hyperemia, foreign body sensation) or nausea and ocular symptoms (eye pain, asthenopia, conjunctival hyperemia). Two patients discontinued from the vehicle group because of lack of efficacy.

OCULAR HYPOTENSIVE EFFICACY

At 8 am on day 14 and day 29, both bimatoprost and latanoprost produced significant (p  .001; paired t-tests) decreases in IOP from baseline (Fig. 1). The mean reductions of IOP by bimatoprost were greater than the mean reductions of IOP by latanoprost, although the differences between groups did not reach statistical significance. On the basis of 95% confidence intervals, bimatoprost was at least as effective or more effective than latanoprost in IOP lowering on day 14. Fig. 1. Reduction in IOP from baseline at 8 am. The reduction in IOP from baseline was measured in patients at 8 am after 14 or 29 days of once daily bimatoprost 0.03%, latanoprost 0.005%, or vehicle. Data shown are means  SEM.

EFFICACY AND SAFETY OF BIMATOPROST

S357 Fig. 2. Response rates. The percentage of patients achieving target IOP levels 13, 14, 15, 16, or 17 mm Hg at 8 am on day 29 is shown.

The percentage of patients that achieved target IOP pressures was calculated for the 8 am measurements on day 29 (Fig. 2). A higher percentage of patients in the bimatoprost group than in the latanoprost group achieved low target pressures. For example, a target IOP  15 mm Hg was achieved by 6/19 (31.6%) of bimatoprost patients and 4/21 (19.0%) of latanoprost patients (p  NS). Diurnal measurements of IOP on day 29 demonstrated that bimatoprost provided very effective diurnal control (Fig. 3). Both bimatoprost and latanoprost provided significant mean decreases in IOP and mean percent decreases in IOP from baseline (p  .001, paired t-tests) at each timepoint measured, up to 24 hours after the last drug instillation. However, bimatoprost provided a greater mean reduction in IOP than latanoprost at all timepoints during the day (8 am, 12 noon, 4 pm, and 8 pm),

whether the reduction was expressed in mm Hg (Fig. 3) or as a percentage of the baseline IOP (Table 2). The difference in mean IOP lowering between groups exceeded 2 mm Hg at the 12 noon and 4 pm timepoints. On the basis of 95% confidence intervals, the ocular hypotensive efficacy of bimatoprost was equal to or greater than that of latanoprost at 12 noon, 4 pm, and 8 pm. At follow-up measurements, the mean reduction in IOP from baseline ranged from 5.92 to 8.89 mm Hg (25–34%) in the bimatoprost group and from 4.38 to 7.93 mm Hg (20–31%) in the latanoprost group. On day 29, the overall mean IOP reduction averaged over the diurnal timepoints (8 am, 12 noon, 4 pm, 8 pm) was 6.96 mm Hg with bimatoprost and 5.48 mm Hg with latanoprost (p  .0572, repeated measures 1-way ANOVA with pairwise t-test). Between-group comparisons of mean AUC of IOP Fig. 3. Diurnal reduction in IOP from baseline on day 29. The reduction in IOP from baseline was measured in patients at 8 am, 12 noon, 4 pm, and 8 pm after 29 days of once-daily bimatoprost 0.03%, latanoprost 0.005%, or vehicle. The last instillation of the drug was at 8 pm on day 28. Data shown are means  SEM.

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DUBINER ET AL TABLE 2

Mean ( SEM) Reduction and Percent Reduction in IOP From Baseline at Each Study Visit Bimatoprost 0.03%

Latanoprost 0.005%

Vehicle

IOP Reduction

IOP Reduction

IOP Reduction

Study Day

Hour

(mm Hg)

(%)

(mm Hg)

(%)

(mm Hg)

(%)

14 29 29 29 29

8 am 8 am 12 noon 4 pm 8 pm

8.9  1 8.0  0.9 7.5  0.7 6.5  0.8 5.9  0.8

34.1  3.5% 30.9  3.3% 30.1  2.7% 26.3  2.8% 25.4  2.6%

7.9  0.5 7.6  0.5 5.5  0.6 4.4  0.4 4.5  0.8

31.4  1.8% 30.0  1.8% 23.1  2.1% 19.8  1.8% 19.8  3.2%

3.5  0.9 1.7  1.2 0.6  0.8

0.3  0.7 0.8  0.6

14.1  3.6% 6.5  4.8% 2.1  3.6%

2.0  3.4% 3.2  2.7%

reductions on day 29 showed that bimatoprost was superior to latanoprost in IOP lowering over the course of the day (bimatoprost: 83.6 mm Hg hr; latanoprost: 63.6 mm Hg hr; p  .0378, 1-way ANOVA with pairwise t-test). At individual timepoints, the bimatoprost vs latanoprost betweengroup differences in IOP reduction did not reach statistical significance, possibly because of the small sample sizes. However, the difference between groups approached statistical significance at 12 noon on day 29 (p  .052, 1-way ANOVA with pairwise t-test). SAFETY/TOLERABILITY

Both bimatoprost and latanoprost had an acceptable safety profile and were well tolerated. No serious adverse events were reported, and few patients discontinued because of adverse events. The most common side effect was conjunctival hyperemia, reported in three patients in each active treatment

group and no patients in the vehicle group (Table 3). Mean ratings of conjunctival hyperemia on days 14 and 29 were in the trace to mild range in all groups (bimatoprost: 0.67–0.79; latanoprost: 0.57– 0.69; vehicle: 0.50–0.61). There were no significant differences in mean hyperemia scores among treatment groups, and there were no other significant biomicroscopy findings in any treatment group. As expected in a short-term study, there were no changes in the cup:disk ratio in any treatment group (Table 4); the cup:disk ratio was similar among treatment groups at prestudy and on day 29. Visual acuity and changes in visual acuity were also comparable among treatment groups. On day 29, visual acuity was improved (increased by at least two lines) or unchanged (within two lines of baseline) in 17/19 (89%) of bimatoprost patients, 19/21 (90%) of latanoprost patients, and 18/19 (95%) of vehicle patients (p  .827 among groups, Kruskal-Wallis test). There were no reports of fundus pathology.

TABLE 3

Number of Patients Experiencing Adverse Events

Any Adverse Event Treatment-Related Adverse Eventa Ocular Conjunctival hyperemia Ocular pruritus Foreign body sensation Visual disturbance Eye pain Dry eye Eyelid edema Eye irritation Systemic Nausea Abdominal pain Dizziness Sinusitis a

Bimatoprost 0.03% (n  21)

Latanoprost 0.005% (n  21)

Vehicle (n  21)

7 5

9 8

9 3

3 2 1 0 1 0 1 0

3 1 0 1 0 1 0 1

0 1 0 1 0 0 0 0

1 0 0 1

0 1 0 0

0 0 1 0

Adverse events considered by the investigator to have a “possible, probable, or definite” relationship to the drug treatment. Some patients reported more than 1 adverse event.

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EFFICACY AND SAFETY OF BIMATOPROST TABLE 4

Additional Safety Analyses (Results from the 8 AM Evaluation) Bimatoprost (n  21) Systolic blood pressure (mm Hg) Baseline (mean) Mean change from baseline on day 29 Diastolic blood pressure (mm Hg) Baseline (mean) Mean change from baseline on day 29 Heart rate (bpm) Baseline (mean) Mean change from baseline on day 29 Cup:disk ratio Prestudy (mean) Mean change from baseline on day 29

There were no clinically significant effects of bimatoprost, latanoprost, or vehicle treatment on heart rate or on systolic or diastolic blood pressure (Table 4), and there were no clinically relevant differences among treatment groups in blood chemistry or hematology on day 0 or day 29.

Discussion In this randomized, double-masked clinical trial, patients diagnosed with open-angle glaucoma or ocular hypertension were treated once daily with bimatoprost (0.03%), latanoprost (0.005%), or vehicle. Both bimatoprost and latanoprost provided significant decreases in IOP. However, bimatoprost provided better diurnal IOP control. Bimatoprost was also safe and well tolerated. Previous large 6-month clinical trials2,3,16 have documented 27–35% decreases in IOP with once-daily latanoprost 0.005% given as monotherapy. The reduction in IOP provided by latanoprost in the current study was comparable with these results. Although latanoprost was very effective in reducing IOP, our results indicate that bimatoprost was at least as effective or more effective than latanoprost. Because the magnitude of IOP reduction correlates with the clinical prognosis in glaucoma and ocular hypertension,1,5,8,9 the degree of ocular hypotensive activity of bimatoprost observed in this study suggests that bimatoprost may prove to be useful for first-line therapy in the management of glaucoma and ocular hypertension. The extent to which IOP must be lowered to prevent the progressive neuropathy of glaucoma is unclear. For any individual patient, an appropriate target IOP will be influenced by the extent of optic nerve damage and the IOP at which damage occurred.12,20 Nonetheless, patients who achieve low IOP are at less risk of visual field deterioration.11,13

Latanoprost (n  22)

Vehicle (n  21)

145.5 0.5

144.1

3.2

147.7

5.6

82.3 0.2

79.6 1.8

85.3

2.6

72.3

0.6

69.0 2.5

69.9

1.5

0.53 0.002

0.49 0.019

0.52

0.003

Interestingly, in this current study a higher percentage of bimatoprost patients than latanoprost patients achieved very low target IOP levels (15 mm Hg), suggesting that bimatoprost may provide greater benefit to more patients than latanoprost. Because glaucoma is a 24-hr/day disease, its management requires IOP control throughout the day.10 In this study bimatoprost provided excellent diurnal control of IOP. The percent reductions from baseline IOP in the bimatoprost treatment group were consistent throughout the day, ranging from 25.4% to 30.9% on day 29. The small sample sizes made it difficult to discern statistically significant differences in IOP lowering between the bimatoprost and latanoprost treatment groups at any individual timepoint. However, when overall mean reductions were analyzed, the difference between bimatoprost and latanoprost approached statistical significance (p  .0572, 1-way repeated measures ANOVA with pairwise t-test). Bimatoprost consistently provided better IOP lowering than latanoprost throughout the day, and the AUC analysis of diurnal IOP demonstrated statistical superiority of IOP lowering with bimatoprost. The difference in mean IOP lowering between groups was clinically relevant, exceeding 2 mm Hg at the 12 noon and 4 pm timepoints. Systemic safety parameters were unaffected by either bimatoprost or latanoprost. No clinically relevant effects on heart rate, blood pressure, hematology, or blood chemistry were observed in either active treatment group. In addition, no serious ocular side effects were associated with bimatoprost treatment. The only ocular finding with bimatoprost was trace to mild conjunctival hyperemia, which was a cosmetic rather than a safety issue. Conjunctival hyperemia was similarly apparent in the latanoprost group. In summary, in this 30-day trial, once-daily bimatoprost 0.03% provided better diurnal IOP control

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Surv Ophthalmol 45 (Suppl 4) May 2001

than latanoprost and was safe and well tolerated in patients with ocular hypertension and glaucoma. The discovery of bimatoprost and the prostamide pathway has suggested a new approach to IOP control.

References 1. ____: Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 126:487–97, 1998 2. Alm A, Stjernschantz J: Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology 102:1743– 52, 1995 3. Camras CB: Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 103:138– 47, 1996 4. Conover WJ, Iman RL: Rank transformations as a bridge between parametric and nonparametric studies. Am Stat 35: 124–33, 1981 5. Epstein DL, Krug JH, Hertzmark E, et al: A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology 96:1460–7, 1989 6. Fleiss JL: Statistical Methods for Rates and Proportions. New York, John Wiley and Sons, 1981, 2nd ed 7. Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. San Francisco, California, Holden-Day, 1975 8. Mao LK, Stewart WC, Shields MB: Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. Am J Ophthalmol 111:51–5, 1991 9. Ritch R, Shields MB, Krupin, T: Preface, in Ritch R, Shields MB, Krupin T (eds): The Glaucomas. St. Louis, Mosby, 1996 10. Sacca SC, Rolando M, Marletta A, et al: Fluctuations of intraocular pressure during the day in open-angle glaucoma, normal-tension glaucoma and normal subjects. Ophthalmologica 212:115–9, 1998 11. Shirakashi M, Iwata K, Sawaguchi S, et al: Intraocular pressure-dependent progression: a 15-year follow-up. Ophthalmologica 207:1–5, 1993

DUBINER ET AL 12. Singh K, Spaeth G, Zimmerman T, Minckler D: Target pressure—glaucomatologists holey grail. Ophthalmology 107: 629–30, 2000 13. The AGIS Investigators. The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429–40, 2000 14. VanDenburgh AM, Laibovitz RA, Felix C: A one-month doseresponse study of AGN 192024, a novel antiglaucoma agent, in patients with elevated intraocular pressure [abstract]. Invest Ophthalmol Vis Sci 40:S830, 1999 15. VanDenburgh AM, Laibovitz RA, Felix C: A novel ocular hypotensive lipid: initial safety and efficacy of AGN 192024 [abstract]. Invest Ophthalmol Vis Sci 39(Suppl):S258, 1998 16. Watson P, Stjernschantz J: A six-month, randomized, doublemasked study comparing latanoprost with timolol in openangle glaucoma and ocular hypertension. The Latanoprost Study Group. Ophthalmology 103:126–37, 1996 17. Woodward DF, Andrews SW, Burk RM, Garst ME: Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents. U.S. Patent 5352708, 1994 18. Woodward DF, Krauss AH-P, Chen J: Replacement of the carboxylic acid group of prostaglandin F2 with a hydroxyl or methoxy substituent provides biologically unique compounds. Br J Pharmacol 130:1933–43, 2000 19. Yu M, Ives D, Ramesha CS: Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–6, 1997 20. Zeyen T: Target pressures in glaucoma. Bull Soc Belge Ophtalmol 274:61–5, 1999

This paper was presented in part at the ARVO Annual Meeting, 30 April–5 May 2000, Fort Lauderdale, FL. Ocular Hypotensive Lipids™ is a trademark of Allergan, Inc., Irvine, CA. This study was carried out at four centers: 1) Clayton Eye Center, Morrow, GA; 2) Great Lakes Eye Care, St. Joseph, MI; 3) Ophthalmology Service, Brooke Army Medical, San Antonio, TX; and 4) Pharmaceutical Research Corporation, Charleston, SC. This study was supported by Allergan, Inc., Irvine, CA. H. DuBiner, D. Cooke, M. Dirks, and W. Stewart have no proprietary interests in bimatoprost or Allergan, Inc. A. VanDenburgh and K. Chen are employees of Allergan, Inc. Reprint address: Dr. Amanda VanDenburgh, Allergan, Inc., Mail Stop T2-4B, 2525 Dupont Drive, Irvine, CA 92612-1599.