Randomized clinical trial of latanoprost and unoprostone in patients with elevated intraocular pressure1

Randomized Clinical Trial of Latanoprost and Unoprostone in Patients With Elevated Intraocular Pressure HENRY D. JAMPEL, MD, MHS, JASON BACHARACH, MD, WANG-PUI SHEU, MA, LISA G. WOHL, MD, ALFRED M. SOLISH, MD, AND WILLIAM CHRISTIE, MD, FOR THE LATANOPROST/UNOPROSTONE STUDY GROUP

● PURPOSE: To compare the intraocular pressure (IOP)lowering effect and safety of latanoprost 0.005% once daily with that of unoprostone 0.15% twice daily for patients with primary open-angle glaucoma or ocular hypertension. ● DESIGN: Randomized clinical trial. ● METHODS: In a prospective, 8-week, investigatormasked, parallel-group study conducted at numerous centers in the United States, 165 previously treated patients with IOP > 25 mm Hg in one or both eyes after washout were randomly assigned to receive either latanoprost 0.005% once daily in the evening or unoprostone 0.15% twice daily. Observations procedures were Goldmann applanation tonometry, best-corrected visual acuity, slit lamp biomicroscopy, and ophthalmoscopy. The main outcome measure was change in the mean of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM between baseline (before treatment) and after 8 weeks of treatment. ● RESULTS: The change in the mean ⴞ SD of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM was ⴚ7.2 ⴞ 3.2 mm Hg (28%) for latanoprost (25.3 ⴞ 2.8 mm Hg at baseline to 18.2 ⴞ 2.8 mm Hg at 8 weeks) and ⴚ3.9 ⴞ 2.6 mm Hg (15%) for unoprostone (25.5 ⴞ 3.3 mm Hg Accepted for publication Aug 7, 2002. InternetAdvance publication at ajo.com Sept 6, 2002. From the Department of Ophthalmology (H.D.J.), The Johns Hopkins University School of Medicine, Baltimore, Maryland, the Pharmacia Corporation (W.-P.S.), Peapack, New Jersey, and private practices in Petaluma, California (J.B.), Bloomingdale, Illinois (L.G.W.), Pasadena, California (A.M.S.), and Pittsburgh, Pennsylvania (W.C.). A complete list of the members of the Latanoprost and Unoprostone Study Group is at the end of this article. This study was presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 5–10, 2002. This study was supported by Pharmacia Corporation, Peapack, New Jersey. Ms. Sheu is an employee of Pharmacia Corporation. Medications used in the study were provided by Pharmacia Corporation. Inquiries to Henry D. Jampel, MD, MHS, Department of Ophthalmology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Baltimore, MD 21287-9205; fax: (410) 502-7493; e-mail: [email protected] 0002-9394/02/$22.00 PII S0002-9394(02)01820-2

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at baseline to 21.6 ⴞ 4.0 mm Hg; P < .001. No serious adverse event related to either medication was reported. ● CONCLUSIONS: Over an 8-week period, latanoprost 0.005% once daily lowered IOP more than unoprostone 0.15% twice daily in patients with elevated IOP. Both agents were safe and well tolerated. (Am J Ophthalmol 2002;134:863– 871. © 2002 by Elsevier Science Inc. All rights reserved.)

H

IGH INTRAOCULAR PRESSURE (IOP) IS A MAJOR

risk factor for progressive damage to retinal ganglion cells, deterioration of the optic nerve, and associated loss of visual field.1– 4 In primary open-angle glaucoma, the most common glaucoma type and second leading cause of blindness worldwide,5 elevated IOP derives primarily from decreased outflow of aqueous humor from the angle of the anterior chamber to the venous system due to reduced permeability of the trabecular meshwork.6 – 8 While laser trabeculoplasty and filtering surgery may be indicated to lower IOP in some cases, ocular hypotensive medications remain the mainstay of treatment for open-angle glaucoma and ocular hypertension.6 These agents act either by lowering IOP through a reduction in ciliary body aqueous humor production or by increasing its outflow through the trabecular route, the less conventional uveoscleral pathway, or both.6,9 –13 Latanoprost 0.005% has been commercially available in Europe and the United States since 1996 and in Japan since 1999. Unoprostone 0.12% was introduced in Japan in 1994.14 These agents were believed to act by increasing uveoscleral outflow.11 However, the presence of FP receptors (the receptors for prostaglandin F2␣) in the human trabecular meshwork,15 the fact that unoprostone has weak agonist activity for FP and almost no affinity for EP1 and EP2 receptors (receptors for prostglandins E1 and E2 respectively),16 and some evidence that unoprostone increases outflow by the trabecular route17,18 may suggest a mechanism of action that differs from that of latanoprost.

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Latanoprost 0.005% applied once daily has been shown to lower IOP more effectively than the ␤-adrenergic receptor antagonist timolol 0.5%.19,20 In contrast, superior efficacy of unoprostone 0.12% applied twice daily over timolol has not been shown.21,22 Direct efficacy comparisons of latanoprost with unoprostone in Asia23–25 and Brazil26 demonstrate that in those populations, latanoprost 0.005% administered once a day provides greater IOP reduction than unoprostone 0.12% instilled twice daily. Based on a dose-response study in patients with elevated IOP, a higher concentration of unoprostone (0.15%) was found to be of greater hypotensive efficacy than the 0.12% concentration27 and was approved for use in the United States in 2000. To date, however, no direct comparisons of IOP-lowering with this higher concentration of unoprostone and other prostaglandin-like agents have been published. Because drug potency may vary with patient population and with concentration, we have conducted a randomized clinical trial comparing the safety and efficacy of latanoprost 0.005% with that of unoprostone 0.15% in subjects with glaucoma or elevated IOP.

FIGURE 1. Study design. 1Timing of screening visit up to 4 weeks before the baseline visit depending on duration of ocular medication washout period. Intraocular pressure (IOP) safety checks at 2 weeks for patients on 4-week washout. 2Baseline visit with randomization and treatment initiation. 3Follow-up of adverse events and serious adverse events.

patients with any abnormal ocular condition or symptom that, in the investigator’s judgment, prevented the patient from entering the study; known hypersensitivity to any of the eye drop components; pregnancy, lactation, or inadequate contraception; concurrent use of any investigational medications; or use of any systemic medication known to affect IOP unless both patient and medication dosage were stable throughout the previous 3 months. A flow diagram of study visits is shown in Figure 1. Up to 4 weeks before the baseline visit, subjects underwent a screening examination that included the following: a review of ocular and medical history, recording of blood pressure and heart rate, IOP measurement with Goldmann applanation tonometry, Snellen visual acuity measurement, visual field testing (automated perimetry) if not done within the past year, slit-lamp biomicroscopy, and ophthalmoscopy. If patients met all inclusion and no exclusion criteria, all ocular hypotensive therapy was discontinued at this time. Required washout periods before the baseline visit were 4 weeks for ␤-adrenergic antagonists and prostaglandin analogs; 2 weeks for adrenergic agonists; and 5 days for cholinergic agonists and carbonic anhydrase inhibitors. A safety check with IOP measurement was required after 2 weeks of all patients on a 4-week washout; at that time, patients whose IOPs had risen to levels deemed by the investigator to be detrimental were excluded from the study. After washout, subjects returned for a baseline visit during which IOP was measured three times in each eye by masked evaluators at 8:00 AM, 12 noon, and 4:00 PM. The mean of the three measurements was used in statistical analyses. Eyes were eligible for the study if the mean IOP was ⱖ 25 mm Hg at 8:00 AM. Either one or both eyes of a subject could be enrolled. If both eyes of a patient were eligible for the study, the mean of the IOP readings in both eyes was used in analyses.

DESIGN THE STUDY WAS AN 8-WEEK, RANDOMIZED, PARALLEL

group, masked-evaluator randomized clinical trial comparing the efficacy and safety of latanoprost 0.005% once daily and unoprostone 0.15% twice daily.

METHODS THIS STUDY WAS CONDUCTED AT 24 SITES IN THE UNITED

States. Investigators used a detailed protocol to maintain uniformity of testing and evaluations across study centers, and multiple site visits were performed to insure uniformity. The protocol was approved by the appropriate regulatory authorities and Institutional Review Board/ Independent Ethics Committee for each study site and was performed in accordance with the ethical standards maintained in the 1964 Declaration of Helsinki. Patients with unilateral or bilateral primary open-angle glaucoma or ocular hypertension (defined as IOP ⱖ 21 mm Hg at diagnosis) were eligible for participation. Other inclusion criteria were age ⱖ18 years, current or previous use of topical monotherapy or dual therapy for IOP control, best-corrected visual acuity ⱖ20/80, and ability to adhere to the study protocol. Signed informed consent was obtained from all patients before study enrollment. Excluded from the study were eyes with closed or barely open anterior chamber angle or history of acute angleclosure glaucoma; any previous filtering surgery; argon laser trabeculoplasty or other ocular surgery within the previous 3 months; and ocular inflammation or infection within the previous 3 months. Further exclusion criteria included 864

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FIGURE 2. Flow diagram of randomization procedures: no record was kept of the number of patients assessed for eligibility. IOP ⴝ intraocular pressure

Randomization codes were generated and medical supplies were prepared by Pharmacia Clinical Supply Logistics (Kalamazoo, Michigan, USA). Patients were enrolled by treating physicians. Each center received prepackaged clinical supplies with patient numbers, which were allocated sequentially. After the 8:00 AM baseline IOP measurement, eligible patients were randomly assigned within blocks to one of two treatment groups (1:1 ratio). One group received latanoprost 0.005% (Xalatan; Pharmacia, Peapack, New Jersey, USA) to be instilled daily at 8:00 PM. The other group received unoprostone 0.15% (Rescula; Novartis Pharmaceuticals, East Hanover, New Jersey, USA) to be instilled twice daily at 8:00 AM and 8:00 PM. No other IOP-reducing therapy was permitted. Medications were dispensed by study coordinators in opaque black containers containing bottles of eyedrops. Patients began study medication on the evening of the baseline visit. Patients were the only ones aware of their treatment assignments and were cautioned not to reveal the treatment assignment or frequency of dosing to masked studysite personnel; verification of masking was confirmed at the week 2 and week 8 visits. The statistician was also masked until the database was closed. After initiation of treatment at baseline, patients returned for study visits after 2 and 8 weeks of therapy. At the 2-week visit, IOP was measured three times at some time during the day. At the final visit (8 weeks or time of earlier discontinuation), IOP was measured three times at 8:00 AM, 12 noon, and 4:00 PM. Patients in the unoprostone group instilled morning drops after the 8:00 AM measurements. To preserve the evaluator mask, all patients, regardless of treatment group, were given privacy at this time. VOL. 134, NO. 6

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Adverse events, defined as any undesired medical occurrence regardless of relationship to treatment, were monitored throughout the study. Based on defined criteria and outcomes, each adverse event was classified as serious or nonserious, and graded in intensity. Any patient with a persistent serious adverse event, an adverse event related to study medication, or an ocular adverse event at the end of study treatment (week 8) was followed up on 2 weeks after the final visit. Follow-up of serious adverse events continued until events were resolved or deemed chronic or stable. A patient could be withdrawn from the study at any time if, in the opinion of the investigator, it was medically necessary. The primary efficacy outcome, change in the mean of IOP measurements obtained at 8:00 AM, 12 noon, and 4:00 PM between baseline and week 8, was analyzed using the analysis of covariance model (ANCOVA), with baseline IOP as the covariate and treatment and center as factors. The 95% confidence interval (CI) of the difference in the mean change was calculated based on the ANCOVA model. Within-treatment group IOP changes were tested with the paired t test, and between-treatment group IOP changes were tested with the independent samples t test. Unless otherwise stated, the values of the mean IOPs presented in this paper are unadjusted means. Secondary outcomes included differences between treatment groups in mean percent change in IOP from baseline and in proportions of patients achieving specified mean IOP levels and mean percentage IOP reductions at week 8. Differences between treatment groups at baseline in continuous variables were tested for statistical significance using the t test and in categorical variables using the ␹2 or the Fisher exact test. Data analyses of both intent-to-treat (ITT) and evaluable populations were performed. Intent-to-treat analyses included all patients who received study medication and who had at least one valid IOP evaluation after treatment. When there were missing IOP data, each patient’s mean IOP was estimated in ITT analyses as follows: if at any measurement time, a patient was missing any of the three IOP measurements for one eye, the average of the available readings in that eye was used; at week 8, if a patient’s IOP was not measured at either 8:00 AM, 12 noon, or 4:00 PM, the mean of the nonmissing IOP values was used; if IOP was not assessed at all at week 8, the week 2 IOP value was carried forward. The evaluable population included all patients who completed 8 weeks of treatment without any major protocol deviations. No missing data were replaced. Safety analyses included all randomized patients. Frequencies of ocular and systemic adverse events and numbers of patients affected were summarized by treatment group. Before the study, it was determined that a sample of at least 64 evaluable patients in each treatment group was required to detect a difference of 2.0 mm Hg in mean

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TABLE 1. Patient Characteristics, Intent-to-Treat Population

Sex Male Female Age (yrs) Mean ⫾ SD Range Race Caucasian African American Hispanic Asian American Indian Family history of glaucoma No Yes Diagnosis of study eye(s) Primary open-angle glaucoma Ocular hypertension Mixed Other Duration of condition ⬍6 months 6 to ⬍36 months 36 to ⬍120 months 120 months Visual field defect in study eyes No Yes Study eyes Right only Left only Both Treated fellow eyes Right Left None Eyedrop treatment prior to study* Adrenergic-receptor agonists ␤-adrenergic antagonists Carbonic anhydrase inhibitors Cholinergic agonist Combination drugs Prostaglandin analogs Baseline IOP (mm Hg) Mean ⫾ SD Concurrent use of systemic ␤-blocker

Latanoprost (n ⫽ 84)

Unoprostone (n ⫽ 80)

37 (44%) 47 (56%)

35 (45%) 44 (55%)

65.1 ⫾ 11.2 33, 84

64.2 ⫾ 11.4 37, 85

65 (77%) 14 (17%) 4 (5%) 1 (1%) 0

68 (85%) 9 (11%) 2 (3%) 0 1 (1%)

47 (56%) 37 (44%)

49 (61%) 31 (39%)

52 (62%) 29 (35%) 2 (2%) 1 (1%)

53 (66%) 27 (34%) — —

9 (11%) 17 (20%) 36 (43%) 22 (26%)

8 (10%) 17 (21%) 37 (46%) 18 (23%)

62 (74%) 22 (26%)

55 (69%) 25 (31%)

19 (23%) 15 (18%) 50 (60%)

13 (16%) 13 (16%) 54 (68%)

12 (14%) 16 (19%) 56 (67%)

13 (16%) 10 (13%) 57 (71%)

19 (23%) 26 (31%) 5 (6%) 4 (5%) 36 (43%)

22 (28%) 23 (29%) 14 (18%) 2 (3%) 3 (4%) 27 (34%)

25.3 ⫾ 2.8 2 (2.4%)

25.5 ⫾ 3.3 6 (7.5%)

Latanoprost Vs Unoprostone

P ⫽ 1.00

P ⫽ .09

P ⫽ .43

P ⫽ .53

P ⫽ .59

P ⫽ .96

P ⫽ .49

P ⫽ .50

P ⫽ .52

P ⫽ .81 P ⫽ .16

IOP ⫽ intraocular pressure. *P value cannot be calculated because some patients received more than one treatment before baseline.

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TABLE 2. Mean* ⫾ SD Intraocular Pressures (IOP) Across Treatment Groups

Baseline (pooled mean‡) Baseline, 8:00 AM Baseline, 12 noon Baseline, 4:00 PM Week 2 Week 8 (pooled mean) Week 8, 8:00 AM Week 8, 12 noon Week 8, 4:00 PM

Latanoprost (n ⫽ 84) IOP (mm Hg)

Unoprostone (n ⫽ 80) IOP (mm Hg)

Latanoprost (n ⫽ 84) IOP Reduction (mm Hg)

Unoprostone (n ⫽ 80) IOP Reduction (mm Hg)

Latanoprost Vs Unoprostone†

25.3 ⫾ 2.8 27.1 ⫾ 2.3 25.1 ⫾ 3.6 23.9 ⫾ 3.7 18.9 ⫾ 3.7 18.2 ⫾ 2.8 18.8 ⫾ 3.0 18.2 ⫾ 3.0 17.6 ⫾ 3.3

25.5 ⫾ 3.3 27.3 ⫾ 3.1 24.8 ⫾ 3.3 24.3 ⫾ 3.5 21.8 ⫾ 4.0 21.6 ⫾ 4.0 22.0 ⫾ 3.9 21.5 ⫾ 4.2 20.6 ⫾ 3.9

6.4 ⫾ 3.6 7.2 ⫾ 3.2 8.3 ⫾ 3.1 6.9 ⫾ 3.9 6.3 ⫾ 4.0

3.7 ⫾ 3.2 3.9 ⫾ 2.6 5.2 ⫾ 3.5 3.2 ⫾ 2.7 3.5 ⫾ 3.7

P⬍.001 P⬍.001 P⬍.001 P⬍.001 P⬍.001

*Means are unadjusted means. † Difference in IOP reduction based on independent samples t test. ‡ Pooled means are a composite of IOPs at all time points during the day.

FIGURE 3. Mean intraocular pressure (IOP) levels (mm Hg) measured at 8:00 AM, 12 noon, and 4:00 PM at baseline and after 8 weeks of monotherapy: baseline IOP did not differ between the latanoprost and unoprostone groups. At 8 weeks, the mean IOP in the latanoprost group was significantly lower than that in the unoprostone group at each time point (P < .001).

diurnal IOP reduction between the two treatment groups at a significance level of 0.05, with a power of 0.80, and assuming a standard deviation of 4.0 mm Hg. A total of 150 patients was planned to be recruited to allow for patient withdrawals.

RESULTS THE STUDY BEGAN FEBRUARY 28, 2001, AND CONTINUED

through August 2, 2001. At baseline, 165 subjects were randomly assigned to treatment, 84 to receive latanoprost 0.005% and 81 to receive unoprostone 0.15%. One patient in the unoprostone group was lost to follow-up after the VOL. 134, NO. 6

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baseline visit but before any posttreatment evaluation, leaving 164 patients in the ITT population (Figure 2). Characteristics of patients in each treatment group are summarized in Table 1. Overall, patients had a mean age of 65 years, 55% were female, 81% were Caucasian, 14% were African-American, and approximately two-thirds had a diagnosis of primary open-angle glaucoma. The overall mean (⫾ standard deviation [SD]) of 8:00 AM, 12 noon, and 4:00 PM IOP levels at baseline were similar in the treatment groups (25.3 ⫾ 2.8 mm Hg in the latanoprost group vs 25.5 ⫾ 3.3 mm Hg in the unoprostone group.) The two treatment groups did not differ with respect to sex, age, race, family history of glaucoma, diagnosis, visual field findings, duration of disease, or concurrent treatment with systemic ␤-blockers.

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TABLE 3. Overall Adverse Events and Ocular Adverse Events Considered Study Medication-Related*

Summary Patients with no adverse events Patients with at least one adverse event Patients with ocular adverse events Patients with systemic adverse events Ocular adverse events† Eye irritation Eye pain Vision blurred Conjunctival vascular disorder Red eye Dry eye

FIGURE 4. (Top) Percentage of patients achieving various percentage intraocular pressure (IOP) reductions: IOP reduction was calculated as the difference in the overall means of the IOP levels measured at 8:00 AM, 12 noon, and 4:00 PM between baseline and 8 weeks. The categories to the right signify greater effectiveness. (Bottom) Percentage of patients achieving various IOP levels: overall mean of the IOP levels was measured at 8:00 AM, 12 noon, and 4:00 PM after 8 weeks of treatment. The categories to the left signify lower IOP.

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Unoprostone (n ⫽ 81)

62 (74%) 22 (26%)

43 (53%) 38 (47%)

19 (23%) 7 (8%)

34 (42%) 17 (21%)

5 (6%) 1 (1%) 1 (1%) 2 (2%) 2 (2%) 0

16 (20%) 12 (15%) 2 (2%) 0 0 2 (2%)

*Number of patients (percent of treatment group). † Events considered related to study medication reported in ⬎1 patient in either group.

was greatest at 8:00 AM in both groups. At every time point assessed (week 2, and 8:00 AM, 12 noon, and 4:00 PM at week 8), latanoprost had a significantly greater IOPlowering effect than unoprostone (P ⬍ .001 for each comparison), with absolute differences in IOP reduction between the two drugs ranging from 2.8 mm Hg to 3.7 mm Hg in favor of latanoprost (Table 2 and Figure 3). Similarly, results of ANCOVA showed significant differences in mean IOP reductions (P ⬍ .001 at all time points). The adjusted mean difference in IOP reduction at the end of treatment was 3.4 mm Hg (95% CI: 2.6 mm Hg, 4.3 mm Hg). The proportion of patients achieving a specified percent reduction in their overall mean 8:00 AM, 12 noon, and 4:00 PM IOP from baseline and a specified overall mean 8:00 AM, 12 noon, and 4:00 PM IOP at week 8 is illustrated in Figure 4. In patients treated with latanoprost, 13 of 84 (15%) and 38 of 84 (45%) achieved ⬎40% and ⬎30% IOP reductions, respectively. In comparison, no unoprostone-treated patient achieved ⬎40% IOP reduction, and five of 80 (6%) reduced IOP ⬎30%. In terms of absolute IOP, 73 of 84 (87%) and 30 of 84 (36%) latanoprost-treated patients achieved IOPs of ⱕ21 mm Hg and ⱕ17 mm Hg, respectively, compared with 39 of 80 (49%) and seven of 80 (9%) unoprostone-treated patients. Overall, 60 of 165 patients reported at least one adverse event (Table 3). Adverse events were more common in patients treated with unoprostone (38/81, 47%) than in the latanoprost group (22/84, 26%). Ocular adverse events (primarily eye irritation and eye pain) were also reported more frequently in patients who received unoprostone

In all, 83 of 84 patients in the latanoprost group and 77 of 81 in the unoprostone group completed the entire 8 weeks of the study (Figure 2). One patient in the latanoprost group was discontinued from the study because it was learned that he failed to meet the inclusion criterion (he had not been previously treated with IOP-lowering medication). In the unoprostone group, two patients were lost to follow-up (one was incarcerated, the other refused study visits but did return study medications), and two were discontinued due to elevated IOPs. Data for three additional patients in the unoprostone group could not be evaluated: two mistakenly administered study medication on the morning of their 8-week visit, and one was found to have not completed the washout period. Because results from analyses of the ITT and the evaluable populations were similar, only the results of ITT analyses are presented. After 8 weeks of therapy, the overall mean (⫾ SD) of the 8:00 AM, 12 noon, and 4:00 PM IOP measurements was reduced in the latanoprost group by 7.2 ⫾ 3.2 mm Hg (28% reduction; from 25.3 ⫾ 2.8 mm Hg at baseline to 18.2 ⫾ 2.8 mm Hg at week 8) and reduced in the unoprostone group by 3.9 ⫾ 2.6 mm Hg (15% reduction; from 25.5 ⫾ 3.3 mm Hg at baseline to 21.6 ⫾ 4.0 mm Hg at week 8); the difference between groups in IOP reduction was highly significant (P ⬍ .001, Table 2). IOP reduction 868

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TABLE 4. Summary of Randomized Clinical Trials Comparing Intraocular Pressure (IOP)-lowering Effects of Monotherapy With Latanoprost 0.005% Vs Unoprostone 0.12% or 0.15%

Unoprostone Location Study design

Patients Baseline IOP* Mean reduction: latanoprost Mean reduction: unoprostone Difference in IOP reduction

Susanna, 200126

Aung, 200123

Kobayashi, 200124

Saito, 200125

Present Study

0.12% Brazil 8-week Double-masked Parallel group

0.12% Singapore 1-month ⫻ 2 Double-masked Crossover

Two centers POAG/OH n ⫽ 60 23 mm Hg 6.1 mm Hg

0.12% Japan 6-week ⫻ 2 Open-label Monotherapy 0-6 weeks; combination therapy 6-12 weeks Single center POAG n ⫽ 52 23 mm Hg 6.0 mm Hg

0.15% United States 8-week Investigator-masked Parallel group

Single center POAG/OH n ⫽ 108 24 mm Hg 6.7 mm Hg

0.12% Japan 8-week Investigator-masked One eye received latanoprost, the other unoprostone Single center OH n ⫽ 18 23 mm Hg 6.3 mm Hg

3.3 mm Hg

4.2 mm Hg

3.6 mm Hg

3.3 mm Hg

3.9 mm Hg

3.4 mm Hg

1.9 mm Hg

2.7 mm Hg

2.7 mm Hg

3.3 mm Hg

Multicenter POAG/OH n ⫽ 164 25 mm Hg 7.2 mm Hg

OH ⫽ ocular hypertension; POAG ⫽ primary open-angle glaucoma. *Mean baseline IOP across the treatment groups.

(34/81, 42% vs 19/84, 23% for latanoprost-treated patients). Red eye occurred in only two patients, both in the latanoprost group. No changes in iris pigmentation were noted in either group. The only adverse event rated as severe was eye pain reported by a unoprostone-treated patient who experienced severe stinging after each instillation but who did not withdraw from the study. No serious adverse event related to either medication was reported.

DISCUSSION THIS STUDY DEMONSTRATES THAT LATANOPROST 0.005%

administered once daily is more effective in lowering IOP over an 8-week period than is unoprostone 0.15% instilled twice daily in patients with open-angle glaucoma or ocular hypertension. Latanoprost reduced the mean 8:00 AM, 12 noon, and 4:00 PM IOP over the 8-week treatment period by 7.2 mm Hg (28%) compared with a reduction of 3.9 mm Hg (15%) by unoprostone. Moreover, at every time point assessed, latanoprost had a significantly greater IOP-lowering effect than unoprostone, with a highly significant adjusted mean difference of 3.4 mm Hg between treatments. After 8 weeks of therapy, patients treated with latanoprost were more than seven times more likely to achieve a more than 30% IOP reduction and four times more likely to achieve a mean IOP ⱕ17 mm Hg when compared with patients treated with unoprostone. The present study therefore confirms the greater efficacy of VOL. 134, NO. 6

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latanoprost 0.005% in reducing IOP when compared with the higher concentration of unoprostone 0.015%. Although four other studies previously demonstrated the superior efficacy of latanoprost over unoprostone 0.12%, this is the first study comparing latanoprost with the higher concentration of unoprostone (0.15%) now used in the United States. The magnitudes of the IOP-lowering effects of latanoprost and unoprostone in this study (⫺7.2 mm Hg vs ⫺3.9 mm Hg, respectively) are comparable with those reported in studies of unoprostone 0.12% by Susanna and associates26 (⫺6.7 mm Hg vs ⫺3.3 mm Hg, respectively), Aung and associates23 (⫺6.1 mm Hg vs ⫺4.2 mm Hg, respectively), Kobayashi and associates24 (⫺6.3 mm Hg vs ⫺3.6 mm Hg, respectively), and Saito and associates25 (⫺6.0 mm Hg vs ⫺3.3 mm Hg, respectively; Table 4). A recent 6-month multicenter trial in Europe and Israel that compared unoprostone 0.15% with betaxolol and timolol reported a ⫺4.3 mm Hg (18%) change in IOP with unoprostone, an effect equivalent to that of betaxolol but not as great as that of timolol.27 In the present study, the frequency of ocular irritation and pain in patients in the unoprostone group was greater than that seen in the latanoprost-treated patients and was similar to that reported elsewhere for the unoprostone 0.15% dosage.27 It is noteworthy that reports of stinging upon instillation were previously shown to be significantly higher in patients receiving a combination of unoprostone 0.12% and latanoprost 0.005% than in those receiving a combination of placebo and latanoprost 0.005%.28

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8. Rohen JW. Why is intraocular pressure elevated in chronic simple glaucoma? Anatomical considerations. Ophthalmology 1983;90:758 –765. 9. Galin MA, Harris L. Acetazolamide and outflow facility. Arch Ophthalmol 1966;76:493–497. 10. Ocklind A. Effect of latanoprost on the extracellular matrix of the ciliary muscle. A study on cultured cells and tissue sections. Exp Eye Res 1998;67:179 –191. 11. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2␣ analog, on aqueous dynamics in human eyes. Ophthalmology 1993;100:1297–1304. 12. Toris CB, Camras CB, Yablonski ME, Brubaker RF. Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function. Surv Ophthalmol 1997; 41(Suppl 2):S69 –S75. 13. Zimmerman TJ, Harbin R, Pett M, Kaufman HE. Timolol and facility of outflow. Invest Ophthalmol Vis Sci 1977;16: 623–624. 14. Linde´ n C, Alm A. Prostaglandin analogues in the treatment of glaucoma. Drugs Aging 1999;14:387–398. 15. Anthony TL, Pierce KL, Stamer WD, Regan JW. Prostaglandin F2␣ receptors in the human trabecular meshwork. Invest Ophthalmol Vis Sci 1998;39:315–321. 16. Goh Y, Kishino J. Pharmacological characterization of prostaglandin-related ocular hypotensive agents. Jpn J Ophthalmol 1994;38:236 –245. 17. Taniguchi T, Sabbir Reza Haque M, Sugiyama K, Hori N, Kitazawa Y. Ocular hypotensive mechanism of topical isopropyl unoprostone, a novel prostaglandin metabolite-related drug, in rabbits. J Ocul Pharmacol 1996;12:489 –498. 18. Thieme H, Stumpff F, Ottlecz A, Percicot CL, Lambrou GN, Wiederbolt M. Mechanisms of action of unoprostone on trabecular meshwork contractility. Invest Opthalmol Vis Sci 2001;42:3193–3201. 19. Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Ophthalmology 1995;102:1743– 1752. 20. Camras CB, for the United States Latanoprost Study Group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. A six-month, masked, multicenter trial in the United States. Ophthalmology 1996; 103:138 –147. 21. Nordmann J-P, Rouland J-F, Mertz BP. A comparison of the intraocular pressure-lowering effect of 0.5% timolol maleate and the docosanoid derivative of a PGF2␣ metabolite, 0.12% unoprostone, in subjects with chronic open-angle glaucoma or ocular hypertension. Curr Med Res Opin 1999;15:87–93. 22. Azuma I, Masuda K, Kitazawa Y, Takase M, Yamamura H. Double-masked comparative study of UF-021 and timolol ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. Jpn J Ophthalmol 1993; 37:514 –525. 23. Aung T, Chew PTK, Yip C-C, Chan Y-H, et al. A randomized double-masked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 2001;131:636 –642. 24. Kobayashi H, Kobayashi K, Okinami S. A comparison of intraocular pressure-lowering effect of prostaglandin F2-␣ analogues, latanoprost, and unoprostone isopropyl. J Glaucoma 2001;10:487–492. 25. Saito M, Takano R, Shirato S. Effects of latanoprost and unoprostone when used alone or in combination for openangle glaucoma. Am J Ophthalmol 2001;132:485–489. 26. Susanna R, Jr, Giampani J, Jr, Borges AS, Vessani RM,

The question of whether latanoprost and unoprostone lower IOP by different hypotensive mechanisms remains unresolved. Studies examining the additive efficacy of unoprostone 0.12% and latanoprost 0.005% have not provided firm evidence to support the use of this combination as a therapeutic tool.25,28 –30 Thus, it is unlikely that the hypotensive mechanisms are sufficiently distinct to permit the IOP-lowering potential of the combination to exceed the IOP reduction obtained by latanoprost alone. Latanoprost and unoprostone represent the first entries of prostaglandin-related agents into the topical ocular hypotensive armamentarium. Of the two, only latanoprost is more effective in lowering IOP than the traditional ␤-adrenergic receptor antagonist, timolol.19 –22 With the recent availability of two additional prostaglandin-like drugs, travoprost and bimatoprost, additional direct comparisons of these agents are warranted. A challenge for the future will be to determine whether ocular hypotensive regimens can be rationally individualized for a given patient. The choice of initial therapy will involve the evaluation of the complexities of each patient’s medical and social history. Evidence-based outcomes data may be used to guide the practitioner’s choice for first-line therapy from which individualization of treatment can proceed. Prostaglandin-related agents have proven to be the most effective IOP-lowering agents available. They do, however, differ in their side effect profiles, and long-term clinical experience together with well-conducted, long-term clinical trials will decide when these drugs should be used as first-line agents.

REFERENCES 1. The AGIS Investigators. Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000;130:429 –440. 2. Mao LK, Stewart WC, Shields MB. Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. Am J Ophthalmol 1991;111:51–55. 3. Quigley HA, Miller NR, George T. Clinical evaluation of nerve fiber layer atrophy as an indicator of glaucomatous optic nerve damage. Arch Ophthalmol 1980;98:1564 –1571. 4. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 1982;100:135–146. 5. Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol 1996;80:389 –393. 6. Alward WLM. Medical management of glaucoma. N Engl J Med 1998;339:1298 –1306. 7. Bill A, Svedbergh B. Scanning electron microscopic studies of the trabecular meshwork and the canal of Schlemm—an attempt to localize the main resistance to outflow of aqueous humor in man. Acta Ophthalmol (Copenh) 1972;50:295– 320.

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Jordao MLS. A double-masked, randomized clinical trial comparing latanoprost with unoprostone in patients with open-angle glaucoma or ocular hypertension. Ophthalmology 2001;108:259 –263. Center for Drug Evaluation and Research New and Generic Drug Approvals: 1998 –2002. Comparison of the effects of different concentrations of unoprostone isopropylate ophthalmic solution on intraocular pressure in subjects with primary open angle glaucoma or ocular hypertension. Available at: http://www.fda.gov/cder/foi/nda/2000/21214_ Rescula_medr_P1.pdf; http://www.fda.gov/cder/foi/nda/2000/ 21214_Rescula_medr_P2.pdf. Accessed on March 29, 2002. Nordmann J-P, Mertz B, Yannoulis NC, et al. A doublemasked randomized comparison of the efficacy and safety of unoprostone with timolol and betaxolol in patients with primary open-angle glaucoma including pseudoexfoliation glaucoma or ocular hypertension. 6 month data. Am J Ophthalmol 2002;133:1–10. Stewart WC, Sharpe ED, Stewart JA, Holmes KT, Latham KE. Additive efficacy of unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;131: 339 –344. Alward WLM. Additive efficacy of isopropyl 0.12% (Rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;132: 449 –450.

VOL. 134, NO. 6

LATANOPROST

AND

MEMBERS OF THE LATANOPROST AND UNOPROSTONE STUDY GROUP JASON

BACHARACH,

MD,

PETALUMA,

CA;

GERALD

Brooksby, MD, Portland, OR; Carl Camras, MD, Omaha, NE; William Christie, MD, Pittsburgh, PA; Douglas Day, MD, Atlanta, GA; Robert M. Feldman, MD, Houston, TX; Robert Flores, MD, Charlotte, NC; David Gieser, MD, Wheaton, IL; Andrew Iwach, MD, San Francisco, CA; Henry D. Jampel, MD, MHS, Baltimore, MD; David Karp, MD, Louisville, KY; Barry Katzman, MD, San Diego, CA; Jeffrey Levenson, MD, Jacksonville, FL; Charles Lin, MD, Redding, CA; Alan I. Mandell, MD, Memphis, TN; Gordon Montgomery, MD, San Diego, CA; Michael W. Pekas, MD, Sioux Falls, SD; Bruce Prum, Jr., MD, Charlottesville, VA; Mark Rubin, MD, Ormond Beach, FL; Elizabeth Sharpe, MD, Charleston, SC; Alfred M. Solish, MD, Pasadena, CA; William Stewart, MD, Charleston, SC; George Tanaka, MD, San Francisco, CA; Lisa G. Wohl, MD, Bloomingdale, IL.

UNOPROSTONE

FOR

ELEVATED IOP

871