Bimatoprost/Timolol Fixed Combination: A 3-month... : Journal of Glaucoma (original) (raw)
Elevated intraocular pressure (IOP) is a major risk factor in the development and progression of glaucomatous optic neuropathy, as recently demonstrated in a series of controlled, large, multicenter studies. In the Early Manifest Glaucoma Trial, over a 6-year period, patients receiving treatment had significantly less glaucomatous progression than the untreated control group.1 A post hoc analysis of data from the Advanced Glaucoma Intervention Study demonstrated that the level and consistency of IOP-lowering after treatment was initiated was correlated with clinically relevant reductions in glaucomatous progression of visual fields.2 The Ocular Hypertension Treatment Study showed that treatment decreased the development of reproducible visual field abnormality or optic disc end points attributable to glaucoma.3 The preponderance of evidence from clinical trials such as these as well as longstanding clinical experience all support the reduction of IOP as the primary therapeutic goal.
Typically, if a pharmacologic single agent is inadequate to satisfactorily lower IOP to a predefined target value, additional therapy can be added.4 For example, in Ocular Hypertension Treatment Study, 39.7% of participants required 2 or more topical medications to reach the study's goal of an ocular hypotensive effect of 20% at 5 years.3
Although multiple therapy may provide additional ocular hypotensive efficacy, the addition of a second medication adds to the complexity of treatment, requiring patients to wait several minutes between doses of individual products,5 as well as creating a regimen with which compliance is more challenging.6 Thus, a fixed combination (FC) of 2 active ingredients in a single product could have many advantages.
We selected bimatoprost (BIM) 0.03% and timolol (TIM) 0.5% as the 2 agents for inclusion in a FC, as they have different and potentially additive mechanisms [reduction of aqueous humor production (“inflow”) by TIM,7,8 and enhancement of pressure-dependent and pressure-independent outflow by BIM],9 and previously have been used concomitantly.10 This FC was found to be noninferior to the same active ingredients in separate bottles [BIM once-daily (q.d.) and TIM twice-daily (b.i.d)].11
MATERIALS AND METHODS
Design
We conducted 2, identical, double-masked, parallel studies at 59 academic centers and private practices in the United States and Canada. The studies were initiated independently. Patients were randomized in a ratio of 2:1:1 to the FC (q.d., mornings), BIM 0.03% (q.d., evenings), or TIM 0.5% (b.i.d.) using a computer-generated randomization list (PROC PLAN, SAS Version 8.2, Cary, NC). The treatment mask was maintained through the use of a vehicle for the q.d. dosing regimens, and separate morning and evening bottles.
Patients and Examinations
Individuals underwent a prestudy examination that included a complete eye examination [visual acuity, central corneal thickness by ultrasonic pachymetry, tonometry with a Goldmann applanation tonometer (using a repeated, 2-person method to mask the value), biomicroscopy, and dilated ophthalmoscopy]. Eligible for entry were adult patients with ocular hypertension, chronic open-angle glaucoma, or chronic angle-closure glaucoma (patent iridotomy required), and who required bilateral ocular hypotensive treatment. At the prestudy visit (hour 0, 0700 to 0900, and hour 2), patients using ocular hypotensive medication for at least 1 month prior, although not for the preceding 12 to 14 hours, were required to have IOP ≥18 mm Hg in at least 1 eye. These patients then underwent a washout of ocular hypotensive medications for 4 days (parasympathomimetics or carbonic anhydrase inhibitors), 2 weeks (adrenergic agonists), or 6 weeks (prostaglandins or prostamides). To maximize potential response to TIM, treatment with ocular β-adrenoceptor antagonists within the preceding 6 months was not allowed. Treatment naive patients with IOP ≥24 mm Hg in at least 1 eye were enrolled in the study at the prestudy visit hours 0 and 2. Best-correct visual acuity was required to be 20/100 or better O.U.
Individuals with uncontrolled systemic disease or active nonglaucomatous ocular disease, contraindications to treatment with any of the study medications or their excipients, conditions that precluded accurate IOP readings, and surgery within the past 3 months, were excluded from the study participation. Other than occasional use of artificial tears or topical ocular antihistamines, no concomitant ocular medications were allowed.
Patients returned for a baseline visit, which included measurement of IOP at hours 0, 2, and 8. An IOP at day 0, hour 0 ≥24 mm Hg was required for study entry. Individuals with clinically significant ocular irritation (+1 or greater grade of conjunctival erythema/hyperemia) at baseline (day 0) were excluded from further participation. The hyperemia scale was 0 to 4 (including a half step at 0.5), with 0 as none and 4 as severe. Recent ultrasonic pachymetry (within 2 wk) and reliable automated threshold perimetry (within 3 mo by Humphrey Field Analyzer, program 24-2 Swedish Interactive Thresholding Algorithm, Zeiss Meditec, Dublin, CA) were required for the study. Iris color assessments were performed using a digital camera (C 2100 Ultra Zoom, Olympus Imaging America Inc, Center Valley, PA). A negative pregnancy test and contraception were required from women of childbearing potential. The study was approved by governing institutional review boards, and all patients provided written informed consent.
Eligible patients were randomized and began dosing O.U. in the evening of the baseline visit (between 1900 and 2100 h). Follow-up examinations were scheduled at the same time of day on week 2, week 6, and month 3, and included measurement of IOP at hours 0, 2, and 8. The month 3 visit included dilated ophthalmoscopy and visual fields.
Statistics
Analyses were performed for the primary efficacy variable, IOP, using the intent-to-treat analysis (all randomized patients) with last observation carried forward. Continuous variables (eg, IOP) were analyzed using analysis of variance with factors of treatment and investigator. The IOP measurements from both eyes were averaged for analysis. Comparisons were made between the combination and each of the 2 monotherapies in a pair wise fashion using contrasts from the analysis of variance model, with the same error term at a significance level of 0.05. Within group changes from baseline for continuous variables were analyzed using paired t tests. The proportions of patients achieving a target IOP <18 mm Hg at all time points, and with a mean percent reduction from baseline in diurnal IOP of greater than 20% across all visits between the combination group and each of the monotherapy groups, were compared using the Cochran-Mantel-Haenszel method stratified by investigator, with modified ridit scores. Each study was designed to investigate whether the combination was simultaneously more efficacious than each of the individual components. Thus, a significance level of 0.05 was used in the hypothesis tests and no adjustment for multiple treatment comparisons was necessary. Point estimates of the between-group differences and 2-sided 95% confidence intervals of the difference were also provided using the normal approximation of binary variables.
Categorical variables were analyzed using the Wilcoxon rank sum tests (ordinal variables) and Fisher exact or Pearson χ2 tests (nominal variables). Within group changes from baseline for categorical variables were analyzed using the Wilcoxon signed ranked test.
A priori, with a total study size of 360 patients (2:1:1 ratio), each study had at least 81% power to detect a difference between treatments in mean change from baseline IOP of 1.6 mm Hg with a standard deviation of 3.8 mm Hg (α=0.05, 2-sided). As well, with a sample size of 480 patients, the study had at least 96% power to detect the difference between a response rate (ie, proportion of patients with IOP <18 mm Hg) of 40% in the combination group and of 20% in the other groups. The study had 76% power to detect a smaller difference of 40% versus 25% (χ2 test for 2 proportions, nQuery Advisor 4.0, 1995-2002, Janet D. Elashoff, Statsol, Saugus, MA). All analyses were performed using SAS Version 8.2.
RESULTS
Prestudy Characteristics
A total of 1061 patients were enrolled in the 2 studies. The treatment groups were similar in prestudy characteristics (_P_=0.101 to 0.753), with the exception of a statistically significant among-group difference in age (_P_=0.008, Table 1). Concomitant use of systemic β-adrenoceptor antagonists (4%) and previous use of prostaglandins/prostamides (63%) was similar in all 3 treatment groups.
Prestudy Characteristics
Disposition
All randomized patients received their assigned study medication and are included in the intent-to-treat efficacy analyses. Overall, 93.0% (987/1061) of patients completed the 3-month treatment period. Of all, 6.6% (35/533) of combination patients, 8.3% (22/265) of BIM patients, and 6.5% (17/263) of TIM patients were discontinued from the study. Adverse events (AEs, 4.0%, 42/1061) and administrative reasons (eg, inability to continue and loss to follow-up, 1.5%, 16/1061) were the main reasons for study discontinuation. Other reasons for discontinuation included lack of efficacy (0.6%, 6/1061), other (0.6%, 6/1061), and protocol violations (0.4%, 4/1061).
Efficacy
Mean IOP at baseline visit (hours 0, 2, and 8) ranged from 23.3±4.1 to 26.2±3.4 mm Hg across the 3 treatment groups (_P_=0.093 to 0.987 for pair wise comparisons with combination group). Mean decreases from baseline IOP across the 3 time points ranged from 7.4 to 9.6 mm Hg in the combination group, 6.7 to 8.8 mm Hg in the BIM group, and 5.2 to 7.4 mm Hg in the TIM group (Table 2). Mean diurnal decreases from baseline IOP at month 3 were 8.1, 7.9, and 6.4 mm Hg for the FC, BIM, and TIM groups, respectively. Each of these was a statistically significant decrease from baseline (P<0.001). IOP results were similar in a per protocol analysis.
IOP at Baseline and Mean Changes From Baseline at Each Scheduled Time Point: Mean±SD (mm Hg)
The proportion of patients with a mean diurnal percent reduction from baseline in IOP of more than 20% across all visits is shown in Figure 1. This criterion was met for 81.8% (436/533) of patients in the combination group, 72.1% (191/265) of patients in the BIM group, and 49.8% (131/263) of patients in the TIM group (P<0.001 for combination vs. BIM, and for combination vs. TIM). The proportion of patients achieving IOP values less than 18 mm Hg at all time points is shown in Figure 1. This criterion was met for 39.2% (209/533) of patients in the combination group, 28.7% (76/265) of patients in the BIM group, and 12.2% (32/263) of patients in the TIM group (_P_=0.001 for combination vs. BIM, and P<0.001 for combination vs. TIM).
The proportion of patients in each treatment group meeting criterion IOP: >20% reduction in diurnal IOP, and <18 mm Hg at all time points. Sample size: Combination (FC, n=533), BIM (n=265), and TIM (n=263); >20% reduction: P<0.001 for combination versus BIM, and for combination versus TIM; <18 mm Hg (_P_=0.003 for combination vs. BIM, and P<0.001 for combination vs. TIM).
Safety
Treatment-related AEs were reported for 41.5% (221/533), 50.9% (135/265), and 24.7% (65/263) patients in the combination, BIM, and TIM groups, respectively (Table 3). This overall incidence was statistically significantly different among groups (P<0.001), with the incidence in the combination group less than in the BIM group (P<0.001) and greater than in the TIM group (P<0.001). The most commonly reported AE was conjunctival hyperemia, with the greatest incidence in the BIM group (38.5%, 102/265), followed by the combination group (22.7%, 121/533) and the TIM group (6.8%, 18/263; P<0.001).
All Treatment-related AEs: Number (Percent) of Patients by Descending Order (Most Frequent >1.5% in Combination Group)
The majority of AEs, whether ocular or nonocular, were mild or moderate in severity. There were 13 serious AEs reported (6, 2, and 5 for the combination, BIM and TIM groups, respectively). All of these events were nonocular, not treatment-related, and none resulted in discontinuation from the study.
A total of 42 patients discontinued study participation owing to AEs: 3.8% (20/533) of patients in the combination group, 6.8% (18/265) of patients in the BIM group, and 1.5% (4/263) of patients in the TIM group. Most of the discontinuations were due to mild or moderate ocular AEs that occurred early in the study (within first 6 wk). There were statistically significantly fewer patients who discontinued because of treatment-related AEs in the combination group [3.0% (16/533)] compared with the BIM group [6.8% (18/265), _P_=0.013], but not the TIM group [1.1% (3/263), _P_=0.106]. Between-group comparisons showed the combination group had statistically significantly lower incidences of patients discontinuing due to conjunctival hyperemia and blepharal pigmentation compared with the BIM group (_P_≤0.044). The most common AEs leading to discontinuations were similar to the most commonly reported treatment-related AEs (ie, conjunctival hyperemia and ocular comfort).
There were no differences between treatments of note in biomicroscopy, ophthalmoscopy, or visual fields other than the conjunctival hyperemia already noted. There were no notable changes in mean heart rate or blood pressure. No clinically confirmed changes in visual fields were observed in any patient during the 3-month study.
DISCUSSION
We desired to evaluate the safety and efficacy of a FC of BIM and TIM compared with each of the active components. These studies were pooled in this report to provide more extensive comparative efficacy and safety information. The combination was evaluated in patients commonly encountered in clinical practice, ranging from newly diagnosed to those with a history of inadequate response to a variety of medications. The patients entering the 3 treatment groups were comparable, other than a clinically insignificant difference in age (62.1 vs. 59.4 vs. 60.4 y). The combination was effective, lowering mean IOP from baseline by up to 9.6 mm Hg, and clinically and statistically superior to each constituent as judged by the overall criterion of a mean diurnal percent reduction from baseline in IOP of more than 20% across all visits and maintaining the IOP below 18 mm Hg at all time points.
The peak effect of BIM occurs 12 to 20 hours after dosing.12 Thus, dosed in evenings, BIM was favored against the combination, which in this study was dosed in the mornings. It is noteworthy that under this study's dosing schedule, the combination was superior.
This study confirmed the observations from an earlier study11 as to the safety of the combination of BIM and TIM. Not only were there no signs or symptoms of intolerance to this new combination formulation, but the incidence of conjunctival hyperemia with the combination was clinically and statistically significantly less than with BIM alone. We do note that patients with hyperemia at baseline were excluded from the study. The reason for the decreased incidence of conjunctival hyperemia is not clear. One plausible hypothesis is the α1-adrenoceptor agonistic effects of endogenous catecholamines, now unopposed by β2-adrenoceptor agonistic effects due to blockade by the TIM. Another potential mechanism is that antagonism of β2-adrenoceptors by TIM could decrease the production of nitric oxide,13 a mediator of BIM-associated hyperemia.14 In a clinical trial of a FC of brimonidine and TIM, a similar reduction in hyperemia was seen, suggesting that TIM's effect on conjunctival hyperemia may be a class effect.15 Irrespective of mechanism, the conjunctival hyperemia associated with BIM is noninflammatory.16
In summary, a FC of BIM and TIM was statistically significantly more effective than either of its active constituents for most comparisons. The clinical significance of this finding is not known at this time. It was also better tolerated and safer than BIM with respect to common ocular AEs. Thus, for patients requiring 2 or more ocular hypotensive medications, this single bottle, FC represents a convenient, therapeutic advantage over separate bottles.
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12. Higginbotham EJ, Schuman JS, Goldberg I, et al. One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension. Arch Ophthalmol. 2002;120:1286–1293.
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APPENDIX
Members of the Ganfort Investigators Group II were:
USA: Louis Alpern, MD, El Paso, TX; Jason Bacharach, MD, Petaluma, CA; Allen Beck, MD, Emory University Eye Center, Atlanta, GA; James Brandt, MD, University of California, Davis, Sacramento, CA; David Brodstein, MD, Ogden, UT; Louis Cantor, MD, Indiana University Medical Center, Indianapolis, IN; David Cooke, MD, St Joseph, MI; E. Randy Craven, MD, Littleton, CO; Douglas Day, MD; Atlanta, GA; Monte Dirks, MD, Rapid City, SD; Harvey DuBiner, MD, Morrow, GA; Efraim Duzman, MD, Irvine, CA; Richard Evans, MD, San Antonio, TX; Robert Feldman, MD, University of Texas Health Science Center, Houston; Robert Foerster, MD, Colorado Springs, CO; John Foley, MD, Virginia Beach, VA; Walter Fried, MD, PhD, Gurnee, IL; Phillip Gendelman, MD, Burlington, MA; Ron Gross MD, Cullen Eye Institute, Baylor College of Medicine, Houston TX; Leonard Gurevich, MD, Orchard Park, NY; Bartlett Hayes, MD, Bangor, ME; L. Jay Katz, MD, Wills Eye Hospital, Philadelphia, PA; Rohit Krishna, MD, Kansas City, MO; Joseph Krug, MD, Charlotte, NC; Richard A. Lewis, MD, Sacramento, CA; Christopher Lin, MD, Redding, CA; Jeffrey Lozier, MD, San Diego, CA; Alan Mandell,✠ MD, Memphis, TN; David McGarey, MD, Flagstaff, AZ; Thomas Mundorf, MD, Charlotte, NC; George Nardin, MD, Kailua, HI; Jonathan Nussdorf, MD, New Orleans, LA; Bernard Perez, MD, Tampa, FL; Michael Price, MD, Malden, MA; Anthony Realini, MD, University of Arkansas for Medical Sciences, Little Rock, AR; Michael Rotberg, MD, Charlotte, NC; Kenneth Sall, MD, Bellflower, CA; Howard Schenker, MD, Rochester, NY; Elizabeth Sharpe, MD, Charleston, SC; John Sheppard, MD, Norfolk, VA; Mark Sherwood, MD, University of Florida, Gainesville, FL; Robert Shields, MD, Denver, CO; Steven Simmons, MD, Slingerlands, NY; Joseph Sokol, MD, Waterbury, CT; Alfred Solish, MD, Pasadena, CA; Richard Sturm, MD, Lynbrook, NY; Michael Tepedino, MD, High Point, NC; George Thorne, MD, MBA, Austin, TX; Jean H. Tibbetts, MD, Bangor, ME ; Thomas Walters, MD, Austin, TX ; Stephen Whiteside, MD, Georgetown, TX; Jacob Wilensky, MD, University of Illinois at Chicago, Chicago, IL; Robert Williams, MD, Louisville, KY; Charles Williamson, MD, Baton Rouge, LA; David Wirta, MD, Newport Beach, CA; Lisa Wohl, MD, Bloomingdale, IL.
Canada: Pierre Blondeau, MD, Sherbrooke, Quebec; Cindy Hutnik, MD, London, Ontario.
✠Deceased.
Keywords:
bimatoprost; timolol; intraocular pressure; fixed combination; glaucoma
© 2008 Lippincott Williams & Wilkins, Inc.