Study Design

The LUNAR study ( Clinicaltrials.gov identifier: NCT01749930 ) was a randomized, multicenter, double-masked, parallel-group, clinical study conducted at 46 investigational sites in the United States (40), the United Kingdom (3), Germany (2), and Italy (1) between January 28, 2013 and November 26, 2014. The study was conducted in accordance with Good Clinical Practices (as described in the International Conference on Harmonization guidelines), the ethical principles of the Declaration of Helsinki, the Code of Federal Regulations, and applicable local regulations. Institutional Review Board/Ethics Committee approval was obtained at each participating site, and all study subjects provided written informed consent prior to participation. The primary objective of the study was to evaluate the noninferiority of the mean IOP-lowering effect of LBN 0.024% over 3 months of treatment to that of timolol 0.5%. If noninferiority of LBN 0.024% was achieved, the secondary objective was to evaluate the statistical superiority of LBN 0.024% to timolol 0.5%. The study was composed of 2 phases: a 3-month active controlled efficacy phase followed by a 3-month open-label safety extension phase, the results of which will be published separately.

Subjects

The study enrolled male and female subjects ≥18 years of age with a diagnosis of OAG (including pigmentary or pseudoexfoliative) or OHT in 1 or both eyes. Intraocular pressure was assessed once at visit 1 (Screening) and at 8 AM, 12 PM, and 4 PM during visit 3 (Eligibility, Day 0) to establish baseline and eligibility values. Subjects who were already receiving treatment with an IOP-lowering medication were required to undergo a washout period prior to visit 3, the duration of which varied depending on the type of IOP-lowering medication used (maximum washout period, 28 + 5 days). At visit 3, and following washout, if required, study participants were required to have an IOP ≥26 mm Hg at a minimum of 1 of 3 time points (8 AM, 12 PM, and 4 PM), ≥24 mm Hg at a minimum of 1 time point, and ≥22 mm Hg at 1 time point, all in the same eye, and IOP ≤36 mm Hg at all 3 measurement time points in both eyes. Potential subjects undergoing washout were excluded from participation in the study if IOP exceeded 36 mm Hg in either eye at any point during the washout period. Eligible subjects also had a best-corrected visual acuity (BCVA) of + 0.7 logarithm of the minimal angle of resolution (logMAR) units (Snellen equivalent of approximately 20/100) or better in either eye.

Subjects were ineligible for study participation if they were involved in another clinical trial during this study, or were involved in another clinical trial within 30 days prior to visit 1 (Screening), for subjects requiring a washout period, or 30 days prior to visit 3 (Eligibility, Day 0) for subjects not requiring a washout period. Subjects were also excluded if they had known hypersensitivity or contraindication to the active or inactive ingredients of the study treatments; were unable to discontinue contact lens use or other eye drop medications (eg, artificial tears) during and for 15 minutes after instillation of study drug and during study visits; had a central corneal thickness >600 μm in either eye; had any condition that prevented reliable applanation tonometry (eg, significant corneal surface abnormalities) in either eye; or had advanced glaucoma (cup-to-disc ratio >0.8 or split fixation) or other significant ophthalmic disease. The study also excluded subjects who required treatment with ocular or systemic corticosteroids, subjects in need of or expected to require additional topical or systemic treatment for OAG or OHT, and subjects with an anticipated need to initiate or modify medication known to affect IOP (eg, β-adrenergic antagonists, α-adrenergic agonists, calcium channel blockers, angiotensin-converting enzyme A inhibitors and angiotensin II receptor blockers) during the study.

Study Treatments and Assessments

The investigational product LBN 0.024%, its vehicle, and the comparator timolol 0.5% were manufactured by Bausch & Lomb Inc (Tampa, Florida, USA). Baseline demographic and clinical data (ie, relevant medical and ocular history, concomitant medications, ocular assessments) were recorded at visit 1 (Screening). The study eye was defined as the eye that qualified per inclusion criteria at visit 3 (Eligibility, Day 0). If both eyes qualified, the study eye was the eye with the higher mean diurnal IOP value (defined as average of IOPs recorded at 8 AM, 12 PM, and 4 PM) at visit 3, or the right eye if both eyes had the same mean diurnal IOP value. If both eyes of a subject had a diagnosis of OAG or OHT, then both eyes were treated for the duration of the study, even if only 1 eye met study inclusion criteria at visit 3.

Eligible subjects were randomized at visit 3 in a 2:1 ratio to receive 3 months of treatment with LBN 0.024% QD in the evening (approximately 8 PM) and vehicle QD in the morning (approximately 8 AM) or timolol 0.5% BID. Each subject received study kits containing 4 eye drop bottles with computer-generated investigational labels (ie, void of commercial labeling) and was instructed to instill 1 drop of study drug from the “Night” dosing bottle into the affected eye(s) at approximately 8 PM each evening and 1 drop from the “Day” dosing bottle at approximately 8 AM each morning. A randomization schedule was created prior to any study enrollment by a statistician not otherwise involved in the study using SAS (SAS Institute, Cary, North Carolina, USA; Version 9.2). Allocation of study drug was completed through the use of IRT (Interactive Response Technology), which determined which kit to assign to each subject. Subjects and study site personnel were fully masked to treatment assignments. Compliance was determined as actual number of instillations, as recorded on a patient diary, divided by number of expected instillations.

Subjects completed 3 study visits (visit 4 [week 2 ± 2 days]; visit 5 [week 6 ± 3 days]; visit 6 [month 3 ± 10 days]) following randomization. Intraocular pressure was assessed at each visit in both eyes at 8 AM, 12 PM, and 4 PM using a Goldman applanation tonometer. On these days, the AM dose of study drug was instilled after the first IOP assessment of the day. Intraocular pressure was measured twice consecutively and the mean IOP was recorded for consecutive measurements within 2 mm Hg. In cases of consecutive measurements differing by >2 mm Hg, a third measurement was taken and the median IOP was recorded. Whenever possible, IOP was measured by the same operator using the same tonometer at each visit for a given subject.

Safety assessments recorded at each visit included ocular and systemic treatment-emergent adverse events (TEAEs), vital sign measurements, BCVA (measured using the ETDRS standard protocol), and slit-lamp examination; in addition, ophthalmoscopy and specular microscopy were performed at day 0 and month 3. Conjunctival hyperemia was graded by the investigator on a 1-4 photographic reference (none, mild, moderate, severe) scale prior to IOP assessment at each time point/study visit.

Endpoints

The primary efficacy endpoint was the IOP in the study eye measured at the specified time points of 8 AM, 12 PM, and 4 PM at each postrandomization visit (week 2, week 6, and month 3). Secondary efficacy endpoints included the proportion of eyes with IOP ≤18 mm Hg; the proportion with IOP reduction ≥25% from baseline consistently across all 9 postrandomization assessments; change from baseline in IOP at 8 AM, 12 PM, and 4 PM; and the change from baseline in diurnal IOP at week 2, week 6, and month 3. Safety endpoints included the incidence of ocular and systemic adverse events (AEs), vital signs, BCVA, and conjunctival hyperemia assessments.

Statistical Analysis

A sample size of 300 subjects in the per-protocol (PP) population was calculated as providing adequate power (90%) to detect an IOP difference (noninferiority margin) of 1.5 mm Hg, assuming a standard deviation (SD) of 3.75 mm Hg and a 2-sided α = 0.05. The SD was obtained by pooling the SD from an LBN 0.024% phase 2b study and the timolol arm of a phase 3 study. A total of 393 subjects were to be randomized in a 2:1 ratio to the LBN 0.024% and timolol 0.5% treatment groups, respectively, to account for potential protocol violations and dropouts.

The primary efficacy analyses were performed using analysis of covariance (ANCOVA) in the intent-to-treat (ITT) population (ie, all randomized subjects who instilled at least 1 dose of study drug and had a baseline and at least 1 postrandomization IOP), with randomized treatment group as a classification variable and time-matched mean IOP as a covariate. Missing data were imputed using the last-observation-carried-forward (LOCF) method for the IOP in the study eye measured at 8 AM, 12 PM, and 4 PM at each postrandomization visit. The 2 treatments, LBN 0.024% and timolol 0.5%, were compared for each time point at each visit by determining the least squares (LS) mean of each treatment group, the difference in the LS mean (LBN 0.024% – timolol 0.5%), and the 2-sided 95% confidence interval (CI) for the difference. Noninferiority was to be established if the upper limit of the CIs for the difference did not exceed 1.5 mm Hg at all 9 IOP assessments and did not exceed 1.0 mm Hg for at least 5 out of the 9 time points. If noninferiority was determined, superiority was concluded if the upper limit of the 95% CI did not exceed 0 mm Hg at any of the 9 IOP measurement time points. These analyses were repeated in the PP population in order to supplement the primary analyses.

Analyses of the secondary endpoints were performed following demonstration of noninferiority of LBN 0.024% to timolol 0.5%. The proportion of subjects with IOP ≤18 mm Hg at all 9 postrandomization IOP measurement time points and the proportion with IOP reduction ≥25% at all 9 time points were summarized categorically. The percentage reduction from baseline in IOP was calculated as 100 × (baseline mean IOP − postbaseline mean IOP)/baseline mean IOP. For each secondary endpoint, the 2-sided 95% CI around the difference in proportions (LBN 0.024% − timolol 0.5%) and the P value from the Pearson χ ² test were presented. An ANCOVA of change from baseline in IOP was performed with fixed-effect terms for treatment and baseline for the 3 postrandomization time points (8 AM, 12 PM, and 4 PM) at visit 4/week 2, visit 5/week 6, and visit 6/month 3. An ANCOVA of change from baseline in mean diurnal IOP was also performed with fixed-effect terms for treatment and diurnal baseline IOP at each postrandomization visit.

Safety analyses were performed on the safety population, which included all randomized subjects who instilled at least 1 dose of study drug. All AEs were coded using Medical Dictionary for Regulatory Activities dictionary version 13.0. Ocular TEAEs were summarized for study eyes and treated fellow eyes separately by treatment group. Nonocular TEAEs were summarized for each treatment group using discrete summaries at the subject and event level by system organ class and preferred term. Ocular and nonocular TEAEs were summarized by relationship to study drug and severity. Data on BCVA, conjunctival hyperemia, slit-lamp biomicroscopy, and ophthalmoscopy were presented separately for study eyes and treated fellow eyes and summarized using descriptive statistics (BCVA) or categorically (conjunctival hyperemia, slit-lamp biomicroscopy, and ophthalmoscopy). Conjunctival hyperemia was classified as none, mild, moderate, or severe through the use of photographic standards.

All CIs, statistical tests, and resulting P values were reported as 2-sided and were evaluated at the 5% significance level. Continuous data were summarized with descriptive statistics (number, mean, SD, median, minimum, and maximum). Statistical analyses were conducted using SAS software (SAS Institute, Cary, North Carolina, USA) version 9.2 or higher.

Subjects

Of 756 subjects screened, 420 were enrolled and randomized to LBN 0.024% (n = 283) or timolol 0.5% (n = 137), and 387 (92.1%) completed the 3 months of study treatment ( Figure 1 ). Overall, 415 subjects received at least 1 instillation of study drug and comprised the safety population. The ITT population included 414 subjects (LBN 0.024%, n = 278; timolol 0.5%, n = 136). The proportion of subjects in the ITT population who completed the study was similar in the LBN 0.024% (259/278; 93.2%) and timolol 0.5% (128/136; 94.1%) groups.

Disposition of patients with open-angle glaucoma or ocular hypertension receiving latanoprostene bunod 0.024% or timolol 0.5%. ^a In 2 latanoprostene bunod (LBN) subjects, including the subject excluded from the intent-to-treat (ITT) population, the study eye could not be derived according to the protocol definition. Thus, the number of evaluable study eyes was n = 277 for both the safety and ITT populations. ^b In 1 timolol subject, the study eye could not be derived according to the protocol definition. Thus, the number of evaluable study eyes was n = 135 for both the safety and ITT populations.

In the ITT population, subjects were on average 64.7 years of age (range, 23–88 years) and were predominantly female (58.2%), white (70.8%), and non-Hispanic/non-Latino (86.7%; Table 1 ). Black/African-American subjects comprised 27.8% of the overall population. Demographic and baseline eye characteristics (mean corneal thickness, refraction sphere, and refraction cylinder) were comparable between treatment groups. The majority of subjects (72%) had been treated with IOP-lowering medications within 30 days prior to enrollment. Nonocular medical history was similar between the treatment groups. Baseline mean (SD) diurnal IOP (average of IOP at 8 AM, 12 PM, and 4 PM) was 26.6 (2.4) mm Hg for subjects randomized to LBN 0.024% and 26.4 (2.3) mm Hg for subjects randomized to timolol 0.5%.

Efficacy

Primary endpoint

The mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group at the majority of time points measured (12 PM, 4 PM at week 2, 8 AM, 12 PM, 4 PM at week 6 and month 3) ( Figure 2 and Table 2 ). Noninferiority of LBN 0.024% to timolol 0.5% was demonstrated based on ANCOVA results (upper limit of the 95% CIs did not exceed 1.0 mm Hg at any of the 9 time points) ( Table 2 ). LBN 0.024% also met the criteria for statistical superiority over timolol 0.5% at all time points except the 8 AM time point at week 2 (upper limit of the 95% CI exceeded 0 mm Hg at this single assessment point) ( Table 2 ). Results in the PP population were consistent with these findings (data not shown). Further exploratory analysis indicated that the primary endpoint results did not differ based on prior IOP-lowering medication treatment status at enrollment or whether or not subjects on concurrent systemic β-blockers (15.1% of LBN and 13.2% of timolol subjects) were included in the analysis (data not shown).

Least squares (LS) mean of mean intraocular pressure (IOP) (mm Hg) and standard error in the study eye by visit, time point, and treatment group among subjects treated with latanoprostene bunod 0.024% (LBN) once daily (n = 278) or timolol maleate 0.5% twice daily (n = 136). Data represent intent-to-treat population with last observation carried forward. * P ≤ .025, analysis of covariance of treatment difference.

Table 2

Analysis of Covariance Results for Comparison of Mean Intraocular Pressure in the Study Eye by Visit and Time Point (Intent-to-Treat Population With Last Observation Carried Forward)

	Least Squares Mean of the Mean IOP, mm Hg		Treatment Difference (95% Confidence Interval)	P Value
	Latanoprostene Bunod 0.024%	Timolol 0.5%
Week 2
8 AM	19.2	19.6	−0.4 (−1.1, 0.3)	.216
12 PM	18.5	19.2	−0.8 (−1.4, −0.1)	.022
4 PM	18.1	18.8	−0.7 (−1.3, −0.1)	.025
Week 6
8 AM	18.7	19.6	−0.9 (−1.6, −0.3)	.005
12 PM	18.0	18.9	−0.8 (−1.5, −0.2)	.007
4 PM	17.9	18.9	−1.0 (−1.6, −0.4)	.003
Month 3
8 AM	18.7	19.6	−0.9 (−1.5, −0.3)	.006
12 PM	17.9	19.2	−1.3 (−1.9, −0.7)	<.001
4 PM	17.7	19.1	−1.3 (−2.0, −0.7)	<.001

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