The investigators for MERCURY-1 and MERCURY-2 (www.clinicaltrials.gov identifiers NCT02558400 and NCT02674854) obtained institutional review board (IRB) approval prior to initiating the studies (MERCURY-1: Schulman Institutional Review Board, Cincinnati, OH, USA; Duke University School of Medicine Institutional Review Board, Durham, NC, USA; Western Institutional Review Board, Puyallup, WA, USA; MERCURY-2: Schulman Institutional Review Board, Cincinnati, OH, USA; Nova Scotia Health Authority Research Ethics Board, Halifax, NS, Canada; Comité d’éthique de la recherche du Centre Intégré Universitaire de Santé et de Services Sociaux de l’Estrie, Sherbrooke, QC, Canada). The studies were conducted in accordance with IRB regulations and Good Clinical Practice Guidelines and adhered to the tenets included in the Declaration of Helsinki. The MERCURY-1 study was conducted in the USA for 12 months . The MERCURY-2 study was conducted in the USA and Canada for 3 months . Both MERCURY-1 and -2 studies were phase 3, randomized, double-masked, multicenter, active controlled, parallel-group, safety and efficacy studies evaluating treatment to reduce elevated IOP in patients with a diagnosis of OAG or OHT.
Patients included in the studies were at least 18 years of age in the USA or at least 19 in Canada (see Table S1 in the supplementary material for key inclusion and exclusion criteria). A diagnosis of OAG or OHT in both eyes was required; however, both eyes did not need to have the same condition. Both eyes had to qualify at all qualification visit time points. Unmedicated (post-washout) IOP in both eyes had to be more than 20 to less than 36 mmHg at 08:00 during two qualification visits (2–7 days apart) and more than 17 to less than 36 mmHg at 10:00 and 16:00 at the second qualification visit. The minimum washout period was 4 weeks for patients using prostaglandin analogues or beta-adrenoreceptor antagonists prior to study entry, 2 weeks for those using alpha-adrenergic agonists, and 5 days for those using muscarinic agonists or carbonic anhydrase inhibitors. An additional inclusion criterion was best corrected visual acuity (BCVA) of + 1.0 logMAR or better (equivalent to 20/200 or better Snellen visual acuity in each eye).
Patients were excluded from the studies if they had clinically significant ocular or systemic disease that might interfere with interpretation of the study results. Excluded conditions included, but were not limited to, pseudoexfoliation or pigment dispersion component glaucoma and a history of angle-closure glaucoma or narrow angles (Shaffer grade 2 or less; extreme narrow angle with complete or partial closure). Patients who had used any ocular hypotensive medications within 30 days of screening were also excluded. Patients with known contraindications or hypersensitivity to latanoprost were ineligible to participate. Pregnant women were excluded, as were women of child-bearing potential if they were nursing, planning a pregnancy, or were not using a medically acceptable form of birth control.
The screening visit (visit 1) occurred up to 28 days prior to the first of two qualification visits (visits 2 and 3) [the second qualifying, or visit 3 is also day 1 of treatment]). Patients were randomized (1:1:1) to receive an FDC of netarsudil (0.02%)/latanoprost (0.005%) ophthalmic solution, single agent netarsudil ophthalmic solution 0.02%, or single agent latanoprost ophthalmic solution 0.005%. Randomization was managed using an interactive internet-based response system and the randomization code was prepared by an independent biostatistician. Treatment assignments were masked to investigators, the clinical study team, and patients. Patients were also stratified by investigative site and maximum baseline IOP (< 25 vs. ≥ 25 mmHg). Patients were instructed to instill one drop of study drug into each eye once per day beginning at day 1 in the evening between 20:00 and 22:00 at approximately 24-h intervals.
The primary efficacy endpoint was comparison of netarsudil/latanoprost FDC ophthalmic solution relative to each of its active components (netarsudil and latanoprost) for mean IOP within a treatment group at 08:00, 10:00, and 16:00 at the week 2, week 6, and month 3 study visits. Secondary endpoints included mean diurnal IOP at each post-treatment visit and proportion of patients achieving prespecified levels for mean diurnal IOP, mean change in diurnal IOP, and percentage mean change in mean diurnal IOP at each post-treatment visit.
Safety data up to 12 months from patients who received at least one dose of study medication were pooled by treatment arm; MERCURY-1 included patients who completed up to 12 months of treatment, and MERCURY-2 included patients who completed up to 3 months of treatment [2, 3].
Qualified individuals measured IOP using a calibrated Goldmann applanation tonometer. Two consecutive IOP measurements were obtained for each eye. If the two measurements differed by more than 2 mmHg, a third measurement was obtained. IOP was analyzed as the mean of two measurements or as the median of three measurements. For enrolled patients, the study eye was the eye with the higher IOP at 08:00 on visit 3 (day 1). If both eyes had the same IOP at 08:00 on visit 3, then the right eye was the study eye. Efficacy data from the intent-to-treat population (ITT) of each study were pooled by treatment arm. The ITT population included all randomized patients who received at least one dose of study medication and was the primary population for all efficacy analyses.
The primary outcome was evaluated using an analysis of covariance (ANCOVA) model with mean IOP at the given visit (week 2, week 6, and month 3) and time point (08:00, 10:00, and 16:00) as the response, baseline IOP as a covariate, and treatment as a main effect factor, using the ITT population with multiple imputation techniques (e.g., Monte Carlo Markov chain [MCMC]) for missing data. Each time point within each visit was modeled separately.
The least-squares mean differences (netarsudil/latanoprost FDC minus comparator) were tested between netarsudil/latanoprost FDC ophthalmic solution and each of the individual ophthalmic solutions (latanoprost 0.005% and netarsudil 0.02%). The two-sided p values and associated 95% confidence intervals were calculated. For a given comparator (latanoprost and netarsudil), statistical superiority was concluded if the p value was less than 0.05 and the point estimate was less than 0 for all time points at the week 2, week 6, and month 3 visits.
All safety analyses were carried out using the safety population, defined as all randomized patients who received at least one dose of investigational product, and included the study eye and fellow eye separately where applicable.
Safety variables evaluated in this study for all enrolled patients included symptoms/adverse events (AEs); comfort testing (ocular tolerability); heart rate; blood pressure; biomicroscopy of the anterior segment including evaluation of the cornea (by fluorescein staining), conjunctiva, and anterior chamber; dilated ophthalmoscopy; best corrected visual acuity; pupil size; visual fields; pachymetry; IOP; and clinical chemistry and hematology laboratory findings. Specular microscopy was performed in MERCURY-2 patients.