This was a prospective, randomized, double-masked, sham-controlled, parallel-group, multicenter, phase 2 clinical trial (ClinicalTrials.gov identifier NCT02754596). The study evaluated the safety and IOP-lowering efficacy of two travoprost intraocular implants with different elution rates versus timolol eye drops (Timolol Maleate Ophthalmic Solution, USP, 0.5%) in patients with OAG or OHT.

Patients were enrolled from 15 March 2016 to 21 July 2020 at 23 sites in the USA and one site in the Philippines.

The study was performed in compliance with good clinical practice and the principles of the Declaration of Helsinki. Institutional review board (Western Institutional Review Board for sites in the USA and the St. Cabrini Medical Center—Asian Eye Institute Ethics Review Committee for the site in the Philippines) approval was obtained at each site before the study began, and all patients provided written informed consent before undergoing any study-related procedure.

A total of 154 patients, 18 years of age and older, diagnosed with OAG (primary, pseudoexfoliative, or pigmentary) or OHT, on 0–3 topical IOP-lowering medications were included. Patients were required to meet all inclusion criteria and none of the exclusion criteria to be eligible for participation. Key inclusion criteria included the ability to provide an adequate interpretable visual field with a mean deviation no worse than − 12 dB, a cup/disc ratio of ≤ 0.8, best-corrected visual acuity score of + 0.6 logMAR (Snellen equivalent of 20/80) or better in each eye, an open iridocorneal angle (Shaffer grade ≥ 3) with normal anatomy, and phakic or pseudophakic with a posterior chamber intraocular lens that had been implanted a minimum of 90 days prior to the screening visit. Phakic eyes were required to have a minimum corneal endothelial cell count between 1600 and 2000 cells/mm2 dependent on age, and pseudophakic eyes were required to have a minimum endothelial cell count between 1120 and 1540 cells/mm2 dependent on age. Additionally, female patients of childbearing potential were required to have a negative urine pregnancy test result at the screening visit and agree to use reliable birth control throughout the study.

Key exclusion criteria included glaucoma of traumatic, uveitic, or neovascular etiology or associated with a vascular disorder; prior glaucoma surgery including filtration surgery, incisional surgery, argon laser trabeculoplasty (ALT), iridectomy/iridotomy, or trabecular bypass or suprachoroidal procedures; a history of selective laser trabeculoplasty (SLT) within the prior 90 days; a visual field status that would place the patient at risk by being washed out of IOP-lowering medication(s); active corneal inflammation or edema; clinically significant corneal dystrophy or guttata; corneal thickness of < 440 microns or > 620 microns; presence of significant corneal scarring or irregularities that could interfere with reliable IOP measurement; corneal opacities or disorders that inhibited visualization of the nasal angle; congenital or traumatic cataract, or visually significant cataract that was likely to require surgical intervention during the study period; choroiditis, choroidal detachment, effusion, neovascularization, or any active choroidopathy; degenerative or evolutive retinal or optic nerve disorders (e.g., proliferative diabetic retinopathy, central retinal artery occlusion, central retinal vein occlusion, wet age-related macular degeneration, advanced dry age-related macular degeneration, significant retinal pigment epithelial changes, or optic atrophy). Additionally, patients were to be excluded if they had uncontrolled systemic disease (e.g., diabetes, hypertension) or an immunodeficiency disorder; used systemic medications (either current, within 30 calendar days of the screening visit, or anticipated) that may cause an increase in IOP [e.g., systemic steroids including oral or intravenous (IV) formulations, topical steroids applied on the periorbital surface within 1/4 inch of the external lid margins] or oral inhaled steroids; were unable to discontinue use of nonsteroidal anti-inflammatory medications (NSAIDs) (topical dermal NSAIDs were acceptable) or aspirin (any dosage) within 7 calendar days prior to surgery and for 1–2 days following surgery; or were unable to discontinue blood thinners for a period of 1–7 days dependent on the type of medication. Additionally, patients were to be excluded from participation if they used an oral carbonic anhydrase inhibitor (CAI); if they had a known allergy or hypersensitivity to the study medication or their components; used any ocular medications, other than IOP-lowering medications, within 1 week prior to the screening visit; and were not on a stable dosing regimen of chronic systemic therapy that could affect IOP within 30 days prior to the screening visit or anticipated a change in such therapy during the study duration.

Patients on no IOP-lowering medications within the 4 weeks prior to the screening visit were required to have an IOP of 21–36 mmHg in the study eye, and then complete a 3 day waiting period and return for a baseline visit. Patients on IOP-lowering medications at the screening visit were required to stop their medication and undergo a washout period dependent on the class of medication: 5 days for miotics, 7 days for CAIs, 3 weeks for alpha adrenergic agonists, and 4 weeks for beta adrenergic antagonists and PGAs. A topical CAI could be substituted to replace a medication requiring a longer washout (e.g., PGA) provided that the CAI was stopped at least 7 days prior to the baseline visit.

At the baseline visit, all patients were required to have unmedicated mean diurnal IOP (average of the 8:00 AM, 10:00 AM, and 4:00 PM values) of 21–36 mmHg in the study eye and meet all other entry criteria.

Eligible patients were randomized 1:1:1 to one of the following three treatments: FE implant, SE implant, and timolol control group. The FE and SE implants were identical in size and appearance, which aided in masking.

To maintain postoperative masking, patients in both implant groups received a placebo topical ophthalmic solution (Advanced Eye Relief Dry Eye Rejuvenation; Bausch & Lomb, Bridgewater, NJ) to be administered twice daily (BID). Patients randomized to the control group underwent a sham surgical procedure before receiving masked timolol maleate ophthalmic solution, 0.5% to be administered BID. Following implantation of the travoprost intraocular implant or sham surgery, all patients were given fluoroquinolone antibiotic eye drops to be administered four times daily for 1 week and topical NSAID eye drops to be used in accordance with the prescribing information. The fellow eye was maintained on pre-study IOP-lowering medication(s).

From week 4 onward, additional topical IOP-lowering therapy was to be initiated in any study eye in which IOP exceeded 18 mmHg.

Following the surgical or sham procedure, patients were evaluated at day 1–2, day 10, week 4, and week 6, as well as at month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36 visits. IOP was measured at 8:00 AM ± 30 minutes at all study visits, with the exception of the day 10, week 6, and month 3 study visits at which diurnal assessments were collected at 8:00 AM ± 30 min, 10:00 AM ± 30 min, and 4:00 PM ± 30 min. IOP was measured by Goldmann applanation tonometry using a two-person technique in which one person unmasked to treatment viewed through the slit lamp and turned the dial, while the second person masked to treatment recorded the measurements.

Additional assessments included measurement of visual acuity (VA), slit lamp examination (of the cornea, anterior chamber, iris, pupil, and lens), gonioscopy, dilated fundus examination (including vertical cup/disc ratio), computerized perimetry, specular microscopy, and pachymetry.

Conjunctival hyperemia was assessed at the slit lamp and graded on a five-point scale (normal, trace, mild, moderate, severe) by comparison to a photographic images, iris color was evaluated for any changes in pigmentation, the periorbital region was assessed to detect PGA-associated periorbitopathy, and the eyelashes were assessed for density and length.

Adverse events were both solicited and based on observations, with any clinically significant worsening from baseline in a parameter reported as an adverse event.

Safety outcomes included surgical complications and adverse events, best-corrected VA (BCVA), gonioscopy, ophthalmoscopy (including cup/disc ratio), central corneal thickness, conjunctival hyperemia, visual field, slit lamp biomicroscopy, endothelial cell density, and periorbital or eyelash changes.

The sample size of this phase 2 study was not determined to have prespecified power for formal hypothesis testing. Instead, the sample size was chosen to obtain appropriate precision around endpoints for subsequent phase 3 trials.

The mean change from baseline in IOP at each timepoint was analyzed with one-sample t tests comparing the reduction from baseline to 0. The percentage of study eyes at months 12, 24, and 36 that maintained or reduced their topical IOP-lowering medication burden was analyzed using a Pearson chi-square test.