3.1 Disposition

The first subject was screened in May 2018, and the last subject completed their month 12 visit in June 2022.

A total of 1973 subjects were screened, of whom 1150 were randomized and comprised the intent-to-treat (ITT) analysis set: 385 FE implant subjects, 380 SE implant subjects, and 385 sham/timolol subjects. The safety analysis set comprised 1149 subjects: 385 FE implant subjects, 378 SE implant subjects, and 386 sham/timolol subjects.

Of the 1150 subjects randomized at the day 0 operative visit, 96.0% completed the 12-month evaluation period.

3.2 Demographics and Baseline Characteristics

Subject demographics and study eye disease characteristics were well balanced across the three treatment groups (Tables 1 and 2, respectively).

Table 1 Demographics of subjects (ITT analysis set)Table 2 Baseline characteristics of the study eye (ITT analysis set)

Most subjects had a diagnosis of OAG in the study eye (83.0%), were on one or more topical IOP-lowering medications at screening (70.4%), and had a post-washout mean diurnal IOP (average of 8AM, 10AM, and 4PM) of 25 mmHg or less (71.0%). The mean number of pre-study topical IOP-lowering medications was 0.9, 0.9, and 1.0 in the FE implant, SE implant, and sham/timolol groups, respectively.

3.3 Efficacy3.3.1 Intraocular Pressure (IOP) Reductions Through Month 12

Mean (SD) baseline diurnal IOP (average of the 8AM, 10AM, and 4PM timepoints) was 24.2 (2.88) mmHg for the overall study population. Reductions from baseline in mean diurnal IOP (i.e., the minimum and maximum across the day 10, week 6, month 3, and month 12 visits) were clinically relevant and statistically significant ranging from 5.4 to 8.2 mmHg for the FE implant group, 5.4 to 8.4 mmHg for the SE implant group, and from 6.1 to 7.2 mmHg for the sham/timolol group across the four visits at which diurnal IOP was prospectively collected. In addition, both the SE and FE implant groups demonstrated statistical non-inferiority to the sham/timolol group in reduction from baseline in mean diurnal IOP across all study visits over the entire 12 months when diurnal IOP was prospectively collected. The upper limit of the two-sided 95% confidence interval on the difference between the implant groups and the sham/timolol group was < 1.5 mmHg at all four visits (Table 3).

Table 3 Change from baseline in mean diurnal IOP over 8AM, 10AM and 4PM at each visit (ITT analysis set)

Mean (SD) baseline 8AM IOP was 24.6 (3.55) mmHg for the overall study population. The 8AM IOP reductions in average IOP from day 10 through the specified visit ranged from 6.9 to 8.5 mmHg in the FE implant group, from 6.8 to 8.5 mmHg in the SE implant group, and from 7.3 to 7.5 mmHg in the sham/timolol group (Fig. 2). The 8AM IOP reductions in average IOP from day 10 through the specified visit were statistically significant (p <  0.0001) and clinically relevant at all visits for all three treatment groups. In the same analysis, these 8AM IOP reductions in both the SE and FE implant groups demonstrated statistical non-inferiority to the sham/timolol group over the entire 12 months.

Fig. 2

Mean (± standard error) 8AM IOP change from baseline for the FE implant, SE implant, and sham/timolol averaged from day 10 through each specified visit. IOP change from baseline was statistically significant (p <  0.0001; one-sample t tests) for all treatment groups at all visits. IOP change from baseline was significantly greater in the FE implant and SE implant groups versus sham/timolol group at day 10 (p = 0.0011 and p = 0.0005, respectively). FE Implant fast-eluting travoprost intracameral implant, IOP intraocular pressure, SE Implant slow-eluting travoprost intracameral implant

3.3.2 Topical IOP-Lowering Medications

Pre-study, subjects in both the FE and SE implant groups were on a mean (SD) of 0.9 (0.8) medications per study eye, and 21.6% and 23.1% of FE and SE implant eyes, respectively, were on two or three pre-study topical IOP-lowering medications.

Over the 12-month evaluation period, the proportion of subjects without additional IOP-lowering medications in the study eye decreased in all three treatment groups (Table 4). However, at month 12, the proportion of implant eyes that remained completely free of topical IOP-lowering medications was high at 77.6% of FE implant eyes and 81.4% of SE implant eyes despite the fairly high treatment burden pre-study.

Table 4 Proportion of subjects in each treatment group without additional study eye IOP-lowering medications by visit (ITT analysis set)

In addition, at month 12, a significantly greater proportion of implant eyes (89.9% of FE implant eyes, 93.0% of SE implant eyes) compared with sham/timolol eyes (66.9%) were on the same or fewer topical IOP-lowering medications compared with pre-study (p <  0.0001), and of eyes that were on IOP-lowering medication at screening, a significantly greater proportion of implant eyes (80.2% of FE implant eyes, 85.1% of SE implant eyes) compared with sham/timolol eyes (22.8%) were on fewer topical IOP-lowering medications compared with pre-study (p <  0.0001).

Of the 93.0% of subjects in the SE implant group who were on the same or fewer topical IOP-lowering medications at month 12 compared with pre-study, the average through month 12 decreased to a mean (SD) of 0.1 (0.2) medications per eye from 1.0 (0.8) medications per eye, and of the 85.1% subjects in the SE implant group who were on fewer topical IOP-lowering medications compared with pre-study, the average through month 12 decreased to a mean (SD) of 0.0 (0.1) medications per eye from 1.4 (0.6) medications per eye.

3.4 Safety3.4.1 Study Eye Treatment-Emergent Adverse Events (TEAEs)

TEAEs were reported in 35.8% and 35.7% of FE implant (138/385) and SE implant (135/378) study eyes, respectively, and in 18.9% of sham/timolol (72/386) eyes (Table 5).

Table 5 Summary of TEAEs (safety analysis set)

Serious TEAEs were reported in 0.3% and 0.8% of FE implant (1/385) and SE implant (3/378) study eyes, respectively, and in no sham/timolol study eyes. These serious TEAEs included IOP increased (one FE implant eye and one SE implant eye), retinal detachment (one SE implant eye), and endophthalmitis (one SE implant eye). Both TEAEs of IOP increased and the TEAE of endophthalmitis were related to study treatment. The TEAEs of IOP increased were reported at study day 19 and day 42 and resolved with the use of topical IOP-lowering medication. The TEAE of retinal detachment, which was unrelated to study treatment, was reported at study day 189 and resolved with surgical intervention (pars plana vitrectomy, laser, and perfluropropane gas). The TEAE of endophthalmitis was reported at study day 8 and resolved following treatment with intravitreal ceftazidime and vancomycin.

TEAEs leading to study discontinuation were reported in a low proportion of study eyes in each treatment group; 1.8%, 1.4%, and 0.8% in the FE implant (7/385), SE implant (4/378) and sham/timolol (3/386) eyes, respectively. One study eye TEAE leading to study discontinuation was characterized as a serious TEAE (endophthalmitis, in an SE implant eye).

Ocular TEAEs in the study eyes were mild or moderate in severity, with only 1.8%, 1.6%, and 0.5% of FE implant (7/385), SE implant (6/378), and sham/timolol (2/386) study eyes, respectively, having severe TEAEs.

Treatment-related TEAEs were reported in 19.2% and 18.5% of FE implant (74/385) and SE implant (70/378) study eyes, and in 2.3% of sham/timolol (9/386) study eyes. The most common treatment-related TEAEs (reported at an incidence of > 2% in any treatment group) included intraocular pressure increased, iritis, and conjunctival/ocular hyperemia.

As shown in Table 6, treatment-related TEAEs of intraocular pressure increased were reported in 5.2% of FE implant eyes (20/385), 2.9% of SE implant eyes (11/378), and 0.3% of sham/timolol eyes (1/386); however, the vast majority of these events were mild or moderate, and transient in nature. In six of the FE implant eyes (1.6%) and in five of the SE implant eyes (1.3%) with a TEAE of increased IOP, the event was observed 1 or 2 days post-operatively and rapidly resolved. In the remaining 14 FE implant (3.6%) and 6 SE implant eyes (1.3%), reports of increased IOP occurred mostly after month 6 and were treated with the addition of topical IOP-lowering medication.

Table 6 Treatment-related study eye TEAEs in > 2% of subjects in any treatment group (safety analysis set)

Treatment-related TEAEs of iritis were reported in 2.1% of FE implant eyes (8/385), 4.8% of SE implant eyes (18/378), and no sham/timolol eyes. Most of these events were mild or moderate, and transient in nature.

Treatment-related TEAEs of conjunctival or ocular hyperemia were reported in 3.9% of FE implant eyes (15/385), 1.9% of SE implant eyes (7/378), and 0.3% of sham/timolol eyes 1/386), with only one study eye (an SE implant eye) having severe conjunctival hyperemia that was transient in nature and coincided with an occurrence of moderate iritis.

Notably, there were no serious corneal TEAEs, no TEAEs related to corneal endothelial cell loss, and no reports of iris hyperpigmentation or periorbital fat atrophy. An adverse event of device dislocation was reported in < 2% of eyes that received an FE or SE implant.

3.4.2 Non-Ocular or Non-Study Eye TEAEs

Non-ocular or non-study eye TEAEs were reported in similar proportions of subjects in the three treatment groups (Table 5). Similarly, serious non-ocular or non-study eye TEAEs were reported in similar proportions of subjects in the three treatment groups, as were severe non-ocular or non-study eye TEAEs. Deaths were reported in 0.8%, 0.3%, and 1.6% of subjects in the FE implant (3/385), SE implant (1/378), and sham/timolol (6/386) groups, respectively. None of the deaths were related to study treatment. Study discontinuation due to non-ocular or non-study eye TEAE was reported in 0.5% of FE implant subjects (2/385) and 0.8% of sham/timolol subjects (3/386). Few subjects had non-ocular or non-study eye TEAEs that were considered related to study treatment; 0.3% and 0.5% of subjects in the FE implant (1/385) and SE implant (2/378) groups, respectively.

3.4.3 Visual Acuity

At baseline, mean (SD) BCVA was 83.0 (6.0), 83.4 (5.4), and 82.4 (5.9) ETDRS letters in the study eyes of subjects in the FE implant, SE implant, and sham/timolol groups, respectively. At month 12, mean (SD) BCVA was 82.5 (5.7), 82.9 (6.0), and 83.0 (6.4) in the FE implant eyes, SE implant eyes, and sham/timolol eyes. This less than one ETDRS letter mean difference between all three treatment groups at month 12 was not clinically meaningful.

Investigators were provided guidance to report a TEAE for any clinically relevant loss of 10 or more ETDRS letters relative to baseline. Less than 2% of subjects in any treatment group had a treatment-related TEAE of reduced visual acuity.

3.4.4 Conjunctival Hyperemia

At baseline, the mean (SD) conjunctival hyperemia score (on a scale of 0 to 3) was 0.26 (0.34), 0.25 (0.36), and 0.27 (0.36) in the FE implant, SE implant, and sham/timolol groups. Post-operatively, hyperemia increased in the implant groups, peaking at day 10 with a mean (SD) of 0.45 (0.56) in the FE implant and 0.44 (0.48) in the SE implant group before decreasing to 0.31 (0.39) and 0.32 (0.41), respectively, at month 12. These low mean values indicate that the vast majority of study eyes experienced no to mild hyperemia.

3.4.5 Endothelial Cell Density

Evaluation of central corneal endothelial cell density via specular microscopy was performed on a subset of subjects (55/385 FE implant subjects [14.3%]; 45/378 SE implant subjects [11.9%]; 53/386 sham/timolol subjects [13.7%]). At baseline, mean (SD) values were 2367.6 (423.34), 2453.4 (406.13), and 2437.1 (358.35) cells/mm2 in the study eyes of subjects in the FE implant, SE implant, and sham/timolol groups, respectively. At month 12, mean (SD) endothelial cell density values were 2308.9 (464.92), 2382.5 (428.92), and 2436.6 (368.49) cells/mm2. There were no TEAEs of corneal endothelial cell loss in any group based on a pre-defined threshold of a confirmed ≥ 30% reduction from baseline.

3.4.6 Visual Fields

At baseline, evaluation of visual fields by automated perimetry indicated that the mean (SD) mean deviation (MD) score in study eyes was −2.14 (2.88), −1.93 (2.86), and −2.26 (3.05) dB in the FE implant, SE implant, and sham/timolol groups, respectively. At month 12, the mean change from baseline in MD was −0.23 (2.86), −0.33 (2.73), and −0.24 (3.00) dB in the FE implant, SE implant, and sham/timolol groups, respectively. There was no clinically meaningful difference in visual field MD between the FE implant and sham/timolol groups or between the SE implant and sham/timolol groups.

3.4.7 Central Corneal Thickness

At baseline, mean (SD) central corneal thickness as measured by ultrasonic pachymetry was 554.9 (35.9), 554.5 (35.4), and 554.5 (34.8) µm in the study eyes of the FE implant, SE implant, and sham/timolol groups. At month 12, the change from baseline was −5.5 (18.2), −4.3 (15.7), and +0.7 (13.4) µm in the FE implant, SE implant, and sham/timolol groups, respectively, with differences in change from baseline considered to be not clinically relevant.

3.4.8 Lens Status

At baseline, 12.1%, 10.1%, and 12.6% of subjects in the FE implant, SE implant, and sham/timolol groups had Grade 2 or greater nuclear lens opacities (on a scale ranging from < 1 to > 3). At month 12, this percentage had increased in all treatment groups with the highest level observed in the sham/timolol group (15.6%, 12.8%, and 16.1% of subjects in the FE implant, SE implant, and sham/timolol groups, respectively). Treatment-related TEAEs of cataract were reported in < 2% of phakic eyes that received an FE or SE implant.