Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Abstract

Objective: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).

Methods: This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD).

Results: Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2-7.4, 6.5-7.8, and 6.1-6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group.

Conclusions: The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. CLINICALTRIALS.

Gov identifier: NCT02250651.

Fig. 1

Patient flow through the study. Adm administration, BID twice daily, Bim bimatoprost, pts patients

Fig. 2

Gonioscopic photographs of the study eye iridocorneal angle in a representative patient in the 10 μg bimatoprost implant treatment group. Photographs were taken at week 2, week 52, and month 20. Implants #1, #2, and #3 were administered at day 1, week 16, and week 32, respectively

Fig. 3

Primary endpoint of mean IOP through week 12. a LS mean IOP in study eyes at hours 0 and 2 at weeks 2, 6, and 12. b The 95% CIs of the between-group differences show that both the 10 and 15 µg bimatoprost implants met the prespecified criteria for statistical and clinical noninferiority to timolol BID. BID twice daily, Bim bimatoprost, CI confidence interval, IOP intraocular pressure, LS least-squares

Fig. 4

Primary endpoint of mean change in IOP from baseline through week 12. a LS mean change in IOP from baseline in study eyes at hours 0 and 2 at weeks 2, 6, and 12. b The 95% CIs of the between-group differences show that both the 10 and 15 µg bimatoprost implants met the prespecified criteria for statistical and clinical noninferiority to timolol BID. BID twice daily, Bim bimatoprost, CI confidence interval, IOP intraocular pressure, LS least-squares

Fig. 5

Kaplan-Meier survival analysis of time to initial use of additional IOP-lowering treatment in the study eye a after the last bimatoprost implant or sham administration and b after the third administration in patients who received three administrations. BID twice daily, IOP intraocular pressure

Fig. 6

Mean CECD in study eyes in the 10 µg bimatoprost implant and timolol treatment groups. The timing of implant or sham administration is shown with arrows. Statistical comparisons are reported in Table 4. BID twice daily, Bim bimatoprost, BL baseline, CECD corneal endothelial cell density, M month, SEM standard error of the mean, W week

Fig. 7

Mean change in the visual field MD from baseline by Humphrey perimetry in study eyes. Test results from eyes that had received rescue IOP-lowering treatment were excluded from the analysis. The number of eyes included in the analysis of change in MD from baseline at visits from week 28 to month 20 ranged from 101 to 143 in the 10 µg bimatoprost implant group, 102 to 143 in the 15 µg bimatoprost implant group, and 123 to 144 in the timolol BID group. *P ≤ 0.037 vs. timolol based on a mixed-effect model for repeated measures including treatment, visit, treatment-by-visit interaction, baseline MD, and visit-by-baseline interaction. BID twice daily, BL baseline, IOP intraocular pressure, MD mean deviation, SEM standard error of the mean