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For patients with glaucoma, reduction of intraocular pressure (IOP) is the only proven treatment to slow or halt disease progression.1Weinreb R.N. Aung T. Medeiros F.A. The pathophysiology and treatment of glaucoma: a review.JAMA. 2014; 311: 1901-1911Crossref PubMed Scopus (1859) Google Scholar However, nonadherence to daily eye drops is a well-documented problem.2Nordstrom B.L. Friedman D.S. Mozaffari E. et al.Persistence and adherence with topical glaucoma therapy.Am J Ophthalmol. 2005; 140: 598-606Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 3Schwartz G.F. Quigley H.A. Adherence and persistence with glaucoma therapy.Surv Ophthalmol. 2008; 53: S57-S68Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Most clinicians acknowledge that it is difficult to determine which patients are likely to be noncompliant. Several methods are being developed to deliver medication in a sustained-release manner via implantable reservoirs or external applications, such as contact lenses or punctal plugs. We report on long-term safety and retention of a bimatoprost ocular ring (BIM ring) that delivers bimatoprost over a 6-month period. Results from a double-masked, randomized, multicenter, phase II study in which the BIM ring was compared against 0.5% timolol ophthalmic drops twice daily were reported previously4Brandt J.D. Sall K. DuBiner H. et al.Six-month intraocular pressure reduction with a topical bimatoprost ocular insert.Ophthalmology. 2016; 123: 1685-1694Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and includes a description of the BIM ring and clinical evaluations. At the conclusion of the 6-month phase II study, participants were invited to enroll in a 13-month open-label extension (OLE) study in which they would use the BIM ring (13 mg) for a 7-month cycle followed by another 6-month cycle. The primary objective of this OLE was to satisfy the Food and Drug Administration's requirement for at least 1 year of safety and exposure data before application for approval. Secondarily, data on retention, comfort, and efficacy were also collected. Unlike the preceding trial, in which masking necessitated twice-daily eyedrop administration for all subjects, OLE represented a more real-world usage of the BIM ring. There was no requirement for daily eyedrops, but patients could use unpreserved artificial tears as needed. The results presented here include 13 months of exposure over 2 cycles of BIM ring wear; all subjects in the present study also participated in the preceding phase II study, which included 6 months of use of the ocular ring (either BIM or placebo rings). Inclusion criteria for the phase II study were typical of monotherapy IOP-lowering studies designed for regulatory review and are described elsewhere.4Brandt J.D. Sall K. DuBiner H. et al.Six-month intraocular pressure reduction with a topical bimatoprost ocular insert.Ophthalmology. 2016; 123: 1685-1694Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar There were 115 subjects who completed the preceding phase II study. Owing to timing of the approval of the OLE study, some subjects had exited the prior study before OLE began, resulting in 75 subjects enrolling in the OLE, of whom 65 completed the initial 7-month extension and 63 completed the entire 13-month extension. The OLE cohort comprised 32 patients who were in the BIM ring arm and 43 who were in the timolol drops arm. The mean age of OLE subjects was 65.3 years. The majority of the cohort was female (58.7%), and non-Hispanic (85.3%). The racial makeup was white (72%), black (24%), and Asian (4%). The majority had a glaucoma diagnosis (66.7%) and the remainder were ocular hypertensive (33.3%). The overall safety profile was very good (Table 1) and consistent with data from prior phase I and II studies. The adverse events were consistent with bimatoprost exposure with the exception of eye discharge (mucus), which is typically not observed with bimatoprost. The incidence of mucus (21.3%) was numerically higher than was observed in the phase II study (BIM ring, 15.6%; placebo, 13.6%). However, this increase was expected; the follow-up period in OLE was 13 months versus 6 months in the prior study. We examined the timing of the adverse events onset for eye discharge and it seems to occur at a relatively steady rate over time. There was 1 protocol-defined serious ocular adverse event of decreased visual acuity secondary to a cataract.Table 1Ocular Treatment Emergent Adverse Events (>3% Incidence; n = 75)Preferred Term∗MedDRA v 16.0.Mild, n (%)Moderate, n (%)Severe, n (%)Any adverse event40 (53.3)11 (14.7)1 (1.3) Conjunctival hyperemia13 (17.3)2 (2.7)1 (1.3) Eye discharge13 (17.3)2 (2.7)1 (1.3) Punctate keratitis11 (14.7)1 (1.3)0 (0.0) Lacrimation increased9 (12.0)1 (1.3)0 (0.0) Vision blurred5 (6.7)4 (5.3)0 (0.0) Eye pruritus7 (9.3)1 (1.3)0 (0.0) Foreign body sensation in eyes6 (8.0)0 (0.0)0 (0.0) Ocular discomfort6 (8.0)0 (0.0)0 (0.0) Dry eye3 (4.0)2 (2.7)0 (0.0) Eye irritation4 (5.3)1 (1.3)0 (0.0)∗ MedDRA v 16.0. Open table in a new tab The most important attributes of an externally delivered sustained-release system are that the product is retained comfortably and that patients are aware if it becomes dislodged or falls out. We defined primary retention of the ring as maintenance in place after initial placement without requiring physician intervention. The OLE cohort had a primary retention rate of 88.0% during the phase II study. The corresponding retention rates during cycles 1 and 2 of OLE were 97.3% and 94.7%, respectively, suggesting that retention improves as patients gain more experience using the ring. Importantly, there were no cases of dislodgement in which the subjects were unaware that the ring had been lost. Subjects were queried about ring comfort at enrollment and months 1, 3, 6, 7, 10, and 13 and rated comfort on a 5-point scale. At every visit, >97% of subjects reported the rings to be tolerable or comfortable, with >80% in the “comfortable” or “very comfortable” range (Fig S1, available at www.aaojournal.org). Diurnal IOP measurements at 8 am, 10 am, and 4 pm were obtained at months 3, 6, 7, and 13, with a single measurement at 8 am at the remaining visits. The phase II study demonstrated sustained IOP reduction of ≤6 mmHg over the first 6 months.4Brandt J.D. Sall K. DuBiner H. et al.Six-month intraocular pressure reduction with a topical bimatoprost ocular insert.Ophthalmology. 2016; 123: 1685-1694Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar There seemed to be some waning of efficacy over the first 12 weeks of follow-up in study FSV5-002. The reason for this is unknown, but it is well-documented that prostaglandins, when delivered in higher doses or at increased frequency, exhibit decreased efficacy, possibly owing to receptor sensitization.5Brandt J.D. Van Denburgh A.M. Chen K. Whitcup S.M. Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP.Ophthalmology. 2001; 108: 1023-1032Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Reduction in IOP during the 13 months of OLE follow-up (Fig S2, available at www.aaojournal.org) was similar to the last 3 months of the preceding study, with a median IOP reduction of 4 mmHg (interquartile range, 2–6). During the OLE period, there was no difference in efficacy between patients who had been in either arm of the preceding study, although it is possible that a difference may have been present within the first month, but was no longer evident at the time of the first OLE measurement. Rescue treatment with topical bimatoprost drops was used in 13 patients over the 13-month follow-up. This study demonstrates that lowering of IOP for up to 19 months with a sustained-release system applied just 3 times over that follow-up period. The data from the OLE show that the BIM ring is safe and well-tolerated. The rings were maintained in place for 95% of the subjects without physician intervention during the 13-month extension period. The drug safety profile is consistent with bimatoprost exposure from eye drops, although the incidence of bimatoprost-related adverse events may even be lower than with drops, perhaps owing to a smaller quantity of circulating drug compared with a bolus application of an eye drop. Combining the OLE data with the phase II study demonstrates that the BIM ring can achieve clinically relevant reduction in IOP over ≤19 months when applied at 6-month intervals. The BIM ring is a novel system designed to deliver IOP-lowering medication to the surface of the eye in a sustained-release manner. The reduction in IOP, combined with the promising safety, comfort, and retention profile, seem to align well with the needs of the large number of nonadherent patients with ocular hypertension and early glaucoma. Download .pdf (.06 MB) Help with pdf files Figure S1 Download .pdf (.13 MB) Help with pdf files Figure S2