Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PurposeTo evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression.DesignTwo randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study).ParticipantsPatients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria).MethodsPatients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed.Main outcome measuresThe predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs).ResultsThe proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea.ConclusionsWith technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population