Oral Tonabersat Connexin-43 Modulator for Diabetic Macular Edema with Good Vision (DRCR Protocol AN)

Abstract Objective Evaluate oral tonabersat, a connexin43 hemichannel modulator, on central subfield thickness (CST) in eyes with center-involved DME (CI-DME) and good vision. Design Phase 2 randomized, double-masked clinical trial. Participants 129 adults with CI-DME and visual acuity 20/32 or better, recruited from 24 sites in the US. Intervention Participants randomly assigned 1:1 to 80-mg tonabersat (N=64, [71 eyes]) or placebo (N=65, [73 eyes]) for 6 months. Main Outcome Measures Change in OCT CST. Results Overall, 37% of participants were female; mean age 63 years. In the tonabersat and placebo groups respectively, baseline mean CST was 359μm and 362μm;the mean (SD) change in CST from baseline to 6 months was -15 (55) μm and +5 (51) μm; (adjusted mean difference: -16 [95% CI, -34 to 2], P=0.08). A post-hoc analysis using last observation carried forward prior to any anti-VEGF treatment showed an adjusted mean difference: -21 [95% CI, -38 to -3], P=0.02. Among participants with thinner eyes at baseline (CST <75-μm above the threshold; tonabersat group (n=45) versus the placebo group (n=43)), the adjusted mean difference was -2 μm (95% CI, –26 to 22). For thicker eyes (CST ≥75-μm above the threshold; tonabersat group (n=20) versus the placebo group (n=24)), the mean difference was -51 μm (95% CI, –83 to –19). In the tonabersat and placebo groups respectively, the mean (SD) change in best-corrected VA from baseline to 6 months was 0.0 (5.7) letters and -0.4 (5.7) letters (adjusted mean difference: 0.82 [95% CI, -1.56 to 3.21], adjusted P=0.39). Dizziness was more common with tonabersat than placebo (27% vs 8%), headaches were more common with placebo (17% vs 6%), and drowsiness occurred at similar rates (11% in both groups). Conclusions In the primary analysis, there was no statistically significant improvement in CST at 6 months in the tonabersat versus placebo groups. However, a post-hoc analysis that limited anti-VEGF impact demonstrated statistically significant benefit in the tonabersat group. Aside from increased dizziness with tonabersat, consistent safety concerns were not identified. Given findings consistent with a potentially favorable biologic effect of tonabersat, further research into the role of the NLRP3 inflammasome in DME is warranted.