Nicotinamide in Glaucoma (NAMinG): a randomised, placebo-controlled, multicentre, Phase III trial

Research question Does oral nicotinamide (NAM) treatment slow visual field (VF) progression in recently diagnosed open-angle glaucoma (OAG) patients? Background OAG is a chronic optic neuropathy causing progressive vision loss; many patients lose vision despite treatment. Current treatments lower eye pressure; we propose a new mechanism – neuroprotection to improve resistance to eye pressure. There is strong evidence that mitochondrial dysfunction is associated with OAG susceptibility and that NAM improves mitochondrial function. A recent study showed short-term vision improvement with high-dose NAM in glaucoma patients. NAM is safe and well-tolerated; nausea, reversible hepatic toxicity and hyperglycaemia have been reported with doses higher than >3g/day. We propose a placebo-controlled randomised multicentre Phase III trial of NAM in OAG to evaluate its long-term safety and efficacy to preserve vision and its mechanism of action. Aims and objectives Primary: Test the hypothesis: treatment with NAM, compared to placebo, reduces the amount of VF loss (VF mean deviation) by 0.158 dB on average over 27 months in patients on IOP-lowering treatment. Secondary: i) Assess for NAM-mediated VF improvement at 3 months ii) Evaluate NAM safety iii) Evaluate interactions between NAM and IOP-lowering treatment type on VF progression Mechanistic evaluation i) Evaluate whether there is an association between mitochondrial function and rate of VF loss ii) Assess whether any effect of NAM on a) rate of VF loss and b) mitochondrial function is greater when a) baseline mitochondrial function is poor and b) when baseline vitamin B3 levels are low. iii) Test hypothesis that lower lymphocyte mitochondrial function correlates with lower plasma NAM levels and lower lymphocyte NAD+; assess as biomarkers for VF progression v) Assess whether NAM lowers IOP Methods Randomised triple-masked placebo-controlled phase III trial. Population: consecutive, recently-diagnosed (within 12 months) patients with early to moderate OAG. Intervention: [standard of care +] oral NAM 3.0g/day Comparator: [standard of care +] Placebo Outcome: primary – VF mean deviation change over 27 months Standard of care = IOP-lowering treatment as per NICE Guidelines. Sample size: For 90% power and two-tailed significance at 5%, we need 210 participants in each arm to detect a difference in change in mean deviation from baseline to 27 months of 0.158 dB, assuming a standard deviation of 0.5 dB; increased to 496 allowing for 15% attrition. Key eligibility criteria: i) OAG in at least one eye ii) age over 18 years, iii) visual acuity 6/12 or better, iv) VF mean deviation better than -12dB, both eyes. Recruitment: 7 UK NHS sites: approx. 160 participants at Moorfields Eye Hospital (MEH) sites (2.3 per week) and 72 at Kings and Norwich over 18 months (1.0 per week) and 56 over 12 months at 4 other sites (1.0 per week). Timelines for delivery 9 months set-up, 6-month internal pilot (MEH, Kings, Norwich), 12-month recruitment, 3-month assessment for VF improvement, 24-month follow-up, 6 months analysis and write-up = total 60 months. Anticipated impact and dissemination A safe, effective, low-cost treatment would reduce the incidence of glaucoma blindness. Results will be presented at national and international conferences and published in peer-reviewed journals, public websites, participant newsletters and the Glaucoma UK newsletter.