Title: Nicotinamide in Glaucoma (NAMinG): a randomised, placebo-controlled, multicentre, Phase III trial
Funder: Medical Research Council

Abstract: What is glaucoma?_x000D_ Glaucoma is a long-term eye disease which can cause permanent loss of sight and sometimes blindness. It is the world’s most common cause of irreversible blindness and affects 1 in 50 people over 50 years of age, rising to 1 in 20 in people over 80. Vision loss happens because of damage to the important nerve at the back of the eye called the optic nerve. Most people receiving modern glaucoma treatment do not experience noticeable vision loss. However, a significant minority do lose vision, even when they are getting our best current treatments. Nearly a quarter become blind in one or both eyes in later life. We cannot cure glaucoma, but we can treat it so that the damage is slowed down or stopped, so more vision is kept for longer._x000D_ _x000D_ What causes glaucoma?_x000D_ There are 2 big risk factors - being an older person and having high pressure inside the eye. High pressure damages the optic nerve and being older makes this damage more likely. People with glaucoma are offered treatment to lower the eye pressure - usually eye drops or laser. This slows down the progress of glaucoma._x000D_ There is still a lot we do not know. Most importantly, some people get worse even if they are treated. And some people get glaucoma even if they have normal eye pressure. So we think that the optic nerve in some people is more easily damaged. At the moment, we cannot tell who these people are._x000D_ Recent research has looked at parts of cells called ‘mitochondria’. These produce energy and might affect how likely it is that vison could be damaged by eye pressure. The nerve cells in the eye need a great deal of energy to function and survive. Older age is associated with mitochondria not working so well and less energy being produced._x000D_ _x000D_ What new treatment are we testing?_x000D_ Vitamin B3, also known as nicotinamide (NAM), may improve the way mitochondria work. In a small study, high doses were given to people with glaucoma and the vision of a quarter of them improved. There were no major side-effects. In a study of mice with high eye pressure, treatment with NAM prevented glaucoma._x000D_ We propose a clinical trial to answer the question:_x000D_ “Does NAM treatment protect against people losing sight because of glaucoma getting worse?” _x000D_ There will be two groups of people recently diagnosed with glaucoma. They will have normal care (drops or laser) to lower eye pressure. One group will be given NAM and the other group will be given a placebo or ‘sugar pill’. The trial will be ‘Randomised’ meaning the type of tablet each person gets happens by chance alone._x000D_ We also want to establish how NAM works and to answer the following questions:_x000D_ • “Can we predict, from looking at mitochondrial, which people with glaucoma will get worse more quickly?”_x000D_ • “Does NAM help mitochondria work better?”_x000D_ • “For people with glaucoma and whose mitochondria work poorly – do they benefit most from NAM?”_x000D_ We will carefully monitor vision during the study. There will be more visits than for ‘normal care’ (about 2 extra over 27 months), and a few more tests during the visits. There will also be blood tests to measure how well the mitochondria are working._x000D_ _x000D_ What difference could the new treatment make?_x000D_ A successful outcome would lead to greatly reduced sight loss due to glaucoma. Treatment with pills may also be easier for patients as it may reduce the need for drops, which many patients find difficult. Additionally, it would significantly reduce the cost to the NHS for glaucoma treatment.

Lay abstract: Research question_x000D_ Does oral nicotinamide (NAM) treatment slow visual field (VF) progression in recently diagnosed open-angle glaucoma (OAG) patients? _x000D_ _x000D_ Background_x000D_ 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._x000D_ _x000D_ Aims and objectives_x000D_ Primary: _x000D_ 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._x000D_ _x000D_ Secondary: _x000D_ i) Assess for NAM-mediated VF improvement at 3 months _x000D_ ii) Evaluate NAM safety _x000D_ iii) Evaluate interactions between NAM and IOP-lowering treatment type on VF progression _x000D_ _x000D_ Mechanistic evaluation _x000D_ i) Evaluate whether there is an association between mitochondrial function and rate of VF loss _x000D_ 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._x000D_ iii) Test hypothesis that lower lymphocyte mitochondrial function correlates with lower plasma NAM levels and lower lymphocyte NAD+; assess as biomarkers for VF progression_x000D_ v) Assess whether NAM lowers IOP_x000D_ _x000D_ Methods_x000D_ Randomised triple-masked placebo-controlled phase III trial. _x000D_ _x000D_ Population: consecutive, recently-diagnosed (within 12 months) patients with early to moderate OAG._x000D_ Intervention: [standard of care +] oral NAM 3.0g/day_x000D_ Comparator: [standard of care +] Placebo_x000D_ Outcome: primary – VF mean deviation change over 27 months_x000D_ _x000D_ Standard of care = IOP-lowering treatment as per NICE Guidelines. _x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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)._x000D_ _x000D_ Timelines for delivery_x000D_ 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._x000D_ _x000D_ Anticipated impact and dissemination _x000D_ 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.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: EYE