Glaucoma is the leading cause of sight impairment and blindness worldwide. It is a long-term eye disease which can cause permanent loss of sight and sometimes blindness and affects 1 in 50 people over 50 years of age. Open-angle glaucoma (OAG) is the most common type of glaucoma. This tends to develop slowly over many years, caused by the drainage pathway in the eye gradually becoming blocked over time due to a build-up of fluid. This build-up causes pressure in the eye to increase (intra-ocular pressure (IOP)), which then damages the important nerve at the back of the eye called the optic nerve, resulting in vision loss. Current treatments offered for glaucoma (eye drops or laser surgery), aim to lower eye pressure and have shown to slow vision loss, however, visual disability and blindness rates remain unacceptably high and many patients continue to lose vision despite these treatments, suggesting that the optic nerve in some patients is more easily damaged. Recent research has looked at cells called 'mitochondria'. These cells produce most of the energy in the body, and the nerve cells in the eye need a lot of energy to function and survive. Nicotinamide (NAM) is a form of Vitamin B3 and evidence so far has shown that mitochondrial function can be improved with this treatment. The aim of this trial is to find out whether taking oral NAM when used with current standard treatment for lowering pressure in the eye, can reduce the amount of sight loss in recently diagnosed patients with OAG, and evaluate the long-term safety and effectiveness of NAM. The trial will use two groups of people recently diagnosed with glaucoma and who have normal care (drops or laser) to lower eye pressure. Using a method of randomisation (randomly allocated to each group using a computer system), one group will be given NAM and the other group will be given a placebo or 'dummy pill'. This is a double masked trial meaning the participant nor the Investigator will be told which treatment group patients have been allocated to.
Patients who have been recently diagnosed (within the last 12 months) with early to moderate open-angle glaucoma (OAG) in at least one eye (including primary OAG, normal tension glaucoma (NTG) and pseudoexfoliation glaucoma)
Open angle on gonioscopy
Adults aged 18 years or over
Snellen visual acuity 6/12 or better in at least one eye meeting the visual field (VF) criteria
Pigment dispersion glaucoma
Pregnancy (or planned pregnancy during the trial) and/or breastfeeding
Women of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraception for the duration of the trial treatment and for the time period specified following last trial treatment administration.
Current treatment with either isoniazid, pyrazinamide, carbamazepine, phenobarbital or primidone
Parallel
Nicotinomide
DrugNicotinamide tablets (750mg)
Matching placebo
DrugMatching placebo
The difference between the treatment arms in change of Visual Field (VF) mean deviation (MD) at 27 months measured by the Humphrey Visual Field Analyser test
The Humphrey Visual Field Analyser test is a diagnostic tool commonly used to assess the retina's ability to detect a light stimulus at specific points within the visual field, called retinal sensitivity. Participants will undergo visual field testing at Screening, Baseline, Months 3, 6,12,18, 24 and Month 27 using the Humphrey Visual Field analyser with the SITA Standard 24-2 programme. The results will be used to measure the progression of vision loss between the active arm (Nicotinamide) and the comparator (matching placebo) The primary endpoint will be analysed using a linear mixed model to estimate the difference between treatment groups in VF MD at 27 months. The model will include month 27 VF MD as the outcome and baseline VF MD, IOP-lowering treatment type (eye drops vs laser) and baseline serum NAM levels as covariates.
The difference in Visual Field (VF) mean deviation (MD) at 3 months (0-3 months - neuro-recovery) between the active treatment group and the placebo group, measured using the Humphrey Visual Field analyser test with the SITA Standard 24-2 programme
The Humphrey Visual Field Analyser test is a diagnostic tool commonly used to assess the retina's ability to detect a light stimulus at specific points within the visual field, called retinal sensitivity. Participants will undergo visual field testing using the Humphrey Visual Field analyser with the SITA Standard 24-2 programme. The results will be used to measure the progression of vision loss between the active arm (Nicotinamide) and the comparator (matching placebo) over the initial 0-3 months
Quality-of-Life outcome differences between the two treatment groups at baseline, month 3 and month 27, as measured by the descriptive system for health-related quality of life, EQ-5D-5L with additional vision specific questions.
The EQ-5D-5L (with vision bolt-on) is a participant self-reported questionnaire which evaluates the generic quality of life at the time of completion. It comprises of one question for each of the five dimensions; no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. A Visual Analogue Scale is also used and is a scale measured from 0 -100 scale where patients are asked to indicate their overall health on the day of questionnaire completion. This version of the questionnaire will also include additional vision related questions as part of the 5 dimensions, known as vision bolt on questions.
Quality-of-Life outcome differences between the two treatment groups at baseline, month 3 and month 27, as measured by the 15-item Glaucoma Quality of Life Questionnaire.
The Glaucoma Quality of Life Questionnaire (GQL-15) is a 15-item which measures the severity of visual disability and comprises of 15 vision-related items. The item-level responses for each factor are coded on a five-point scale (1 meaning no difficulty and 5 meaning severe difficulty), while 0 is marked if the participant does not perform the activity as a result of non-visual cause. These items are grouped into four subscales: 1) "Central and near vision" (two items); 2) "Peripheral vision" (six items); 3) "Dark adaptation and glare" (six items); and 4) "Outdoor mobility" (one item). Total score is derived by summing all item-level response scores.
The safety profile of high dose NAM, measured by liver function tests (LFTs) at Screening, Month 3 and Month 18
The Liver Function test is a standard diagnostic laboratory assay used to diagnose and monitor liver disease or damage. The tests measure the levels of certain enzymes and proteins in the blood.
The impact of NAM treatment on mitochondrial function in the active treatment group between baseline and month 27, measured using the Seahorse mitochondrial function test.
The Seahorse mitochondrial function test measures oxygen during energy production processes that occur in the mitochondria by directly measuring the oxygen consumption rate (OCR) of cells. The measurement will be performed on Peripheral Blood Mononuclear Cell (PBMC) blood samples. NAM, which is a form of Vitamin B3 is crucial for cell metabolism, normal functioning of the central nervous system and the formation of red blood cells.
The impact of NAM treatment on mitochondrial function in the placebo group between baseline and month 27, measured using the Seahorse mitochondrial function test.
The Seahorse mitochondrial function test measures oxygen during energy production processes that occur in the mitochondria by directly measuring the oxygen consumption rate (OCR) of cells. The measurement will be performed on Peripheral Blood Mononuclear Cell (PBMC) blood samples. NAM, which is a form of Vitamin B3 is crucial for cell metabolism, normal functioning of the central nervous system and the formation of red blood cells.
The association between lymphocyte mitochondrial function, measured by the Seahorse mitochondrial function test, and rate of visual field loss in the placebo group between baseline and month 27.
The Seahorse mitochondrial function test measures oxygen during energy production processes that occur in the mitochondria by directly measuring the oxygen consumption rate (OCR) of cells. The measurement will be performed on Peripheral Blood Mononuclear Cell (PBMC) blood samples. Mitochondrial function will be regarded as time-varying covariate and a repeated measures model will be used.
The association between nicotinamide adenine dinucleotide levels, from peripheral blood mononuclear cells, and the rate of visual field loss in the placebo group between baseline and month 27.
Nicotinamide (NAM) is a major precursor of nicotinamide adenine dinucleotide (NAD) in neurones. NAD is an essential cofactor in oxidative phosphorylation and adenosine triphosphate (ATP) production. It plays a central role in mitochondrial function. Peripheral blood mononuclear cell (PBMC) are used to measure immunological functions and will be used to measure NAD. Cells are isolated from blood samples using standardised density gradient technique (Ficoll-Paque). Mitochondrial function will be regarded as time-varying covariate and a repeated measures model will be used.
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University College, London
Lead sponsor
National Institute for Health Research, United Kingdom
Collaborator
