Clinical trial NCT05405868: Nicotinamide in Glaucoma (NAMinG): A Randomised, Placebo-controlled, Multi-centre, Phase III Trial
Official title: A Phase III, Double-masked, Randomised, Placebo-controlled Trial Investigating the Safety and Efficacy of Nicotinamide (NAM) to Slow Visual Field Loss in Adults With Open-angle Glaucoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Glaucoma, Open-Angle
Keywords: Nicotinamide
Vitamin B3
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research, United Kingdom
First posted: 2022-06-06
Enrollment: 496
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible participants will be randomised 1:1 to receive oral Nicotinamide 3g/day or matching Placebo
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Open Angle Glaucoma (OAG) is a chronic optic neuropathy causing progressive vision loss. It is well established that IOP is the only currently modifiable risk factor for glaucoma progression, and it is widely accepted that other risk factors modulate the susceptibility of an eye to IOP. This has led to a considerable body of research into neurodegenerative mechanisms and potential neuroprotective approaches. Various pathways contributing to the neurodegeneration have been implicated, and many have focussed on the role of mitochondria. Neuroprotection would significantly reduce sight loss and the burden of IOP-lowering eye drop treatment needed for disease control. There is evidence that susceptibility to IOP is related to mitochondrial function and ageing is associated with mitochondrial functional decline. The knowledge gap addressed in this trial is the relative contribution that mitochondrial function makes to glaucomatous neurodegeneration and whether boosting mitochondrial function with NAM slows progression in humans in the same way that it does in animal models. Biomarkers for mitochondrial-related susceptibility have not yet been established in humans. The proposal therefore is a new mechanism neuroprotection to improve resistance to eye pressure and evaluate the long-term safety and efficacy of NAM to preserve vision and its mechanism of action. There is strong evidence that mitochondrial dysfunction is associated with OAG susceptibility and that NAM improves mitochondrial function. Research has shown short-term vision improvement with high-dose NAM in glaucoma patients. NAM is safe and well-tolerated.

Eligibility criteria: Inclusion Criteria:

1. 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)
2. Open angle on gonioscopy
3. Adults aged 18 years or over
4. Snellen visual acuity 6/12 or better in at least one eye meeting the visual field (VF) criteria
5. Visual Field (VF) mean deviation (MD) no worse than -12dB in either eye
6. A negative pregnancy test result at the screening and baseline visit prior to randomisation for women of childbearing potential
7. Ability to provide informed consent to participate
8. Able and willing to attend trial visits and comply with trial procedures for the duration of the trial

Exclusion Criteria:

1. Pigment dispersion glaucoma
2. Pregnancy (or planned pregnancy during the trial) and/or breastfeeding
3. 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.
4. Current treatment with either isoniazid, pyrazinamide, carbamazepine, phenobarbital or primidone
5. Current liver disease or laboratory results with elevated levels of liver transaminases (AST or ALT \>3 x ULN) at screening visit.
6. Renal failure (eGFR \<30mL/min/1.73m²) at screening visit.
7. Conditions affecting both eyes which may affect the Visual Field test result:

   1. Diabetic retinopathy or any other retinal disease causing VF loss
   2. Clinically relevant cataract (likely to require cataract surgery within the next 2 years)
   3. Dementia or other non-glaucomatous neurological disease causing VF loss
   4. Adnexal conditions causing VF loss (including but not limited to blepharochalasis)
8. Diagnosed with cancer in the last 5 years (with exception of non-melanoma skin cancer).
9. Any clinical condition that, in the investigator's opinion would make the participant unsuitable for the trial.
10. Concurrently enrolled in any other interventional trial or participation in previous clinical trial of glaucoma.
11. Current use of, and unwilling to abstain from, over-the-counter additional vitamin B3/NAM oral supplements (including skin preparations such as ointments/emulsions), Ginkgo Biloba and/or Coenzyme Q10 supplements, throughout the duration of their participation in the trial.

Primary outcomes:
measure: 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
timeFrame: Month 27; end of trial treatment
Secondary outcomes:
measure: 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
timeFrame: From Baseline until Month 3
measure: 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.
timeFrame: At Baseline, Month 3 and Month 27
measure: 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.
timeFrame: At Baseline, Month 3 and Month 27
measure: The safety profile of high dose NAM, measured by liver function tests (LFTs) at Screening, Month 3 and Month 18
timeFrame: At Screening, Month 3 and Month 18
measure: The safety profile of high dose NAM, measured from blood glucose test, HbA1c at Screening, Month 3 and Month 18
timeFrame: At Screening, Month 3 and Month 18
measure: The safety profile of high dose NAM, measured by estimated glomerular filtration rate (eGFR) at Screening, Month 3 and Month 18
timeFrame: At Screening, Month 3 and Month 18
measure: The number of adverse events as assessed by CTCAE v5.0 from baseline to month 27
timeFrame: From Baseline until end of trial treatment and trial completion at Month 27
Other outcomes:
measure: 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.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: The impact of NAM treatment on mitochondrial function in the placebo group between baseline and month 27, measured using the Seahorse mitochondrial function test.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: 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.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: 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.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: Test the hypothesis that lower mitochondrial function, measured using the Seahorse mitochondrial function test, is associated with lower nicotinamide (NAM) levels collected from vitamin B3 blood samples in the placebo group at baseline
timeFrame: Baseline only
measure: Test the hypothesis that lower mitochondrial function, measured using the Seahorse mitochondrial function test, is associated with lower nicotinamide (NAM) levels collected from vitamin B3 blood samples in the active treatment group at baseline
timeFrame: Baseline only
measure: Test hypothesis that lower mitochondrial function, measured by the Seahorse mitochondrial function test, is associated with lower nicotinamide adenine dinucleotide levels collected from peripheral blood mononuclear cells in the placebo group at baseline
timeFrame: Baseline only
measure: Test hypothesis that lower mitochondrial function, measured by the Seahorse mitochondrial function test, is associated with lower nicotinamide adenine dinucleotide levels collected from PBMC blood samples in the active treatment group at baseline
timeFrame: Baseline only
measure: Test the hypothesis that lower mitochondrial function, measured using the Seahorse mitochondrial function test, is associated with higher oxidised glutathione levels collected from peripheral blood mononuclear cells in the placebo group at baseline
timeFrame: Baseline only
measure: Test hypothesis that lower mitochondrial function, measured using the Seahorse mitochondrial function test, is associated with higher oxidised glutathione levels collected from PBMC blood samples in the active treatment group at baseline
timeFrame: Baseline only
measure: The connection between nicotinamide (NAM) levels, measured from vitamin B3 blood samples, and the EPIC Food Frequency Questionnaire responses in the placebo group at baseline
timeFrame: Baseline only
measure: The connection between nicotinamide (NAM) levels, measured from vitamin B3 blood samples, and the EPIC Food Frequency Questionnaire responses in the active treatment group at baseline
timeFrame: Baseline only
measure: The connection between NAD levels, measured from peripheral blood mononuclear cells, and the EPIC Food Frequency Questionnaire responses in the placebo group at baseline
timeFrame: Baseline only
measure: The connection between NAD levels, measured from peripheral blood mononuclear cells, and the EPIC Food Frequency Questionnaire responses in the active treatment group at baseline
timeFrame: Baseline only
measure: The connection between oxygen consumption rate (OCR) levels, measured from peripheral blood mononuclear cells, and the EPIC Food Frequency Questionnaire responses in the placebo group at baseline
timeFrame: Baseline only
measure: The connection between oxygen consumption rate (OCR) levels, measured from peripheral blood mononuclear cells, and the EPIC Food Frequency Questionnaire responses in the active treatment group at baseline
timeFrame: Baseline only
measure: The effect of NAM on the rate of visual field loss between Month 3 and Month 27,measured by the Humphrey Visual Field Analyser test
timeFrame: From Month 3 until end of trial treatment at Month 27
measure: The effect of NAM on the level of mitochondrial function in participants with low vs high baseline mitochondrial function and low vs high baseline NAM levels between month 3 and month 27, measured from Vitamin B3 blood samples .
timeFrame: From Baseline until end of trial treatment at Month 27
measure: The association between lymphocyte mitochondrial function, measured by the Seahorse mitochondrial function test, and quality of life measures, as measured by the EQ-5D-5L and GQL-15 questionnaires, in the placebo group between baseline and month 27.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: The association between lymphocyte mitochondrial function, measured by the Seahorse mitochondrial function test, and quality of life measures, measured by the EQ-5D-5L and GQL-15, in the active treatment group between baseline and month 27.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: The association between baseline NAM levels and rate of visual field loss in the placebo group between baseline and month 27, as measured by the Humphrey Visual Field Analyser test and Vitamin B3 blood samples.
timeFrame: From Baseline until end of trial treatment at Month 27
measure: The association between NAM dosing and IOP in the active and placebo groups between baseline and month 27, measured by applanation tonometers .
timeFrame: From Baseline until end of trial treatment Month 27
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
state: Northern Ireland
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust
city: East Grinstead
country: United Kingdom
facility: Queen Victoria Hospital NHS Foundation Trust
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital
city: London
country: United Kingdom
facility: Moorfields Eye Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Barnet Hospital, Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester Royal Eye Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
Study officials:
affiliation: UCL
name: David Garway-Heath
role: PRINCIPAL_INVESTIGATOR
References: