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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 496
- 试验地点
- 10
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
double-masked
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Visual Field (VF) mean deviation (MD) no worse than -12dB in either eye
- •A negative pregnancy test result at the screening and baseline visit prior to randomisation for women of childbearing potential
- •Ability to provide informed consent to participate
- •Able and willing to attend trial visits and comply with trial procedures for the duration of the trial
排除标准
- •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
- •Current liver disease or laboratory results with elevated levels of liver transaminases (AST or ALT >3 x ULN) at screening visit.
- •Renal failure (eGFR <30mL/min/1.73m²) at screening visit.
- •Conditions affecting both eyes which may affect the Visual Field test result:
- •Diabetic retinopathy or any other retinal disease causing VF loss
- •Clinically relevant cataract (likely to require cataract surgery within the next 2 years)
- •Dementia or other non-glaucomatous neurological disease causing VF loss
- •Adnexal conditions causing VF loss (including but not limited to blepharochalasis)
- •Diagnosed with cancer in the last 5 years (with exception of non-melanoma skin cancer).
- •Any clinical condition that, in the investigator's opinion would make the participant unsuitable for the trial.
- •Concurrently enrolled in any other interventional trial or participation in previous clinical trial of glaucoma.
- •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.
研究组 & 干预措施
Nicotinamide
Participants will receive Nicotinamide for up to 27 months (treatment period) in addition to an initial treatment of Standard of Care IOP- lowering therapy (prior to randomisation and start of trial treatment) . They will receive 1.5g/day for the first 6 weeks, then dose increase to 3.0g/day for remainder of the treatment period.
干预措施: Nicotinomide (Drug)
Matching Placebo
Participants will receive matching placebo for up to 27 months (treatment period) in addition to an initial treatment of Standard of Care IOP- lowering therapy (prior to randomisation and start of trial treatment) . They will receive 1.5g/day for the first 6 weeks, then dose increase to 3.0g/day for remainder of the treatment period.
干预措施: Matching placebo (Drug)
结局指标
主要结局
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
时间窗: Month 27; end of trial treatment
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.
次要结局
- The safety profile of high dose NAM, measured by estimated glomerular filtration rate (eGFR) at Screening, Month 3 and Month 18(At Screening, Month 3 and Month 18)
- The number of adverse events as assessed by CTCAE v5.0 from baseline to month 27(From Baseline until end of trial treatment and trial completion at Month 27)
- 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(From Baseline until Month 3)
- 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.(At Baseline, Month 3 and Month 27)
- 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.(At Baseline, Month 3 and Month 27)
- The safety profile of high dose NAM, measured by liver function tests (LFTs) at Screening, Month 3 and Month 18(At Screening, Month 3 and Month 18)
- The safety profile of high dose NAM, measured from blood glucose test, HbA1c at Screening, Month 3 and Month 18(At Screening, Month 3 and Month 18)