A Phase II Clinical Trial on the Effect of a Mitophagy Inducer Urolithin A on Alzheimer's Disease
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Mean between-group differences in plasma p-Tau217
研究概览
简要总结
The overall aim of MITO-AD is to evaluate if the nutritional supplement urolithin A is associated with favourable changes in Alzheimer's disease-related biomarkers, cognitive measures, and safety/tolerability outcomes in symptomatic patients with early-stage, biomarker-defined Alzheimer's disease. To do this, we will use two groups: one will be given standard care plus the food supplement urolithin A (the test group), and the other will be given just standard care plus a placebo (the control group). To measure potential differences between the groups, we will:
- Do clinical and neuropsychological assessments at baseline and follow-up visits, with main biomarker sampling at baseline, week 24, and week 48. (Additional safety, tolerability, compliance, and questionnaire-based assessments will be performed during the study.)
- Test blood samples from these patient groups for differences in various biomarkers to assess biological differences between them, and
- Test cerebrospinal fluid (CSF) from a voluntary sub-cohort who will undergo CSF sampling at baseline and Week 4 to assess urolithin A exposure.
N.B. Both groups will continue standard-of-care symptomatic Alzheimer's disease treatment as prescribed by the treating physician (where applicable). Standard of care may include acetylcholinesterase inhibitors and/or memantine. Participants receiving standard symptomatic Alzheimer's disease treatment must have been on a stable dose for at least 8 weeks prior to screening. Participants receiving anti-amyloid disease-modifying therapy will not be enrolled
详细描述
Alzheimer's disease (AD) is one of the leading causes of dementia and, eventually, death in the elderly. Although AD has been known for generations, its causes have proven to be quite elusive, slowing the development of treatment options and limiting the progression of the disease through its various stages.
Researchers have identified that the inability of the brain to clear amyloid-beta (Aβ) and tau filaments is a core hallmark of progressive disease in the AD brain. One potential cause of this inability to clear the filaments is a lack of available energy, and the main cause is likely the mitochondria's natural reduction in the production of NAD+, the primary energy source for cellular respiration.
Recently, naturally derived chemicals have moved to the forefront of research as the search for causes and cures moves forward. Many naturally derived molecules are showing good promise in the support of the mitochondria, including urolithin A (UA), a natural post-biotic produced by the gut microbiome after consuming pomegranates, nuts, and other berries, which has been shown to support control of symptoms associated with AD in both animal models and human neural cells.
This Phase II clinical trial seeks to evaluate the efficacy of UA in reducing levels of core AD biomarkers (including p-Tau217), biomarkers of non-specific processes involved in AD pathophysiology (such as neuroinflammation and oxidative stress), and biomarkers of autophagy/mitophagy function, and in slowing cognitive decline in patients with AD. This strategy lays the groundwork for the development of a novel dietary intervention strategy targeting mitochondria through nutritional supplementation.
For this study, Mitopure®/urolithin A and its matching placebo have been supplied by Amazentis/Timeline.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All participants, caregivers, clinical investigators, care providers, and outcome assessors will remain blinded to treatment allocation. Emergency unblinding will be available through an independent unblinded safety/randomisation contact if required for participant safety.
入排标准
- 年龄范围
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must be between 55 and 85 years of age at the time of inclusion.
- •Participants must meet the National Institute on Aging-Alzheimer's Association (NIA-AA) diagnostic criteria for Alzheimer's disease (AD)
- •Participants must have evidence of AD pathology, confirmed by either a positive amyloid PET imaging result or cerebrospinal fluid (CSF) biomarkers reflecting amyloid pathology (e.g., decreased Aβ42 levels or decreased Aβ42/40 ratio, and increased levels of p-Tau181, and total Tau)
- •Participants must have a Mini-Mental State Examination (MMSE) score of ≥
- •Participants must have been on stable doses of FDA-approved AD medications (e.g., cholinesterase inhibitors) for at least 8 weeks prior to screening
- •Participants must possess adequate visual and auditory acuity to complete testing
- •Participants must speak fluent Czech.
- •Participants must have a reliable study partner.
- •Participants must have the ability to provide written consent to participate.
- •Participants must be capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
排除标准
- •Participants will be excluded if they do not have clinically diagnosed AD.
- •Participants will be excluded if they have significant neurological conditions other than AD (e.g., Parkinson's disease, frontotemporal dementia, or vascular dementia), a history of head trauma with persistent neurological deficits, or baseline neuroimaging indicating cortical stroke or severe ischemic disease
- •Participants will be excluded if they have suffered from psychiatric conditions such as major depressive disorder (within the past year), bipolar disorder, or schizophrenia will be excluded
- •Participants will be excluded if they have had recent substance use disorder (past 2 years)
- •Participants will be excluded if they have unstable systemic illnesses including hepatic or renal failure
- •Participants will be excluded if they have decompensated diabetes
- •Participants will be excluded if they are taking medications with anticholinergic effects
- •Participants will be excluded if they are taking dietary supplements containing nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR)
- •Participants will be excluded if they have significant spinal disease complicating lumbar puncture or with anticoagulant therapy (only for the CSF group)
- •Participants will be excluded if they have participated in another investigational trial within the past 3 months or have medical conditions that could jeopardise their safety or affect study results, as judged by the investigator
研究组 & 干预措施
1000 mg Mitopure®
干预措施: Urolithin A (Dietary Supplement)
Placebo
干预措施: Placebo Control (Dietary Supplement)
结局指标
主要结局
Mean between-group differences in plasma p-Tau217
时间窗: Baseline and Week 48.
Mean overall between-group differences in plasma p-Tau217 (as the core blood-based biomarker of AD) from baseline to week 48.
次要结局
- Mean difference from baseline in GFAP in patients receiving Urolithin A versus placebo(Baseline, and then at Week 24 and Week 48.)
- Mean difference in mitophagy/autophagy biomarkers in patients receiving urolithin A versus placebo(Baseline, and then week 24 and week 48.)
- Change from baseline in blood lipofuscin-like pigment relative fluorescence intensity(Baseline, and then at week 24 and week 48.)
- Change from baseline in cellular reactive oxygen species fluorescence intensity in erythrocytes and plasma.(Baseline, and then week 24 and week 48.)
- Change from baseline in mitochondrial reactive oxygen species fluorescence intensity in PBMCs(Baseline, and then Week 24 and Week 48.)
- Multi-omic profiling for systemic variation from baseline in cytokines and markers of inflammation between those receiving UA versus placebo.(Baseline, and then at Week 24 and Week 48.)
- Change from baseline in the modified Preclinical Alzheimer's Cognitive Composite (mPACC) score(Baseline, and then at Week 24 and Week 48.)
- Number of participants with adverse events and serious adverse events(From baseline through Week 48, including scheduled safety/tolerability assessments at Weeks 12, 24, 36, and 48.)
- Study supplement adherence(Throughout the study (mobile app), and at participant control visits at Weeks 12, 24, 36, and 48.)
- To identify UA exposure in cerebrospinal fluid (CSF)(Baseline and week 4.)
研究者
Evandro Fei Fang-Stavem
Principal Investigator
University Hospital, Akershus