A Double-Blind-Randomized, Placebo-Controlled Adaptive Design Trial of Nicotinamide in Mild Cognitive Impairment Due to Alzheimer's Disease and Mild Alzheimer's Disease Dementia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 2
- 主要终点
- Vital Signs - Systolic Blood Pressure
研究概览
简要总结
The purpose of this research study is to test whether nicotinamide, also known as vitamin B3 or niacinamide, taken in high doses, can reduce phosphorylation of tau (the protein that accumulates in neurofibrillary tangles) in people with Mild Cognitive Impairment or mild Alzheimer's disease (AD) dementia.
详细描述
Nicotinamide, the amide of nicotinic acid (vitamin B3/niacin), is an oral therapy with a wealth of clinical data in a variety of therapeutic areas, including preliminary data supporting its safety in Alzheimer's disease (AD). Preclinical work in a mouse model that develops both plaques and tangles supports the hypothesis that nicotinamide can act as a histone deacetylase (HDAC) inhibitor to reduce phosphorylation of tau.
The study will implement a group sequential design, incorporating a futility analysis with a go/no-go decision conditional on cerebral spinal fluid CSF biomarker outcomes at 12-months. The primary outcome for the trial is change in p-tau231.
This study timeline includes a screening phase of up to 60 days and treatment phase which is expected to last about 48 weeks and will include 4 study visits.
An additional 12-month treatment and follow-up period is planned, contingent upon a "go" decision based on the primary outcome (CSF p-tau231) or one planned secondary outcome (CSF p-tau181)
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, Care Provider, Investigator)
盲法说明
Double-Blind-Randomized
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Mild Cognitive Impairment (MCI) or dementia due to Alzheimer's disease (AD)
- •Biomarker criteria:
- •Cerebral Spinal Fluid (CSF) Amyloid Beta 1-42 (Aβ42) <= 600 pg/mL, or A ratio of total tau to Aβ42 ≥ 0.
- •Mini-Mental State Exam (MMSE) ≥ 20
- •Blood laboratories, urinalysis, and electrocardiogram are within normal limits or deemed clinically not significant by the site investigator
- •Stable medications (including approved AD therapies) for at least 4 weeks
- •At least 6 years of education
- •Able to swallow oral tablets
- •Speaks English fluently
- •Available qualified study partner (≥3 times per week in-person communication with the participant)
排除标准
- •Active neurological or psychiatric diagnosis other than AD that may affect cognition and/or function. (Obstructive sleep apnea is permitted, if treated.)
- •Inability to undergo lumbar puncture, including use of Coumadin, novel oral anticoagulants, clopidogrel, or dipyridamole. Use of aspirin <= 325mg daily is permitted.
- •Hachinski ischemic scale > 4
- •Magnetic Resonance Imaging (MRI) incompatibility
- •MRI evidence of cortical stroke >1cm, superficial siderosis, or extensive white matter hyperintensity (Cardiovascular Health Study score 7-8+)
- •Diagnosis of cancer in the previous 5 years (with the exception of basal or squamous cell carcinoma)
- •Geriatric Depression Scale (GDS) score >6
- •History within the past 5 years of alcohol or substance use disorder
- •Laboratory evidence of a clinically significant abnormality that may interfere with study assessments
- •Active partial or total malabsorptive disease (e.g., celiac disease)
- •Resides in a skilled nursing facility
- •Participation in a clinical trial of a potential disease-modifying therapy for AD in previous 6-months (time between last investigational drug administration and baseline for the current study)
- •Pregnant, lactating or of child bearing potential (that is, women must be 2 years post-menopausal or surgically sterile to be considered not child bearing potential).
- •Unwillingness to abstain from over-the-counter nicotinamide for the duration of the trial
研究组 & 干预措施
Nicotinamide
1500mg twice daily: 2, 750mg tablets taken orally twice daily
干预措施: Nicotinamide (Drug)
Placebo
1500mg twice daily: 2, 750mg tablets taken orally twice daily
干预措施: Placebo Comparator (Drug)
结局指标
主要结局
Vital Signs - Systolic Blood Pressure
时间窗: Screening through end of study (week 48)
Systolic blood pressure was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)
Count of Adverse Events by Severity
时间窗: Baseline to 48 weeks
Count of treatment emergent adverse events (TEAEs) over the duration of the study period (baseline to 48 weeks).
Change in QTC
时间窗: Baseline to 48 weeks
Average within-subject change in electrocardiogram QT interval.
Change in P-tau 231
时间窗: Baseline to 48 weeks
Change in key peptide in cerebrospinal fluid (CSF) from baseline to 48 weeks. Higher phosphorylated tau (p-tau) is associated with a severity of Alzheimer's disease pathology.
Vital Signs - Weight
时间窗: Screening through end of study (week 48)
Weight in kg was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)
Vital Signs - BMI
时间窗: Screening through end of study (week 48)
Body Mass Index (BMI) was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)
Vital Signs - Diastolic Blood Pressure
时间窗: Screening through end of study (week 48)
Diastolic blood pressure was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)
Vital Signs - Pulse
时间窗: Screening through end of study (week 48)
Pulse rate was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)
Count of Treatment Emergent Adverse Events
时间窗: Baseline to 48 weeks
Count of treatment emergent adverse events (TEAEs) over the duration of the study period (baseline to 48 weeks).
Columbia-Suicide Severity Rating Scale
时间窗: Baseline to 48 weeks
The Columbia-Suicide Severity Rating Scale (C-SSRS) captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the corresponding assessment period. The scale includes suggested questions to elicit the type of information needed to determine if a suicide-related thought or behavior occurred. The number and proportion of subjects with treatment emergent Suicidal ideation or behavior during the study period of (baseline to week 48) will be reported overall and by study arm. Treatment emergent suicidal ideation or behavior is defined as a "yes" answer at any time during treatment to any one of the questions in the ten suicidal ideation and behavior categories (Categories 1- 10) on the C-SSRS. Self-injurious behavior without suicidal intent, while assessed on the C-SSRS, does not form part of this outcome.
ECG Abnormalities
时间窗: Baseline to 48 weeks
Count of participants experiencing at least one electrocardiogram (ECG) abnormality.
QTC Abnormalities
时间窗: Baseline to 48 weeks
Count of participants experiencing at least one electrocardiogram (ECG) QT interval abnormality. Abnormal defined as above 460 for men and above 470 for women.
次要结局
- Change in ab40(Baseline to 48 weeks)
- Change in ab42(Baseline to 48 weeks)
- Change in Total Tau(Baseline to 48 weeks)
- Change in Ratio of Total Tau/ab42(Baseline to 48 weeks)
- Activities of Daily Living - Mild Cognitive Impairment(Baseline to 48 weeks)
- ADASCog-13(Baseline to 48 weeks)
- Change in P-tau 181(Baseline to 48 weeks)
- Change in Ratio of Total Tau/ab40(Baseline to 48 weeks)
- CDR Sum of Boxes(Baseline to 48 weeks)
研究者
Joshua Grill
Associate Professor, Psychiatry & Human Behavior
University of California, Irvine