Nicotinamide as an Early Alzheimer's Disease Treatment

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

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.

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)

Inclusion Criteria:

1. Mild Cognitive Impairment (MCI) or dementia due to Alzheimer's disease (AD)

2. Biomarker criteria:

   Cerebral Spinal Fluid (CSF) Amyloid Beta 1-42 (Aβ42) <= 600 pg/mL, or A ratio of total tau to Aβ42 ≥ 0.39.

3. Mini-Mental State Exam (MMSE) ≥ 20

4. Blood laboratories, urinalysis, and electrocardiogram are within normal limits or deemed clinically not significant by the site investigator

5. Stable medications (including approved AD therapies) for at least 4 weeks

6. At least 6 years of education

7. Able to swallow oral tablets

8. Speaks English fluently

9. Available qualified study partner (≥3 times per week in-person communication with the participant)

Exclusion Criteria:

1. Active neurological or psychiatric diagnosis other than AD that may affect cognition and/or function. (Obstructive sleep apnea is permitted, if treated.)
2. Inability to undergo lumbar puncture, including use of Coumadin, novel oral anticoagulants, clopidogrel, or dipyridamole. Use of aspirin <= 325mg daily is permitted.
3. Hachinski ischemic scale > 4
4. Magnetic Resonance Imaging (MRI) incompatibility
5. MRI evidence of cortical stroke >1cm, superficial siderosis, or extensive white matter hyperintensity (Cardiovascular Health Study score 7-8+)
6. Diagnosis of cancer in the previous 5 years (with the exception of basal or squamous cell carcinoma)
7. Geriatric Depression Scale (GDS) score >6
8. History within the past 5 years of alcohol or substance use disorder
9. Laboratory evidence of a clinically significant abnormality that may interfere with study assessments
10. Active partial or total malabsorptive disease (e.g., celiac disease)
11. Resides in a skilled nursing facility
12. 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)
13. 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).
14. Unwillingness to abstain from over-the-counter nicotinamide for the duration of the trial