Nicotinamide as an Early Alzheimer’s Disease Treatment

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: July 30, 2022

Detailed Description

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)

Interventions

  • Drug: Nicotinamide
    • Niacinamide (nicotinamide; 99%) is produced in a 750 mg sustained release tablet.
  • Drug: Placebo Comparator
    • Oral Tablet

Arms, Groups and Cohorts

  • Experimental: Nicotinamide
    • 1500mg twice daily: 2, 750mg tablets taken orally twice daily
  • Placebo Comparator: Placebo
    • 1500mg twice daily: 2, 750mg tablets taken orally twice daily

Clinical Trial Outcome Measures

Primary Measures

  • Change in p-tau 231
    • Time Frame: 12 Months
    • Change in CSF phosphorylated tau (p-tau231) in individuals with mild Alzheimer’s disease (AD) dementia or Mild Cognitive Impairment due to AD.

Secondary Measures

  • Change in p-tau 181
    • Time Frame: 12 Months
    • Change in CSF phosphorylated tau (p-tau181) in individuals with mild Alzheimer’s disease (AD) dementia or Mild Cognitive Impairment due to AD.
  • Change in total tau
    • Time Frame: 12 Months
    • Change in CSF total tau in individuals with mild Alzheimer’s disease (AD) dementia or Mild Cognitive Impairment due to AD.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 50 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of California, Irvine
  • Provider of Information About this Clinical Study
    • Principal Investigator: Joshua Grill, Associate Professor, Psychiatry & Human Behavior – University of California, Irvine
  • Overall Official(s)
    • Joshua Grill, Ph.D., Principal Investigator, Associate Professor of Psychiatry and Human Behavior
  • Overall Contact(s)
    • Joshua Grill, Ph.D., 949-824-5905, jgrill@uci.edu

References

Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008 Nov 5;28(45):11500-10. doi: 10.1523/JNEUROSCI.3203-08.2008.

Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP. Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging. 2013 Jun;34(6):1564-80. doi: 10.1016/j.neurobiolaging.2012.11.020. Epub 2012 Dec 25. Erratum in: Neurobiol Aging. 2013 Sep;34(9):e3.

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