Nicotinamide as an Early Alzheimer's Disease Treatment

NCT03061474 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 20163246
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Alzheimer's Disease; Mild Cognitive Impairment

Keywords

Mild Cognitive Impairment; Alzheimer's Disease; Nicotinamide; Niacinamide; Niacin; Nicotinic Acids; Vitamin; Neurodegenerative Diseases; Tauopathies; Dementia

Outcome Measures

Primary Outcomes (12)

• Change in P-tau 231

  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.

  Baseline to 48 weeks

• Vital Signs - Weight

  Weight in kg was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)

  Screening through end of study (week 48)

• Vital Signs - BMI

  Body Mass Index (BMI) was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)

  Screening through end of study (week 48)

• Vital Signs - Systolic Blood Pressure

  Systolic blood pressure was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)

  Screening through end of study (week 48)

• Vital Signs - Diastolic Blood Pressure

  Diastolic blood pressure was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)

  Screening through end of study (week 48)

• Vital Signs - Pulse

  Pulse rate was recorded at every study visit (screening, baseline, week 12, week 24, and week 48)

  Screening through end of study (week 48)

• Count of Treatment Emergent Adverse Events

  Count of treatment emergent adverse events (TEAEs) over the duration of the study period (baseline to 48 weeks).

  Baseline to 48 weeks

• Count of Adverse Events by Severity

  Count of treatment emergent adverse events (TEAEs) over the duration of the study period (baseline to 48 weeks).

  Baseline to 48 weeks

• Columbia-Suicide Severity Rating Scale

  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.

  Baseline to 48 weeks

• ECG Abnormalities

  Count of participants experiencing at least one electrocardiogram (ECG) abnormality.

  Baseline to 48 weeks

• QTC Abnormalities

  Count of participants experiencing at least one electrocardiogram (ECG) QT interval abnormality. Abnormal defined as above 460 for men and above 470 for women.

  Baseline to 48 weeks

• Change in QTC

  Average within-subject change in electrocardiogram QT interval.

  Baseline to 48 weeks

Secondary Outcomes (9)

• Change in ab40

  Baseline to 48 weeks

• Change in ab42

  Baseline to 48 weeks

• Change in P-tau 181

  Baseline to 48 weeks

• Change in Total Tau

  Baseline to 48 weeks

• Change in Ratio of Total Tau/ab40

  Baseline to 48 weeks

Study Arms (2)

Nicotinamide

EXPERIMENTAL

1500mg twice daily: 2, 750mg tablets taken orally twice daily

Drug: Nicotinamide

Placebo

PLACEBO COMPARATOR

1500mg twice daily: 2, 750mg tablets taken orally twice daily

Drug: Placebo Comparator

Interventions

Nicotinamide DRUG

Niacinamide (nicotinamide; 99%) is produced in a 750 mg sustained release tablet.

Also known as: Niacinamide

Nicotinamide

Placebo Comparator DRUG

Oral Tablet

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ≥ 0.39.
• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Irvine: lead

Study Sites (2)

University of California, Irvine

Irvine, California, 92697, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (4)

• 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.

  PMID: 18987186 BACKGROUND

• 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.

  PMID: 23273573 BACKGROUND

• Ketron GL, Grun F, Grill JD, Feldman HH, Rissman RA, Brewer GJ. Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer's disease. Alzheimers Res Ther. 2025 Mar 11;17(1):59. doi: 10.1186/s13195-025-01693-y.

  PMID: 40069789 DERIVED

• Grill JD, Tam S, Thai G, Vides B, Pierce AL, Green K, Gillen DL, Teng E, Kremen S, Beigi M, Rissman RA, Leger GC, Balasubramanian A, Revta C, Morrison R, Jennings R, Pa J, Zhang J, Jin S, Messer K, Feldman HH. Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease. Neurology. 2025 Jan 14;104(1):e210152. doi: 10.1212/WNL.0000000000210152. Epub 2024 Dec 13.

  PMID: 39671543 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Neurodegenerative Diseases; Tauopathies; Dementia

Interventions

Niacinamide

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Joshua Grill
• Organization: University of California, Irvine

jgrill@uci.edu

(949) 824-5905

Study Officials

• Joshua Grill, Ph.D.

  Associate Professor of Psychiatry and Human Behavior

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-Blind-Randomized
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Psychiatry & Human Behavior

Study Record Dates

• First Submitted: February 13, 2017
• First Posted: February 23, 2017
• Study Start: July 12, 2017
• Primary Completion: August 30, 2022
• Study Completion: August 30, 2022
• Last Updated: October 17, 2023
• Results First Posted: October 17, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 6 months after publication
• Access Criteria: Data requestors must complete ADCS data and sample sharing request form. Upon approval, requestors must complete a data use agreement prior to accessing data.

Locations

US (2)