Nicotinamide as an Early Alzheimer's Disease Treatment (NEAT)

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.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment; Alzheimer's Disease
• Intervention / Treatment: Drug: Nicotinamide; Drug: Placebo Comparator

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)

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Irvine, California, United States, 92697
      • University of California, Irvine
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nicotinamide; 1500mg twice daily: 2, 750mg tablets taken orally twice daily	Drug: Nicotinamide; Niacinamide (nicotinamide; 99%) is produced in a 750 mg sustained release tablet.; Other Names: Niacinamide
Placebo Comparator: Placebo; 1500mg twice daily: 2, 750mg tablets taken orally twice daily	Drug: Placebo Comparator; Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ab40	Change in key peptide in cerebrospinal fluid (CSF) from baseline to 48 weeks. Lower ab40 is associated with a greater probability of fibrillar amyloid burden in the brain.	Baseline to 48 weeks
Change in ab42	Change in key peptide in cerebrospinal fluid (CSF) from baseline to 48 weeks. Lower ab42 is associated with a greater probability of fibrillar amyloid burden in the brain.	Baseline to 48 weeks
Change in P-tau 181	Change in key peptide in cerebrospinal fluid (CSF) from baseline to 48 weeks. Higher total value is associated with greater severity of Alzheimer's disease pathology.	Baseline to 48 weeks
Change in Total Tau	Change in CSF total tau in individuals with mild Alzheimer's disease (AD) dementia or Mild Cognitive Impairment due to AD.	Baseline to 48 weeks
Change in Ratio of Total Tau/ab40	Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 48 weeks. A lower ab40/tau ratio is associated with a higher risk of dementia.	Baseline to 48 weeks
Change in Ratio of Total Tau/ab42	Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 48 weeks. A lower ab42/tau ratio is associated with a higher risk of dementia.	Baseline to 48 weeks
ADASCog-13	ADAS-Cog13 is a structured scale that evaluates memory (immediate and delayed word recall; immediate word recognition), receptive and expressive language, orientation, ideational praxis (preparing a letter for mailing), constructional praxis (copying figures), and attention (number cancellation). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions also are obtained. Range: 0-85; higher scores indicate greater impairment.	Baseline to 48 weeks
Activities of Daily Living - Mild Cognitive Impairment	The ADCS-ADL-MCI is a measure of patient functional performance in Alzheimer's Disease and Mild Cognitive Impairment trials. The informant-based questionnaire assesses conduct of basic and instrumental Activities of Daily Living (ADLs). A total of 24 ADLs are evaluated. Scores range from 0 to 53, with higher scores representing more maintained function.	Baseline to 48 weeks
CDR Sum of Boxes	CDR-SB is a composite rating of cognition and everyday function which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview three cognitive domains (memory, orientation, and judgement/problem solving) and three everyday functional domains (community affairs, home and hobbies, personal care). Level of impairment in each of the six domains is rated from none (score=0) to severe (score=3). The six domain scores are then summed to create the CDR-SB. Range 0-18; higher scores indicate greater impairment.	Baseline to 48 weeks

Collaborators and Investigators

• Sponsor: University of California, Irvine
• Investigators: Principal Investigator: Joshua Grill, Ph.D., Associate Professor of Psychiatry and Human Behavior

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2017
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: February 13, 2017
• First Submitted That Met QC Criteria: February 17, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Mild Cognitive Impairment; Dementia; Niacinamide; Neurodegenerative Diseases; Niacin; Tauopathies; Nicotinamide; Nicotinic Acids; Vitamin
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 20163246

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data sharing is integral to the ADCS's mission to develop and execute innovative clinical trials focused on interventions that may prevent, delay, or treat the expression of Alzheimer's disease and related dementias. The ADCS is committed to sharing resources and tools, including data, biospecimens, trial designs, outcome and analysis measures following NIH guidelines.

DATA Sharing: The ADCS Data and Sample Sharing Committee (DSSC) grants access to de-identified data to individuals who complete the request process and agree to the conditions in an ADCS/UCSD Data Us Agreement (DUA). After approval and receipt of the fully executed DUA, applicants are authorized to acquire data. Non-compliance with the DUA, including the requirement to provide requested updates will jeopardize further access to data.

• IPD Sharing Time Frame: 6 months after publication
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No