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

• ClinicalTrials.gov Identifier: NCT03061474
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Results First Posted: October 17, 2023
• Last Update Posted: October 17, 2023
• Sponsor: University of California, Irvine
• Information provided by (Responsible Party): Joshua Grill, University of California, Irvine

Tracking Information

• First Submitted Date: February 13, 2017
• First Posted Date: February 23, 2017
• Results First Submitted Date: August 22, 2023
• Results First Posted Date: October 17, 2023
• Last Update Posted Date: October 17, 2023
• Actual Study Start Date: July 12, 2017
• Actual Primary Completion Date: August 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2023)

• Change in P-tau 231 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 - Systolic Blood Pressure [ Time Frame: 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)
• Vital Signs - Diastolic Blood Pressure [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to 48 weeks ]
  Count of treatment emergent adverse events (TEAEs) over the duration of the study period (baseline to 48 weeks).
• Count of Adverse Events by Severity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to 48 weeks ]
  Count of participants experiencing at least one electrocardiogram (ECG) abnormality.
• QTC Abnormalities [ Time Frame: 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.
• Change in QTC [ Time Frame: Baseline to 48 weeks ]
  Average within-subject change in electrocardiogram QT interval.

Original Primary Outcome Measures (submitted: February 17, 2017)

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.

Current Secondary Outcome Measures (submitted: August 22, 2023)

• Change in ab40 [ Time Frame: Baseline to 48 weeks ]
  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.
• Change in ab42 [ Time Frame: Baseline to 48 weeks ]
  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.
• Change in P-tau 181 [ Time Frame: Baseline to 48 weeks ]
  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.
• Change in Total Tau [ Time Frame: Baseline to 48 weeks ]
  Change in CSF total tau in individuals with mild Alzheimer's disease (AD) dementia or Mild Cognitive Impairment due to AD.
• Change in Ratio of Total Tau/ab40 [ Time Frame: Baseline to 48 weeks ]
  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.
• Change in Ratio of Total Tau/ab42 [ Time Frame: Baseline to 48 weeks ]
  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.
• ADASCog-13 [ Time Frame: Baseline to 48 weeks ]
  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.
• Activities of Daily Living - Mild Cognitive Impairment [ Time Frame: Baseline to 48 weeks ]
  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.
• CDR Sum of Boxes [ Time Frame: Baseline to 48 weeks ]
  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.

Original Secondary Outcome Measures (submitted: February 17, 2017)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Nicotinamide as an Early Alzheimer's Disease Treatment
• Official Title: 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
• 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.

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
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Double-Blind-Randomized

Primary Purpose: Treatment

Condition

• Alzheimer's Disease
• Mild Cognitive Impairment

Intervention

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

Study Arms

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

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 22, 2023): 46
• Original Estimated Enrollment (submitted: February 17, 2017): 48
• Actual Study Completion Date: August 30, 2022
• Actual Primary Completion Date: August 30, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03061474
• Other Study ID Numbers: 20163246
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (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.
• URL: https://www.adcs.org/data-sharing

• Current Responsible Party: Joshua Grill, University of California, Irvine
• Original Responsible Party: Same as current
• Current Study Sponsor: University of California, Irvine
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Joshua Grill, Ph.D.; Associate Professor of Psychiatry and Human Behavior

• PRS Account: University of California, Irvine
• Verification Date: September 2023