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

Primary Purpose

Alzheimer's Disease, Mild Cognitive Impairment

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Nicotinamide

Placebo Comparator

About this trial

This is an interventional treatment trial for Alzheimer's Disease focused on measuring Mild Cognitive Impairment, Alzheimer's Disease, Nicotinamide, Niacinamide, Niacin, Nicotinic Acids, Vitamin, Neurodegenerative Diseases, Tauopathies, Dementia

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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)

Exclusion Criteria:

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

Sites / Locations

University of California, Irvine
University of California, Los Angeles

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nicotinamide

Placebo

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Vital Signs - Weight

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

Vital Signs - BMI

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

Vital Signs - Diastolic Blood Pressure

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

Vital Signs - Pulse

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

Count of Adverse Events by Severity

Count of treatment emergent adverse events (TEAEs) over the duration of the study period (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.

ECG Abnormalities

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

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.

Change in QTC

Average within-subject change in electrocardiogram QT interval.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT03061474

First Posted

February 13, 2017

Last Updated

September 22, 2023

Sponsor

University of California, Irvine

1. Study Identification

Unique Protocol Identification Number

NCT03061474

Brief Title

Nicotinamide as an Early Alzheimer's Disease Treatment

Acronym

NEAT

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

July 12, 2017 (Actual)

Primary Completion Date

August 30, 2022 (Actual)

Study Completion Date

August 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, Irvine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer's Disease, Mild Cognitive Impairment

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Masking Description

Double-Blind-Randomized

Allocation

Randomized

Enrollment

46 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nicotinamide

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Nicotinamide

Other Intervention Name(s)

Niacinamide

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo Comparator

Intervention Description

Oral Tablet

Primary Outcome Measure Information:

Title

Change in P-tau 231

Description

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.

Time Frame

Baseline to 48 weeks

Title

Vital Signs - Weight

Description

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

Time Frame