Nicotinamide as an Early Alzheimer's Disease Treatment

University of California, Irvine46 enrolled

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Alzheimer's Disease Mild Cognitive Impairment

Interventions

NicotinamideDRUG

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

Placebo ComparatorDRUG

Oral Tablet

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

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

Locations (2)

University of California, Irvine

Irvine, California, United States

University of California, Los Angeles

Los Angeles, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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).

Time frame: Baseline to 48 weeks

Count of Adverse Events by Severity

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline to 48 weeks