Clinical trial NCT03061474: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Mild Cognitive Impairment
Keywords: Mild Cognitive Impairment
Alzheimer's Disease
Nicotinamide
Niacinamide
Niacin
Nicotinic Acids
Vitamin
Neurodegenerative Diseases
Tauopathies
Dementia
Lead sponsor: University of California, Irvine
Sponsor class: OTHER
First posted: 2017-02-23
Enrollment: 46
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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

Primary outcomes:
measure: Change in P-tau 231
timeFrame: Baseline to 48 weeks
measure: Vital Signs - Weight
timeFrame: Screening through end of study (week 48)
measure: Vital Signs - BMI
timeFrame: Screening through end of study (week 48)
measure: Vital Signs - Systolic Blood Pressure
timeFrame: Screening through end of study (week 48)
measure: Vital Signs - Diastolic Blood Pressure
timeFrame: Screening through end of study (week 48)
measure: Vital Signs - Pulse
timeFrame: Screening through end of study (week 48)
measure: Count of Treatment Emergent Adverse Events
timeFrame: Baseline to 48 weeks
measure: Count of Adverse Events by Severity
timeFrame: Baseline to 48 weeks
measure: Columbia-Suicide Severity Rating Scale
timeFrame: Baseline to 48 weeks
measure: ECG Abnormalities
timeFrame: Baseline to 48 weeks
measure: QTC Abnormalities
timeFrame: Baseline to 48 weeks
measure: Change in QTC
timeFrame: Baseline to 48 weeks
Secondary outcomes:
measure: Change in ab40
timeFrame: Baseline to 48 weeks
measure: Change in ab42
timeFrame: Baseline to 48 weeks
measure: Change in P-tau 181
timeFrame: Baseline to 48 weeks
measure: Change in Total Tau
timeFrame: Baseline to 48 weeks
measure: Change in Ratio of Total Tau/ab40
timeFrame: Baseline to 48 weeks
measure: Change in Ratio of Total Tau/ab42
timeFrame: Baseline to 48 weeks
measure: ADASCog-13
timeFrame: Baseline to 48 weeks
measure: Activities of Daily Living - Mild Cognitive Impairment
timeFrame: Baseline to 48 weeks
measure: CDR Sum of Boxes
timeFrame: Baseline to 48 weeks
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
Study officials:
affiliation: Associate Professor of Psychiatry and Human Behavior
name: Joshua Grill, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.