Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer
Joshua D Grill1, Steven Tam1, Gaby Thai1
1From the Institute for Memory Impairments and Neurological Disorders (J.D.G., S.T., G.T., B.V., K.G., D.L.G.), University of California, Irvine; Department of Psychiatry and Human Behavior (J.D.G.), University of California, Irvine; Department of Neurobiology and Behavior (J.D.G., K.G.), University of California, Irvine; Division of Geriatric Medicine (S.T.), Department of Medicine, University of California, Irvine; Department of Neurology (G.T.), University of California, Irvine; Department of Neurology (A.L.P.), Oregon Health and Science University; Department of Statistics (D.L.G.), University of California, Irvine; Department of Neurology and Neurological Sciences (E.T.), Stanford University; Department of Neurology (S.K.), Cedars Sinai Medical Center; Department of Neurology (M.B.), University of California, Los Angeles; Alzheimer's Disease Cooperative Study (R.A.R., G.C.L., A.B., C.R., R.M., R.J., J.P., J.Z., S.J., K.M., H.H.F.), University of California, San Diego; and Department of Neurosciences (G.C.L., J.P., H.H.F.), University of California, San Diego.
Background And Objectives:
Nicotinamide is a coenzyme involved in cellular oxidation-reduction reactions that can inhibit Class III histone deacetylases (HDACs) or sirtuins. HDAC inhibition can affect numerous therapeutic pathways, including tau phosphorylation. We tested the hypothesis that nicotinamide treatment could reduce tau phosphorylation in early Alzheimer disease (AD).
Methods:
We performed a randomized, placebo-controlled, phase 2a proof-of-concept trial to evaluate the safety and tolerability of 48 weeks of treatment with 1,500 mg of nicotinamide twice a day. The primary outcome was level of tau phosphorylated at threonine 231 (p-tau231) in CSF. Prespecified secondary outcomes were levels of p-tau181, total tau, amyloid β40 (Aβ40), and Aβ42 in CSF and the clinical measures Alzheimer's Disease Assessment Scale (ADAS-cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Mild Cognitive Impairment (ADCS-ADL-MCI), and Clinical Dementia Rating Summary of Boxes (CDR-SB). Participants were recruited at 2 academic clinical centers. Enrollment criteria included diagnosis of mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD. The Holm-Bonferroni procedure was used to control type I error within biomarker and clinical domains.
Results:
Of 47 participants enrolled (mean age = 73.8 years; 43% female), 1 dropped out before treatment initiation and 6 before completion, including 2 in the nicotinamide and 4 in the placebo arm. Adverse events (AEs) were balanced by arm, with few attributed to treatment. Common AEs included infections and nervous system disorders. There was no statistically significant benefit of nicotinamide on the primary outcome of week 48 change from baseline in CSF p-tau231 (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; p = 0.61), with observed mean decline in CSF p-tau231 greater in the nicotinamide arm (-4.7 ± 14.5) than in the placebo arm (-2.3 ± 10.6). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p-tau181, Aβ40, Aβ42, and total tau) in similar models (all p values >0.05), with observed mean changes in CSF p-tau181 (0.4 ± 29.8 vs 10.4 ± 41.8) and total tau (8.4 ± 228.6 vs 60.5 ± 237.5) favoring nicotinamide compared with placebo. At week 48, nicotinamide-treated participants experienced less decline on CDR-SB (mixed-effect model with repeated measures; estimate = -1.42, SE = 0.65; p = 0.03 unadjusted for multiple comparisons), without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; p = 0.32) or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; p = 0.10) outcomes.
Discussion:
Nicotinamide was safe but did not alter AD biomarkers.
Classification Of Evidence:
This study provides Class I evidence that in patients with MCI or mild dementia with positive CSF AD biomarkers, 48 weeks of nicotinamide, 3,000 mg daily, is no better than placebo in reducing CSF p-tau231.
Trial Registration Information:
ClinicalTrials.gov: NCT03061474.
Insights
Nicotinamide treatment did not reduce tau phosphorylation in early Alzheimer disease (AD). The study found no significant changes in key AD biomarkers, although nicotinamide was safe and well-tolerated.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Nicotinamide, a coenzyme, inhibits Class III histone deacetylases (HDACs)/sirtuins, enzymes influencing tau phosphorylation.
- HDAC inhibition is a potential therapeutic pathway for Alzheimer disease (AD).
Purpose of the Study:
- To test if nicotinamide treatment reduces tau phosphorylation in early AD.
- To evaluate the safety and tolerability of nicotinamide in AD patients.
Main Methods:
- A 48-week randomized, placebo-controlled phase 2a trial involving 47 participants with mild cognitive impairment or mild dementia and confirmed AD biomarkers.
- Primary outcome: change in cerebrospinal fluid (CSF) phosphorylated tau at threonine 231 (p-tau231). Secondary outcomes included other AD biomarkers and clinical measures.
Main Results:
- Nicotinamide did not significantly reduce CSF p-tau231 levels compared to placebo (p=0.61).
- No significant effects were observed on other CSF AD biomarkers (p-tau181, total tau, Aβ40, Aβ42).
- A non-significant trend favored nicotinamide on the Clinical Dementia Rating Sum of Boxes (CDR-SB) score (p=0.03 unadjusted).
Conclusions:
- Nicotinamide (3,000 mg daily) was safe and well-tolerated in patients with early AD.
- The treatment did not alter key AD biomarkers, including CSF p-tau231.
- Nicotinamide is not effective in reducing tau phosphorylation in early AD.
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