Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease

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). 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-tau ) in CSF. Prespecified secondary outcomes were levels of p-tau , total tau, amyloid β40 (Aβ ), and Aβ 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. 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-tau (analysis of covariance; estimated mean difference in change between arms = -2.06, SE = 4.03; = 0.61), with observed mean decline in CSF p-tau 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-tau , Aβ , Aβ , and total tau) in similar models (all values >0.05), with observed mean changes in CSF p-tau (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; = 0.03 unadjusted for multiple comparisons), without significant differences in cogni