A Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease

Abstract

AbstractBackgroundNicotinamide is a co‐enzyme involved in cellular oxidation‐reduction reactions that can act as an inhibitor of the class III histone deacetylases (HDACs), or sirtuins. HDAC inhibition may have myriad therapeutic pathways, including reducing phosphorylation of tau.MethodWe performed a randomized, placebo‐controlled, Phase 2a proof‐of‐concept trial to evaluate the safety and tolerability of nicotinamide, and its effects on change in cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 231 (p‐tau231) and other Alzheimer’s disease (AD) biomarkers and clinical measures in participants with early AD (Mild Cognitive Impairment or mild dementia) as confirmed by CSF biomarkers. We tested whether 1500 mg BID nicotinamide was superior to placebo in reducing CSF p‐tau231 (primary outcome), with secondary outcomes of p‐tau181, total tau, amyloid beta 40 (Ab40), Ab42, ADAS‐cog13, ADCS‐ADL‐MCI, and CDR‐SB.ResultArms were well balanced for demographic and clinical characteristics (Table 1). Of 47 participants enrolled, one dropped out prior to treatment initiation and six dropped before completion, 2 in the nicotinamide and 4 in the placebo arm. Nicotinamide was well‐tolerated; adverse events were largely balanced by study arm, with few attributed to treatment. There was no statistically significant benefit of nicotinamide on the primary outcome of change in CSF p‐tau231 (ANCOVA; estimated mean difference in change between arms = 2.06, std. error = 4.03; p = 0.61), although the observed mean decline in CSF p‐tau231 was greater in the nicotinamide arm (‐4.7±14.5) than in the placebo arm (‐2.3±10.6; Table 2). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p‐tau181, Ab40, Ab42, and total tau) in similar models (all p‐values>0.05), although 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) favored nicotinamide compared to placebo. Nicotinamide was associated with significantly less change on CDR‐SB (MMRM; estimate = ‐1.42, std. error = 0.65; p = 0.03), but not on cognitive (ADAS‐cog; estimate = ‐1.93, std. error = 1.93; p = 0.32) or functional (ADCS‐ADL‐MCI; estimate = ‐3.10, std. error = 1.86; p = 0.10) assessments. No adjustments for multiple comparisons were performed.ConclusionThese results may suggest that nicotinamide warrants further study as a treatment for early AD.