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

  • 2025-01-14
  • Neurology 104(1)
    • Joshua D Grill
    • Steven Tam
    • Gaby Thai
    • Beatriz Vides
    • Aimee L Pierce
    • Kim Green
    • Daniel L Gillen
    • Edmond Teng
    • Sarah Kremen
    • Maryam Beigi
    • Robert A Rissman
    • Gabriel C Léger
    • Archana Balasubramanian
    • Carolyn Revta
    • Rosemary Morrison
    • Robin Jennings
    • Judy Pa
    • Jing Zhang
    • Shelia Jin
    • Karen Messer
    • Howard H Feldman

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 47
Population
47 participants (mean age = 73.8 years; 43% female) with mild cognitive impairment or mild dementia with CSF biomarker confirmation of AD
Methods
randomized, placebo-controlled, phase 2a proof-of-concept trial; 1,500 mg of nicotinamide twice a day
Blinding
Double-blind
Duration
48 weeks
Funding
Unclear

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.

Research Insights

  • Vitamin B3→Improved Clinical Dementia Rating

    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)

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Improved Cognitive Function

    without significant differences in cognitive (ADAS-cog; estimate = -1.93, SE = 1.93; p = 0.32)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Improved Functional Ability

    or functional (ADCS-ADL-MCI; estimate = -3.10, SE = 1.86; p = 0.10) outcomes

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Reduced Amyloid Beta 40 Level

    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)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Reduced Amyloid Beta 42 Level

    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)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Reduced Tau Phosphorylated at Threonine 181

    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)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Reduced Tau Phosphorylated at Threonine 231

    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)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)
  • Vitamin B3→Reduced Total Tau Level

    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)

    Effect
    Neutral
    Effect size
    Small
    Dose
    1,500 mg twice a day (3,000 mg daily)

Adverse Events Reported

  • Vitamin B3→Overall tolerability

    Adverse events (AEs) were balanced by arm, with few attributed to treatment.

    Finding
    Reported
  • Vitamin B3→infections

    Common AEs included infections and nervous system disorders.

    Finding
    Reported
  • Vitamin B3→nervous system disorders

    Common AEs included infections and nervous system disorders.

    Finding
    Reported
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