Innovative Phase 2 Proof-of-Concept Trial to Test Effects of Benfotiamine as Alzheimer Treatment

Jose A. Luchsinger, MD, MPH

At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, investigators presented the design of an innovative phase 2a/b clinical trial (NCT06223360), dubbed BenfoTeam, to assess the effects of benfotiamine as a potential medication for patients with early-stage Alzheimer disease (AD). This proof-of-concept study is expected to include more than 400 patients across 50 sites and employs an early adaptive dose approach powered to validate treatment effects.¹

Benfotiamine, a prodrug of thiamine, raises blood levels by 50 to 100 times to achieve pharmacologic effects. In this randomized, double-blind, placebo-controlled trial, phase 2a determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2b. During phase 2a, real-time monitoring of predefined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2b.

Presented by lead author Jose A. Luchsinger, MD, MPH, the Robert F. Loeb Professor of Medicine and professor of epidemiology at the Columbia University Medical Center, the study enrolls only patients with mild cognitive impairment (MCI) or mild dementia because of AD with a positive plasma biomarker test result (C2N PrecivityAD2). Supported by a grant from the National Institute on Aging, the trial enrolls patients aged 50 to 89 years who are living in the community and not in a long-term care nursing facility. Potential participants go through a screening process that includes memory and thinking tests; a physical examination, and blood tests.

The dose decision in phase 2a will be determined at the first of either 21 total adverse tolerability events (TEs) or, alternatively, when 160 person–months of exposure have accumulated. If the 1200 mg/day dosed group does not show a significantly higher rate of TEs, this dose will be taken forward to phase 2b and tested against placebo without stopping the trial, otherwise 600 mg/day will be carried forward.

READ MORE: Alzheimer Vaccine ALZ-101 Shows Safety, Oligomer-Specific Humoral Immune Response in Early-Stage Trial

Phase 2b will evaluate the efficacy and long-term safety of benfotiamine in the full study sample through 72 weeks of treatment, at the selected dose. With a 20% dropout rate, and a 5% drop-in rate from the placebo arm to active treatment, the trial will be powered at 80% overall to detect a difference between arms on the co-primary end points at 72 weeks, corresponding to a Cohen’s D effect size of 0.38 (small to moderate effect size). The study will employ the Clinical Dementia Rating-Sum of Boxes and Alzheimer’s Disease Assessment Scale-Cognitive subscale 13 (ADAS-Cog13) as the primary end points.

In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define AD, including impaired cognition, amyloid-ß plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, advanced glycation end products, and inflammation. Its feasibility, safety, and efficacy were studied in a preliminary trial, published in the Journal of Alzheimer’s Disease in 2021.²

The 12-month study featured patients with MCI or mild dementia due to AD who were randomly assigned to either benfotiamine (n = 34) or placebo (n = 36). In addition to showing a tolerable safety profile, treatment with benfotiamine resulted in 43% lowered scores on ADAS-Cog than placebo, which was statistically significant (P = .125). In addition, worsening in CDR was 77% lower (P = .034) in the benfotiamine group compared with placebo, and this effect was stronger in apolipoprotein e4 non-carriers. An exploratory analysis derived from an fluorodeoxyglucose PET pattern score showed a treatment effect at 1 year (P = .002).

For more information about this trial, including eligibility, how to enroll, and where to find a clinical study site, visit https://www.benfoteam.org.

Click here for more coverage of AAIC 2024.

REFERENCES
1. Luchsinger JA, Feldman HH, Messer K, et al. A Seamless Phase 2A-Phase 2B Multi-Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer's Disease-Benfoteam: Design and Methods. Presented at: AAIC 2024; July 28-August 1; Philadelphia, PA. ABSTRACT 91963
2. Gibson GE, Luchsinger JA, Cirio R, et al. Benfotiamine and cognitive decline in Alzheimer’s Disease: results of a randomized placebo-controlled phase 2a clinical trial. J Alzheimers Dis. 2020;78(3):989-1010. doi:10.3233/JAD-200896