Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam)

Background: Benfotiamine provides an important novel therapeutic direction in Alzheimer’s disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. Objective: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. Methods: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. 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 pre-defined 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. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. Conclusion: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.  Trial Registration: ClinicalTrials.gov identifier: [NCT06223360][1], registered on January 25, 2024. ### Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: SDE is a Data Safety Monitoring Board statistician for clinical trials performed by Janssen Research & Development LLC and Suven. For this manuscript, HHF reports grant funding from the National Institute of Aging (R01AG076634) with no personal funds received and all payments to UC San Diego. HHF also discloses grant funding from Annovis (QR Pharma), Vivoryon (Probiodrug), Biohaven Pharmaceuticals, AC Immune, and LuMind Foundation service agreements for consulting activities with LuMind, Genentech (DSMB), Roche/Banner (DMC), Tau Consortium (SAB), Axon Neuroscience, Biosplice Therapeutics, Janssen Research & Development LLC (DMC), Arrowhead Pharmaceuticals, Samus Therapeutics Advisory Board activities: Translating Research in Elder Care (TREC), Association for Frontotemporal Dementia, Tau Consortium and Rainwater Charitable Foundation support for travel from Novo Nordisk, Royal Society of Canada, Tau Consortium, Canadian Consortium for Neurodegeneration in Aging (CCNA), Translating Research in Elder Care (TREC), World Events Forum (ADDF) and a philanthropic donation for the Epstein Family Alzheimer Research Collaboration. For these activities, no personal funds have been received with all payments to UC San Diego. HHF personally receives royalties for patent: Feldman HH (filed November 26, 2008). Detecting and Treating Dementia Serial Number 12/3-2691 U.S. Patent No. PCT/US2007/07008. Washington, DC: U.S. Patent and Trademark Office. DMJ reports support from grants to UC San Diego from NIH/NIA, Vivoryon Therapeutics, Biohaven Pharmaceuticals, and the Epstein Family Foundation. SAF reports grant funding from the NIH. GEG reports a pending patent. KJ received funding from BBSRC and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre. AK receives funding from the UKRI (MRC & BBSRC), the Wellcome Trust, and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre and is a paid consultant for the company Juvenescence. JAL was a consultant for Merck KGaA in 2022 (no longer active) receives drug/placebo from EMD Serono, Merck Subsidiary, for another clinical trial and receives a stipend from Wolters Kluwer as Editor In Chief of the journal Alzheimer's Disease and Associated Disorders. KEY, PBV, and VV are employed by and have equity interests in C2N Diagnostics. C2N Diagnostics has received support from the NIH (grant No. R44 AG059489), BrightFocus Foundation (grant No. CA2016636), The Gerald and Henrietta Rauenhorst Foundation, and the Alzheimer?s Drug Discovery Foundation (grant No. GC-201711-2013978). HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). ### Clinical Trial NCT06223360 ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Advarra I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This protocol does not report experimental results and data collection is ongoing. De-identified data will be made available to qualified researchers upon study completion, following publication of the primary manuscript. URL: https://www.adcs.org/data-sharing/ [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06223360&atom=%2Fmedrxiv%2Fearly%2F2024%2F04%2F19%2F2024.04.19.24306070.atom