{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T03:40:03Z","timestamp":1772250003633,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG076634"],"award-info":[{"award-number":["R01AG076634"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"\n Background<\/jats:title>\n Benfotiamine provides an important novel therapeutic direction in Alzheimer\u2019s disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n \n ClinicalTrials.gov identifier:\n NCT06223360<\/jats:ext-link>\n , registered on January 25, 2024.\n https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT06223360<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0302998","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T13:31:57Z","timestamp":1716989517000},"page":"e0302998","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["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\u2019s disease (BenfoTeam)"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-4538","authenticated-orcid":true,"given":"Howard H.","family":"Feldman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 A.","family":"Luchsinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel C.","family":"L\u00e9ger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane M.","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Salmon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven D.","family":"Edland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Messer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn","family":"Revta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Flowers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7380-9797","authenticated-orcid":true,"given":"Kerry S.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Koulman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin E.","family":"Yarasheski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip B.","family":"Verghese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venky","family":"Venkatesh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"January","family":"Durant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-5727","authenticated-orcid":true,"given":"Jody-Lynn","family":"Lupo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary E.","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the ADCS BenfoTeam Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"issue":"4","key":"pone.0302998.ref001","first-page":"325","article-title":"2017 Alzheimer\u2019s disease facts and figures","volume":"13","author":"Alzheimer\u2019s Association","year":"2017","journal-title":"2017, Alzheimer\u2019s Dementia"},{"key":"pone.0302998.ref002","article-title":"Succinylation Links Metabolic Reductions to Amyloid and Tau Pathology","author":"Y. 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Rosen","year":"1984","journal-title":"Am J Psychiatry"},{"issue":"Suppl 2","key":"pone.0302998.ref024","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1097\/00002093-199700112-00003","article-title":"Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer\u2019s Disease Assessment Scale that broaden its scope. The Alzheimer\u2019s Disease Cooperative Study","volume":"11","author":"R.C. Mohs","year":"1997","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"6","key":"pone.0302998.ref025","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/archneurol.2010.115","article-title":"Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer\u2019s coordinating center database","volume":"67","author":"S.E. O\u2019Bryant","year":"2010","journal-title":"Arch Neurol"},{"issue":"8","key":"pone.0302998.ref026","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1001\/archneur.65.8.1091","article-title":"Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer\u2019s research consortium study","volume":"65","author":"S.E. O\u2019Bryant","year":"2008","journal-title":"Arch Neurol"},{"key":"pone.0302998.ref027","article-title":"Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial","author":"J. Gallant","year":"2021","journal-title":"Am J Clin Nutr"},{"issue":"1","key":"pone.0302998.ref028","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/nyas.14547","article-title":"Erythrocyte transketolase activity coefficient (ETKAC) assay protocol for the assessment of thiamine status","volume":"1498","author":"K.S. Jones","year":"2021","journal-title":"Annals of the New York Academy of Sciences"},{"issue":"1","key":"pone.0302998.ref029","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/nyas.14962","article-title":"Protocol and application of basal erythrocyte transketolase activity to improve assessment of thiamine status","volume":"1521","author":"K.S. Jones","year":"2023","journal-title":"Annals of the New York Academy of Sciences"},{"issue":"Suppl 2","key":"pone.0302998.ref030","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1097\/00002093-199700112-00005","article-title":"An inventory to assess activities of daily living for clinical trials in Alzheimer\u2019s disease. The Alzheimer\u2019s Disease Cooperative Study","volume":"11","author":"D. Galasko","year":"1997","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"4","key":"pone.0302998.ref031","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","article-title":"The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment","volume":"53","author":"Z.S. Nasreddine","year":"2005","journal-title":"J Am Geriatr Soc"},{"issue":"5 Suppl 6","key":"pone.0302998.ref032","first-page":"S10","article-title":"The Neuropsychiatric Inventory: assessing psychopathology in dementia patients","volume":"48","author":"J.L. Cummings","year":"1997","journal-title":"Neurology"},{"issue":"1","key":"pone.0302998.ref033","doi-asserted-by":"crossref","first-page":"e12059","DOI":"10.1002\/trc2.12059","article-title":"Development of a novel cognitive composite outcome to assess therapeutic effects of exercise in the EXERT trial for adults with MCI: The ADAS-Cog-Exec","volume":"6","author":"D.M. Jacobs","year":"2020","journal-title":"Alzheimers Dement (N Y)"},{"key":"pone.0302998.ref034","volume-title":"The Boston Naming Test","author":"E. Kaplan","year":"1983"},{"key":"pone.0302998.ref035","volume-title":"Army Individual Test Battery","author":"A.G.s. Office","year":"1944"},{"key":"pone.0302998.ref036","article-title":"Wechsler Adult Intelligence Scale-Revised.; 1981","author":"D. Wechsler","year":"1981","journal-title":"The Psychological Corporation"},{"key":"pone.0302998.ref037","volume-title":"L\u2019examen Clinique en psychologie","author":"A. Rey","year":"1964"},{"key":"pone.0302998.ref038","article-title":"Version 3 of the National Alzheimer\u2019s Coordinating Center\u2019s Uniform Data Set","author":"L. Besser","year":"2018","journal-title":"Alzheimer Dis Assoc Disord"},{"issue":"9","key":"pone.0302998.ref039","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1212\/WNL.39.9.1159","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer\u2019s disease","volume":"39","author":"J.C. Morris","year":"1989","journal-title":"Neurology"},{"issue":"18","key":"pone.0302998.ref040","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa2100708","article-title":"Donanemab in Early Alzheimer\u2019s Disease","volume":"384","author":"M.A. Mintun","year":"2021","journal-title":"N Engl J Med"},{"issue":"3\u20134","key":"pone.0302998.ref041","first-page":"313","article-title":"Homogeneity of results in testing samples from Poisson series: With an application to testing clover seed for dodder","volume":"31","author":"J. 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