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)

被引:1
作者
Feldman, Howard H. [1 ,2 ,3 ]
Luchsinger, Jose A. [4 ]
Leger, Gabriel C. [1 ,2 ]
Taylor, Curtis [1 ,2 ]
Jacobs, Diane M. [1 ,2 ,3 ]
Salmon, David P. [1 ,2 ,3 ]
Edland, Steven D. [1 ,2 ,3 ]
Messer, Karen [1 ,2 ]
Revta, Carolyn [1 ,2 ]
Flowers, Sarah A. [5 ]
Jones, Kerry S. [6 ]
Koulman, Albert [6 ]
Yarasheski, Kevin E. [7 ]
Verghese, Philip B. [7 ]
Venkatesh, Venky [7 ]
Zetterberg, Henrik [8 ,9 ,10 ,11 ,12 ,13 ]
Durant, January [1 ,2 ]
Lupo, Jody-Lynn [1 ,2 ]
Gibson, Gary E. [14 ]
机构
[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Alzheimers Dis Cooperat Study, La Jolla, CA 92093 USA
[3] Shiley Marcos Alzheimers Dis Res Ctr, La Jolla, CA 92037 USA
[4] Columbia Univ, Irving Med Ctr, New York, NY USA
[5] Univ Virginia, Charlottesville, VA USA
[6] Univ Cambridge, MRC Epidemiol Unit, Nutr Biomarker Lab, Cambridge, England
[7] C2N Diagnost, St Louis, MO USA
[8] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
[9] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
[10] UCL Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London, England
[11] UCL, UK Dementia Res Inst, London, England
[12] Hong Kong Ctr Neurodegenerat Dis, Clear Water Bay, Hong Kong, Peoples R China
[13] Univ Wisconsin Sch Med & Publ Hlth, Univ Wisconsin Madison, Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA
[14] Burke Neurol Inst, Weill Cornell Med, White Plains, NY USA
来源
PLOS ONE | 2024年 / 19卷 / 05期
基金
瑞典研究理事会; 美国国家卫生研究院;
关键词
RATING-SCALE SUM; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; COGNITIVE IMPAIRMENT; NATIONAL INSTITUTE; CLINICAL-TRIALS; DEMENTIA; THIAMINE; RECOMMENDATIONS; INVENTORY;
D O I
10.1371/journal.pone.0302998
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
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