一项无缝的 2A 期-2B 期随机双盲安慰剂对照试验方案，旨在评估苯磷硫胺（BenfoTeam）治疗早期阿尔茨海默病患者的安全性和疗效。
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).
机构信息
Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
Alzheimer's Disease Cooperative Study, University of California San Diego, La Jolla, California, United States of America.
出版信息
PLoS One. 2024 May 29;19(5):e0302998. doi: 10.1371/journal.pone.0302998. eCollection 2024.
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.
背景
苯磷硫胺是一种重要的新型治疗阿尔茨海默病（AD）的药物，对靶向淀粉样蛋白的治疗方法可能具有附加或协同作用。
目的
进行一项无缝的 2A-2B 概念验证试验，以评估苯磷硫胺（硫胺素的前体药物）作为治疗早期 AD 的首创小分子口服治疗药物的耐受性、安全性和疗效。
方法
这是一项针对 406 名早期 AD 患者的随机、双盲、安慰剂对照的 72 周苯磷硫胺临床试验方案。2A 期确定苯磷硫胺的最高安全耐受剂量，以便推进至 2B 期。在 2A 期，对最初约 150 名入组者中预先定义的安全性停止标准进行实时监测，有助于确定将哪个剂量（600mg 或 1200mg）推进至 2B 期。2A 期的主要分析将检验高剂量组的耐受性事件（TE）发生率是否明显高于安慰剂组。2A 期的主要安全性终点是在每个剂量组中，活性药物组与安慰剂组之间的 TE 发生率。2A 期完成后将无缝过渡到 2B 期，无需暂停或停止试验。2B 期将在选定剂量下，通过 72 周的治疗，评估更大组患者的苯磷硫胺疗效和长期安全性。2B 期的主要疗效终点是 CDR-Sum of Boxes 和 ADAS-Cog13。次要终点包括安全性和耐受性措施；硫胺素及其酯类的药代动力学测量、红细胞转酮醇酶活性作为药物递送疗效的血液标志物；ADCS-ADL-MCI；和 MoCA。
结论
BenfoTeam 试验利用创新的无缝 2A-2B 设计实现了概念验证。它包括一个适应性剂量决策规则，从而优化了对最高和最佳耐受剂量的暴露。
试验注册
ClinicalTrials.gov 标识符：NCT06223360，于 2024 年 1 月 25 日注册。https://classic.clinicaltrials.gov/ct2/show/NCT06223360。
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