Phase II randomized controlled trial of benfotiamine in early Alzheimer's Disease

苯磷硫胺治疗早期阿尔茨海默病的 II 期随机对照试验

• 批准号: 10420686
• 负责人: Howard Feldman
• 金额: $ 966.42万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420686
• 关键词: Address; Advanced Glycosylation End Products; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-42; Animal Model; Behavioral; Bioenergetics; Biological; Blood; Brain; Cell Respiration; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Dementia; Development Plans; Dose; Double-Blind Method; Drug Kinetics; Early treatment; Elderly; Esters; Foundations; Functional disorder; Funding; Glial Fibrillary Acidic Protein; Goals; Human; Impairment; Individual; Light; Link; Magnetic Resonance Imaging; Measures; Memory impairment; Metabolic Pathway; Metabolism; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Outcome; Participant; Pathology; Patients; Pattern; Persons; Pharmacodynamics; Phase; Pilot Projects; Placebo Control; Placebos; Plasma; Prevention strategy; Process; Prodrugs; Randomized; Randomized Controlled Trials; Research; Safety; Serum; Side; Site; Sum; Testing; Thiamine; Thiamine Deficiency; Thiamine Pyrophosphate; Thick; Transketolase; Translating; Wernicke-Korsakoff Syndrome; arm; base; benphothiamine; brain abnormalities; brain metabolism; brain tissue; clinical development; clinical efficacy; clinical outcome measures; cognitive benefits; cost; drug discovery; effective therapy; efficacy evaluation; fluorodeoxyglucose positron emission tomography; functional outcomes; glucose metabolism; mild cognitive impairment; neurofibrillary tangle formation; neurofilament; neuroinflammation; neuron loss; neuropathology; novel; pharmacokinetics and pharmacodynamics; phase II trial; pre-clinical; primary endpoint; primary outcome; programs; randomized placebo-controlled clinical trial; response; small molecule; tau Proteins; tau-1; treatment duration; treatment effect; treatment strategy

We propose a seamless Phase 2A-2B trial investigating benfotiamine, a prodrug of thiamine, as a first-in- class small molecule treatment for early Alzheimer's disease (AD). We call this proposed trial `Benfotiamine in early Alzheimer's disease (BEAD)”. Brain tissue thiamine deficiency causes memory deficits that are reversible with thiamine treatment in preclinical AD models and in human conditions including Wernicke Korsakoff syndrome. In animal models of mild impairment of oxidative metabolism (i.e., thiamine deficiency), neuronal loss is accompanied by changes in neurofilament light (NfL), by increased neuroinflammation (glial fibrillary acid protein GFAP), by elevation of advanced glycation end products (AGE) and by increased plaque and by tangle pathology, all of which occur in AD. Benfotiamine dramatically raises blood and brain tissue thiamine in these models, conferring behavioral benefit and reduced plaque and tangle formation. We previously conducted an early Phase 2 pilot single-site 12-month double blind placebo controlled RCT of 600 mg of benfotiamine in 71 persons with early AD. Benfotiamine was well tolerated, had encouraging pharmacokinetic (PK) and pharmacodynamic (PD) responses and showed benefits on the Clinical Dementia Rating (CDR), the ADAS-Cog, and markers of brain metabolism. There is new evidence in mice that a 1200 mg of Benfotiamine further increases thiamine levels with greater cognitive benefits. Thus, we are proposing an 18-month Phase 2A/2B randomized placebo controlled RCT of Benfotiamine testing 600 mg/day and 1200 mg/day in 400 participants early AD, including mild cognitive impairment (MCI) and mild dementia with plasma evidence of amyloid positivity. Our overarching hypothesis is that significant benefits in cognition and global function will occur with doses of Benfotiamine that are safe, well tolerated, and achieve sufficient target engagement. If this Phase 2 trial is successful we have a consolidated seamless phase 3 development plan to expedite Benfotiamine reaching patients. We will test our overarching hypothesis through the following aims:(1) To efficiently determine the highest safe and well-tolerated dose of Benfotiamine in phase 2A (600 mg or 1200 mg) that can be advanced to long term clinical endpoints at 72 weeks; (2) To evaluate the efficacy of benfotiamine in Phase 2B, to benefit (a) global function measured with the CDR sum of boxes (CDR-SB) and (b) cognition measured with ADAS-Cog13 during a treatment period of 72 weeks in early AD; (3) To evaluate the PK (serum thiamine and it's esters) and PD effects (thiamine pyrophosphate activation of transketolase and advanced glycation end-products (AGEs)) of Benfotiamine, and their relation to the primary outcomes; (4) To evaluate the downstream biological effects of treatment with Benfotiamine in early AD on measures of neurodegeneration (cortical thickness on MRI, plasma neurofilament light and total tau), neuroinflammation (glial fibrillary acid protein) and AD pathophysiology including p-tau 231, and Aβ 42/40 ratio.

我们提出了一个无缝的2A-2B期试验调查苯磷硫胺，硫胺素的前药，作为第一个在 类小分子治疗早期阿尔茨海默病（AD）。我们称这项拟议的试验为“苯磷硫胺 早期阿尔茨海默病（BEAD）脑组织硫胺素缺乏会导致记忆缺陷， 在临床前AD模型和人类疾病（包括Wernicke）中，硫胺素治疗可逆 科尔萨科夫综合征在氧化代谢轻度损伤的动物模型中（即，硫胺素缺乏症）， 神经元损失伴随着神经丝光（NfL）的变化，神经炎症（神经胶质细胞）的增加， 晚期糖基化终产物（AGE）升高和斑块增加 和缠结病理学，所有这些都发生在AD中。苯磷硫胺显著提高血液和脑组织 硫胺素在这些模型中，赋予行为益处并减少斑块和缠结形成。我们 之前进行了一项早期II期试点单中心12个月双盲安慰剂对照RCT， 71例早期AD患者服用苯磷硫胺mg。苯磷硫胺耐受性良好， 药代动力学（PK）和药效学（PD）反应，并显示出对临床痴呆的益处 评估（CDR）、ADAS-Cog和脑代谢标志物。小鼠中有新证据表明1200 毫克的苯磷硫胺素进一步增加硫胺素水平，具有更大的认知益处。因此，我们建议 一项为期18个月的2A/2B期随机安慰剂对照RCT，试验苯磷硫胺600 mg/天和1200 mg/天 在400名参与者中，早期AD，包括轻度认知障碍（MCI）和轻度痴呆， 淀粉样蛋白阳性的血浆证据我们的总体假设是，认知和 使用安全、耐受性良好并达到足够的剂量的苯磷硫胺时， 瞄准目标如果第2阶段试验成功，我们将有一个整合的无缝第3阶段 发展计划，以加快苯磷硫胺到达病人。我们将测试我们的总体假设 通过以下目的：（1）有效地确定最高安全和耐受良好的剂量 苯磷硫胺在2A期（600 mg或1200 mg），可提前至长期临床终点，72 （2）评价苯磷硫胺在2B期的疗效，以使（a）用 治疗期间使用ADAS-Cog 13测量的框（CDR-SB）和（B）认知的CDR总和 AD早期72周;（3）评估PK（血清硫胺素及其酯）和PD效应（硫胺素 焦磷酸活化转酮醇酶和晚期糖基化终产物（AGEs））， 及其与主要结局的关系;（4）评价治疗的下游生物学效应 在早期AD中使用苯磷硫胺对神经变性的测量（MRI上的皮质厚度，血浆 神经丝轻蛋白和总tau）、神经炎症（胶质细胞酸性蛋白）和AD病理生理学 包括p-tau 231和Aβ 42/40比值。