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.

我们建议进行一项无缝的2A-2B期试验，研究硫胺素的前体药物苯福硫胺，作为首例... 治疗早期阿尔茨海默病(AD)的一类小分子药物。我们把这项拟议的试验称为‘本福硫明’ 在早期阿尔茨海默氏症(珠子)“。脑组织硫胺素缺乏会导致记忆缺陷 临床前AD模型和包括WerNicke在内的人类条件下硫胺素治疗的可逆性 科萨科夫综合征。在氧化代谢轻度受损(即硫胺素缺乏)的动物模型中， 伴随着神经元丢失的是神经丝光(NFL)的变化，并伴随着神经炎症(神经胶质细胞 纤维酸性蛋白(GFAP)、晚期糖基化终产物(AGE)升高和斑块增加 通过缠绕病理学，所有这些都发生在AD。苯福硫胺显著增加血液和脑组织 硫胺素在这些模型中，赋予行为益处，并减少斑块和缠结的形成。我们 之前进行了为期12个月的早期第二阶段单部位双盲安慰剂对照随机对照试验，试验人数为600人 71例早期阿尔茨海默病患者服用苯福硫胺。苯福硫胺耐受性良好，令人鼓舞 药代动力学(PK)和药效学(PD)反应及对临床痴呆的益处 评分(CDR)、ADAS-Cog和脑代谢标志物。在老鼠身上有新的证据表明1200 服用毫克苯福硫胺会进一步提高硫胺素水平，从而对认知有更大的益处。因此，我们提议 一项为期18个月的2A/2B期随机安慰剂对照的苯福硫胺RCT试验，每天600 mg，每天1200次 400名早期AD参与者，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。我们最重要的假设是，在认知和 使用安全、耐受性好的剂量的苯福硫胺将产生全局功能，并达到足够的效果 目标交战。如果此阶段2试验成功，我们将拥有整合的无缝阶段3 开发计划，以加快本福硫胺对患者的治疗。我们将检验我们的首要假设 通过以下目标：(1)有效地确定最高安全和耐受性良好的剂量 2A期的苯福硫胺(600毫克或1200毫克)，可在72岁时进入长期临床终点 两周；(2)评估苯福硫胺在2B期的疗效，以受益(A)用 用ADAS-Cog13评定治疗期间的CDR盒总和(CDR-SB)和(B)认知 (3)评价PK(血清硫胺素及其酯)和PD(硫胺素)对AD的影响 苯福硫胺的转酮醇酶和晚期糖基化终末产物(AGEs)的焦磷酸活化)， 以及它们与主要结果的关系；(4)评价治疗的下游生物学效应 阿尔茨海默病早期应用苯福硫胺对神经退行性变的测量(MRI上皮质厚度，血浆 神经丝光和总tau)、神经炎症(胶质纤维酸性蛋白)和AD的病理生理学 包括p-tau231和Aβ42/40比率。