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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

我们提出了一项无缝的2A-2B试验，该试验调查了Benfotiamine，thiamine的前药，作为第一次。班级小分子治疗早期阿尔茨海默氏病（AD）。我们称此拟议的审判`benfotiamine 在阿尔茨海默氏病早期（珠）”。脑组织硫胺素缺乏会导致记忆缺陷在临床前广告模型和人类条件下，在包括韦尼克（Wernicke）的人类条件下可逆科萨科夫综合征。在轻度损害氧化物代谢的动物模型（即硫胺素缺乏）中，神经元丧失伴随着神经丝光（NFL）的变化，通过增加神经炎症（神经胶质纤维酸蛋白GFAP），通过高级糖基化终产物（年龄）的升高和斑块增加通过缠结病理，所有这些都发生在AD中。班佛胺显着增加血液和脑组织硫胺素在这些模型中，会议行为益处，减少了斑块和纠缠形成。我们以前在第2阶段进行了早期飞行员单站点12个月的双盲安慰剂控制RCT为600 benfotiamine的毫克，有71名早期广告的人。本菲敏的耐受性良好，令人鼓舞药代动力学（PK）和药效学（PD）反应，并在临床痴呆症上显示出益处评分（CDR），ADA-COG和大脑代谢的标记。有新的证据表明1200 MG的Benfotiamine进一步提高了硫胺素水平，并具有更大的认知益处。那我们提出了 18个月2A/2B的班菲敏测试的随机安慰剂控制RCT 600 mg/天和1200 400名参与者的毫克/天，包括轻度认知障碍（MCI）和轻度痴呆淀粉样蛋白积极性的血浆证据。我们的总体假设是，认知和全球功能将以安全，耐受性且实现足够的苯二胺剂量发生目标参与。如果此第2阶段试验成功，我们有一个合并的无缝阶段3 开发计划，加快苯二胺覆盖患者。我们将检验我们的总体假设通过以下目的：（1）有效确定最高安全且耐受良好的剂量 2A期（600 mg或1200 mg）中的benfotiamine可以在72时长期前进到长期临床终点几周；（2）评估Benfotiamine在2B阶段中的效率，以受益（a）通过在治疗期间用ADAS-COG13测量的盒子（CDR-SB）和（b）认知的CDR总和公元早期72周；（3）评估PK（血清硫胺素及其是酯）和PD效应（硫胺素苯酮酚酶和晚期糖基化终产物（年龄）的焦磷酸激活，以及他们与主要结果的关系；（4）评估治疗的下游生物学效应与Benfotiamine在AD早期有关神经变性的测量（MRI，等离子体的皮质厚度）神经丝的光和总tau），神经炎症（神经胶质纤维酸蛋白）和AD病理生理学包括P-TAU 231和Aβ42/40的比例。