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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：
10661607
负责人：
Howard Feldman
金额：
$ 1103.89万
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 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661607
关键词：
Address Advanced Glycosylation End Products Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein 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 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 improved 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.

我们建议进行一项无缝 2A-2B 期试验，研究苯磷硫胺（硫胺素的前药）作为首个类小分子治疗早期阿尔茨海默病（AD）。我们将这项提议的试验称为“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 模型和包括 Wernicke 在内的人类状况中，通过硫胺素治疗可逆转科尔萨科夫综合症。在氧化代谢轻度受损（即硫胺素缺乏）的动物模型中，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）的增加纤维酸性蛋白 GFAP），通过晚期糖基化终末产物 (AGE) 升高和斑块增加以及缠结病理学，所有这些都发生在 AD 中。苯磷硫胺显着提高血液和脑组织水平这些模型中含有硫胺素，可带来行为益处并减少斑块和缠结的形成。我们此前进行了 600 项早期 2 期试验单中心 12 个月双盲安慰剂对照随机对照试验 71 毫克苯磷硫胺治疗早期 AD 患者。苯磷硫胺耐受性良好，令人鼓舞药代动力学 (PK) 和药效学 (PD) 反应，并显示出对临床痴呆症的益处评级 (CDR)、ADAS-Cog 和大脑代谢标记。第 1200 章毫克苯磷硫胺进一步提高硫胺素水平，具有更大的认知益处。因此，我们建议苯磷硫胺测试 600 毫克/天和 1200 毫克/天的 18 个月 2A/2B 期随机安慰剂对照随机对照试验 400 名 AD 早期参与者每天服用 1 毫克，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认知方面的显着益处使用安全、耐受性良好并达到足够剂量的苯磷硫胺即可实现整体功能目标参与。如果第二阶段试验成功，我们将拥有一个整合的无缝第三阶段加快苯磷硫胺到达患者手中的开发计划。我们将测试我们的总体假设通过以下目标：（1）有效确定最高安全和耐受性良好的剂量 2A 期苯磷硫胺（600 毫克或 1200 毫克）可在 72 年后达到长期临床终点几周； (2) 评估 2B 期苯磷硫胺的功效，以有益于 (a) 用治疗期间使用 ADAS-Cog13 测量的 CDR 框 (CDR-SB) 和 (b) 认知的 CDR 总和公元早期 72 周； (3)评价PK（血清硫胺素及其酯类）和PD效应（硫胺素苯磷硫胺的转酮醇酶和晚期糖基化终产物（AGE）的焦磷酸激活，及其与主要结果的关系； (4) 评估治疗的下游生物学效应在早期 AD 中使用苯磷硫胺来测量神经变性（MRI 上的皮质厚度、血浆神经丝光和总 tau 蛋白）、神经炎症（胶质纤维酸性蛋白）和 AD 病理生理学包括 p-tau 231 和 Aβ 42/40 比率。