Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects

T3D-959 在轻度至中度阿尔茨海默病受试者中的 2 期随机、双盲、安慰剂对照临床试验

• 批准号: 10444130
• 负责人: John Didsbury
• 金额: $ 552.65万
• 依托单位: T3D THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444130
• 关键词: Administrative Supplement; Agonist; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-42; Biological Markers; Blinded; Brain; CD3D gene; COVID-19 pandemic; COVID-19 testing; Chemicals; Clinical Drug Development; Clinical Research; Clinical Trials; Cognition; Contracts; Controlled Clinical Trials; Disease; Dose; Double-Blind Method; Energy Metabolism; Enrollment; Ensure; FDA approved; Funding; Glucose; Health; Health Care Costs; Homeostasis; Human; Inflammation; Institutional Review Boards; Investigational Drugs; Measures; Metabolic; Metabolism; Multicenter Trials; Nerve Degeneration; Nuclear Receptors; Oral; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Plasma; Protocols documentation; Randomized; Severities; Signal Transduction; Site; Test Result; Testing; Time; TimeLine; Work; brain dysfunction; brain metabolism; cohort; coronavirus disease; cost; data management; disability; electronic data; executive function; improved; inclusion criteria; lipid metabolism; neurofibrillary tangle formation; novel; pandemic disease; phase 3 testing; primary outcome; prospective; protein misfolding; research clinical testing; response; restoration; screening; secondary outcome; small molecule; success

T3D-959 is a novel (non-amyloid/non-tau-directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). T3D-959 is an orally delivered small molecule dual nuclear receptor agonist that works to restore and maintain metabolic homeostasis, which when altered in AD, leads to protein misfolding which causes plaque formation, tangle formation and inflammation. Exploratory human clinical test results (Phase 2a study) of T3D-959 in mild to moderate severity AD patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of disease. The next stage in clinical development of this drug is to validate these observed efficacy signals in a larger and longer Phase 2 clinical trial statistically powered to measure significant differences versus placebo in outcome measures of cognition, function, and biomarkers of disease. The Phase 2 randomized, placebo-controlled ‘PIONEER’ Study (Prospective therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration) is assessing multiple T3D-959 dose strengths vs. placebo (15mg, 30mg & 45mg QD and placebo in a 1:1:1:1 ratio) to identify the most safe and effective dose or doses to use in subsequent Phase 3 testing. The multi-center trial involves 256 mild to moderate AD patients (MMSE=14-26) dosed orally once-a-day for 24-weeks. Co-primary outcome measures include the ADAS- cog11 cognition and ADCS-CGIC global function measures. Secondary outcome measures include executive function as measured by DSCT and change from baseline in plasma Aβ 42/40 ratio. PIONEER began enrollment in February 2020. Six weeks later, amid a growing Covid-19 pandemic, all screening and randomization of new subjects was discontinued with 33 already-randomized subjects continuing their dosing (“Covid Cohort”). In early April, due to the insurmountable barriers to study conduct posed by the COVID-19 pandemic, the trial was halted with cessation of study medication dosing for all randomized subjects. After two attempted resumptions of the study, each thwarted by pandemic surges, PIONEER successfully re-started on March 1, 2021, under an amended protocol with trial adaptations in response to the pandemic (DSMB, NIA, IRB and FDA approved). A new CRO has been contracted and new U.S. clinical trial sites have been added to replace those lost due to the pandemic. The pandemic-elicited delay of ca. 13 months resulted in significant unpredicted ‘sunk’ costs . The requested Administrative Supplement (AS) funding will be utilized to ensure that PIONEER can be completed in its totality and within the original proposed timeline, despite the pandemic- related delay. Pandemic-related adaptations to the study have been implemented including Covid-19 testing of all subjects, new inclusion criteria (e.g., CDR-SOB >3.0 and expanding MMSE range from 16-26 to 14-26), all electronic data management (CRIO eSource and eRegulatory), reducing patient test burdens, addition of a pre-planned, blinded interim analysis, and incorporation of additional biomarker assessments.

T3D-959是一种新的(非淀粉样蛋白/非tau导向的)新化学实体，旨在改善大脑功能障碍 阿尔茨海默病(AD)中的葡萄糖、能量和脂代谢。T3D-959是一种口服的小型 分子双核受体激动剂，作用于恢复和维持代谢稳态，当 在AD中发生改变，导致蛋白质错误折叠，导致斑块形成、缠结形成和炎症。 T3D-959在轻至中度AD患者中的探索性临床试验结果(2a期研究) 已经显示出多种疗效信号，表明有可能减缓、阻止或逆转病程。这个 该药物临床开发的下一阶段是在更大范围内验证这些观察到的疗效信号 更长的第二阶段临床试验，从统计学上衡量结果与安慰剂的显著差异 疾病的认知、功能和生物标志物的测量。第二阶段随机、安慰剂对照 PIONEER研究(通过以下途径抑制和克服阿尔茨海默病神经变性的前瞻性治疗 脑能学和新陈代谢恢复)正在评估T3D-959与安慰剂的多重剂量强度 (15毫克、30毫克和45毫克，每日一次，安慰剂按1：1：1：1的比例)以确定最安全有效的一个或多个剂量 在随后的阶段3测试中使用。这项多中心试验涉及256名轻中度AD患者 (MMSE=14-26)，每天口服一次，共24周。共同主要成果衡量标准包括ADAS-- COG11认知和ADCS-CGIC全球功能测量。次要结果衡量标准包括执行力 DSCT测量的功能和血浆Aβ42/40比值与基线相比的变化。先驱者开始了 2020年2月招生。六周后，在日益严重的新冠肺炎疫情中，所有筛查和 停止了新受试者的随机化，33名已经随机化的受试者继续服药 (“Covid Cohort”)。4月初，由于新冠肺炎对学习行为构成了不可逾越的障碍 在大流行期间，随着所有随机受试者停止研究用药剂量，试验停止。两点后 尝试恢复研究，每次都因大流行激增而受挫，先锋成功地重新启动 2021年3月1日，根据一项修正后的议定书，并进行试验调整，以应对大流行(DSMB，NIA， IRB和FDA批准)。一家新的CRO已经签约，新的美国临床试验地点已经增加到 替换那些因大流行而失去的人。大流行导致的大约13个月的延误导致了严重的 不可预测的“沉没”成本。所要求的行政补编资金将用于确保 先锋号可以在最初提出的时间表内全部完成，尽管发生了大流行- 相关延迟。已对该研究进行了与大流行有关的适应，包括对 所有科目，新的纳入标准(例如，CDR-SOB&>3.0和扩展的MMSE范围从16-26到14-26)，所有 电子数据管理(Crio eSource和eRegulatory)，减少患者测试负担，增加 预先计划的、盲目的中期分析，并纳入额外的生物标志物评估。