A TRIAL OF TTP488 TO SLOW THE RATE OF CLINICAL PROGRESSION OF PATIENTS WITH AD

TTP488 减缓 AD 患者临床进展速度的试验

• 批准号: 7726536
• 负责人: DOUGLAS R GALASKO
• 金额: $ 154.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7726536
• 关键词: Adverse event; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Astrocytes; Behavior; Behavioral; Binding; Biological Markers; Blood - brain barrier anatomy; Boxing; Brain; Chronic; Clinical; Cognition; Controlled Clinical Trials; Daily; Data; Defect; Deposition; Disease; Dose; Double-Blind Method; Elderly; Equipment and supply inventories; Functional disorder; In Vitro; Inflammation; Lead; Ligands; Link; Measures; Multicenter Trials; Neuronal Dysfunction; Neurons; Oral; Outcome Measure; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Placebo Control; Placebos; Plasma; Process; Randomized; Rate; Relative (related person); Safety; Screening procedure; Standards of Weights and Measures; Sum; Toxic effect; Transgenic Mice; cognitive change; glycation; human subject; in vivo; indexing; neuropsychiatry; receptor; receptor for advanced glycation endproducts; small molecule; therapeutic target

Project 3: A Trial of TTP488 to Slow the Rate of Clinical Progression of Patients with AD Currently FDA-approved drugs for Alzheimer's disease (AD) are primarily symptomatic and do not target pathogenic pathways. Deposition of amyloid beta protein (Ali) in plaques and inflammation may offer therapeutic targets. The receptor for advanced glycation endproducts (RAGE) is expressed in neurons and astrocytes and is upregulated in AD. RAGE interacts with multiple ligands, including AIJ, and may link AS to inflammation and neuronal dysfunction. Inhibition of RAGE/ligand interactions may slow the progression of neuropathological defects and cognitive changes induced by AH. TTP488 is a small molecule identified by a screening process, that binds to RAGE in vitro, and inhibits the interaction of RAGE with its ligands. In vivo, TTP488 crosses the blood brain barrier and, in transgenic mouse AD models, reduces brain amyloid load and behavioral dysfunction. The compound is well tolerated in healthy human subjects, including daily oral dosing for 1 month in elderly subjects, and longer safety studies in patients with AD are ongoing (data available in February 2006). We propose to carry out a randomized, double blind, multicenter trial in 350 patients with mild to moderate AD treated with one dose of TTP488 or placebo for 18 months. Subjects will be randomized 60:40 to receive active drug or placebo. The hypothesis is that treatment with TTP488, relative to placebo, will lead to slower clinical decline. Subjects will be followed at regular intervals to assess cognition, function, behavior, safety and tolerability. Primary outcome measures are the ADAS-cog and CDR Sum of Boxes (CDR-SOB). Secondary outcome measures are the ADCS-ADL and Neuropsychiatric Inventory (NPI). Drug levels and biomarkers will be measured in plasma. Standard therapy for AD will be permitted. The study has 90% power to detect a 41% or larger change on the ADAS-cog assuming a 3.8 point mean annual change in the placebo group, and has 80% power to detect a 35% change.

项目3：TTP488的试验减慢AD患者的临床进展速度 目前，阿尔茨海默氏病（AD）的FDA批准药物主要是症状，不针对 致病途径。斑块和炎症中淀粉样蛋白β蛋白（ALI）的沉积可能会提供 治疗靶标。晚期糖基化最终产物（RAGE）的受体在神经元中表达， 星形胶质细胞并在AD中上调。愤怒与包括Aij在内的多个配体互动，并可能链接到 炎症和神经元功能障碍。抑制愤怒/配体相互作用可能会减慢 AH引起的神经病理缺陷和认知变化。 TTP488是一个小分子 筛选过程，与体外结合，并抑制愤怒与配体的相互作用。体内， TTP488越过血脑屏障，在转基因鼠标AD模型中，减少了大脑淀粉样蛋白负荷 和行为功能障碍。该化合物在健康的人类受试者中耐受性良好，包括每日口腔 在老年受试者中服用1个月，并且正在进行AD患者的较长的安全研究（数据 2006年2月提供）。我们建议在350中进行随机，双盲，多中心试验 用一剂TTP488或安慰剂治疗的轻度至中度AD患者持续18个月。受试者会 随机分配60:40接受活跃的药物或安慰剂。假设是用TTP488的治疗 相对于安慰剂，将导致临床下降较慢。将定期遵循主题以评估 认知，功能，行为，安全性和耐受性。主要结果指标是ADAS-COG和CDR 框之和（CDR-SOB）。次要结果指标是ADCS-ADL和神经精神病学 库存（NPI）。药物水平和生物标志物将在血浆中测量。广告的标准疗法将是 允许。该研究具有90％的功率，可在ADAS-COG上检测41％或更大的变化，假设3.8 点平均年度变化的安慰剂组，并且具有80％的能力来检测35％的变化。