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: 7726543
• 负责人: DOUGLAS R GALASKO
• 金额: $ 151.73万
• 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/7726543
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Astrocytes; Behavior; Behavioral; Binding; Biological Markers; Blood - brain barrier anatomy; Boxing; Brain; Clinical; Cognition; Daily; Data; Defect; Deposition; 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; Placebos; Plasma; Process; Randomized; Rate; Relative (related person); Safety; Screening procedure; Standards of Weights and Measures; Sum; Transgenic Mice; cognitive change; human subject; in vivo; neuropsychiatry; 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：TTP 488减缓AD患者临床进展速度的试验 目前FDA批准的阿尔茨海默病（AD）药物主要是对症治疗， 致病途径淀粉样β蛋白（Ali）在斑块和炎症中的沉积可能提供 治疗目标晚期糖基化终产物受体（AGEs）在神经元中表达， 星形胶质细胞，并在AD中上调。AS与多种配体相互作用，包括AIJ，并可能将AS连接到 炎症和神经元功能障碍。抑制配体/配体相互作用可能会减缓肿瘤的进展。 AH引起的神经病理学缺陷和认知改变。TTP 488是一种小分子， 筛选过程，其在体外结合至α-淀粉样蛋白，并抑制α-淀粉样蛋白与其配体的相互作用。在体内， TTP 488穿过血脑屏障，在转基因小鼠AD模型中降低脑淀粉样蛋白负荷 和行为障碍该化合物在健康人类受试者中耐受良好，包括每日口服 在老年受试者中给药1个月，在AD患者中进行的更长时间的安全性研究正在进行中（数据 2006年2月）。我们拟进行一项随机、双盲、多中心试验，在350例 用一剂TTP 488或安慰剂治疗18个月的轻度至中度AD患者。受试者将 以60：40的比例随机接受活性药物或安慰剂。假设用TTP 488治疗， 相对于安慰剂，将导致临床下降较慢。将定期随访受试者，以评估 认知、功能、行为、安全性和耐受性。主要结局指标为ADAS-cog和CDR 方框总和（CDR-100）。次要结局指标是ADCS-ADL和神经精神病学 库存（NPI）。将测量血浆中的药物水平和生物标志物。AD的标准治疗将是 允许的本研究有90%的把握度检测到ADAS-cog上41%或更大的变化，假设3.8 安慰剂组的点平均年变化，并有80%的把握度检测到35%的变化。