Pioglitazone in Alzheimer's Disease Progression

吡格列酮在阿尔茨海默病进展中的作用

• 批准号: 6532554
• 负责人: DAVID S GELDMACHER
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532554
• 关键词: Alzheimer's disease; geriatrics; human subject; human therapy evaluation; mental disorder chemotherapy; microglia; nervous system disorder chemotherapy; patient oriented research; peroxisome proliferator activated receptor; thiazoles

Alzheimer's disease (AD) is a major public health problem and there is an urgent need for more effective therapies. Activation of the brain's microglial immune cells and subsequent inflammatory processes are now recognized as playing an important role in the progression of AD. Laboratory evidence strongly suggests that agonists of Peroxisome Proliferator Activated Receptor-gamma (PPARgamma) act to downregulate the transduction of inflammatory signals in microglia exposed to AD-related amyloid peptide. Therefore, agents that activate PPARgamma have great potential for reducing the progressive neuronal loss in AD. Drugs of the thiazolidinedione class, developed to reduce insulin resistance in type II diabetes mellitus have significant PPARgamma activation, suggesting that they may be useful for treating AD progression. Of this class, the most favorable clinical experience and safety profile exists for pioglitazone (PGZ). This application proposes a double-blind, placebo controlled, parallel group, pilot study to determine the safety and tolerability of PGZ in patients with AD. Another goal of the study is assess how clinical measures might demonstrate sensitivity to the potential effect of PGZ in slowing AD progression. Since there are no prior data for PGZ effects in AD, efficacy measures from this pilot will be used primarily to inform effect-size determinations for future studies. Thirty patients diagnosed with probable AD by NINCDS-ADRDA criteria, at a mild or moderate level of severity (CDR = 1-2) will be enrolled. One-half of the subjects will be randomized to receive PGZ at the best tolerated dose of 15, 30, or 45mg daily; the others will receive placebo. All subjects will take Vitamin E 200mg daily. Subjects will be followed for safety and tolerability at monthly intervals for 1 year, then again at 15 and 18 months. All adverse events will be recorded and compared between treatment groups. Human subjects' safety will monitored by an independent and unblinded safety committee. Efficacy measures will be the Alzheimer's Disease Assessment Scale- cognitive score (ADAS-cog), the Clinical Dementia Rating-Sum of Boxes score (CDR-SB), and the Clinician's Interview-based Impression of Change (CIBIC-Plus). Secondary measures will include the Neuropsychiatric Inventory, Nurse's Observation Scale for Geriatrics (NOSGER) and the ADFACS scale for activities of daily living. Comparison of mean differences (using last observation carried forward imputation techniques) and survival analyses will be employed to assess for group differences in clinical measures AD of progression.

阿尔茨海默氏病（AD）是一个主要的公共卫生问题，迫切需要更有效的疗法。现在，大脑的小胶质细胞的激活和随后的炎症过程被认为是在AD进展中起重要作用。 实验室证据强烈表明，过氧化物酶体增殖物激活的受体伽马（Ppargamma）作用下调了暴露于与AD相关淀粉样蛋白肽的小胶质细胞中炎症信号的转导。 因此，激活ppargamma的药物具有降低AD进行性神经元丧失的巨大潜力。噻唑烷二酮类的药物是为了降低II型糖尿病中胰岛素耐药性而开发的，具有明显的ppargamma激活，这表明它们可能对治疗AD进展有用。 在此类中，吡格列酮（PGZ）的最有利的临床经验和安全性。 该应用提出了一项双盲，安慰剂控制的平行组，试点研究，以确定PGZ在AD患者中的安全性和耐受性。 该研究的另一个目标是评估临床测量方法如何证明对PGZ在减慢AD进展中的潜在影响的敏感性。 由于AD中没有PGZ效应的先前数据，因此该飞行员的功效措施将主要用于为未来研究的效应大小确定提供信息。 将在轻度或中等程度的严重程度（CDR = 1-2）中纳入30名被NINCDS-ADRDA标准诊断为AD的患者。一半的受试者将被随机分配，以每天15、30或45mg的最佳耐受剂量接受PGZ；其他人会得到安慰剂。 所有受试者每天将服用维生素E 200mg。将遵循受试者的安全性和每月1年间隔的安全性，然后在15和18个月再次。 将记录所有不良事件，并在治疗组之间进行比较。 人类受试者的安全将由一个独立且无盲的安全委员会监控。 疗效措施将是阿尔茨海默氏病评估量表 - 认知评分（ADAS-COG），临床痴呆症盒子评分（CDR-SB）和临床医生基于访谈的变化印象（CIBIC-PLUS）。 次要措施将包括神经精神库存，护士的老年医学观察量表（Nosger）和日常生活活动的ADFACS量表。 将使用平均差异（使用最后一次观察到的前进归合技术）和生存分析的比较来评估临床测量中的群体差异。