Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer's Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study
Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer's Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study
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DOI：
10.1159/000318845
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发表时间：
2010-01-01
影响因子：
2.4
通讯作者：
Sawchak, Sharon
中科院分区：
文献类型：
--
作者：
Gold, Michael;Alderton, Claire;Sawchak, Sharon
背景/目的：一项针对过氧化物酶体增殖物激活受体 -γ激动剂罗格列酮缓释剂（RSG XR）用于轻至中度阿尔茨海默病（AD）的II期研究发现，在载脂蛋白E（APOE）-ε4阴性受试者中对认知有治疗益处。当前这项按APOE基因型进行前瞻性分层的III期研究旨在确认RSG XR在轻至中度AD中的疗效和安全性。一项开放标签扩展研究评估了8mg RSG XR的长期安全性和耐受性。
方法：这项双盲、随机、安慰剂对照研究纳入了693名受试者。在2个APOE等位基因分层（ε4阳性、ε4阴性）内，受试者按（2∶2∶2∶1）的比例随机接受每日一次的安慰剂、2mg RSG XR、8mg RSG XR或10mg多奈哌齐（对照）。共同主要终点是从基线到第24周阿尔茨海默病评定量表 - 认知分量表（ADAS - Cog）评分的变化，以及第24周基于临床医生访谈的变化印象加照顾者意见（CIBIC +）。
结果：在第24周，在APOE - ε4阴性受试者中或总体上，RSG XR的任一剂量在共同主要终点从基线的变化方面与安慰剂相比均未检测到显著差异。对于多奈哌齐，在ADAS - Cog中未检测到显著的治疗差异；然而，在CIBIC +上检测到显著差异（p = 0.009）。外周水肿是8mg RSG XR（15%）和安慰剂（5%）最常见的不良事件，而2mg RSG XR最常见的不良事件是鼻咽炎（7%）。
结论：在APOE - ε4阴性或其他分析人群中，未检测到2mg或8mg RSG XR单药治疗在认知或整体功能方面有效的证据。RSG XR的安全性和耐受性与其已知的药理学特性一致。版权所有（C）2010 S. Karger AG，巴塞尔
Background/Aims: A phase II study of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E (APOE)-epsilon 4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. Methods: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (epsilon 4-positive, epsilon 4-negative), subjects were randomized (2: 2: 2: 1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). Results: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in A POE-epsilon 4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). Conclusion: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-epsilon 4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology. Copyright (C) 2010 S. Karger AG, Basel