Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease
Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease
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DOI：
10.1212/wnl.0000000000000364
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发表时间：
2014-04-29
期刊：
影响因子：
9.9
通讯作者：
Aisen, Paul S.
中科院分区：
文献类型：
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作者：
Galasko, Douglas;Bell, Joanne;Aisen, Paul S.
目的：研究晚期糖基化终产物受体（RAGE）抑制剂PF-04494700治疗轻中度阿尔茨海默病（AD）的安全性、耐受性和有效性。方法：在美国40个学术中心进行双盲、安慰剂对照试验。轻度精神状态检查评分为14-26分的AD受试者随机接受PF-04494700 60 mg/天x 6天，然后20 mg/天（高剂量）；15mg /天x 6天，然后5mg /天（低剂量）；或者安慰剂，持续18个月。采用临床和实验室措施评价安全性和耐受性。主要疗效测量是阿尔茨海默病评估量表-认知（ADAS-cog）。二次测量评估临床分期、功能、行为、MRI和脑脊液生物标志物。结果：共399名受试者被随机化。在预先指定的中期分析中，当50%的受试者完成6个月的访问时，高剂量与精神错乱、跌倒和更大的ADAS-cog下降有关，并停止使用。第二个预先指定的分析比较了低剂量组和安慰剂组在所有受试者随机化后大约12个月的有效性和安全性。该分析符合无效标准，并停止治疗。低剂量组没有安全问题。包括不孕后数据在内的分析显示，低剂量组在第18个月时ADAS-cog的下降有所减少。其他临床和生物标志物测量显示低剂量治疗和安慰剂之间没有差异。结论：20mg /d的PF-04494700与不良事件增加和认知能力下降相关。在5 mg/d时，PF-04494700具有良好的安全性。这种低剂量ADAS-cog的潜在益处尚不确定，因为中期分析后的退药和停药率很高。证据分类：本研究提供I类证据，高剂量PF-04494700在AD患者6个月时增加认知能力下降，IV类证据，低剂量PF-04494700在18个月时减缓认知能力下降。
Objective:To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD).Methods:Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14-26 were randomized to PF-04494700 60 mg/day x 6 days, then 20 mg daily (high dose); 15 mg/day x 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers.Results:A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo.Conclusions:PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses.Classification of evidence:This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.