Understanding Placebo Responses in Alzheimer's Disease Clinical Trials from the Literature Meta-Data and CAMD Database
Understanding Placebo Responses in Alzheimer's Disease Clinical Trials from the Literature Meta-Data and CAMD Database
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DOI：
10.3233/jad-130575
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Lalonde, Richard
中科院分区：
文献类型：
--
作者：
Ito, Kaori;Corrigan, Brian;Lalonde, Richard
背景：在纵向阿尔茨海默氏病 (AD) 研究中，很难区分安慰剂反应和潜在的疾病进展，但理解这一点对于设计临床试验和解释结果至关重要。目标：根据历史安慰剂数据得出的模型预测，对来自各种研究的 ADAS-cog(11) 中的安慰剂反应进行评估，以证明使用对预期疾病进展的事先了解对研究结果的潜在解释。方法：使用先前发表的疾病进展模型中的安慰剂反应成分来估计纵向安慰剂反应，并将在各种案例研究中评估了安慰剂组的疾病进展。此外，还描述了来自抗击重大疾病联盟 (CAMD) 数据库的轻度至中度 AD 患者的安慰剂数据。 结果：案例研究证明了安慰剂组中疾病进展的潜在不同结果，以及对了解药物作用程度的影响。基线认知功能是疾病进展的重要协变量，因此，在比较试验结果时评估基线严重程度并相应预测疾病进展非常重要。此外，研究持续时间、样本量和研究设计可能会影响安慰剂反应，所有这些都有可能混淆对研究结果的理解。 结论：近期 AD III 期研究的失败不太可能是由于对照组认知能力下降不足所致。使用所有可用数据的荟萃分析方法提供了对安慰剂效应、疾病进展和治疗效果的潜在解释的深入了解，并提供了帮助试验设计和解释的有用工具。
Background: The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer's disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results.Objectives: The placebo response in ADAS-cog(11) from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression.Methods: The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described.Results: The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug effect. Baseline cognitive function is an important covariate of disease progression, therefore, it is important to evaluate the baseline severity and predict disease progression accordingly when comparing trial results. Furthermore, study duration, sample size, and study design may affect the placebo response, all of which have the potential to confound understanding of study results.Conclusion: The recent failures in Phase III AD studies are not likely due to insufficient cognitive decline in the control groups. A meta-analytic approach using all available data provides a robust understanding of placebo effect, disease progression, and potential interpretation of treatment effects, and offers a useful tool to aid in both trial design and interpretation.