Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
AZTherapies Inc., Boston, MA, USA.
J Alzheimers Dis. 2019;71(3):715-732. doi: 10.3233/JAD-190507.
Alzheimer's disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease.
阿尔茨海默病（AD）临床试验集中于疾病修饰药物，在轻度至中度 AD 患者以及前驱（早期）AD 患者中进行，但迄今为止，大多数情况下都未能达到改善认知功能的疗效终点，或者由于不良事件而终止。使用网络资源（如 clinicaltrials.gov、alzforum.org、公司新闻稿和同行评议文献）审查已进入临床阶段的药物，以确定后期（II 期和 III 期）疗效临床试验，并总结其失败的原因。对于每种药物，仅将最新的临床试验和旨在改善认知功能的正在进行的临床试验纳入分析。在这里，我们重点介绍了阻碍临床成功的潜在原因，包括临床试验设计和结局测量的选择、患者人群的异质性、疾病诊断和分期的困难、药物设计、作用机制以及与长期使用相关的毒性。我们审查并提出了 AD 临床试验设计的方法，旨在提高我们识别这种破坏性疾病新疗法的能力。
