Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.
Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.
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DOI：
10.3233/jad-179901
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Zhong K
中科院分区：
文献类型：
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作者：
Cummings J;Ritter A;Zhong K
阿尔茨海默病（AD）目前还没有批准的疾病修饰疗法（DMT），迫切需要预防、延迟发作或减缓进展的治疗。如果到2025年可以延迟5年，到2050年AD患者总数将减少50%。为了满足DMT的定义，药物必须在AD的过程中产生持久的变化; DMT的临床试验旨在证明这种效果。AD药物发现需要靶点鉴定，然后进行高通量筛选和药物样化合物的先导物优化。一旦优化的药物可用，并已在动物中进行了疗效和毒性评估，它将通过健康志愿者的I期测试，II期学习试验以建立机制和剂量的证明，以及III期验证性试验以证明在更大人群中的疗效和安全性。第三阶段之后是食品和药物管理局的审查，并在适当的情况下，市场准入。试验人群包括预防试验中认知正常的高危受试者、前驱AD试验中有AD生物标志物证据的轻度受损受试者以及AD痴呆试验中有认知和功能障碍的受试者。生物标志物在DMT试验中至关重要，有助于参与者表征和诊断，目标参与和药理学证明，疾病修饰的证明以及监测副作用。临床试验设计包括随机、平行组、延迟开始、交错退出和适应性。从已完成的审判中吸取的经验教训为今后的审判提供了信息，并增加了成功的可能性。
Alzheimer’s disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.