Jessica Langbaum, PhD, Banner Alzheimer's Institute, 901 E. Willetta Street, Phoenix, AZ 85006, USA,
J Prev Alzheimers Dis. 2023;10(3):453-463. doi: 10.14283/jpad.2023.27.
Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease.
Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique.
The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring.
Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid.
Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype.
At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening.
It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.
阿尔茨海默病（AD）预防试验需要一个庞大的外展和筛选漏斗，以确定符合研究纳入标准的认知正常成年人，例如某些临床或人口统计学标准、遗传风险因素和/或疾病的生物标志物证据。
描述策略和方法，以确定和招募携带一个（杂合子[HT]）或两个（纯合子[HM]）载脂蛋白 E ε4 等位基因的认知正常成年人，该基因是 AD 导致痴呆的遗传风险因素，入组阿尔茨海默病预防倡议（API）Generation 计划，这是使用这种富集技术进行的最大和唯一的针对迟发性 AD 的预防试验。
Generation 计划由两项全球、随机、双盲、安慰剂对照、平行组适应性设计、可变治疗持续时间临床试验组成。Generation 研究 1 将参与者随机分为两个队列之一：队列 1 评估 CAD106 与安慰剂或队列 2 评估 umibecestat 与安慰剂。Generation 研究 2 将参与者随机分为 umibecestat 与安慰剂的两个剂量。Generation 计划于 2019 年初提前终止，而招募仍在进行中。
Generation 研究 1 和 Generation 研究 2 均招募认知正常的 APOE ε4 HM 年龄 60-75 岁；Generation 研究 2 还招募了 APOE ε4 HT 年龄 60-75 岁，且大脑淀粉样蛋白水平升高。
描述集中和本地化外展、招募、筛选策略和策略的结果，以及成功招募遗传合格参与者的地点的特征，特别关注 APOE ε4 HM，因为这种基因型的患病率为 2-3%。
在试验计划终止时，已有 35333 人同意进行可选的预筛选 ICF1a/ICFA 并提供了 DNA 样本进行 APOE 基因分型，1138 名 APOE ε4 HM 同意接受 Generation 研究 1（ICF1b）的筛选，1626 名 APOE ε4 携带者被随机分配到 Generation 研究 1 或 Generation 研究 2。遗传检测登记处、与遗传检测/咨询公司的合作关系以及可选的预筛选 ICF1a/ICFA 是识别遗传合格参与者进行筛选的最成功策略。
招募、筛选和随机分配认知正常的 APOE ε4 携带者，特别是 APOE ε4 HM 进行全球 AD 预防试验是可行的。Generation 计划有望按计划在 2019 年底前完成入组。成功的关键因素包括：与各站点合作，根据其站点需求制定可定制的外展、招募和筛选计划，为站点提供交流最佳实践的论坛，并在赞助商团队和试验站点之间建立合作伙伴关系。
