Dominantly Inherited Alzheimer's Network Trials Unit - Adaptive Prevention Trial

常染色体显性阿尔茨海默病（AD）为阿尔茨海默病的研究领域提供了信息——此外，常染色体显性阿尔茨海默病的分子和生化机制被认为是阿尔茨海默病突变的病理学基础，为开发抗阿斯海默病药物提供了动物和细胞模型。常染色体显性阿尔茨海默病的预防试验可能是预防所有形式阿尔茨海默病的先驱方法。目前正在进行的2期显性遗传性阿尔茨海默病网络试验单元（DIAN TU）生物标志物试验的3期关键认知终点试验提议，旨在预防常染色体显性阿尔茨海默病人群的认知丧失。结果-将推动寻找替代生物标志物和途径，以预防阿尔茨海默病的一般人群。如果这个单一的三期试验是积极的，它可能会导致一种用于预防的疾病修饰药物的批准。我院与补足性阿尔茨海默病预防倡议（API）和ADCS抗无症状AD淀粉样蛋白治疗（A4）共同成立了阿尔茨海默病预防合作（CAP），以确保流程高效，公共资金得到充分利用，结果将推动整个领域的发展。DIAN TU建立了DIAN扩展注册表（www.DIANXR.org），并确定了其他潜在的D-IAN-TU试验地点，通过将参与者人数增加到3000多人，实现更大规模的3期预防试验。2012年12月，针对常染色体显性阿尔茨海默病（AD）风险人群的第一个预防试验（2期生物标志物试验）启动。DIAN- tu适应性预防试验（APT）利用DIAN观察性研究和DIAN- tu的现有基础设施，招募了DIAN- tu参与者以及来自相关位点的常染色体显性AD风险人群。DIANTU APT是DIAN观察研究的下一个合乎逻辑的步骤。病人们都很有动力，因为这个试验是大多数人在参与了几十年的研究之后遇到的第一个具体的希望。该试验设计是一项随机、双盲、安慰剂对照的两组试验，在266例（每组133例）无症状常染色体显性AD突变携带者中，选择了安全性、耐受性和生物标志物疗效最佳的纤原抗ß抗体、可溶性抗ß抗体或β -分泌酶抑制剂。受试者将接受药物或安慰剂治疗四年，以确定中枢神经系统作用机制和下游AD生物标志物的临床和认知益处参与。药物组将与安慰剂组进行比较，主要终点是CDR和方框，次要终点是认知测量、计算机认知电池、安全性和AD生物标志物。

DESCRIPTION: Autosomal dominant Alzheimer's disease (AD) has informed the field of AD research about the - Further, molecular and biochemical mechanisms that are believed to underlie the athological basis of AD mutations from autosomal dominant AD have provided animal and cellular models that are utilized to develop anti-Aß drugs. Prevention trials of autosomal dominant AD are likely to pioneer approaches for prevention - trials for all forms of AD. This proposal for a phase 3 pivotal cognitive endpoint trial of the leading amyloid- - beta modifying treatment from the ongoing phase 2 Dominantly Inherited Alzheimer's Network - Trial Unit (DIAN TU) biomarker trial aims to prevent cognitive loss in the autosomal-dominant AD population. Results - will advance the search for surrogate biomarkers and for a pathway to preventing AD in the general population. If this single phase 3 trial is positive, it may lead to te approval of a disease modifying drug for prevention. The DIAN-TU has founded the Collaboration for Alzheimer's Prevention (CAP) with the complementary-Alzheimer Prevention Initiative (API) and the ADCS Anti Amyloid treatment in Asymptomatic AD (A4) to ensure processes are efficient, public dollars are well spent, and results will advance the entire field. The DIAN TU established the DIAN Expanded Registry (www.DIANXR.org) and identified additional potential D-IAN-TU trial sites to enable the larger phase 3 prevention trial by increasing the number of participants to more than 3,000. The first prevention trial, a phase 2 biomarker trial, for people at risk of autosomal dominant AD was launched in December, 2012. The DIAN-TU Adaptive Prevention Trial (APT) leverages the existing infrastructure of the DIAN observational study and the DIAN-TU, and enrolls DIAN-TU participants as well as people at risk of autosomal dominant AD from associated sites. The DIANTU APT is the logical next step of the DIAN observational study. The patients are motivated, as this trial is the first concrete hope most have encountered after decades of research participation. The trial design is a randomized, double-blinded placebo controlled two arm trial of the selected best performing safety, tolerability and biomarker efficacy fibrillar anti-Aß antibody, a soluble anti-Aß antibody,or a beta-secretase inhibitor in 266 (n=133 per arm) asymptomatic autosomal dominant AD mutation carriers. Subjects will receive either drug or placebo for four years to determine clinica and cognitive benefit engagement of the CNS mechanism of action and downstream AD biomarkers. The drug arm will be compared to the placebo arm with the primary outcome of CDR Sum-of-Boxes and secondary outcomes of cognitive measures, computerized cognitive battery, safety, and AD biomarkers.