A biomarker-driven trial of angiotensin receptor blockers for prodromal Alzheimer

 描述（由申请人提供）：肾素血管紧张素醛固酮系统（RAAS）是一种理想的系统，用于安全有效地药理学调节阿尔茨海默病（AD）发病机制中涉及的血管因子。具体而言，血管紧张素受体阻滞剂（ARB）可能会积极改变AD的神经病理学标志物，包括淀粉样蛋白β和Tau。ARB还改变血管功能和炎症、脑灌注和内皮功能障碍。轻度认知障碍患者的脑脊液（CSF）中可能含有AD标志性生物标志物（MCI-AD），这为AD的最早临床阶段的药物检测提供了一个黄金窗口。使用CSF生物标志物驱动的临床试验是AD研究中的重要方法，并且可以解决AD药物开发中的先前失败。它提高了诊断的准确性，并确定患者在转换为临床AD的边缘。这两个因素都提高了II期试验的效率并降低了风险 失败的第三阶段过渡。此外，探索有希望的现有药物（即"再利用"）如ARB的潜在益处缩短了为这种毁灭性疾病提供急需的管理选择的时间。外周和中枢血管功能的生物标志物可能是检测坎地沙坦作为AD新型治疗方法的有效性的重要替代标志物，特别是用于评价假设的作用机制和验证靶点结合。我们计划在这项II期研究中纳入一组神经血管生物标志物（Tau、淀粉样蛋白β成像、灌注、海马体积和血管功能），以确定坎地沙坦治疗MCI-AD的大型试验的理想替代终点。因此，我们建议在40名具有CSF AD特征的非高血压MCI-AD患者中使用坎地沙坦进行一项为期1年的II期双盲随机临床试验。我们的过度假设是，在MCI-AD患者中，坎地沙坦治疗是安全的，并且与改善的神经元和血管AD相关生物标志物相关。 在MCI-AD中进行的试验，（ii）评估坎地沙坦在非高血压MCI-AD患者中的安全性，（iii）帮助我们从纳入的神经系统疾病组中选择替代终点。 和血管生物标志物的研究参与者将从大亚特兰大地区招募，并在埃默里阿尔茨海默病研究中心（ADRC）的临床站点进行评估。评估将包括腰椎穿刺、神经影像学、非侵入性血管评估以及循环细胞和蛋白质炎症测量。这些数据将指导未来的III期试验。

 DESCRIPTION (provided by applicant): The renin angiotensin aldosterone system (RAAS) is an ideal system to target for safe and effective pharmacological modulation of vascular factors centrally involved in Alzheimer's disease (AD) pathogenesis. Specifically, angiotensin receptor blockers (ARBs) may positively alter neuropathological markers of AD including Amyloid beta and Tau. ARBs also alter vascular function and inflammation, cerebral perfusion, and endothelial dysfunction. Patients with mild cognitive impairment may harbor AD-signature biomarkers (MCI- AD) in their cerebrospinal fluid (CSF) which offers a golden window of opportunity for drug testing in the earliest clinical stages of AD. The use of a CSF biomarker-driven clinical trial is an important approach in AD research and may address prior failures in AD drug development. It improves diagnostic accuracy and identifies patients at the verge of conversion to clinical AD. Both factors improve efficiency of phase II trials and decrease the risk of failed Phase III transition. Further, exploring the potential benefit of promising existing drug (i.e. "repurposing") such as ARBs shortens the time to provide urgently needed management options for this devastating illness. Biomarkers of peripheral and central vascular function may be important surrogate markers to test the effectiveness of candesartan as a novel treatment for AD, specifically to evaluate hypothesized mechanisms of action and to validate target engagement. We plan to incorporate a set of neuro- vascular biomarkers (Tau, Amyloid β imaging, perfusion, hippocampal volume, and vascular function) in this phase II study to identify the ideal surrogate endpoint for a larger trial of candesartan in MCI-AD. Therefore, we are proposing to conduct a 1-year PHASE II double-blind randomized clinical trial using candesartan in 40 non-hypertensive individuals with MCI-AD who have CSF AD signature profiles. Our over-arching hypothesis is that in individuals with MCI-AD, treatment with candesartan is safe and is associated with improved neuronal and vascular AD-related biomarkers This pilot study will (i) test the feasibility of conducting a biomarker-driven clinical trial in MCI-AD, (ii) assess the safety of candesartan in non-hypertensive individuals with MCI-AD, and (iii) aid us in the selection of the surrogate endpoint (s) from the included set of neuro- and vascular biomarkers for an ARB trial. Participants will be recruited from the greater Atlanta area and evaluated at the clinical site of the Emory Alzheimer's disease research center (ADRC). Evaluations will include lumbar puncture, neuroimaging, non-invasive vascular assessments, and circulating cellular and protein inflammatory measures. These data will guide a future PHASE III trial.