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

血管紧张素受体阻滞剂治疗前驱阿尔茨海默病的生物标志物驱动试验

• 批准号: 9030268
• 负责人: IHAB M HAJJAR
• 金额: $ 75.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030268
• 关键词: Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Angiotensin II; Angiotensin Receptor; Area; Autopsy; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cardiovascular system; Cerebrospinal Fluid; Cerebrum; Clinical; Clinical Trials; Cognitive; Creatinine; Data; Data Analyses; Dose; Double-Blind Method; Effectiveness; Evaluation; Event; Executive Dysfunction; Failure; Future; Goals; Hippocampus (Brain); Hypotension; Image; Individual; Inflammation; Inflammatory; Lead; Magnetic Resonance Imaging; Measures; Memory; Modeling; Neurofibrillary Tangles; Neurons; Outcome; Participant; Pathogenesis; Pathology; Patients; Perfusion; Peripheral; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Positron-Emission Tomography; Proteins; Randomized Clinical Trials; Rattus; Recruitment Activity; Renin-Angiotensin-Aldosterone System; Research; Risk; Safety; Serum; Spin Labels; Spinal Puncture; Staging; Stem cells; Surrogate Endpoint; Surrogate Markers; System; Testing; Therapeutic Agents; Time; Work; base; biomarker-driven; cerebrovascular; clinical research site; diagnostic accuracy; drug development; drug testing; endothelial dysfunction; executive function; hemodynamics; hyperkalemia; improved; inflammatory marker; mild cognitive impairment; neuroimaging; neurovascular; neurovascular injury; novel; phase 1 study; phase 2 study; phase II trial; phase III trial; pre-clinical; public health relevance; tau Proteins; uptake; vascular factor

 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.