REPRIEVE - DCC

缓刑 - DCC

基本信息

批准号：
8730997
负责人：
UDO HOFFMANN
金额：
$ 135.91万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-08 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730997
关键词：
AIDS clinical trial group Acquired Immunodeficiency Syndrome Address Ancillary Study Angiography Archives Arteries Authorization documentation Bacterial Infections Biological Markers Biology Blood Blood Tests Blood Vessels Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Characteristics Clinical Clinical Data Clinical Trials Clinical Trials Data Monitoring Committees Coagulation Process Collaborations Collection Communication Companions Computers Controlled Clinical Trials Coronary Data Data Analyses Data Collection Data Coordinating Center Data Reporting Databases Diabetes Mellitus Disease Electronics Enrollment Ensure Event Grant Guidelines HIV Heart Heart Arrest Heart Diseases Hospitalization Image Immune Inflammation Inflammatory Lead Leadership Letters Liver Low-Density Lipoproteins Malignant Neoplasms Mediating Medicine Morphology Muscle Myocardial Infarction National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Disease Organization and Administration Participant Patients Peripheral Placebo Control Placebos Preparation Prevalence Prevention strategy Primary Prevention Principal Investigator Procedures Process Quality Control Randomized Research Research Design Risk Risk Factors Safety Site Stroke Study models System Testing Training United States Unstable angina Work X-Ray Computed Tomography adjudication antiretroviral therapy atherogenesis attenuation blood glucose regulation clinical Diagnosis clinical research site data acquisition data exchange data management data sharing design follow-up high risk immune activation indexing low density lipoprotein inhibitor meetings monocyte mortality novel pragmatic trial prevent protocol development public health relevance randomized trial tool treatment strategy vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is increased 50-100% among HIV- infected patients, occurring often among relatively younger HIV patients despite minimal traditional risk factors, and normal LDL. Indeed, the mechanisms of atherogenesis in HIV are unique and relate to increased immune activation, as demonstrated by increased indices of monocyte activation and chemoattraction. Moreover, detailed coronary imaging by cardiac computed tomography angiography (CCTA) demonstrates a significantly increased prevalence of non-calcified plaque, with high risk morphological characteristics, including positive remodeling and low CT attenuation. Despite the significant increase in CVD among HIV-infected patients, no treatment strategies as yet exist to prevent this disease. Treatment with statins represents an attractive option to prevent CVD in HIV. Statins demonstrate potent effects to lower LDL and are known to uniquely reduce monocyte activation, chemoattraction and endothelial activation, potential pathogenetic mechanisms of atherogenesis in HIV. In this grant, we will perform a multicenter, randomized placebo-controlled clinical trial (REPRIEVE) of pitavastatin, as a primary prevention strategy for CVD in HIV. 5300 HIV-infected subjects without known heart disease and with LDL<130 mg/dL and Framingham Risk Score < 20 will be enrolled. Pitavastatin has been shown to safely and effectively lower LDL in HIV and is known to have minimal interactions with antiretroviral therapy. The primary endpoint will be the effects of statin therapy on major adverse cardiac events (MACE) including atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, resuscitated cardiac arrest, nonfatal stroke. In addition, we will perform an embedded mechanistic study among 800 subjects using detailed CCTA imaging and sophisticated biomarker assessments to determine efficacy and mechanisms of statin therapy to reduce non-calcified plaque volume, and high risk morphological features. Change in specific inflammatory biomarkers, including monocyte activation, endothelial activation, arterial inflammation and coagulation, will be determined in the mechanistic study and then assessed with regard to MACE in the primary study, to provide critically needed information on the mechanisms of statin effects in HIV. Detailed safety indices, including effects on glucose homeostasis, liver and muscle will be determined, and effects on non CVD events will be explored The trial will be performed in collaboration with the AIDS Clinical Trial Group, as well as clinical research sites within the NIAID research network, including sites from the INSIGHT network. With 5300 planned participants the trial is well powered (90%) to detect a HR of 0.65, assuming a baseline event rate of 18/1000 PY. This novel trial will provide much needed information on a critical problem for HIV- infected patients and will serve as a model for the study of tailored primary prevention strategies for other inflammatory diseases in which immune mediated atherogenesis is an important contributing factor.

描述（由申请人提供）：尽管传统危险因素很少且 LDL 正常，但 HIV 感染患者的心血管疾病 (CVD) 增加 50-100%，通常发生在相对年轻的 HIV 患者中。事实上，HIV 中动脉粥样硬化形成的机制是独特的，并且与免疫激活增加有关，单核细胞激活和化学吸引指数增加就证明了这一点。此外，通过心脏计算机断层扫描血管造影 (CCTA) 进行的详细冠状动脉成像显示，非钙化斑块的患病率显着增加，具有高风险形态特征，包括正性重塑和低 CT 衰减。尽管艾滋病毒感染者的心血管疾病显着增加，但目前尚无预防这种疾病的治疗策略。他汀类药物治疗是预防 HIV CVD 的一个有吸引力的选择。他汀类药物具有降低 LDL 的有效作用，并且已知可以独特地减少单核细胞活化、化学吸引和内皮细胞活化，以及 HIV 中动脉粥样硬化形成的潜在发病机制。在这笔拨款中，我们将进行一项匹伐他汀的多中心、随机安慰剂对照临床试验 (REPRIEVE)，作为 HIV CVD 的一级预防策略。将招募 5300 名无已知心脏病且 LDL<130 mg/dL 且弗雷明汉风险评分 <20 的 HIV 感染受试者。匹伐他汀已被证明可以安全有效地降低艾滋病毒中的低密度脂蛋白，并且已知与抗逆转录病毒治疗的相互作用最小。主要终点是他汀类药物治疗对主要不良心脏事件（MACE）的影响，包括动脉粥样硬化或其他心血管疾病死亡、非致命性心肌梗死、不稳定型心绞痛住院、冠状动脉或外周动脉血运重建、心脏骤停复苏、非致命性中风。此外，我们将使用详细的 CCTA 成像和复杂的生物标志物评估在 800 名受试者中进行嵌入式机制研究，以确定他汀类药物治疗减少非钙化斑块体积和高风险形态特征的功效和机制。特定炎症生物标志物的变化，包括单核细胞活化、内皮活化、动脉炎症和凝血，将在机制研究中确定，然后在初步研究中针对 MACE 进行评估，以提供关于他汀类药物在 HIV 中作用机制的急需信息。将确定详细的安全指标，包括对葡萄糖稳态、肝脏和肌肉的影响，并探讨对非 CVD 事件的影响该试验将与艾滋病临床试验组以及 NIAID 研究内的临床研究中心合作进行网络，包括来自 INSIGHT 网络的站点。假设基线事件率为 18/1000 PY，该试验计划有 5300 名参与者（90%）检测到 HR 为 0.65。这项新颖的试验将为艾滋病毒感染患者的一个关键问题提供急需的信息，并将作为研究针对其他炎症性疾病的定制一级预防策略的模型，在这些炎症性疾病中，免疫介导的动脉粥样硬化形成是一个重要的促成因素。