REPRIEVE - CCC - Lead Application

REPRIEVE - CCC - 主导应用

• 批准号: 8909176
• 负责人: Pamela Susan Douglas
• 金额: $ 336.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/8909176
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adverse effects; Angiography; Arterial Fatty Streak; Arteries; Atherosclerosis; Authorization documentation; Biological Factors; Biological Markers; Biology; Blood Tests; CCL2 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Coagulation Process; Collaborations; Controlled Clinical Trials; Coronary; Data; Data Coordinating Center; Disease; Dyslipidemias; Enrollment; Event; Glucose; Grant; HIV; Health; Heart; Heart Arrest; Heart Diseases; Hemoglobin; High Density Lipoprotein Cholesterol; Hospitalization; Image; Immune; Immunologics; Incidence; Infection; Inflammation; Inflammatory; Insulin; LDL Cholesterol Lipoproteins; Lead; Lipids; Liver; Liver Dysfunction; Low-Density Lipoproteins; Malignant Neoplasms; Mediating; Medicine; Morphology; Muscle; Myocardial Infarction; Myositis; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Organization and Administration; Participant; Particle Size; Pathway interactions; Patients; Peripheral; Placebo Control; Population; Prevalence; Prevention strategy; Primary Prevention; Property; Randomized; Relative (related person); Research; Risk; Risk Factors; Safety; Site; Smoking; Stroke; Study models; T-Lymphocyte; Testing; Thromboplastin; Time; United States; Unstable angina; Update; Viral Load result; Work; X-Ray Computed Tomography; antiretroviral therapy; atherogenesis; attenuation; blood glucose regulation; cardiovascular disorder risk; cardiovascular risk factor; cardiovascular visualization; clinical research site; dimer; follow-up; high risk; immune activation; immune function; improved; indexing; lipoprotein-associated phospholipase A(2); low density lipoprotein inhibitor; monocyte; mortality; novel; oxidized low density lipoprotein; prevent; response; treatment strategy; vascular inflammation

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）：心血管疾病（CVD）在HIV感染患者中增加50-100%，通常发生在相对年轻的HIV患者中，尽管传统风险因素最小，LDL正常。事实上，艾滋病毒中动脉粥样硬化形成的机制是独特的，并与增加的免疫激活有关，如单核细胞激活和化学吸引指数增加所示。此外，通过心脏计算机断层扫描血管造影术（CCTA）进行的详细冠状动脉成像显示非钙化斑块的患病率显著增加，具有高风险形态学特征，包括正重塑和低CT衰减。尽管艾滋病毒感染者的心血管疾病显著增加，但目前还没有预防这种疾病的治疗策略。他汀类药物治疗是预防HIV CVD的一种有吸引力的选择。他汀类药物显示出降低LDL的有效作用，并且已知独特地减少单核细胞活化、化学吸引和内皮活化，这些是HIV中动脉粥样硬化形成的潜在发病机制。在这项资助中，我们将进行一项多中心，随机安慰剂对照临床试验（REPRIEVE）的匹伐他汀，作为一种一级预防策略，心血管疾病的艾滋病毒。将招募5300名无已知心脏病且LDL<130 mg/dL且Fragrance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HIV中的LDL，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CVD死亡、非致死性心肌梗死、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、非致死性卒中。此外，我们将在800名受试者中进行一项嵌入式机制研究，使用详细的CCTA成像和复杂的生物标志物评估，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学特征的疗效和机制。将在机制研究中确定特定炎症生物标志物（包括单核细胞活化、内皮活化、动脉炎症和凝血）的变化，然后在主要研究中评估MACE，以提供他汀类药物对HIV作用机制的急需信息。将确定详细的安全性指标，包括对葡萄糖稳态、肝脏和肌肉的影响，并探索对非CVD事件的影响。 该试验将与艾滋病临床试验组合作进行， 作为NIAID研究网络中的临床研究中心，包括INSIGHT网络中的临床研究中心。假设基线事件发生率为18/1000 PY，在5300例计划的受试者中，试验具有良好的把握度（90%）检测到HR为0.65。这项新的试验将为HIV感染患者的关键问题提供急需的信息，并将作为研究其他炎症性疾病的定制一级预防策略的模型，其中免疫介导的动脉粥样硬化是一个重要的促成因素。