1/2 REPRIEVE Extension for Trial Completion

1/2 REPRIEVE 延期以完成试验

• 批准号: 10479464
• 负责人: Pamela Susan Douglas
• 金额: $ 656.79万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10479464
• 关键词: Acquired Immunodeficiency Syndrome; Angiography; Antibodies; Antibody Response; Arterial Fatty Streak; Biological Factors; Black race; CCL2 gene; COVID-19 severity; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Characteristics; Clinical; Coagulation Process; Communities; Coronary; Coronary Arteriosclerosis; Country; Data; Data Coordinating Center; Diet; Dyslipidemias; Enrollment; Ensure; Environment; Epidemiology; Event; Female; Fibrin fragment D; Funding; Genes; Genetic; Glucose; Goals; Guidelines; HIV; Health; Heart failure; Immune; Immunoglobulin A; Immunoglobulin G; Immunologics; Incidence; Infection; Inflammation; Inflammatory; Insulin; Integration Host Factors; Interleukin-6; Investments; Knowledge; Latino; Life Style; Link; Lipids; Liver Dysfunction; Long-Term Effects; Low-Density Lipoproteins; Malignant Neoplasms; Mediating; Morphology; Myositis; National Heart, Lung, and Blood Institute; Outcome; Participant; Pathway interactions; Persons; Phenotype; Population; Populations at Risk; Positioning Attribute; Prevention strategy; Prevention trial; Primary Prevention; Proteins; Proteomics; Protocols documentation; Risk; Risk Factors; SARS-CoV-2 infection; Safety; Serotyping; Severities; Site; Smoking; Symptoms; T-Lymphocyte; Time; United States National Institutes of Health; Update; Viral Load result; adjudication; attenuation; burden of illness; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; clinical application; clinically actionable; cohort; coronary computed tomography angiography; coronary plaque; coronavirus disease; data management; efficacy evaluation; experience; follow-up; high risk; immune activation; immune function; improved; indexing; lipoprotein-associated phospholipase A(2); monocyte; mortality; novel; oxidized low density lipoprotein; participant enrollment; pleiotropism; predictive marker; prevent; primary endpoint; recruit; transcriptomics; trial design

Project Summary-Abstract Globally, cardiovascular disease (CVD) burden is increasing and a major cause of mortality among people with HIV (PWH). However, data are not yet available from large trials on an effective primary CVD prevention strategy for PWH. The ongoing REPRIEVE trial will address this critical knowledge gap, hypothesizing that statin therapy, with pleiotropic effects on LDL, immune activation and inflammatory pathways, will modify traditional and nontraditional risks and prevent major adverse cardiovascular events (MACE) in PWH. REPRIEVE is well-positioned to provide high quality, clinically actionable and generalizable information to shift the current paradigm of HIV care, in alignment with the goals of NHLBI and OAR to reduce CVD and improve the overall health of PWH. REPRIEVE has met major challenges, anticipated for a large trial. 7,770 participants (31% female, 43% Black, 25% Latino) were enrolled from over 100 sites in 12 countries, a diverse, generalizable population. Retention is high, >90%. Endpoint (MACE) are accumulating steadily despite a low median ASCVD risk score of 4.5%, consistent with the hypothesis that nontraditional risks contribute to CVD in HIV. The Mechanistic Substudy has met its goal, enrolling over 800 participants for serial coronary CT angiography (CTA) and immune function. Preliminary baseline data from the substudy support our hypothesis, linking plaque to CVD risk but also independently to IL-6 and Lp-PLA2, key indices of immune function and arterial inflammation that are being targeted in REPRIEVE. Moreover, REPRIEVE is being leveraged to assess statin effects on COVID severity, and long-term effects in PWH, critical unanswered questions for the field. REPRIEVE has executed well over 6 years and is fundamentally strong. However, with a long duration of recruitment and protocol revisions to identify the optimal at-risk group given new guidelines, median duration of follow up is still short at 3.5 years. REPRIEVE needs additional time, projected at 2 years, plus a close out year, to collect necessary MACE to ensure adequate power, analyze, and disseminate this data. The pressing need for data from a large global primary prevention trial has only grown since REPRIEVE was initiated. Completion of the trial will protect the value of the initial NIH investment and honor the commitment to our participants and scientific community to meet the Aims of the trial. This application for the Clinical Coordinating Center (CCC) of the REPRIEVE Extension for Trial Completion focuses on the clinical rationale and coordination of the trial. The Data Coordinating Center (DCC) application focuses on data management, including the coronary CTA data of the Mechanistic Substudy, and the statistical rationale for the trial design.

项目摘要-摘要 在全球范围内，心血管疾病（CVD）的负担正在增加，并且是心血管疾病患者死亡的主要原因。 艾滋病毒（PWH）。然而，关于有效的一级心血管疾病预防的大型试验数据尚未获得 威尔斯亲王医院的策略。正在进行的REPRIEVE试验将解决这一关键的知识差距，假设 他汀类药物治疗对低密度脂蛋白、免疫激活和炎症通路具有多效性， 传统和非传统风险，并预防PWH的主要不良心血管事件（MACE）。 REPRIEVE定位良好，可提供高质量、临床可操作和可推广的信息， 目前的艾滋病毒护理模式，与NHLBI和OAR的目标保持一致，以减少CVD和改善 威尔斯亲王医院的整体健康状况。REPRIEVE遇到了重大挑战，预计将进行大规模审判。7,770 参与者（31%女性，43%黑人，25%拉丁美洲人）来自12个国家的100多个地点， 可推广的人口。保留率高，> 90%。终点（MACE）尽管较低，但仍在稳步累积 ASCVD风险评分中位数为4.5%，与非传统风险导致CVD的假设一致， 艾滋病。机械子研究达到了其目标，招募了800多名参与者进行连续冠状动脉CT 血管造影（CTA）和免疫功能。子研究的初步基线数据支持我们的假设， 将斑块与CVD风险联系起来，但也独立于IL-6和Lp-PLA 2，免疫功能的关键指标， 动脉炎症是REPRIEVE的目标。此外，还利用REPRIEVE来评估 他汀类药物对COVID严重程度的影响，以及对PWH的长期影响，这是该领域尚未回答的关键问题。 REPRIEVE已经执行了6年多，基本上是强大的。然而，随着时间的推移， 招募和方案修订，以确定最佳的风险组，考虑到新的指南， 随访时间仍然较短，为3.5年。保留需要额外的时间，预计为2年，加上关闭 一年，收集必要的MACE以确保足够的电力、分析和传播这些数据。按压 自REPRIEVE启动以来，对大型全球一级预防试验数据的需求不断增长。 试验的完成将保护NIH最初投资的价值，并荣誉对我们的承诺。 参与者和科学界，以满足试验的目的。本申请为临床协调 试验完成延期中心（CCC）重点关注临床依据， 协调审判。数据协调中心（DCC）应用程序侧重于数据管理， 包括机制子研究的冠状动脉CTA数据和试验设计的统计学依据。