Planning grant for CMV suppression to reduce mortality in hospitalized, HIV-exposed children

为抑制巨细胞病毒（CMV）提供规划拨款，以降低感染艾滋病毒的住院儿童的死亡率

• 批准号: 10620961
• 负责人: Jennifer Ann Slyker
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620961
• 关键词: Administrator; Admission activity; Adult; Africa South of the Sahara; African; Age; Agreement; Antiviral Agents; Antiviral Therapy; Applications Grants; Biological Markers; Blood; Budgets; Case Report Form; Cause of Death; Cessation of life; Child; Child Health; Childhood; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Communities; Consent; County; Critical Illness; Cytomegalovirus; Cytomegalovirus Infections; Data; Databases; Dependence; Detection; Development; Drug Kinetics; Educational Curriculum; Enrollment; Ensure; Etiology; Europe; Future; Ganciclovir; Gastroenteritis; Goals; Government; Grant; HIV; HIV Seronegativity; Health; Hospitalization; Hospitalized Child; Hospitals; Hypoxia; Immunocompetent; Individual; Information Dissemination; Inpatients; Institution; Intensive Care; International; Intervention; Investigation; Kenya; Laboratories; Link; Logistics; Manuals; Mechanical ventilation; Monitor; Neutropenia; Observational Study; Outcome; Outpatients; Oxygen; Pathologic; Pathology; Patients; Physicians; Placebos; Pneumonia; Policy Maker; Prevalence; Procedures; Prophylactic treatment; Protocols documentation; Public Health; Publications; Randomized; Randomized, Controlled Trials; Research; Research Design; Research Personnel; Risk; Role; Safety; Seminal; Sepsis; Site; Statistical Data Interpretation; Training; Treatment Efficacy; Universities; Ventilator; Viral Load result; Viremia; Washington; Woman; Work; aged; antiretroviral therapy; clinical trial protocol; cohort; data management; design; early childhood; high risk; improved; improved outcome; instrument; intestinal injury; lung injury; material transfer agreement; meetings; mortality; multi-site trial; neutrophil; operation; organizational structure; primary endpoint; primary outcome; quality assurance; randomized trial; recruit; respiratory; standard of care; wasting

ABSTRACT Increasing evidence suggests the detection of cytomegalovirus (CMV) viremia during serious illness may identify a subset of individuals at elevated risk for poor outcomes. Associations between CMV viremia and mortality have been found in immunocompetent adults admitted to intensive care in the US and Europe, and in children living with HIV (CLHIV) and HIV-exposed uninfected (HEU) children hospitalized in Kenya. A trial in HIV-negative adults with severe sepsis found that randomization to ganciclovir prophylaxis reduced the risk of CMV reactivation and decreased oxygen dependency, suggesting a potential causal link between CMV replication and outcomes. Together these data suggest suppression of CMV viremia may improve outcomes in severely ill patients, and our goal is to conduct a randomized controlled trial (RCT) in HIV-exposed (CLHIV and HEU) children in Kenya, where CMV prevalence nears 100% and inpatient mortality rates for severely ill children are ~30%. The proposed trial will enroll children aged <24 months, with CMV viremia >1000 IU/ml, and will randomize children to receive either standard of care or antiviral therapy to suppress CMV viremia. Primary endpoints will be 6-month all-cause mortality, risk of neutropenia, and the combined outcome of death or continued hospitalization at 15 days. Clinical and blood biomarkers of lung and intestinal injury, and pathological investigations will inform mechanisms of intervention efficacy. This proposal brings together an international team of clinical and scientific experts to develop a randomized trial which will determine whether suppression of CMV viremia using antiviral therapy is safe and reduces mortality and other deleterious outcomes in highly vulnerable children. This Planning Period will optimally prepare the team and sites to conduct the proposed RCT. In Aim 1 we will finalize the protocol and all study instruments, including the statistical analysis and data management plans, data safety and monitoring plan (DSMP), data safety and monitoring board (DSMB) and charter, development of recruitment and consent materials, case report forms (CRFs), and a detailed grant proposal budget for the clinical trial. In Aim 2 we will convene the study investigators, clinical and scientific advisors and key government and community stakeholders, and to develop a roles and responsibilities plan for multisite trial coordination and results dissemination. In Aim 3 we will finalize the Manual of Operations (MOP) and prepare the sites to implement the clinical trial protocol. If the intervention is found to be safe and effective, the collaborative team is ideally poised to work with Kenyan facilities and policymakers to develop further trials and/or scale the intervention.

抽象的 越来越多的证据表明，在严重疾病期间检测到巨细胞病毒（CMV）病毒血症可能 识别出不良结果风险较高的一小部分人。 CMV 病毒血症与 在美国和欧洲，在接受重症监护的免疫功能正常的成年人中发现了死亡 肯尼亚住院的艾滋病毒感染儿童 (CLHIV) 和未感染艾滋病毒暴露的儿童 (HEU)。审判于 患有严重脓毒症的 HIV 阴性成人发现，随机接受更昔洛韦预防可降低感染的风险 CMV 重新激活和氧依赖性降低，表明 CMV 之间存在潜在因果关系 复制和结果。这些数据共同表明，抑制 CMV 病毒血症可能会改善以下患者的预后： 重症患者，我们的目标是对 HIV 暴露者（CLHIV 和 HEU）肯尼亚儿童，CMV 患病率接近 100%，重症患者住院死亡率 儿童约为 30%。拟议的试验将招募年龄 <24 个月、CMV 病毒血症 >1000 IU/ml 的儿童， 并将随机分配儿童接受标准护理或抗病毒治疗以抑制 CMV 病毒血症。 主要终点是 6 个月全因死亡率、中性粒细胞减少症风险以及死亡综合结果 或继续住院15天。肺和肠道损伤的临床和血液生物标志物，以及 病理学研究将为干预功效机制提供信息。 该提案汇集了一个由临床和科学专家组成的国际团队来开发随机 试验将确定使用抗病毒疗法抑制 CMV 病毒血症是否安全并可减少 高度脆弱儿童的死亡率和其他有害后果。本规划期将最佳 准备团队和地点来进行拟议的 RCT。在目标 1 中，我们将最终确定方案和所有研究 工具，包括统计分析和数据管理计划、数据安全和监测计划 (DSMP)、数据安全和监控委员会 (DSMB) 和章程、招募和同意的制定 材料、病例报告表 (CRF) 以及临床试验的详细拨款提案预算。在目标 2 中，我们将 召集研究研究者、临床和科学顾问以及主要政府和社区 利益相关者，并制定多地点试验协调和结果的角色和职责计划 传播。在目标 3 中，我们将最终确定操作手册 (MOP) 并准备实施地点 临床试验方案。如果发现干预措施安全有效，那么协作团队是理想的选择 准备与肯尼亚机构和政策制定者合作，开展进一步的试验和/或扩大干预规模。