1/2 Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients with Acute Respiratory Failure and Sepsis

1/2 更昔洛韦预防急性呼吸衰竭和脓毒症患者巨细胞病毒再激活

• 批准号: 9976966
• 负责人: MICHAEL J BOECKH
• 金额: $ 234.19万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976966
• 关键词: Acute respiratory failure; Admission activity; Adult; Age; Animal Model; Antiviral Agents; Area; Caring; Clinical; Clinical Trials; Collaborations; Critical Illness; Cytomegalovirus; Cytomegalovirus Infections; Data Analyses; Data Coordinating Center; Disease; Double-Blind Method; Enrollment; Event; Exposure to; Functional disorder; Funding; Ganciclovir; Gender; Grant; Health Expenditures; Herpesviridae; Hospitalization; Hour; Human; Immunocompetent; Immunocompromised Host; Incidence; Infrastructure; Intervention; Intervention Studies; Investigation; Investigational Therapies; Kinetics; Length of Stay; Life; Lung; Lymphocyte Count; Measures; Mechanical ventilation; Morbidity - disease rate; Multi-Institutional Clinical Trial; National Heart, Lung, and Blood Institute; Nature; Observational Study; Organ; Outcome; Patient Care; Patient Recruitments; Patient-Focused Outcomes; Patients; Persons; Pharmacology; Phase; Plasma; Population; Positioning Attribute; Predictive Factor; Prevention; Prophylactic treatment; Publishing; Race; Randomized; Recovery; Research; Research Design; Respiratory Failure; Respiratory System; Safety; Sepsis; Severity of illness; Site; Survivors; Testing; Time; Ventilator; Viral Load result; Virus; Virus Replication; adverse outcome; base; cell type; clinical practice; clinical research site; clinically relevant; comorbidity; experience; improved; improved outcome; insight; lung injury; mortality; prevent; randomized placebo controlled trial; secondary outcome; seropositive; trend; virology

PROJECT SUMMARY Sepsis-associated acute respiratory failure is a leading cause of morbidity, mortality and health care expenditure world-wide, and is increasing in incidence. Despite intensive investigation, there are few pharmacologic interventions, and care is largely supportive. Cytomegalovirus (CMV) is a human herpesvirus that infects 50- 80% of healthy adults and establishes lifelong latency in the lung, generally causing overt disease only in severely immunosuppressed patients. CMV reactivation (viral replication) from latency occurs in ~40% of CMV seropositive, otherwise immunocompetent persons during critical illness and is associated with worse clinical outcomes including increased mortality, prolonged mechanical ventilation, and increased ICU length of stay. Compelling evidence implicating CMV reactivation as a causal contributor to morbidity and mortality in sepsis- associated respiratory failure comes from animal models and our recently completed NHLBI-funded phase 2 randomized placebo-controlled trial (RCT) of ganciclovir prophylaxis. In this trial, among CMV seropositive adults with sepsis-associated respiratory failure, ganciclovir effectively suppressed CMV replication, had an acceptable safety profile, and was associated with improved clinical outcomes, including increased ventilator-free days (VFD), shorter duration of mechanical ventilation among survivors, shorter ICU length of stay, and improved PaO2/FiO2 ratio in day-7 survivors. We hypothesize that IV ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure, thereby reducing lung damage, accelerating recovery, and leading to improved clinical outcomes. We propose to conduct a phase 3 RCT to determine whether the antiviral drug ganciclovir given as prophylaxis improves VFDs and other clinically relevant outcomes when administered within 5 days of ICU admission to CMV seropositive immunocompetent adults with sepsis-associated acute respiratory failure. We will measure the effect of the study intervention on the primary trial outcome (VFDs) and secondary outcomes (mortality at 28 days, duration of mechanical ventilation in survivors, oxygenation, static respiratory system compliance, CMV plasma and lung reactivation, and a core set of longer-term outcomes at 6 months). In exploratory analyses, we will assess baseline factors as predictors for CMV reactivation, and characterize the relationship of CMV viral load kinetics with VFDs and other clinical outcomes. Our interdisciplinary team has unique experience in successfully coordinating multi-site multi-PI ICU-based RCTs. We have established a network of 19 clinical sites in the US, all of which have robust infrastructure for ICU clinical trials and proven ability to recruit patients into RCTs. If it is effective, this inexpensive and feasible intervention has the potential to significantly improve care of patients with sepsis-associated respiratory failure, substantially change clinical practice, and offer new insights into the sepsis-CMV reactivation relationship.

项目摘要 脓毒症相关的急性呼吸衰竭是发病率、死亡率和卫生保健支出的主要原因 在世界范围内，发病率正在上升。尽管深入研究，但很少有药理学 干预和护理在很大程度上是支持性的。巨细胞病毒（CMV）是一种人类疱疹病毒，感染50- 80%的健康成年人，并在肺中建立终身潜伏期，通常仅在 严重免疫抑制的患者。潜伏期的CMV再激活（病毒复制）发生在约40%的CMV 血清阳性，否则免疫功能正常的人在危重病期间，并与更差的临床 结果包括死亡率增加、机械通气延长和ICU住院时间延长。 有令人信服的证据表明CMV再激活是脓毒症发病率和死亡率的原因- 相关的呼吸衰竭来自动物模型和我们最近完成的NHLBI资助的第2阶段 更昔洛韦预防的随机安慰剂对照试验（RCT）。在这项试验中，在CMV血清阳性成人中， 脓毒症相关的呼吸衰竭，更昔洛韦有效地抑制CMV复制，具有可接受的 安全性特征，并与临床结局改善相关，包括无呼吸机天数增加 (VFD)，存活者机械通气时间缩短，ICU住院时间缩短， 第7天存活者的PaO 2/FiO 2比值。我们假设在危重病早期静脉注射更昔洛韦， 有效抑制CMV血清阳性成人脓毒症相关急性呼吸道感染中CMV再激活 失败，从而减少肺损伤，加速恢复，并导致改善的临床结果。 我们建议进行一项3期随机对照试验，以确定是否给予抗病毒药物更昔洛韦作为预防 在ICU入院后5天内给药可改善VFD和其他临床相关结局， CMV血清阳性免疫活性成人脓毒症相关急性呼吸衰竭我们将测量 研究干预对主要试验结局（VFD）和次要结局（28岁时的死亡率）的影响 天数、存活者机械通气持续时间、氧合、静态呼吸系统顺应性、CMV 血浆和肺再活化，以及6个月时的一组核心长期结果）。在探索性分析中，我们 将评估基线因素作为CMV再激活的预测因子，并描述CMV病毒与 VFD的负荷动力学和其他临床结局。 我们的跨学科团队在成功协调多中心多PI ICU方面拥有独特的经验 RCT。我们在美国建立了由19个临床中心组成的网络，所有这些中心都拥有强大的基础设施， ICU临床试验和已证实的招募患者进入RCT的能力。如果它是有效的，这是廉价和可行的 干预有可能显著改善脓毒症相关呼吸衰竭患者的护理， 实质上改变了临床实践，并为脓毒症-CMV再激活关系提供了新的见解。