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: 10274819
• 负责人: MICHAEL J BOECKH
• 金额: $ 71.35万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274819
• 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 败血症相关的急性呼吸衰竭是发病，死亡率和医疗保健支出的主要原因 在世界范围内，发病率正在增加。尽管进行了深入的调查，但药理学很少 干预和护理在很大程度上是支持的。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部建立终生潜伏期，通常仅在 严重免疫抑制的患者。潜伏期的CMV重新激活（病毒复制）发生在约40％的CMV中 血清阳性，否则在重症患者期间具有免疫能力的人，并且与临床较差有关 结果，包括增加死亡率，延长机械通气和ICU住院时间增加。 令人信服的证据，暗示CMV重新激活是败血症的发病率和死亡率的因果关系。 相关的呼吸衰竭来自动物模型，而我们最近完成的NHLBI资助了2期 Ganciclovir预防的随机安慰剂对照试验（RCT）。在此试验中，在CMV血清阳性成年人中 随着败血症相关的呼吸衰竭，Ganciclovir有效地抑制了CMV复制，可接受 安全性概况，并与改善的临床结果有关，包括无通风机的日子 （VFD），幸存者的机械通气持续时间较短，较短的ICU住院时间和改进 第7天幸存者的PAO2/FIO2比率。我们假设IV Ganciclovir在重症疾病的早期服用 有效抑制与败血症相关急性呼吸道的CMV血清阳性成年人中的CMV重新激活 失败，从而减少肺部损伤，加速恢复并改善临床结果。 我们建议进行3阶段RCT，以确定是否给予预防性的抗病毒药物ganciclovir 当ICU入院后5天内给药时，改善VFD和其他临床相关结果 CMV血清阳性免疫能力成年人与败血症相关的急性呼吸衰竭。我们将衡量 研究干预对主要试验结果（VFD）和次级结果的影响（死亡率为28 天数，幸存者的机械通气持续时间，氧合，静态呼吸系统依从性，CMV 血浆和肺部重新激活，以及6个月时的长期结局核心。在探索性分析中，我们 将评估基线因子作为CMV重新激活的预测因子，并表征CMV病毒的关系 带有VFD和其他临床结果的动力学。 我们的跨学科团队在成功协调多站点的基于ICU的多站点方面拥有独特的经验 RCT。我们已经在美国建立了一个由19个临床站点组成的网络，所有这些网站都有强大的基础设施 ICU临床试验和招募患者进入RCT的能力。如果有效，这个便宜且可行 干预有可能显着改善败血症相关呼吸衰竭患者的护理， 实质上改变了临床实践，并为败血症-CMV重新激活关系提供了新的见解。