A Phase III Randomized Controlled Trial of Azithromycin for RSV-induced Respiratory Failure in Children

阿奇霉素治疗 RSV 引起的儿童呼吸衰竭的 III 期随机对照试验

• 批准号: 10458679
• 负责人: Michele Kong
• 金额: $ 65.64万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458679
• 关键词: Academy; Acute; Acute respiratory failure; Admission activity; Age; Airway Disease; American; Anti-Inflammatory Agents; Antibiotics; Applications Grants; Arrhythmia; Aspirate substance; Azithromycin; Biological Markers; Bronchiolitis; Cannulas; Cessation of life; Child; Child Health; Childhood; Chronic; Clinical; Critical Care; Data; Disease Outcome; Dose; Double-Blind Method; Drug usage; Effectiveness; Electrocardiogram; Enrollment; Exclusion Criteria; Future; Gelatinase B; Guidelines; Heart Diseases; Heart Rate; Home; Hospitalization; Human; IL8 gene; Immune response; Inflammatory; Injury; Lead; Length; Length of Stay; Leukocyte Elastase; Lung; Lung diseases; Macrolides; Masks; Measurement; Measures; Mechanical ventilation; Mediating; Nose; Outcome; Oxygen Therapy Care; Pathway interactions; Patients; Pediatrics; Peptide Hydrolases; Phase; Physicians; Placebo Control; Placebos; Pneumonia; Positive-Pressure Respiration; Primary Infection; Public Health; Pulmonary Inflammation; Pyloric Stenosis; Randomized Controlled Trials; Recording of previous events; Recovery; Research; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Safety; Secondary to; Severity of illness; Supportive care; System; Techniques; Testing; Time; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Viral; Viral Load result; Viral Pathogenesis; Virus Diseases; Virus Replication; Wheezing; Work; acute infection; base; burden of illness; cost; effective intervention; effectiveness evaluation; endotracheal; immunoregulation; inclusion criteria; infant morbidity; millisecond; mouse model; novel marker; outcome prediction; positive airway pressure; randomized placebo controlled trial; respiratory; therapeutic target; ventilation

Lung disease caused by Respiratory Syncytial Virus (RSV) is associated with substantial short and long-term morbidity for infants and children. Despite this far-reaching disease burden, current management is limited. Developing an effective intervention for acute infection with RSV would have an enormous impact on the public health of children. Matrix metalloproteinase (MMP)-9 is a protease that has been implicated in RSV pathogenesis. Azithromycin (AZM) is a commonly used macrolide antibiotic with a well-known safety profile that has immunomodulatory effects that have been beneficial against other inflammatory airway diseases and may work through an MMP-9-based mechanism of action. We completed a Phase II, randomized controlled trial (RCT) of high-dose AZM [20 mg/kg (IV) x 3 days], and demonstrated that the treatment was safe and associated with decreased hospital length of stay and decreased endotracheal MMP-9 concentrations in mechanically-ventilated children. Taken together, these data provide compelling evidence that justifies a multi-centered Phase III RCT to determine the effectiveness of AZM. The overarching hypothesis of the ARRC Trial (AZM treatment for RSV-induced Respiratory Failure in Children) is administration of AZM during acute, RSV-induced respiratory failure will be beneficial, mediated through an MMP-9 pathway. To test this overall hypothesis, we have developed a research network of pediatric critical care physicians to enroll 370 children in a double-masked placebo-controlled RCT of high-dose AZM. Inclusion criteria will be age less than 2 years and acute respiratory failure secondary to RSV infection requiring ICU admission with intensive respiratory support [defined as mechanical ventilation, non-invasive bi-level positive airway pressure (BiPAP), continuous positive end-expiratory pressure (CPAP) or high-flow nasal cannula (HFNC) therapy of > 1L/kg/min of flow]. Exclusion criteria includes previous use of AZM within 7 days, cardiac arrhythmias, chronic home ventilation/oxygenation and immunosuppressive conditions. We will test the following aims: 1: High-dose AZM administration will result in decreased length of hospital stay, decreased duration of oxygen therapy and decreased ICU length of stay. Enrolled patients will be administered high-dose AZM or placebo, receive all other therapies based on standard American Academy of Pediatrics guidelines for RSV infection, and outcomes will be assessed; 2: Administration of high-dose AZM will result in reduced number of wheezing episodes over 12 months after primary infection and the time to the first wheezing episode and 3: Nasal markers of MMP-9 driven lung inflammation will be decreased in patients receiving AZM, and predictive of outcome. Successful completion of this impactful grant application will determine the effectiveness of AZM on the recovery of children with severe RSV infection. A positive result from this trial will represent a paradigm shift in the management of severe RSV infection, as the first successful treatment for acute and post-RSV related respiratory exacerbation and has the potential to identify novel biomarkers of disease outcome.

由呼吸道合胞病毒（RSV）引起的肺部疾病与大量的短期和长期疾病相关。 婴儿和儿童的发病率。尽管有这种影响深远的疾病负担，但目前的管理是有限的。 开发一种有效的RSV急性感染干预措施将对 儿童的公共健康。基质金属蛋白酶（MMP）-9是一种蛋白酶，其已经被牵连到 RSV发病机制。阿奇霉素（Azithromycin，AZM）是一种常用的大环内酯类抗生素，其安全性众所周知 具有免疫调节作用，对其他炎症性气道有益 疾病，并可能通过基于MMP-9的作用机制发挥作用。我们完成了一项II期随机 高剂量AZM [20 mg/kg（IV）× 3天]的对照试验（RCT），并证明治疗是 安全且与住院时间缩短和气管内MMP-9浓度降低相关 在机械通风的儿童中。综合起来，这些数据提供了令人信服的证据，证明 一项多中心III期RCT，旨在确定AZM的有效性。最重要的假设是 ARRC试验（AZM治疗RSV诱导的儿童呼吸衰竭）是在治疗期间给予AZM。 通过MMP-9途径介导的急性RSV诱导的呼吸衰竭将是有益的。为了验证这一 总体假设，我们已经建立了一个儿科重症监护医生的研究网络，招募了370名 一项高剂量AZM的双盲安慰剂对照RCT中的儿童。入选标准为年龄小于 2年以上和继发于RSV感染的急性呼吸衰竭，需要ICU住院， 呼吸支持[定义为机械通气，无创双水平气道正压通气（BiPAP）， 持续呼气末正压通气（CPAP）或高流量鼻插管（HFNC）治疗> 1 L/kg/min 流）。排除标准包括7天内既往使用AZM、心律失常、慢性家庭 通气/氧合和免疫抑制状况。我们将测试以下目标：1：高剂量 AZM给药将导致住院时间缩短，氧疗持续时间缩短， 缩短ICU住院时间。入组患者将接受高剂量AZM或安慰剂，接受所有 基于美国儿科学会RSV感染标准指南的其他疗法，以及 将评估结局; 2：给予高剂量AZM将导致喘息次数减少 原发性感染后12个月内的发作和首次喘息发作的时间，以及3：鼻 接受AZM的患者中MMP-9驱动的肺部炎症的标志物将减少，并且预测 结果。成功完成这一有影响力的赠款申请将决定AZM的有效性 严重RSV感染儿童的康复。这次试验的积极结果将代表一种范式 严重RSV感染管理的转变，作为急性和RSV感染后的首次成功治疗 相关的呼吸恶化，并有可能确定新的生物标志物的疾病结果。