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: 10670177
• 负责人: Michele Kong
• 金额: $ 65.91万
• 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/10670177
• 关键词: Academy; Acute; Acute respiratory failure; Admission activity; Age; Airway Disease; American; Anti-Inflammatory Agents; Antibiotics; Applications Grants; Arrhythmia; Azithromycin; Bronchiolitis; Cannulas; Cessation of life; Child; Child Health; Childhood; Chronic; Clinical; Continuous Positive Airway Pressure; 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; 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; Randomized, Controlled Trials; Recording of previous events; Recovery; Research; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Safety; Secondary to; Severity of illness; Suction; 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; aspirate; biomarker identification; burden of illness; cost; effective intervention; effectiveness evaluation; endotracheal; immunoregulation; inclusion criteria; infant morbidity; millisecond; mouse model; novel marker; outcome prediction; participant enrollment; 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）引起的肺疾病与大量短期和长期有关 婴儿和儿童的发病率。尽管疾病负担很大，但目前的管理仍然有限。 开发有效的RSV急性感染干预措施将对 儿童的公共卫生。基质金属蛋白酶（MMP）-9是一种与之相关的蛋白酶 RSV发病机理。阿奇霉素（AZM）是一种常用的大环内酯类抗生素，具有众所周知的安全性 具有免疫调节作用的特征对其他炎症气道有益 疾病并可能通过基于MMP-9的作用机理起作用。我们完成了第二阶段，随机 高剂量AZM的对照试验（RCT）[20 mg/kg（iv）x 3天]，并证明治疗是 安全且与住院时间降低和气管气管MMP-9浓度降低有关 在机械通风的儿童中。综上所述，这些数据提供了令人信服的证据 以多为中心的III期RCT来确定AZM的有效性。总体假设 ARRC试验（用于儿童RSV诱导的呼吸衰竭的AZM治疗）是在施用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。测试这个 总体假设，我们已经开发了一个小儿重症监护医师的研究网络，以招募370 高剂量AZM的双掩盖安慰剂对照RCT的儿童。纳入标准的年龄较小 超过2年，急性呼吸道衰竭继发于RSV感染，需要大量入院ICU 呼吸支持[定义为机械通气，非侵入性双层正气道压力（BIPAP）， 持续阳性急性压力（CPAP）或高流量鼻套管（HFNC）治疗> 1L/kg/min 流]。排除标准包括以前在7天内使用AZM，心律不齐，慢性家庭 通风/氧合和免疫抑制条件。我们将测试以下目标：1：高剂量 AZM给药将导致住院时间减少，氧疗法持续时间减少 ICU住院时间降低。注册患者将接受高剂量AZM或安慰剂的管理，接受全部 其他基于标准美国儿科学院RSV感染指南的疗法，以及 结果将被评估； 2：高剂量AZM的给药将导致喘息数量减少 初次感染后12个月内的情节和第一次喘息情节和3：鼻腔 接受AZM的患者将减少MMP-9驱动的肺部炎症的标记，并预测 结果。成功完成此有影响力的赠款申请将决定AZM的有效性 患有严重RSV感染的儿童的恢复。该试验的积极结果将代表范式 严重RSV感染的管理转移，作为急性和RSV后的首次成功治疗 相关的呼吸加剧，并有可能鉴定疾病预后的新生物标志物。