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

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 婴儿和儿童的发病率。尽管疾病负担深远，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-9是一种蛋白水解酶，参与了 RSV致病机制。阿奇霉素(Azm)是一种常用的大环内酯类抗生素，安全性众所周知 具有免疫调节作用，有利于对抗其他炎症性呼吸道的轮廓 可能通过基于基质金属蛋白酶-9的作用机制发挥作用。我们完成了第二阶段的随机试验 大剂量阿司匹林[20 mg/kg(Iv)×3天]的对照试验(RCT)，证明治疗为 安全且与住院时间减少和气管内基质金属蛋白酶-9浓度降低有关 在机械通风的儿童中。总的来说，这些数据提供了令人信服的证据，证明 一项多中心的III期随机对照试验，以确定AZM的有效性。最重要的假设是 ARRC试验(AZM治疗呼吸道合胞病毒引起的儿童呼吸衰竭)是在 急性呼吸道合胞病毒引起的呼吸衰竭将是有益的，通过基质金属蛋白酶-9途径。为了测试这一点 总体而言，我们已经建立了一个儿科重症监护医生研究网络，招募了370名 接受高剂量阿奇明的双面罩安慰剂对照RCT的儿童。纳入标准将低于年龄 2年以上，呼吸道合胞病毒感染继发急性呼吸衰竭，需要重症监护室入院 呼吸支持[定义为机械通气、无创双水平正压(BiPAP)、 持续呼气末正压(CPAP)或高流量鼻插管(HFNC)治疗1L/kg/min 流量]。排除标准包括7天内曾使用阿司匹林、心律失常、慢性家族性疾病 换气/充氧和免疫抑制条件。我们将测试以下目标：1：高剂量 使用AZM将导致住院时间缩短，氧疗持续时间缩短， 减少了ICU的住院时间。入选的患者将接受大剂量阿奇米或安慰剂，接受所有 基于美国儿科学会关于RSV感染的标准指南的其他治疗方法，以及 将对结果进行评估；2：使用大剂量阿奇米将减少喘息次数 首次感染后超过12个月的发作和第一次喘息发作的时间和3：鼻腔 接受AZM治疗的患者中，基质金属蛋白酶-9引起的肺部炎症标志物将减少，并预测 结果。成功完成这项有影响力的赠款申请将决定AZM在 严重呼吸道合胞病毒感染的儿童的康复。这项试验的积极结果将代表一种范例 严重呼吸道合胞病毒感染管理的转变，作为急性和呼吸道合胞病毒后的第一个成功治疗 与呼吸恶化相关，并有可能确定疾病结局的新生物标记物。

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.