OPTIMIZE - CCC - Lead Application

描述（由申请人提供）：项目摘要囊性纤维化（CF）患者的主要疾病和死亡原因是进行性肺病。CF是由氯离子通道基因突变引起的，该基因突变使CF患者易患慢性气道感染和炎症，最终导致进行性气道损伤。铜绿假单胞菌（Pa）是CF慢性肺部感染最常见的病原体，持续感染是发病率和死亡率的重要预测因子。幸运的是，PA的早期感染对抗生素治疗更敏感，为根除生物体和延迟慢性感染提供了机会。最近完成的一项在CF和新发Pa儿童中进行的为期18个月的NIH试验（EPIC试验）的结果表明，仅在呼吸道培养为Pa阳性时给予妥布霉素吸入溶液（TIS）的抗假单胞菌治疗策略与更频繁的治疗策略相比，可导致相当的临床和微生物学结局。然而，50%的试验受试者仍然发生了肺部加重，这是CF急性临床恶化的关键体征之一，与Pa感染复发时间较短和长期临床结局较差相关。降低恶化频率的治疗方法可能会延长再感染和最终慢性Pa获得的时间。因此，除抗菌药物外，其他补充治疗策略可能有助于改善新发Pa儿童的临床和微生物学结局。阿奇霉素（AZ）是一种大环内酯类抗生素，对Pa无杀菌作用，但已证明具有抗炎作用，并在6个月内显著减少未感染Pa的6岁以下CF儿童的病情加重。然而，尚未在新感染Pa的CF年幼儿童中进行研究，也未在安慰剂对照环境中正式评估其长期安全性。我们假设，在接受标准化抗假单胞菌治疗的早期Pa感染儿童中，与安慰剂相比，使用慢性口服AZ治疗将降低肺部恶化的风险，减轻炎症，并延迟向慢性Pa感染的转变。该申请是一项多中心、随机、安慰剂对照试验，旨在评估来自45个中心的324名6个月至18岁的早期Pa感染儿童在18个月内口服AZ治疗TIS的疗效和安全性。主要终点是至肺部加重的时间，采用专家共识小组制定的加重定义。关键次要终点包括至Pa复发的时间、炎症标志物的变化和安全性，以及其他临床疗效结局，如体重、生长、住院率和肺功能测定的变化。将确定先前未研究的预测不良微生物学和/或临床应答的呼吸道微生物组特征。此CCC领导申请与DCC申请一起提交。

DESCRIPTION (provided by applicant): Project Summary The primary cause of illness and death in individuals with cystic fibrosis (CF) is progressive lung disease. CF is caused by a mutation in a chloride channel gene which predisposes individuals with CF to chronic airway infection and inflammation, ultimately contributing to progressive airway damage. Pseudomonas aeruginosa (Pa) is an organism which is the most frequent cause of chronic pulmonary infection in CF and persistent infection is a significant predictor of morbidity and mortality. Fortunately, early infection with Pa is more responsive to antibiotic therapies, providing an opportunity to eradicate the organism and delay chronic infection. Results from a recently completed 18-month NIH trial in children with CF and new onset Pa (the EPIC trial) demonstrated that an anti-pseudomonal treatment strategy with tobramycin inhalation solution (TIS) given only when respiratory cultures are positive for Pa leads to comparable clinical and microbiologic outcomes when tested against more frequent treatment strategies. However 50% of trial participants still experienced a pulmonary exacerbation, one of the key signs of acute clinical worsening in CF and one associated with a shorter time to recurrence of Pa infection and poorer long-term clinical outcomes. A therapeutic approach that reduces the frequency of exacerbation may prolong the time to re-infection and eventual chronic Pa acquisition. Thus additional complementary therapeutic strategies, in addition to antimicrobials, may be beneficial to improve clinical and microbiologic outcome in children with new onset Pa. Azithromycin (AZ), a macrolide antibiotic, is not bactericidal to Pa but has been demonstrated to have anti- inflammatory effects and significantly reduce exacerbations over a 6 month period in children with CF e6 years of age uninfected with Pa. It has not however been studied in younger children with CF newly infected with Pa or been formally evaluated in a placebo-controlled setting for long term safety. We hypothesize that the use of chronic oral AZ therapy as compared to placebo among children with early Pa infection receiving standardized anti-pseudomonal therapy with TIS will reduce the risk of pulmonary exacerbation, reduce inflammation, and delay the transition to chronic Pa infection. The application is for a multicenter, randomized, placebo controlled trial to assess efficacy and safety of oral AZ therapy with TIS over 18 months among 324 children with early Pa infection ages 6 months to 18 years from 45 centers. The primary endpoint is time to pulmonary exacerbation, utilizing a definition for exacerbation developed by an expert consensus panel. Key secondary endpoints include time to Pa recurrence, change in inflammatory markers, and safety, in addition to other clinical efficacy outcomes such as changes in weight, growth, hospitalization rate, and spirometry. Previously unstudied characteristics of the respiratory microbiome predictive of poor microbiologic and/or clinical response will be identified. This CCC lead application is submitted with a DCC application.