OPTIMIZE - CCC - Lead Application

优化 - CCC - 主要应用

• 批准号: 8502016
• 负责人: Bonnie W Ramsey
• 金额: $ 115.91万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502016
• 关键词: 10 year old; Acute; Affect; Age; Age-Years; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Azithromycin; Biological Markers; Breathing; Bronchiectasis; Caucasians; Caucasoid Race; Cessation of life; Characteristics; Child; Chloride Channels; Chronic; Clinical; Complex; Consensus; Controlled Clinical Trials; Cystic Fibrosis; Data; Disease; Disease Progression; Edema; Exposure to; Frequencies; Funding; Future; Genes; Growth; Height; Hospitalization; Incidence; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Lead; Life; Link; Lung; Lung diseases; Macrolide Antibiotics; Macrolide-resistance; Measures; Morbidity - disease rate; Mucous body substance; Multicenter Trials; Mutation; Oral; Organism; Outcome; Participant; Penetration; Phenotype; Placebo Control; Placebos; Prevalence; Protocols documentation; Pseudomonas aeruginosa; Public Health; Randomized; Recurrence; Regimen; Respiratory Failure; Risk; Route; Safety; Serum; Solutions; Specimen; Spirometry; Symptoms; System; Testing; Therapeutic; Time; Tobramycin; Treatment Protocols; United States; United States National Institutes of Health; Weight; airway inflammation; airway obstruction; antimicrobial; arm; bactericide; base; children with cystic fibrosis; clinical efficacy; disease mechanisms study; early cystic fibrosis; experience; high risk; improved; inflammatory marker; microbiome; mortality; novel; novel therapeutic intervention; pathogen; predictive modeling; prevent; public health relevance; pulmonary function; randomized placebo controlled trial; repository; respiratory; response; standard of care; theories; treatment strategy

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.

囊性纤维化（CF）患者发病和死亡的主要原因是进行性肺部疾病。CF是由氯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慢性肺部感染的最常见原因，持续感染是发病率和死亡率的重要预测因子。幸运的是，早期感染Pa对抗生素治疗更有反应，这为根除细菌和延缓慢性感染提供了机会。最近完成的一项针对CF和新发Pa患儿的为期18个月的NIH试验（EPIC试验）结果表明，仅在Pa呼吸培养呈阳性时给予妥布霉素吸入溶液（TIS）抗假单胞菌治疗策略，与更频繁的治疗策略相比，临床和微生物学结果可比较。然而，50%的试验参与者仍然经历了肺恶化，这是CF急性临床恶化的关键标志之一，并且与较短的Pa感染复发时间和较差的长期临床结果相关。减少恶化频率的治疗方法可能会延长再次感染和最终慢性Pa获得的时间。因此，除抗菌剂外，其他补充治疗策略可能有助于改善新发Pa患儿的临床和微生物学预后。阿奇霉素（AZ）是一种大环内酯类抗生素，对Pa没有杀菌作用，但已被证明具有抗炎作用，并在6个月内显著减少未感染Pa的CF儿童的恶化。然而，尚未对新感染Pa的年幼CF儿童进行研究，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，与安慰剂相比，在接受标准化抗假单胞菌治疗的早期Pa感染儿童中，使用慢性口服阿斯利康治疗可以降低肺恶化的风险，减少炎症，并延迟向慢性Pa感染的过渡。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岁早期Pa感染儿童口服阿斯利康治疗TIS超过18个月的疗效和安全性。主要终点是肺恶化的时间，使用由专家共识小组制定的恶化定义。关键的次要终点包括到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果，如体重、生长、住院率和肺活量的变化。将确定以前未研究的呼吸微生物组预测不良微生物学和/或临床反应的特征。此CCC前置申请与DCC申请一起提交。