OPTIMIZE - CCC - Lead Application

优化 - CCC - 主要应用

• 批准号: 8920186
• 负责人: Bonnie W Ramsey
• 金额: $ 8.75万
• 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/8920186
• 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; Health; 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; 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.

描述（由申请人提供）： 项目摘要 囊性纤维化 (CF) 患者患病和死亡的主要原因是进行性肺病。 CF 是由氯离子通道基因突变引起的，该突变使 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原因，持续感染是发病率和死亡率的重要预测因素。幸运的是，早期 Pa 感染对抗生素治疗更敏感，从而提供了根除微生物并延缓慢性感染的机会。最近完成的一项针对 CF 和新发 Pa 儿童的为期 18 个月的 NIH 试验（EPIC 试验）的结果表明，仅当呼吸道培养物 Pa 呈阳性时才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进行测试时，可产生可比较的临床和微生物学结果。然而，50% 的试验参与者仍然经历了肺部病情加重，这是 CF 急性临床恶化的关键症状之一，并且与 Pa 感染复发时间较短和长期临床结果较差有关。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，除抗菌药物外，其他补充治疗策略可能有利于改善新发 Pa 儿童的临床和微生物学结果。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，并可显着减少 6 岁 CF e6 岁儿童 6 个月内的病情加重。 然而，尚未在新感染 Pa 的年幼 CF 儿童中进行研究，也没有在安慰剂对照环境中对其长期安全性进行正式评估。我们假设，在接受 TIS 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 疗法将降低肺部病情恶化的风险，减少炎症，并延缓向慢性 Pa 感染的转变。该申请适用于一项多中心、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 感染儿童在 18 个月内口服 AZ 疗法联合 TIS 的疗效和安全性。主要终点是肺部恶化的时间，采用专家共识小组制定的恶化定义。关键的次要终点包括 Pa 复发时间、炎症标志物变化和安全性，以及其他临床疗效结果，例如体重、生长、住院率和肺量测定的变化。将确定先前未研究的可预测微生物学和/或临床反应不良的呼吸道微生物组特征。此 CCC 主要申请是与 DCC 申请一起提交的。