OPTIMIZE - CCC - Lead Application

优化 - CCC - 主要应用

• 批准号: 9310069
• 负责人: Bonnie W Ramsey
• 金额: $ 91.1万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310069
• 关键词: 10 year old; Acute; Affect; Age; Age-Years; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Azithromycin; Breathing; Bronchiectasis; Caucasians; Cessation of life; Characteristics; Child; Chloride Channels; Chronic; Clinical; Clinical Microbiology; 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; Microbiology; Morbidity - disease rate; Mucous body substance; Multicenter Trials; Mutation; Oral; Organism; Outcome; Participant; Penetration; Phenotype; Placebo Control; Placebos; Prevalence; Protocols documentation; Pseudomonas aeruginosa; Pulmonary Fibrosis; Randomized; Recurrence; Regimen; Respiratory Failure; Respiratory Signs and Symptoms; Risk; Route; Safety; Serum; Specimen; Spirometry; Standardization; Testing; Therapeutic; Time; Tobramycin; Treatment Protocols; United States; United States National Institutes of Health; Weight; airway inflammation; airway obstruction; antimicrobial; arm; base; children with cystic fibrosis; clinical efficacy; disease mechanisms study; early cystic fibrosis; experience; high risk; improved; inflammatory marker; microbiome; mortality; novel; novel marker; novel therapeutic intervention; pathogen; predicting response; predictive modeling; prevent; public health relevance; pulmonary function; randomized placebo controlled trial; rate of change; 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）：囊性纤维化患者疾病和死亡的主要原因（CF）是进行性肺部疾病。 CF是由氯化物通道基因突变引起的，该突变使患有CF的个体对慢性气道感染和炎症产生，最终导致了渐进气道损害。铜绿假单胞菌（PA）是一种生物体，是CF中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指标。幸运的是，PA早期感染对抗生素疗法的反应更快，提供了消除生物体并延迟慢性感染的机会。最近在CF和新发作PA儿童（EPIC试验）中进行的18个月NIH试验的结果表明，仅当PA可与可比的临床和微生物生物学抗药性抗衡时，抗毒素吸入溶液（TIS）仅给出了毒素吸入溶液（TIS）。然而，有50％的试验参与者仍然经历了肺部恶化，这是CF急性临床恶化的关键征兆，并且与PA感染复发和长期临床结局更短的时间有关。一种减少加重频率的治疗方法可能会延长重新感染和最终慢性PA获取的时间。因此，除了抗菌药物外，其他互补的治疗策略可能有益于改善新发作PA的儿童的临床和微生物学结果。未经PA的未感染。但是，尚未在患有PA的CF的年幼儿童中进行研究，也没有在安慰剂对照的环境中正式评估以确保长期安全。我们假设在早期PA感染的儿童接受标准化的抗孕症治疗的儿童中，使用慢性口服AZ治疗与安慰剂相比，使用TIS疗法将降低肺部恶化的风险，减少炎症并延迟过渡到慢性PA感染。该申请适用于一项多中心，随机，安慰剂对照试验，以评估324名早期PA感染的儿童在45个中心的6个月至18岁的PA感染儿童中，在18个月以上的口服AZ治疗的疗效和安全性。主要终点是使用专家共识面板开发的加重定义肺部加剧的时间。关键的次要终点包括PA复发的时间，炎症标记的变化以及安全性，以及其他临床功效结果，例如体重，生长，住院率和肺活量测定法的变化。将确定呼吸微生物组的未研究特征，可预测微生物学和/或临床反应的差。此CCC Lead应用程序与DCC申请一起提交。