OPTIMIZE - CCC - Lead Application

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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.