AZithromycin ThErapy for Chronic lung disease (AZTEC): A randomised, placebo controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants

Design/setting: We plan a randomised, placebo controlled, double-blind trial of azithromycin to show improvement in survival without CLD (defined as oxygen dependency at 36 weeks’ postmenstrual age) in preterm-born infants <30 weeks completed gestation who are cared for in Level III neonatal units in the UK. Target population: In- and out-born <30 completed weeks’ gestational age at birth who require respiratory support for at least 2 hours during the first 72 hours of life. Babies with a realistic chance of survival; no exposure to other macrolide antibiotics (not maternal) before enrolment; no major surgical or congenital abnormalities. Health technology: Azithromycin or placebo will be commenced within 72 hours (20mg/kg once daily iv for 3 days then 10 mg/kg once daily iv for 7 days). The dosage and duration are based on achieving therapeutic levels of the drug to eradicate Ureaplasma colonisation and to utilise the drug’s anti - inflammatory activities on pulmonary inflammation that is frequently observed in babies who develop CLD. Measurement of costs and outcomes: Oxygen dependency at 36 weeks’ postmenstrual age will be physiologically assessed to define CLD. Secondary outcomes will be based on safety parameters (survival rates, adverse reactions, complications of prematurity including NEC, ROP); rates of Ureaplasma colonisation, and on development of antibiotic resistance in commensal microbes. Routinely collected data including duration/type of ventilation, overall length of respiratory support and hospital stay will be recorded. Additional resources will be sought to obtain respiratory and neurodevelopmental data at two years of corrected age, which most units now routinely collect and feed into national databases. Given the early antibiotic exposure and potential for development of antibiotic resistance, we shall also assess the carriage of resistant organisms in the gut and respiratory tract. Sample size: Based on existing data predicting survival without CLD of 50%, a 20% death rate and a 30% rate of CLD, we aim to detect a 12% improvement in survival without CLD with azithromycin, from 50% to 62%. Using a two-group chi-squared test with a 5% level for alpha and a power of 0.90, 358 patients with will be required in each group; including a 10% dropout rate, we plan to recruit 796 patients. Project timetable and recruitment rate: We plan a 49-month project: Setup: 9 months; Recruitment: 30 months; Follow up: 4 months; Analysis/writing: 6 months. The recruitment period is based on 25 neonatal units enrolling approximately 1.5 infants per month. This is balanced against the number of recruiting units with the complexities of follow-up (each recruiting unit will have on average, 3 stepdown units). Expertise: SK has expertise in inflammatory/infective processes in the development and in long term outcomes of CLD. JB has expertise in large trials in neonates and microbial role in gastrointestinal disorders of the newborn. MT has enormous experience in IMP studies of preterm infants. CG has extensive expertise in statistical analysis and trial design. HH has the necessary expertise in research design and conduct. NK has in microbial diseases in human health including development of drug resistance and role of microbes in preterm labour. JM has expertise in the microbiome including development of drug resistance in human health.