Title: 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
Funder: Health and Care Research Wales (Welsh Government)

Abstract: 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.

Lay abstract: Ten per cent of the world’s babies are born prematurely. Those born extremely prematurely may not survive and many of the survivors develop the lung disease called Chronic Lung Disease of Prematurity (CLD, often also called BPD or bronchopulmonary dysplasia). CLD develops due to underdeveloped lungs and also because they may need breathing machines (mechanical ventilators) and oxygen to keep them alive. CLD is variously defined but most commonly as needing oxygen at 28 days of age or at 36 weeks “corrected” gestation. Most babies will come off their oxygen therapy as their lungs continue to grow at least for the first 2-3 years of age. Some babies go home on oxygen placing enormous burden on the parents. Babies with CLD also have many hospital admissions and chest infections in childhood. We have noted that inflammation (redness or soreness) of the lungs is often seen in babies who develop CLD. In addition, we believe that the germ called Ureaplasma is found more frequently in the lungs of babies who develop CLD. Because the germ is acquired from the mother’s birth canal or from the womb, some doctors think that it is a simple 'bystander' not causing disease, but others believe that it can cause CLD. We have shown that babies who have Ureaplasma have lung inflammation. We have also reviewed all the published articles and found that babies who have Ureaplasma in their lungs have a greater chance of developing CLD than those who do not have Ureaplasma in their lungs. Studies have used antibiotic of the group called macrolides to treat the Ureaplasma. Early studies used erythromycin but the studies are small. More recent studies use azithromycin (AZM) with less experience of an alternative called clarithromycin. With AZM, a recent report put together the data from 3 studies and showed that CLD rates may improve after AZM treatment but total numbers studied are small. Therefore, most published papers call for a large enough trial using AZM to see if AZM can really improve CLD rates. AZM is very attractive as it has two important actions: firstly, it decreases inflammation important as lung inflammation is seen in babies who develop CLD. Secondly, it is an antibiotic against Ureaplasma. AZM and other macrolides are attractive to treat lung conditions as cells in the lung called macrophages concentrate the antibiotic. AZM has quickly become established to treat lung diseases such as cystic fibrosis and COPD. We, therefore, plan to study if a ten-day course of intravenous AZM improves survival without CLD in premature babies born at less than 30 weeks in gestation. During the treatment period, we shall collect lung fluid samples from babies via their breathing tube or from their nose/back of the mouth during routine care by the nurse and stool samples. The samples will be used to: a) see if lung Ureaplasma is removed by AZM; and b) if common germs found in the gut and lungs develop antibiotic resistance. We believe that studying antibiotic resistance is important as AZM will be widely used if the study shows that AZM improves rates of CLD. The study will find out if AZM can decrease rates of CLD in premature babies.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH