Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial

Lowe, John ORCID: https://orcid.org/0000-0003-4772-1879, Gillespie, David ORCID: https://orcid.org/0000-0002-6934-2928, Aboklaish, Ali, Lau, Tin Man Mandy ORCID: https://orcid.org/0000-0001-5894-570X, Consoli, Claudia, Babu, Malavika, Goddard, Mark, Hood, Kerenza ORCID: https://orcid.org/0000-0002-5268-8631, Klein, Nigel, Thomas-Jones, Emma ORCID: https://orcid.org/0000-0001-7716-2786, Turner, Mark, Hubbard, Marie, Marchesi, Julian ORCID: https://orcid.org/0000-0002-7994-5239, Berrington, Janet and Kotecha, Sailesh ORCID: https://orcid.org/0000-0003-3535-7627 2024. Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet Respiratory Medicine 10.1016/S2213-2600(24)00079-1

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Abstract

Background Systematic reviews have reported conflicting evidence on whether macrolide antibiotics reduce rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants born at less than 30 weeks’ gestation, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we aimed to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe CLD in preterm infants. Methods AZTEC was a multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the UK. Infants were eligible if they were born at less than 30 weeks’ gestation and had received at least 2 h of either non-invasive (continuous positive airway pressure or humidified high flow nasal cannula therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth. Eligible infants were randomly allocated in a 1:1 ratio using random permuted blocks of four to receive either intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or to placebo. Allocation was stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). Azithromycin and placebo vials were encased in tamper-evident custom cardboard cartons to ensure masking for clinicians, parents, and the research team. The primary outcome was survival without development of physiologically defined moderate or severe CLD at 36 weeks’ postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). The study was registered with ISRCRN (11650227) and is closed. Findings Infants were recruited between Oct 9, 2019, and March 22, 2022. 799 (53·1%) of 1505 eligible infants underwent random allocation; three infants were withdrawn, including consent to use their data, leaving 796 infants for analysis. Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted OR [aOR] 0·84, 95% CI 0·55–1·29, p=0·43). Pulmonary Ureaplasma spp colonisation did not influence treatment effect. Overall, seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate), and six serious adverse events were reported in the placebo group (two severe, two moderate, and two mild), as assessed by the local principal investigators. Interpretation Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp colonisation, it cannot be recommended in clinical practice.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine Centre for Trials Research (CNTRR)
Publisher:	Elsevier
ISSN:	2213-2600
Funders:	NIHR
Date of First Compliant Deposit:	9 May 2024
Date of Acceptance:	5 March 2024
Last Modified:	10 May 2024 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/168806

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