Double-dose azithromycin mass drug administration, facial cleanliness, and fly control measures for trachoma control in Oromia, Ethiopia (Stronger SAFE): a cluster-randomised controlled trial

Abstract

BACKGROUND: Trachoma is caused by the bacterium Chlamydia trachomatis. WHO recommends the SAFE strategy for trachoma elimination: surgery for trichiasis (S), antibiotics (A), facial cleanliness (F), and environmental improvement (E). Multiple rounds of SAFE implementation have proven insufficient to eliminate trachoma in Ethiopia, where over 50% of the global trachoma burden remains. We aimed to evaluate a package of interventions to reduce the prevalence of conjunctival C trachomatis and accelerate trachoma elimination. METHODS: Stronger SAFE was an open-label, cluster-randomised controlled trial done in rural communities in the trachoma-endemic region of Oromia, Ethiopia. Clusters, each of about 90 households, were randomly assigned (1:1:1:1) using Stata 17 to: (1) standard A plus standard F and E (Standard SAFE; control group), (2) standard A plus enhanced F and E, (3) enhanced A plus standard F and E, or (4) enhanced A plus enhanced F and E (Stronger SAFE group). Standard A consisted of annual, single-dose, mass drug administration (MDA) of azithromycin. Enhanced A included two height-based doses of oral azithromycin (equivalent to 20 mg/kg) given as single doses in two MDA campaigns, 2 weeks apart, annually. Standard F and E involved promotion of latrine construction and facial hygiene, whereas enhanced F and E used additional fly control measures (permethrin-treated headwear [PTH] and odour-baited traps) and a household-level, facial hygiene behaviour change intervention. The interventions were implemented and reinforced over 3 years. Laboratory technicians and the trial statistician were masked. The primary outcome was the prevalence of conjunctival C trachomatis by quantitative PCR at 3 years in the control group versus the Stronger SAFE group, assessed on an intention-to-treat basis in a cross-sectional sample of 60 children aged 1-9 years from each cluster. Adverse events were monitored in all participants receiving MDA and/or PTH. The trial is registered with ISRCTN (ISRCTN40760473) and is complete. FINDINGS: Between March 6, 2021, and Aug 31, 2024, 68 clusters were enrolled and randomly assigned to an intervention. From these clusters we surveyed 4419 children aged 1-9 years at baseline (control group n=1095; Stronger SAFE group n=1203) and 3480 (mean 50·7 [SD 9·9] per cluster) at endline (control group n=970; Stronger SAFE group n=862). At baseline, the cluster mean prevalence of conjunctival C trachomatis was 14·6% (15·5) in the control group and 13·3% (11·8) in the Stronger SAFE group. Following 3 years of intervention, the cluster-adjusted prevalence of conjunctival C trachomatis was 2·7% (95% CI 1·3-5·0) in the control group and 2·2% (0·6-7·9) in the Stronger SAFE group (adjusted prevalence difference of -0·02% [-2·73 to 2·68], p=0·99). Azithromycin was well tolerated with only 13 mild, self-limiting adverse events (almost exclusively nausea, diarrhoea, and headache) reported related to the MDA (eight in single-dose MDA communities and five in double-dose MDA communities). No serious adverse events were reported. INTERPRETATION: Enhanced A, F, and E (Stronger SAFE) had no additional effect compared with standard of care on reducing the prevalence of conjunctival C trachomatis at 3 years in this setting. It is therefore unlikely that these enhanced intervention measures will accelerate trachoma elimination beyond well implemented, high coverage of single-dose MDA as part of standard SAFE. FUNDING: Wellcome Trust and Children's Investment Fund Foundation. TRANSLATIONS: For the Amharic and Afan Oromo translations of the abstract see Supplementary Materials section.