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.

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.

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.

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.

Wellcome Trust and Children’s Investment Fund Foundation.

For the Amharic and Afan Oromo translations of the abstract see Supplementary Materials section.