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Summary: Background: WHO promotes the SAFE strategy for the elimination of trachoma as a public health programme, which promotes surgery for trichiasis (ie, the S component), antibiotics to clear the ocular strains of chlamydia that cause trachoma (the A component), facial cleanliness to prevent transmission of secretions (the F component), and environmental improvements to provide water for washing and sanitation facilities (the E component). However, little evidence is available from randomised trials to support the efficacy of interventions targeting the F and E components of the strategy. We aimed to determine whether an integrated water, sanitation, and hygiene (WASH) intervention prevents the transmission of trachoma. Methods: The WASH Upgrades for Health in Amhara (WUHA) was a two-arm, parallel-group, cluster-randomised trial in 40 rural communities in Wag Hemra Zone (Amhara Region, Ethiopia) that had been treated with 7 years of annual mass azithromycin distributions. The randomisation unit was the school catchment area. All households within a 1·5 km radius of a potential water point within the catchment area (as determined by the investigators) were eligible for inclusion. Clusters were randomly assigned (at a 1:1 ratio) to receive a WASH intervention either immediately (intervention) or delayed until the conclusion of the trial (control), in the absence of concurrent antibiotic distributions. Given the nature of the intervention, participants and field workers could not be masked, but laboratory personnel were masked to treatment allocation. The WASH intervention consisted of both hygiene infrastructure improvements (namely, construction of a community water point) and hygiene promotion by government, school, and community leaders, which were implemented at the household, school, and community levels. Hygiene promotion focused on two simple messages: to use soap and water to wash your or your child's face, and to always use a latrine for defecation. The primary outcome was the cluster-level prevalence of ocular chlamydia, measured annually using conjunctival swabs in a random sample of children aged 0–5 years from each cluster at 12, 24, and 36 month timepoints. Analyses were done in an intention-to-treat manner. This trial is ongoing and is registered at ClinicalTrials.gov, NCT02754583. Findings: Between Nov 9, 2015, and March 5, 2019, 40 of 44 clusters assessed for eligibility were enrolled and randomly allocated to the trial groups (20 clusters each, with 7636 people from 1751 households in the intervention group and 9821 people from 2211 households in the control group at baseline). At baseline, ocular chlamydia prevalence among children aged 0–5 years was 11% (95% CI 6 to 16) in the WASH group and 11% (5 to 18) in the control group. At month 36, ocular chlamydia prevalence had increased in both groups, to 32% (24 to 41) in the WASH group and 31% (21 to 41) in the control group (risk difference across three annual monitoring visits, after adjustment for prevalence at baseline: 3·7 percentage points; 95% CI –4·9 to 12·4; p=0·40). No adverse events were reported in either group. Interpretation: An integrated WASH intervention addressing the F and E components of the SAFE strategy did not prevent an increase in prevalence of ocular chlamydia following cessation of antibiotics in an area with hyperendemic trachoma. The impact of WASH in the presence of annual mass azithromycin distributions is currently being studied in a follow-up trial of the 40 study clusters. Continued antibiotic distributions will probably be important in areas with persistent trachoma. Funding: National Institutes of Health—National Eye Institute. Translation: For the Amharic translation of the abstract see Supplementary Materials section.

Summary: Background: The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial found that biannual mass distribution of azithromycin to children younger than 5 years in Niger reduced the primary outcome of all-cause mortality by 18%. We aimed to determine the causes of mortality among deceased children using verbal autopsy. Methods: In this 2-year cluster-randomised controlled trial, 594 community clusters in Niger were randomly allocated (1:1 ratio) to receive biannual mass distributions of either oral azithromycin (approximately 20 mg per kg of bodyweight) or placebo targeted to children aged 1–59 months. Participants, study investigators, and field workers were masked to treatment allocation. Between Nov 23, 2014, and July 31, 2017, 3615 child deaths were recorded by use of biannual house-to-house censuses, and verbal autopsies were done between May 26, 2015, and May 17, 2018, to identify cause of death. Cause-specific mortality, as assessed by verbal autopsy, was a prespecified secondary outcome. This trial is completed and is registered with ClinicalTrials.gov, NCT02047981. Findings: Between Nov 23, 2014, and July 31, 2017, 303 communities (n=40 375 children at baseline) in Niger received mass azithromycin and 291 communities (n=35 747 children at baseline) received placebo. Treatment coverage was 90·3% (SD 10·6) in the azithromycin group and 90·4% (10·1) in the placebo group. No communities were lost to follow-up. In total, 1727 child deaths in the azithromycin group and 1888 child deaths in the placebo group were reported from the population censuses. Of these, the cause of death for 1566 (90·7%) children in the azithromycin group and 1735 (91·9%) children in the placebo group were ascertained by verbal autopsy interviews. In the azithromycin group, 437 (27·9%) deaths were due to malaria, 252 (16·1%) deaths were due to pneumonia, and 234 (14·9%) deaths were due to diarrhoea. In the placebo group, 493 (28·4%) deaths were due to malaria, 275 (15·9%) deaths were due to pneumonia, and 251 (14·5%) deaths were due to diarrhoea. Relative to communities that received placebo, child mortality in communities that received azithromycin was lower for malaria (incidence rate ratio 0·78, 95% CI 0·66–0·92; p=0·0029), dysentery (0·65, 0·44–0·94; p=0·025), meningitis (0·67, 0·46–0·97; p=0·036), and pneumonia (0·83, 0·68–1·00; p=0·051). The distribution of causes of death did not differ significantly between the two study groups (p=0·98). Interpretation: Mass azithromycin distribution resulted in approximately a third fewer deaths in children aged 1–59 months due to meningitis and dysentery, and a fifth fewer deaths due to malaria and pneumonia. The lack of difference in the distribution of causes of death between the azithromycin and placebo groups could be attributable to the broad spectrum of azithromycin activity and the study setting, in which most childhood deaths were due to infections. Funding: Bill & Melinda Gates Foundation.