Background. MORDOR I found that 2 years of biannual mass azithromycin administration reduced post-neonatal childhood mortality by 18% in Niger. Over time, this benefit could increase with each distribution or wane due to antibiotic resistance. Here in MORDOR II, we treated communities in both arms for an additional year with azithromycin, resulting in a randomized comparison of the first versus the third year of treatment. Methods. MORDOR I-Niger originally randomized 594 communities to 4 biannual distributions of either azithromycin or placebo to children aged 1-59 months. In MORDOR II, all communities received 2 additional biannual azithromycin distributions. All-cause mortality was assessed during a biannual census by enumerators masked to original assignment. Results. Mean azithromycin coverage was 91.3% (SD ±7.2%) in the communities receiving the first year and 92.0% (±6.6%) in those receiving the third year of azithromycin. Mortality was 24.0 per 1,000 person-years (95% CI, 22.1—26.3) in communities randomized to the first year, and 23.3 per 1,000 person-years (95% CI, 21.4—25.5) in those randomized to the third year of treatment, with no significant difference between arms ( p =0.55). In communities originally receiving placebo, mortality decreased 13.3% (95% CI, 5.8%—20.2%, p =0.007) when treated with azithromycin. In communities continuing to receive azithromycin, the mortality reduction was not significantly different in the third year (-3.6%, 95% CI, -12.3%—4.5%, p =0.50). Conclusions. We found no evidence that the effect of mass azithromycin on childhood mortality waned in the third year of treatment. Childhood mortality fell significantly when placebo-treated communities were provided azithromycin.

Background Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria. Methods and findings In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%–15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%–12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%–14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%–5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%–20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%–6.4%; 28 of 592 children across all communities) ( P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio [OR] 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root–transformed outcome; density estimates were 7,540 parasites/μl lower [95% CI −350 to −12,550 parasites/μl; P = 0.02] at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI −0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of...

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IMPORTANCEMass azithromycin distributions may decrease childhood mortality, although the causal pathway is unclear. The potential for antibiotics to function as growth promoters may explain some of the mortality benefit. OBJECTIVE To investigate whether biannual mass azithromycin distributions are associated with increased childhood growth. DESIGN, SETTING, AND PARTICIPANTS This cluster-randomized trial was performed from December 2014 until March 2020 among 30 rural communities in Boboye and Loga departments in Niger, Africa, with populations from 200 to 2000 individuals. Communities were randomized in a 1:1 ratio to biannual mass distributions of azithromycin or placebo for children ages 1 to 59 months. Participants, field-workers, and study personnel were masked to treatment allocation. Height and weight changes from baseline to follow-up at 4 years were compared between groups. Data were analyzed from June through November 2021. INTERVENTIONS Participants received azithromycin at 20 mg/kg using height-based approximation or by weight for children unable to stand every 6 months at the participants' households. Placebo contained the vehicle of the azithromycin suspension. MAIN OUTCOMES AND MEASURES Longitudinal anthropometric assessments were performed on a random sample of children before the first treatment and then annually for 5 years. Height and weight were the prespecified primary outcomes. RESULTS Among 3936 children enrolled from 30 communities, baseline characteristics were similar between 1299 children in the azithromycin group and 2637 children in the placebo group (mean 48.2% [95% CI, 45.5% to 50.8%] girls vs 48.0% [95% CI, 45.7% to 50.3%] girls; mean age, 30.8 months [95% CI, 29.5 to 32.0 months] vs 30.6 months [95% CI, 29.2 to 31.6 months]). Baseline anthropometric assessments were performed among 2230 children, including 985 children in the azithromycin group and 1245 children in the placebo group, of whom follow-up measurements were available for 789 children (80.1%) and 1063 children (85.4%), respectively. At the prespecified 4-yearfollow-up visit, children in the azithromycin group gained a mean 6.7 cm (95% CI, 6.5 to 6.8 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year and children in the placebo group gained a mean 6.6 cm (95% CI, 6.4 to 6.7 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year.Height at 4 years was not statistically significantly different between groups when adjusted for baseline height (0.08 cm [95% CI, −0.12 to 0.28 cm] greater in the azithromycin group; P = .45), and neither was weight when adjusted for height and baseline weight (0.02 kg [95% CI, −0.10 to 0.06 kg] less in the azithromycin group; P = .64). However, among children in the shortest quartile of (continued) Key Points Question Do biannual mass azithromycin distributions, which have been shown to decrease child mortality in sub-Saharan Africa, promote child growth? Findings In this placebo-controlled cluster-randomized trial with longitudinal anthropometric monitoring among 22...

IMPORTANCEBecause transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources. OBJECTIVE To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease. DESIGN, SETTING, AND PARTICIPANTS In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022. INTERVENTIONS Every 6 months, a single dose of either oral azithromycin (20 mg/kg using heightbased approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months. MAIN OUTCOMES AND MEASURES Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens. RESULTS At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6]months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07).