IMPORTANCE: World Health Organization guidelines on azithromycin mass drug administration for child survival target infants aged 1 to 11 months, although prior studies included those aged 1 to 59 months. The AVENIR trial suggested that infants aged 1 to 11 months have lower mortality if children aged 12 to 59 months in the same household are also included.

OBJECTIVE: To assess the possibility of a spillover effect by examining the association of azithromycin and mortality among children aged 1 to 11 months in subgroups defined by the presence of a child aged 12 to 59 months in the same household.

DESIGN, SETTING, AND PARTICIPANTS: This exploratory secondary analysis of the AVENIR (Azithromycine Pour la Vie des Enfants au Niger: Implementation et Recherche) adaptive cluster-randomized clinical trial was performed in 3000 rural and periurban communities in Niger. AVENIR communities were randomized to 3 arms and followed up for 2 years (November 24, 2020, to July 31, 2023). Study arms consisted of children aged 1 to 59 months receiving azithromycin (child arm); infants aged 1 to 11 months receiving azithromycin with placebo to children aged 12 to 59 months (infant arm); and children aged 1 to 59 months receiving placebo (placebo arm). Participants, investigators, data collectors, and data analysts were masked to randomization.

INTERVENTION: A single 20-mg/kg dose of oral azithromycin or placebo administered by study staff biannually.

MAIN OUTCOMES AND MEASURES: All-cause mortality in infants aged 1 to 11 months (deaths per 1000 person-years) measured through biannual census. Subgroups were defined by the presence of a child aged 12 to 59 months in the household recorded during the census.

RESULTS: After exclusions, 2883 communities and 98 969 infants aged 1 to 11 months were included in the analysis. Among the 23 770 infants in allocation 1 at baseline, mean (SD) age was 6.2 (3.1) months and 11 974 (50.4%) were female. Mortality was 18.5 (95% CI, 16.7-20.4) deaths per 1000 person-years in the child arm, 22.3 (95% CI, 20.0-24.7) in the infant arm, and 23.9 (95% CI, 21.6-26.2) in the placebo arm. The incidence rate ratio comparing mortality in the child and infant arms among children with an older sibling was 0.78 (95% CI, 0.65-0.93) compared with 0.91 (95% CI, 0.73-1.15; P = .26 for interaction) among those without. Comparing the infant and placebo arms, the incidence rate ratio among children with an older sibling was 0.96 (95% CI, 0.81-1.14) compared with 0.90 (95% CI, 0.71-1.12; P = .61 for interaction) among those without.

CONCLUSIONS AND RELEVANCE: In this secondary analysis of a cluster-randomized clinical trial, interaction for the presence of a older sibling was not statistically significant, but results were consistent with lower mortality among infants aged 1 to 11 months living with older, treated children.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04224987.