@article {1646, title = {Azithromycin mass drug administration to reduce child mortality in Niger (AVENIR II): a master protocol for a cluster-randomized adaptive platform trial to evaluate community-based health interventions.}, journal = {medRxiv}, year = {2025}, month = {2025 Jun 18}, abstract = {

BACKGROUND: Trials have demonstrated that azithromycin mass drug administration (MDA) to children 1-59 months old reduces mortality, but increases antimicrobial resistance (AMR). The World Health Organization recommends that programs include mortality and AMR monitoring. Niger is expanding the azithromycin MDA for child survival program nationwide.

METHODS: To establish program monitoring and leverage the infrastructure to evaluate other community health interventions, AVENIR II is designed as a cluster-randomized adaptive platform trial with monitoring and re-randomization every 2 years. The initial focus is to monitor under-5 mortality, AMR, implementation, and safety as the program expands in Niger. All eligible primary health center catchment areas (Centre de Sant{\'e} Int{\'e}gr{\'e}s, CSIs) will be included in biannual oral azithromycin MDA to children 1-59 months old. A subset will be randomized to delay MDA for the first 2 years, after which they will receive MDA and another subset will be randomized to stop MDA for the next 2 years. The proportion randomized to delay or stop will be determined using an adaptive algorithm including: 1) results of prior azithromycin MDA mortality trials, 2) expert opinion on the appropriate ethical balance between delivering the program and monitoring AMR, and 3) statistical power to detect a programmatically relevant difference between arms. We anticipate 5-10\% of CSIs will be randomized to delay or stop at each randomization. Mortality and AMR will be monitored at baseline and every 2 years. Implementation and safety outcomes will be monitored continuously. To enable ongoing monitoring while ensuring program access, CSIs receiving MDA will be re-randomized using the adaptive algorithm updated with new mortality results and no CSI will go without MDA for more than 2 years. In this platform design, additional arms may be added or dropped based on information from other studies, updates to guidelines, or preferences of Niger policymakers, and other interventions may be evaluated.

DISCUSSION: The risk of AMR has led to caution in the implementation of azithromycin MDA. We present a design that enables continued rigorous evaluation of program impact on key outcomes, with flexibility to evaluate other interventions as well.

TRIAL REGISTRATION: clinicaltrials.gov (NCT06358872), registered April 2024.

}, doi = {10.1101/2025.06.17.25329431}, author = {Arzika, Ahmed M and Amza, Abdou and Ousmane, Sani and Maliki, Ramatou and Almou, Ibrahim and Galo, Nasser and Harouna, Nasser and Mankara, Alio and Aichatou, Bawa and Boubacar, Ousseini and Lebas, Elodie and Peterson, Brittany and Brandt, Carolyn and Picariello, Andrea and Cheng, Angela and Porco, Travis C and Doan, Thuy and Arnold, Benjamin F and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @article {1651, title = {Spillover of Azithromycin Mass Drug Administration and Child Survival: A Secondary Analysis of a Cluster-Randomized Clinical Trial.}, journal = {JAMA Netw Open}, volume = {8}, year = {2025}, month = {2025 Jul 01}, pages = {e2519693}, abstract = {

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.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Cluster Analysis, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2025.19693}, author = {Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Aichatou, Bawa and Bello, Ismael Mamane and Beidi, Diallo and Galo, Nasser and Harouna, Nasser and Karamba, Alio M and Mahamadou, Sani and Abarchi, Moustapha and Ibrahim, Almou and Brandt, Carolyn and Lebas, Elodie and Peterson, Brittany and Liu, Zijun and Oldenburg, Catherine E and Doan, Thuy and Porco, Travis C and Arnold, Benjamin F and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} }