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

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 Santé Intégrés, 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.

Keywords: adaptive trial; antimicrobial resistance; azithromycin; mass drug administration; under-5 mortality.

Figure 1.. Trial Design Overview.

Flow diagram of national program, Trial 1 (effectiveness) and Trial 2 (stopping). Blue boxes describe enrollment and random selection, green boxes describe randomization, and pink boxes describe intervention and monitoring activities.

Figure 2.. Implementation Rollout Plan.

Map of the regions of Niger colored according to the progressive scale-up plan. Borders indicate the 7 regions in Niger plus the capital of Niamey, which is not included in the scale-up. All regions are included in the national program and the Dosso, Tahoua, Maradi, and Zinder regions are included in the trial. Phase 1 is expected to begin in the second and third quarters of 2024. Phase 2 is expected to begin in the fourth quarter of 2024. Phase 3 is expected to begin in the second quarter of 2025. and Phase 4 is expected to begin in the second quarter of 2026.