Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR)

Abstract

Background Biannual distribution of azithromycin to children 1–59\u2009months old reduced mortality by 14% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1–11\u2009months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance. Methods AVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1–11: biannual azithromycin to children 1–11\u2009months old with placebo to children 12–59\u2009months old, 2) azithromycin 1–59: biannual azithromycin to children 1–59\u2009months old, or 3) placebo: biannual placebo to children 1–59\u2009months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1–59\u2009months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5\u2009years from the first enrollment in 1) children 1–59\u2009months old comparing the azithromycin 1–59 and placebo arms, 2) children 1–11\u2009months old comparing the azithromycin 1–11 and placebo arm, and 3) children 12–59\u2009months in the azithromycin 1–11 and azithromycin 1–59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2\u2009years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1–59\u2009months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1–59\u2009months old. Discussion As high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival. Trial registration This trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).