EBNEO Commentary: The LAKANA Trial: Mass Administration of Azithromycin to Infants in Mali Did Not Reduce Mortality

The LAKANA trial: a randomized control trial evaluating the impact of mass administration of azithromycin to infants 1 to 11 months of age in Mali showed no reduction in mortality. Under-5 mortality is highest in Sub-Saharan Africa at 68 per 1000 live births [1], with the infant mortality rate (IMR) comprising a significant portion of those deaths at 44 per 1000 live births [2]. Recently, mass azithromycin administration has been studied to help decrease under-5 mortality. The MORDOR [3] and AVENIR [4] trials respectively showed 13.5% and 14% reductions in under-5 mortality across Malawi, Niger, and Tanzania. Based on these findings, the World Health Organization recommends [5] mass azithromycin administration limited to infants 1–11 months old in high-mortality regions, targeting the highest-risk populations while minimizing antimicrobial resistance. The LAKANA (Large-Scale Assessment of the Key Health-Promoting Activities of Two New Mass Drug Administration Regimens with Azithromycin) trial [6] specifically studied the impact of mass azithromycin in infants in Mali, finding no reduction in IMR. Study strengths include a thoughtful design and analysis plan, using simulations to generate sample size estimates for sufficient power based on prior available data, randomizing groups in a 3:4:2 ratio to allow for an adaptive model and accounting for factors that may modify the effect of azithromycin administration. Limitations include the utilization of select sites in a single country; while simplifying study logistics, this limits generalizability to other countries/regions in Sub-Saharan Africa. The largest limitation, unfortunately, is that the trial encountered a lower-than-expected baseline mortality rate. Based on recent census data from Mali, LAKANA trial authors used an infant mortality estimate of 60 to 70 deaths per 1000 live births for calculations of sample size and power. However, the control group had a mortality rate of ~12 deaths per 1000 person-years, corresponding to approximately 36 deaths per 1000 live births. This discrepancy, possibly attributed to a national decrease in infant mortality or the Hawthorne effect (change in behaviour by nature of being observed), may have decreased the study's statistical power to detect smaller differences between groups and thus the study's conclusion may be affected by Type II error (not finding a difference when one exists). Finally, the pathologies by which azithromycin administration may decrease under-5 mortality, such as malaria, pneumonia, and dysentery [3, 7], may be less prevalent overall within the context of lower baseline mortality, resulting in a decreased observed impact of this intervention. Mass azithromycin administration is a relatively cost-effective [8] intervention with the potential to save a significant number of lives, but its effectiveness in decreasing mortality specifically among infants aged 1 to 11 months remains uncertain. Additionally, antimicrobial resistance has not been fully elucidated, but increased macrolide resistance among children treated as part of mass azithromycin administration efforts has been demonstrated [9]. In this case, the LAKANA trial exemplifies the dangers in extrapolating data from other patient populations and sites. Reducing the IMR is paramount, but this study highlights the importance of rigorous testing across patient populations and sites to determine the impact of interventions prior to development of generalized guidelines. Future studies are necessary to identify the target age range, with consideration of baseline mortality, for optimal mortality benefit from mass administration of azithromycin, better understand the potential community-level risks such as increased antimicrobial resistance, and track mortality trends to ensure maximal impact of interventions in areas with the highest infant mortality. URL LINK: https://ebneo.org/ebneo-commentary-the-lakana-trial Maya I. Brasher: conceptualization, writing – original draft, writing – review and editing, data curation. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.