TITLE OF WRITE-UP

The LAKANA Trial: Mass Administration of Azithromycin to Infants in Mali did not Reduce Mortality

MANUSCRIPT CITATION

Haidara FC, Adubra L, Abdou M, Alber D, Ashorn U, Cheung YB, et al. Mass Administration of Azithromycin to Infants in Mali to Reduce Mortality. N Engl J Med 2025; 395(15): 1498-1508. PMID 41092331.

REVIEWED BY

Maya I. Brasher, MD, FAAP
Assistant Professor of Pediatrics
Baylor College of Medicine
mbrasher@bcm.edu

Monika S. Patil, MD, FAAP
Associate Professor of Pediatrics
Baylor College of Medicine
Monika.patil@bcm.edu

TYPE OF INVESTIGATION

Prevention

QUESTION

Among children aged 1 to 11 months, does mass administration of azithromycin (2 doses versus 4 doses) administered over the first year of life result in decreased infant mortality when compared to placebo?

METHODS

• Design: Randomized control trial
• Allocation: Concealed
• Blinding: Yes
• Follow-up period: 2 years
• Setting: Villages in the Kayes, Kita, and Koulikoro regions (considered as nonurban, accessible, and safe regions) in Mali
• Patients: Infants aged 1 to 11 months (29 to 364 days) old, residing in a trial village, with a body weight of at least 3 kg, and with consent from the caregiver
• Intervention: Provision of a total of one to four doses of azithromycin or placebo, under direct observation with a dose of 20 mg per kilogram, depending on the infant’s age at enrollment and village’s randomization
• Outcomes: Death from any cause among infants 1 to 11 months of age
• Primary outcome: Mortality measured at 3-month time periods (interval between successive study visits), used to calculate person-years at risk
• Secondary outcomes: 1) All-cause mortality among children 12 to 59 months of age at the time of the village’s most recent drug distribution. 2) Assessment of whether infant characteristics (age, sex, weight-for-age z-score), seasonal factors (rainy or not rainy, exposure to seasonal malaria chemoprovention), logistics (order of mass administration, district of residence, distance from nearest health facility, and national outreach strategy), and socioeconomic factors (household asset index, WASH (water, sanitation, and hygiene) index) modified the effect of azithromycin on infant mortality.
• Analysis and Sample Size: 1170 villages were invited, of which 1151 were randomized. Villages were randomized in a 3:4:2 ratio as part of an adaptive trial design, to achieve adequate statistical power to test 3 distinct hypotheses: that twice-yearly azithromycin was more effective than placebo, quarterly administration was more effective than placebo, and quarterly administration was more effective than twice-yearly azithromycin at decreasing mortality in this patient population. Mortality outcomes were analyzed by intention-to-treat. Sample size was determined using simulations to obtain the power necessary to test the above hypotheses. An interim analysis was pre-specified to be performed once approximately 60% of total person-years were collected. Primary outcome was analyzed using one-sided hypothesis testing to estimate incidence rate ratios (IRR) with 95% confidence intervals (CI). Mixed-effect Poisson models with random intercepts for clusters (to account for similar outcomes among infants from the same village) and log-link function (with person-years as an offset variable) were used, and models were adjusted for the village size of <100 or 100+ infants (randomization stratification factor) as a fixed effect. Secondary outcomes were analyzed using two-sided tests, and effect modification was assessed using individual interaction terms to the mixed-effect Poisson models.
• Patient follow-up: Patients were followed-up through a systematic, house-to-house census performed every 3 months (+/-4 weeks) over a period of 2 years. Follow-up was recorded in units of person-years, to account for the fact that participants were followed for varying amounts of time.

MAIN RESULTS

In this study, also known as the LAKANA (Large-Scale Assessment of the Key Health-Promoting Activities of Two New Mass Drug Administration Regimens with Azithromycin) trial, 1151 villages were randomly assigned to the control (386), twice yearly azithromycin (511), or quarterly azithromycin (254) groups. Baseline characteristics were assessed at the initiation of mass distribution, and the villages comprising the three groups were found to be similar in the number of eligible infants per village and the distribution of infants by age, sex, and weight-for-age. Azithromycin administration was also timed to avoid overlap with the national malaria chemoprophylaxis program in the twice-yearly group. 9,085 visits were planned, with 7,831 (86.2%) completed on time, and 263 (2.9%) missed. In total, 285,227 households were registered, and a total of 149,090 infants received at least one dose of azithromycin or placebo, with 274,896 medication administrations and 82,600 person-years recorded. 968 deaths were documented over 82,600 person-years of follow-up. There was no statistically significant difference in the mortality rates of the three groups: mortality rate was 11.9 deaths 1000 person-years in the control group, 11.8 deaths per 1000 person-years in the twice-yearly group, and 11.3 deaths per 1000 person-years in the quarterly group. IRR for mortality was 1.00 (95% CI 0.83-1.19) in the twice-yearly group compared to the control group, 0.93 (95% CI 0.75-1.15) in the quarterly group compared to the control group, and 0.93 (95% CI 0.76-1.15) in the quarterly group compared to the twice-yearly group.

In assessing secondary outcomes, mortality among untreated children aged 12 to 59 months was similar regardless of age stratification and study group. Subgroup analyses indicated no significant difference in mortality of infants 1 to 11 months old, suggesting no apparent effect modification by infant characteristics, seasonal factors, study logistics, or socioeconomic factors examined.

CONCLUSION

Large-scale studies in Sub-Saharan Africa have demonstrated significant mortality reduction in children aged 1 to 59 months of age with twice yearly azithromycin administration. However, the World Health Organization recommends that if mass administration of azithromycin is implemented for child survival, it should target infants aged 1 to 11 months old to minimize risks of antimicrobial resistance while maximizing potential survival. In the LAKANA trial, no reduction in infant or child mortality was seen with mass administration of azithromycin, either two or four times per year, to infants between 1 and 11 months of age in Mali.

COMMENTARY

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 to 11 months old in high-mortality regions, targeting highest-risk populations while minimizing antimicrobial resistance. The LAKANA 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 effect of azithromycin administration. Limitations include 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 Hawthorne effect (change in behavior 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 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 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 highest infant mortality.

REFERENCES

1. [Available from: https://data.worldbank.org/indicator/SH.DYN.MORT?locations=ZG.
2. [January 29, 2026]. Available from: https://data.worldbank.org/indicator/SP.DYN.IMRT.IN?locations=ZG.
3. Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med 2018;378(17):1583-92.
4. O’Brien KS, Arzika AM, Amza A, Maliki R, Aichatou B, Bello IM, et al. Azithromycin to Reduce Mortality – An Adaptive Cluster-Randomized Trial. N Engl J Med 2024;391(8):699-709.
5. WHO Guideline on Mass Drug Administration of Azithromycin to Children under Five Years of Age to Promote Child Survival. WHO Guidelines Approved by the Guidelines Review Committee. Geneva: World Health Organization; 2020:viii-x. License: CC BY-NC-SA 3.0 IGO.
6. Haidara FC, Adubra L, Abdou M, Alber D, Ashorn U, Cheung YB, et al. Mass Administration of Azithromycin to Infants in Mali to Reduce Mortality. N Engl J Med 2025;393(15):1498-508.
7. Oldernburg CE, Ouattara M, Bountogo M, Boudo V, Ouedraogo T, Compaoré G, et al. Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial. JAMA 2024;331(6):482-490.
8. Brander RL, Weaver MR, Pavlinac PB, John-Stewart GC, Hawes SE, Walson JL. Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa. Clin Infect Dis 2020;74(3):375-86.
9. Doan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, et al. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med 2020;383(20):1941-50.