Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali (LAKANA): study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial

Abstract

Background: Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen.

Methods: LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1-11-month-old (29-364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024.

Discussion: If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa.

Trial registration: ClinicalTrials.gov NCT04424511. Registered on 11 June 2020.

Keywords: Antibiotic; Antimicrobial resistance; Azithromycin; Growth; Infant; Infection; Inflammation; Morbidity; Mortality; Placebo; Randomized controlled trial.

Fig. 1

LAKANA trial design summary. Eligible infants in the villages randomized to (i) placebo (control), receive placebo mixture every 3 months; (ii) 4-dose AZI, receive azithromycin every 3 months; (iii) 2-dose AZI, receive azithromycin twice at a 3-month interval between January and June and placebo twice at a 3-month interval between July and December. AMR, antimicrobial resistance; AZI, azithromycin; LAKANA, Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin; MDA, mass drug administration

Fig. 2

Schedule of enrolment, intervention, and follow-up assessments for the LAKANA trial. ^aNo upper or lower limit in the number of participants per study village, i.e., all households and infants who can be enrolled or treated with study drugs during any MDA visit will be included in the study^{. b}Maximum number of treatments given to any single individual 1–11-month-old infant is four. ^cData collection on secondary outcomes only in the subset of villages selected for the AMR monitoring. AMR, antimicrobial resistance; AZI, azithromycin; LAKANA, Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin; MDA, mass drug administration; SMC, seasonal malaria chemoprevention

Fig. 3

LAKANA trial adaptive design. LAKANA, Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin; MDA, mass drug administration; SMC, seasonal malaria chemoprevention