Trial design
malaria
MALARIA, SECONDARY, STAGGERED
The study is a three-arm cluster randomized, placebo-controlled, double-blinded, parallel-group clinical trial. The trial was designed to estimate the impact of azithromycin on 1–11-month-old infant mortality in Mali, Western Africa, with a sample size of 1151 villages (clusters). The area is covered by a national seasonal malaria chemoprevention (SMC) program that was designed to include distribution of sulfadoxine-pyrimethamine plus amodiaquine to all l–59-month-old-children monthly during the rainy season (July to October). Details of the trial design are described in a separate protocol article [Participating study villages were randomly allocated into the three intervention groups at 3:4:2 ratio: placebo (control), two-dose AZI (azithromycin-MDA treatments given every 3 months to 1–11-month-old infants between January and June), and four-dose AZI (azithromycin-MDA treatments given every 3 months to 1–11-month-old infants). The randomization was stratified by village size: villages for which the estimated number of eligible infants was 100 or more (later referred to as “big villages”) or villages for which the estimated number of eligible infants was fewer than 100 (later referred as “small village”). The village size categorization was done based on 2018 Demographic and Health Survey [The data collection team visits the villages at quarterly intervals, eight times for MDA visits and one time for close-out visit (visit 9) during which the data collection team interviews the household representatives but do not administer study drug. A single child can receive up to four doses of study drug between the age range of 1 and 11 months, even though the villages are visited eight times at maximum. The trial may have equal stopping time for all of the villages, despite staggered starting time, if the target person-years-at risk will be reached before all the villages have had full visit cycle of nine visits. If the target person-years-at-risk requires full visits for all of the villages, there will be nine visits for all villages. The decision will be made by the Project Steering Group (PSG) after the interim analysis based on the recommendation by the Data Safety and Monitoring Board (DSMB). At minimum, all villages will be visited six times.In a subset sample of 59 villages, the study team is collecting additional biological samples and measurements to address secondary study questions about AMR, growth and nutritional status, and mechanisms of action of azithromycin. The 59 villages were chosen based on their proximity to health centers in Kita area, as well as their location in clearly rural area. The selection was based both on the possibility to deliver biological samples to a laboratory in reasonable time, as well as being rural and therefore representative of most of Mali.The trial DSMB will conduct a single interim analysis when approximately 60% of the mortality data has been collected, and based on the results of the interim analysis, a trial arm may be dropped, or the trial may be stopped early [