Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Mali

Tampere University149,201 enrolled

Overview

The LAKANA trial will assess the impact on mortality and other health outcomes of quarterly and biannual azithromycin mass drug administration (MDA) when delivered to 1-11-month (29-364 days) old infants in a high-mortality setting where malaria is holoendemic but there is also a functioning seasonal malaria chemoprevention (SMC) program in place. The long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood mortality, and to determine the most effective treatment regimen. The main study hypotheses in terms of mortality effect are: i) Biannual azithromycin MDA to 1-11 month old infants reduces their mortality, ii) Quarterly azithromycin MDA to 1-11 month old infants reduces their mortality, iii) Quarterly azithromycin MDA has a bigger mortality effect than biannual MDA.

Mass drug administration (MDA) of azithromycin has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. Because of the observed heterogeneity and possible effect modification by SMC or other co-interventions, further trials in new settings are needed in order to make evidence-based public health recommendations about the use of this treatment. The objectives of the LAKANA trial are: * To evaluate the impact of two azithromycin MDA regimens on infant mortality and other health outcomes, when provided in a rural West-African high-mortality context with an ongoing seasonal malaria chemoprevention program. * To evaluate the effect of alternative MDA frequencies on antimicrobial resistance (AMR) and host microbiota composition. * To test hypotheses that azithromycin MDA eliminates malaria parasitaemia and reduces systemic and intestinal inflammation in asymptomatic children and to collect and store biological samples for assessing other possible mechanisms of azithromycin effect. * To investigate the feasibility of alternative azithromycin MDA strategies, including economic analysis. The LAKANA trial will be conducted in 1151 villages from 7-10 health districts in the Kayes, Kita and Koulikoro regions of Mali. LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design. Participating villages will be randomly allocated to three different intervention groups in a ratio of 3 : 2 : 4 (control : azithromycin quarterly : azithromycin biannually). Within each participating village, consenting households will be visited quarterly (at 3-month intervals), nine times. At the first eight of these visits, 1-11-month-old eligible infants (age 29-364 days), for whom there is a consent for study drug provision, will be given a single dose of study drug (azithromycin mixture or respective placebo mixture). Mortality and serious adverse events (SAEs) data will be collected, and mortality-related questions answered using data from all the included 1151 villages. Mixed-effect Poisson regression model will be used to estimate the intervention effects on mortality, with random intercepts for the clusters. The investigators will explore effect modification by testing for interaction between the MDA intervention and the following variables: * Age at the time of the MDA * Sex of the child * Weight-for-age * Seasonality: rainy season vs non-rainy season at the time of the MDA * SMC given to the child within 3 months before an MDA * Order of MDA in the village * District of residence * Distance from the nearest health facility (in km) * Household asset index * Water, Sanitation, and Hygiene (WASH) index * National outreach strategy category (standard/advanced) The investigators will address the other study questions using a smaller separate secondary sample of 59 villages located around four selected health centers close to the city of Kita and a similar number of villages closer to Bamako, i.e. in Koulikoro or Kati (tertiary sample).

Eligibility

Sex: ALLMin age: 29 DaysMax age: 364 DaysHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: On a cluster (village) level: 1. Location within Kayes, Kita, or Koulikoro region of Mali 2. Considered accessible and safe by the local health authorities and research team 3. Considered non-urban by the local health authorities and research team 4. Permission from community leadership On a household level (for trial enrollment): 1. Location within a cluster that is included in the study 2. Verbal consent from a head of household or an adult authorized by her / him On a child level (for receiving study medication): 1. Residence in a household enrolled in the trial 2. Age between 29 and 364 days 3. Verbal consent from at least one caregiver Exclusion Criteria: On child level (for not receiving study medication): 1. Weight below 3.0 kg 2. Known allergy to macrolides, as judged by a caregiver report of the infant experiencing an adverse reaction after oral ingestion of medication, which was deemed likely to be a macrolide by the interviewing data collector.

Outcomes

Primary Outcomes

Mortality

Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.

Time frame: 3-month time interval (total of 8 intervals per cluster)

Secondary Outcomes

Morbidity

Morbidity (14-day period prevalence of fever with respiratory symptoms (ARI), fever without respiratory symptoms (malaria), and diarrhea) in children aged 4-14 months assessed in each participating cluster (village) from the secondary outcome sample.

Time frame: 3-month time interval (total of 8 intervals per cluster)

Length-for-age Z-score

Length-for-age Z-score in 6-8 and 12-14 months old children from the secondary outcome sample. Length measures will be taken at 15, 18, 21, and 24 months after the enrollment of the village into the trial. Length-for-age Z-score will be calculated using the WHO Child Growth Standards.