Impact of oral azithromycin and intermittent preventive treatment with sulfadoxine-pyrimethamine regimen on child mortality in Sierra Leone: trial protocol for a randomised, two-arm, double-blinded, placebo-controlled clinical trial (ICARIA).

Background: Azithromycin has been shown to be beneficial in preventing infectious diseases, including malaria, infectious diarrhoea and pneumonia. A cluster randomised control trial on azithromycin MDA in children in Niger, Malawi and Tanzania found a reduction in all-cause under-five (U5) mortality in communities who received azithromycin compared to placebo. However, the reduction was largest and statistically significant only in Niger. The purpose of this trial is to evaluate the impact of azithromycin plus intermittent preventive treatment in infants (IPTi), recently renamed by the World Health Organisation as perennial malaria chemoprevention (PMC), with sulfadoxine-pyrimethamine (SP) on all-cause mortality up to 18 months of age in children living in areas of high mortality burden through the Expanded Program on Immunisation (EPI) in Sierra Leone.

Methods: The Improving Care through Azithromycin Research for Infants in Africa (ICARIA) trial is a phase III two-arm, individually randomised, double-blinded, placebo-controlled trial administering oral AZI (20 mg/kg bodyweight) at three time points to children attending EPI visits in Sierra Leone. A total of 20,560 infants attending the first EPI contact at around 6 weeks of age are recruited and randomised to AZI or placebo in a 1:1 ratio. The second and third AZI/placebo doses are given at 9 and 15 months of age. The primary outcome of the trial is all-cause mortality rate at 18 months of age assessed through mortality surveillance. Other trial outcomes include the impact on antimicrobial resistance, and on the immune response to certain key routine EPI immunisations, the safety of the intervention, the prevalence of SP resistance markers and the feasibility, and acceptability of adding AZI to the EPI programme.

Discussion: The trial will provide the evidence needed to inform policy regarding the adoption and large-scale implementation of AZI in areas of high-mortality burden in sub-Saharan Africa.

Trial Registration: ClinicalTrials.gov NCT04235816. Registered on 22 January 2020. Pan-African Clinical Trials Registry PACTR202004540256535. Registered on 14 April 2020.