A hybrid effectiveness-implementation study protocol to assess the effectiveness and chemoprevention efficacy of implementing seasonal malaria chemoprevention in five districts in Karamoja region, Uganda

Background: The World Health Organization (WHO) recommends seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine for children aged 3 to 59 months, living in areas where malaria transmission is highly seasonal. However, due to widespread prevalence of resistance markers, SMC has not been implemented at scale in East and Southern Africa. An initial study in Uganda showed that SMC with SPAQ was feasible, acceptable, and protective against malaria in eligible children in Karamoja region. Nonetheless, exploration of alternative regimens is warranted since parasite resistance threats persist. Objective: The study aims to test the effectiveness of SMC with DP or SPAQ (DP-SMC & SPAQ-SMC), chemoprevention efficacy as well as the safety and tolerability of DP compared to that of SPAQ among 3-59 months old children in Karamoja region, an area of Uganda where malaria transmission is highly seasonal. Methods: A Type II hybrid effectiveness-implementation study design consisting of four components: 1) a cluster randomized controlled trial (cRCT) using passive surveillance to establish confirmed malaria cases in children using both SPAQ and DP; 2a) a prospective cohort study to determine the chemoprevention efficacy of SPAQ and DP (if SPAQ or DP clears sub-patent  infection and provides 28 days of protection from new infection) and whether drug concentrations and/or resistance influence the ability to clear and prevent infection; 2b) a sub study examining pharmacokinetics of DP in children between 3 to <6 months; 3) a resistance markers study in children 3–59 months in the research districts plus the standard intervention districts to measure changes in resistance marker prevalence over time and finally; 4) a process evaluation. Discussion: This study evaluates the effects of a clinical intervention on relevant outcomes whilst collecting information on implementation. Conclusion: This study will inform malaria policy in high-burden countries and contribute to progress in malaria control.