Delivery strategies for malaria chemoprevention in the post-discharge management of children hospitalised with severe anaemia or severe malaria: protocol for a cluster randomised controlled implementation trial in Benin

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INTRODUCTION: Children discharged after in-hospital treatment for severe anaemia or severe malaria in sub-Saharan Africa remain at high risk of readmission and death, particularly in malaria-endemic settings where recurrent infections are common. Post-discharge malaria chemoprevention (PDMC) has demonstrated substantial reductions in mortality and hospital readmissions and is now recommended by the WHO. However, optimal PDMC delivery strategies, via existing health systems, that optimise adherence remain unclear, particularly in West Africa where implementation and evidence of impact on clinical outcomes are limited. This trial aims to determine the effectiveness of different PDMC delivery strategies and adherence support mechanisms in optimising completion of PDMC courses. Secondary objectives include assessing clinical outcomes (readmissions, outpatient visits, mortality), evaluating health system linkage mechanisms and examining the acceptability and feasibility of the different delivery approaches. METHODS AND ANALYSIS: A cluster-randomised implementation trial will be conducted in central and southern Benin across urban and rural settings. Clusters, defined as villages within the catchment areas of two referral hospitals, will be randomly allocated (1:1:1) to one of three arms: (A) facility-based drug distribution (all courses) at discharge with community health worker (CHW) home visit reminders; (B) monthly community-based drug delivery by CHWs combined with phone reminders; and (C) dispensing all courses to caregivers at discharge without adherence support (control). Eligible participants are children under 10 years hospitalised with severe anaemia or severe malaria and clinically stable at discharge. All participants should receive three courses of dihydroartemisinin-piperaquine at weeks 2, 6 and 10 post-discharge and will be followed for 14 weeks. The primary endpoint is incomplete adherence to the full PDMC regimen (3 courses/9 doses). Secondary endpoints include all-cause and malaria-specific readmissions, outpatient visits and mortality. Quantitative outcomes will be analysed using mixed-effects regression models under an intention-to-treat approach. Qualitative methods will assess acceptability and feasibility among caregivers, providers and policymakers. ETHICS AND DISSEMINATION: Ethical approval was received from the institutional review boards of the Benin Institute of Applied Biomedical Sciences and Liverpool School of Tropical Medicine. Trial findings will be disseminated to national and international stakeholders through meetings, peer-reviewed publications and major conferences to inform PDMC policy, implementation guidelines and global malaria scale-up efforts, particularly through engagement with the World Health Organization and major malaria funding partners TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT06601712, registered on 14 September 2024 (https://clinicaltrials.gov/study/NCT06601712); and Pan African Clinical Trials Registry, PACTR202411682724094, registered on 5 November 2024 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=31962).