Abstract
BACKGROUND: Severe malaria remains a major global health challenge, particularly in endemic regions, where it causes substantial morbidity and mortality, especially among children and pregnant women. Although numerous clinical trials have evaluated treatments for severe malaria, heterogeneity in outcome selection, definition, and measurement limits comparability across studies, hampers evidence synthesis, and contributes to research waste. There is currently no established core outcome set (COS) for trials specifically focused on severe malaria treatment. Developing a COS is therefore essential to improve outcome standardization, strengthen evidence synthesis, and support evidence-based clinical practice. OBJECTIVE: This study aims to develop a COS for trials evaluating the treatment of severe malaria. METHODS: This protocol follows guidance from the Core Outcome Measures in Effectiveness Trials (COMET) Initiative and the Core Outcome Set-Standardised Protocol Items (COS-STAP) checklist. An updated systematic review of outcomes reported in randomized controlled trials of severe malaria treatment has been conducted. Searches covered the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, and Literatura Latino-Americana em Ciências da Saúde (LILACS), as well as clinical trial registries, including the International Standard Randomised Controlled Trial Number (ISRCTN) registry, ClinicalTrials.gov, and the Pan-African Clinical Trial Registry (PACTR). Study selection followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. Outcomes important to patients and families are being identified through qualitative interviews with parents and caregivers of patients treated for severe malaria, with data analyzed using thematic synthesis. Outcomes identified across these sources will be prioritized through a 2-round, multistakeholder Delphi survey, with rounds separated by 4 weeks and a target sample of 60 to 80 participants. An online consensus meeting will then be held to agree on the final COS. Subsequently, outcome measurement instruments used in severe malaria trials will be identified and assessed, and a dissemination and implementation strategy will be developed to support uptake of the final COS. RESULTS: Preliminary results from the updated systematic review identified 326 records through database and registry searches. Following screening and full-text review, 5 eligible randomized controlled trials conducted between 2020 and 2024 in Africa and Asia were included. Qualitative interviews with parents and caregivers have been conducted with 26 participants recruited and interviewed. The Delphi survey, consensus meeting, and outcome measurement instrument selection are ongoing and expected to be completed by September 2026. CONCLUSIONS: This protocol outlines a rigorous and inclusive approach to developing the first COS for severe malaria treatment trials. The resulting COS aims to improve outcome standardization, reduce reporting bias, and enhance the comparability and impact of future severe malaria trials.