Defining safety parameters for first-trimester malaria treatment trials: stakeholder views from Real-Time Delphi survey

BACKGROUND: In 2022, the World Health Organisation recommended artemether-lumefantrine as the first-line treatment for uncomplicated malaria in first-trimester pregnancy. However, emerging drug resistance and WHO's recommendation for treatment diversification necessitate research on alternative artemisinin-based combination therapies (ACTs). We conducted a Real-Time (RT) Delphi survey to establish stakeholder views on safety endpoints and non-inferiority margins for a randomised controlled trial evaluating ACTs in first-trimester pregnancy. METHODS: An international RT Delphi study was conducted between September and October 2024, including clinical researchers, regulators, policymakers, ethicists, and healthcare practitioners. Stakeholders completed an online survey, rating the importance of composite endpoints and maternal and infant safety-related outcomes on a 5-point Likert scale. Outcomes were ranked, and acceptable non-inferiority safety margin were explored. Quantitative responses were summarised descriptively, and free-text comments were analysed thematically. RESULTS: Of the 54 stakeholders invited, 30 responded (56%). Most (23/30, 77%) agreed that a composite safety endpoint consisting of miscarriage, stillbirth, and major congenital anomalies was informative for evaluating ACT safety in the first trimester. Maternal outcomes rated as critical included maternal death (27/30, 90%), severe maternal anaemia (23/30, 77%), renal failure (20/30, 67%), and maternal intensive care admission (19/29, 66%). For infant outcomes, major congenital anomalies (28/30, 94%), stillbirth (26/30, 87%), and neonatal death (25/30, 83%) were considered essential. Most respondents endorsed a non-inferiority margin of HR = 1.2 as a pragmatic balance between trial feasibility and acceptable uncertainty around safety. Qualitative analysis highlighted support for the composite endpoint to address competing risks. However, concerns were raised regarding the non-specificity of some outcomes, such as preterm birth and small-for-gestational-age, which may be influenced by factors unrelated to treatment. CONCLUSIONS: This study provides a framework for researchers to determine key safety outcomes and acceptable non-inferiority margins for malaria treatment trials in the first trimester. Incorporating stakeholder perspectives into trial design can support evidence-informed policy and facilitate the deployment of a wider range of antimalarial treatments considered safe in early pregnancy.