Abstract
BackgroundChildren hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether-lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post-discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post-discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas.ObjectiveWe aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisinin-piperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause.Methods/designThis is a multi-centre, two-arm, placebo-controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge. At 2 weeks after discharge, surviving children will be randomised to receive either 3-day courses of dihydroartemisinin-piperaquine at 2, 6 and 10 weeks or an identical placebo and followed for 26 weeks through passive case detection. The trial will be conducted in hospitals in malaria endemic areas in Kenya and Uganda. The study is designed to detect a 25% reduction in the incidence of all-cause readmissions or death (composite primary outcome) from 1152 to 864 per 1000 child years (power 80%, α = 0.05) and requires 520 children per arm (1040 total children).ResultsParticipant recruitment started in May 2016 and is ongoing.Trial registrationClinicalTrials.gov, NCT02671175. Registered on 28 January 2016.
Highlights
Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge
Longitudinal follow-up of children aged less than 5 years admitted with severe anaemia in Malawi showed that 8.2% died by 6 months post-discharge and 5.9% were readmitted with severe anaemia, compared to those without severe anaemia, among whom 1.6% died and 0.5% were readmitted [8, 9]
By creating a prophylactic time-window post-transfusion for malaria, more time is assured for bone marrow recovery, resulting in a more sustained haematological recovery post-discharge. We refer to this strategy as post-discharge malaria chemoprevention (PMC) to illustrate the similarities with Seasonal malaria chemoprevention (SMC) rather than with intermittent preventive therapy (IPT) in pregnancy as it aims to provide complete, rather than intermittent prophylaxis. Design overview This will be a multi-centre, parallel group, two-arm, placebo-controlled, individually randomised, superiority trial with 1:1 allocation ratio comparing the safety and efficacy of three courses of monthly PMC with dihydroartemisinin-piperaquine (PMC-DP) or placebo post-discharge provided in addition to the standard single 3-day treatment course with artemether-lumefantrine given as part of routine in-hospital care (ClinicalTrials.gov, NCT02671175; registered 28 January 2016)
Summary
We aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisininpiperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause. Methods/design: This is a multi-centre, two-arm, placebo-controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge.
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