Intermittent preventive therapy for malaria with monthly artemether–lumefantrine for the post-discharge management of severe anaemia in children aged 4–59 months in southern Malawi: a multicentre, randomised, placebo-controlled trial

Abstract

Young children with severe malarial anaemia in Africa are at high risk of readmittance to hospital or death within 6 months of discharge. We aimed to assess whether 3 months of chemoprevention with artemether-lumefantrine reduced this risk. We did a randomised, placebo-controlled, multicentre trial in four hospitals in Malawi testing the efficacy and safety of intermittent preventive therapy post-discharge (IPTpd) in children aged 4-59 months admitted for severe malarial anaemia. All convalescent children who had completed a blood transfusion received artemether-lumefantrine at discharge and were randomly assigned by a computer-generated sequence to receive placebo or artemether-lumefantrine at 1 month and 2 months after discharge, providing about 1 month and 3 months of protection, respectively. Patients and study staff were masked throughout the study. The primary endpoint was a composite of all-cause mortality or hospital readmittance because of all-cause severe anaemia or severe malaria between 1 and 6 months after enrolment. This trial is registered, number ISRCTN89727873. Of 1414 children enrolled, 708 were assigned to receive placebo and 706 the intervention. By 6 months, 192 children (14%) had died or were readmitted with severe malaria or severe anaemia. 1-6 months after randomisation, 109 primary events occurred in 85 children in the placebo group and 86 in 74 children in the intervention group (adjusted protective efficacy [PE] 31%, 95% CI 5-50; absolute rate reduction 11·7 per 100 children years, 95% CI 1·8-18·9; p=0·024). The protective effect was greatest during the IPTpd period (1-3 months), when 58 primary events occurred in 49 children in the placebo group and 37 in 34 children in the intervention group (PE 41%, 10-62; p=0·01), but was not sustained after the third month (4-6 months, PE 17%, -27 to 45; p=0·395). When episodes in the first month were included--ie, before the first dose of IPTpd, when both groups benefited from the post-treatment prophylactic effect of artemether-lumefantrine provided at discharge--the overall cumulative PE by 6 months was 26% (-2 to 46; p=0·06). In areas with intense malaria transmission, chemoprevention with IPTpd given to children with severe malarial anaemia might reduce rates of readmittance to hospital for severe anaemia or malaria. Studies to confirm these findings and to investigate different delivery mechanisms and cost-effectiveness are needed. The Netherlands African Partnership for Capacity Development and Clinical Interventions Against Poverty Related Diseases, the UBS-Optimus Foundation, and the Gates Malaria Partnership.