Malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: study protocol for a multi-centre, two-arm, randomised, placebo-controlled, superiority trial

Titus K Kwambai, Aggrey Dhabangi, Richard Idro, Robert Opoka, Simon Kariuki, Aaron M Samuels, Meghna Desai, Michael Boele van Hensbroek, Chandy C John, Bjarne Robberstad, Duolao Wang, Kamija Phiri, Feiko O Ter Kuile, Titus K Kwambai, Aggrey Dhabangi, Richard Idro, Robert Opoka, Simon Kariuki, Aaron M Samuels, Meghna Desai, Michael Boele van Hensbroek, Chandy C John, Bjarne Robberstad, Duolao Wang, Kamija Phiri, Feiko O Ter Kuile

Abstract

Background: Children 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.

Objective: We 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/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. 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).

Results: Participant recruitment started in May 2016 and is ongoing.

Trial registration: ClinicalTrials.gov, NCT02671175 . Registered on 28 January 2016.

Keywords: Chemoprevention; Cost-effectiveness; Dihydroartemisinin-piperaquine; Malaria; Mortality; Post-discharge; Protocol; Readmission; Severe anaemia.

Conflict of interest statement

Ethics approval and consent to participate

This protocol, the informed consent documents and the patient information sheets have been reviewed and approved by the KEMRI Scientific and Ethics Review Unit (SERU) (protocol #2965), the Makerere University School of Medicine Research and Ethics Committee (SOMREC) (protocol #2015-125), the LSTM Research Ethics Committee (protocol #14.034) and the Regional Committee for Medical and Health Research Ethics, western Norway (REK vest) (protocol #2014/1911). The CDC gave approval for reliance on the KEMRI SERU (CDC Protocol #6919) (see Additional file 2: ethics approvals).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Map of study setting in Kenya and Uganda. Study sites in both western Kenya and Uganda are in the lake endemic region. These are large referral hospitals in the region with adequate diagnostic and treatment capacities for malaria and other conditions
Fig. 2
Fig. 2
Study Design and Schedule of Assessment (Spirit figure)

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