Delivery Strategies for Malaria Chemoprevention in the Post-discharge Management of Children Hospitalised With Severe Anaemia or Severe Malaria: a Cluster Randomised Controlled Implementation Trial in Benin

Introduction : Severe anaemia is a major cause of morbidity and mortality in children in malaria-endemic areas of sub-Saharan Africa, accounting for a large fraction of paediatric hospitalisations and in-hospital mortality [1] However, these children also remain at high risk of dying or being readmitted after discharge from hospital due to a wide range of clinical, epidemiological, behavioural and nutritional factors [2,3]. A recent trial in East Africa showed that about a third of discharged children after recovery from severe anaemia were readmitted or died in the first 6 months post-discharge [4]. In highly endemic settings, malaria is a major cause of this post-discharge morbidity and mortality [5,6].

In June 2022, the World Health Organization (WHO) recommended PDMC for the post-discharge management of children with severe anaemia in settings with moderate to high perennial malaria transmission to reduce hospital readmissions and deaths after discharge [7,8]. However, there is no obvious delivery platform for PDMC, unlike for intermittent preventive treatment in infants (IPTi) or pregnant women (IPTp). Furthermore, a potential limitation of PDMC is adherence to the 3-day dosing regimen, which is provided monthly three times after discharge. Therefore, implementation research is urgently needed to support the introduction and scale-up of PDMC. We propose to conduct two implementation trials to evaluate delivery strategies to optimise adherence to PDMC in different contexts: one in East Africa (Kenya) and one in West Africa (Benin). The current protocol presents the trial description in Benin.

Rationale of the trial: The WHO recommendation highlighted the need for implementation research on optimal delivery strategies for PDMC to help guide decision-making. The WHO recommendation stopped short of recommending which antimalarial drug should be used and how best to deliver PDMC, indicating that these decisions are to be made at the national level and adapted to suit local contexts. Importantly, the recommendation does not recommend any one specific drug or regimen to be used for PDMC, stating "SP, AL and DP were used in three trials and all regimens were found to be effective for PDMC" and "the medicines used for PDMC can be the same as the first-line malaria treatment, but an alternative medicine is preferred". Neither does the recommendation provide guidance on the optimal delivery mechanism(s) for giving the post-discharge chemoprevention regimen to caregivers in a way that promotes adherence and public health impact. A major challenge with implementing PDMC is that there is no pre-existing platform that could be utilised for its delivery. This is in contrast to other malaria prevention strategies, such as seasonal malaria chemoprevention (SMC), intermittent preventive treatment in pregnant women (IPTp), and perennial malaria chemoprevention (PMC, previously known as IPTi) and the recently recommended RTS,S malaria vaccine. Currently, the evidence on how to implement PDMC is limited to a single implementation trial in Malawi [8]. Furthermore, it must be appreciated that health systems, particularly in the community, vary from country to country. The adherence to monthly 3-day courses of PDMC after discharge under real-life conditions is unknown.

Study objectives:

The primary objective is to determine the effectiveness of different community delivery mechanisms and adherence support strategies to optimise end-user adherence to PDMC. Secondary objectives are to: i) determine the clinical effectiveness of the different PDMC delivery strategies (all-cause and malaria-specific readmissions and sick-child clinic visits, all-cause mortality); ii) evaluate the effectiveness of the linkage mechanisms between the various health facility levels along the PDMC delivery continuum; iii) determine the acceptability and feasibility of the different PDMC delivery and adherence support strategies; iv) determine the incremental cost-effectiveness (cost per DALY averted) of the different PDMC delivery and adherence support strategies.