临床试验雷达

The proposed research aims to conduct implementation trials in Benin, co-designed with national stakeholders, to evaluate different delivery strategies for optimizing health system delivery of post-discharge malaria chemoprevention (PDMC) drugs and adherence to PDMC. This chemoprevention strategy is effective in reducing hospital readmissions and deaths after discharge. However, there is no clear delivery platform for PDMC, and adherence to the 3-day dosing regimen, provided monthly three times after discharge, is a potential limitation. The current trial will provide evidence-based data on acceptability, feasibility, and cost-effectiveness to aid decision-makers. The evidence generated will be used to support the effective implementation and scale-up of PDMC in high malaria-endemic areas such as 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.

Study design: The trial is a cluster randomized implementation trial with three arms at health facilities and their catchment communities (clusters) to enhance end-user adherence to the three PDMC courses compared to a control arm of PDMC without specific adherence support strategies. Its goal is to translate PDMC research findings into national policy guidelines and encourage their adoption in clinical practice, ensuring that caregivers of vulnerable children in Benin, and more broadly across sub-Saharan Africa, gain access to life-saving, proven medicines that help prevent or reduce hospital readmissions and deaths.

Study sites: Two health facilities with blood transfusion services will include in the trial in Benin. The recruitment will be competitive between the two selected hospitals over approximately 14 months to reach the study sample size. The first site, CHU-MEL has a higher annual incidence of severe anaemia (approximately 800-1000 cases per year) than the second site, Goho departmental hospital centre. Therefore, the proportion of participants enrolled at CHU-MEL could be slightly higher than in Goho.

Study population:

Inclusion criteria: convalescent children aged below 10 years, weighing above or equal to 5 kg admitted with severe anaemia (haemoglobin below 5g/dL) or severe malaria; clinically stable, able to take or switch to oral medication; post-transfusion Hb below 5g/dL.

Exclusion criteria: blood loss due to trauma, malignancy, known bleeding disorders or sickle cell disease, known hypersensitivity to study drug, known heart conditions, non-resident in the study area, previous participation in the study, known need at enrolment for prohibited medication and scheduled surgery during the 6-month course of the study. HIV infection and cotrimoxazole prophylaxis are not exclusion criteria.

Study intervention: The final choice of drug, the delivery strategy and the adherence support mechanisms to be evaluated have been co-designed with MoH and key national public health stakeholders through formative research conducted under a separate standalone protocol and through a stakeholder co-design workshop. In Benin, PDMC will comprise of 3-day treatment courses either dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 after discharge. PDMC will consist of three courses of dihydroartemisinin-piperaquine at the end of weeks 2, 6, and 10 after discharge.

Two community delivery strategies combined with adherence supports will be assessed during the trial: (i) all the drugs given at discharge to the caregivers (strategy A); (ii) all the drugs will be given by the community health workers (CHWs) to the caregivers at home, supervised by the qualified community health officers (ASCQ) (strategy B). Clusters will be randomly allocated in a 1:1:1 ratio to intervention (a, b) and the control (c) arms. The unit of randomization will be health facilities's catchment villages to avoid contamination related to adherence supports in community. Each health facility and its respective community will form a cluster. In arm "a", all PDMC drugs will be given to the caregivers at discharge with the CHW support through monthly home visits to remind the caregiver to administrate the PDMC drugs; and in arm "b" all PDMC drugs will be given by the community health workers (CHWs) to the caregivers at home, with a SMS/phone reminder from the qualified community health officers (ASCQ). Arm "c" represents the control arm (no reminder), in which all PDMC drug given to the caregivers at discharge with no other adherence support approaches.

All participating children will receive standard in-hospital care for severe anaemia or severe malaria (blood transfusion, often combined parenteral artesunate, followed by a 3-day course of artemether-lumefantrin (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication. Many children are likely to receive parenteral antibiotics as well as part of the standard of care.

Economic evaluation: The cost of delivering the intervention from the providers perspective and the cost of receiving the intervention from the beneficiary's perspective will be assessed through an economic evaluation (cost-effectiveness analysis) involving all children (and their caregivers) participating in the trials in both countries...

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