| Protocol No: | ECCT/24/12/01 | Date of Protocol: | 06-09-2024 |
| Study Title: | Delivery strategies for malaria chemoprevention in the post-discharge management of hospitalised children with severe anaemia or severe malaria: cluster and individually randomised controlled implementation trials with nested economic evaluation in Kenya and Benin |
| Study Objectives: |
Primary Objectives
1. Cluster RCT of health systems delivery mechanism:
- To determine the effectiveness of different delivery strategies to optimise health system delivery of PDMC
2. Individually RCT of end-user adherence support
- To determine the effectiveness of different adherence support strategies to optimise end-user adherence to PDMC
Secondary Objectives
1. Cluster RCT of health systems delivery mechanism:
- To evaluate the adoption of the health system delivery mechanisms and adherence support mechanisms for the 3 courses of PDMC
2. Individually RCT of end-user adherence support:
To determine the clinical effectiveness of the different PDMC delivery strategies (all-cause and malaria-specific readmissions and sick-child clinic visits, all-cause mortality).
3. To evaluate the effectiveness of the linkage mechanisms between the various health facility levels along the PDMC delivery continuum
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| Laymans Summary: |
Background: The World Health Organization (WHO) recommended post-discharge malaria chemoprevention (PDMC) in June 2022 for managing children with severe anaemia in areas with moderate to high perennial malaria transmission. The goal is to reduce 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. Implementation research is necessary to support the introduction and scale-up of PDMC.
Aim: Implementation trials in Kenya and Benin will be co-designed with national stakeholders to evaluate alternative health system delivery strategies for optimizing delivery of PDMC drugs and adherence to PDMC. The trials will provide evidence on the acceptability, feasibility, and cost-effectiveness of each strategy to inform effective implementation and scale-up of PDMC in different country and health system contexts.
Methods: The project involves two separate trials, one in each country. Formative research with the Ministries of Health in the two countries and their stakeholders has informed the delivery strategy interventions selected to be evaluated in each trial. In Kenya, a multi-centre, 2-arm cluster randomised trial will compare two “delivery strategies” for the 3 courses of monthly PDMC with dihydroartemisinin-piperaquine (DP). The trial will randomize 10 hospitals (the clusters) to one of two delivery platforms (A and B) in a 1:1 ratio, with the final choice of intervention informed by formative research. The primary endpoint will be the proportion of eligible participants prescribed with incomplete courses of PDMC. A nested 3-arm individually randomised trial involving 600 children ( 200 per arm) will evaluate 3 different “adherence support” strategies, including SMS reminders to caregivers, Community Health Worker (CHW) support through home visits, and a control arm comprising of provision of all 3 PDMC courses by the hospital where the child was admitted i.e. standard of care. The primary endpoint will be the proportion of children with incomplete adherence (i.e. not receiving all 9 doses of PDMC).
Secondary endpoints include clinical effectiveness, cost-effectiveness, acceptability and feasibility, provision of adherence support mechanisms, and linkage to subsequent levels of service provision along the PDMC delivery continuum. All participating children will receive standard in-hospital care for severe anaemia or severe malaria and a 3-day course of artemether-lumefantrine (AL), started in-hospital as soon as they can take oral medication.
In Benin, a 3-arm individually randomised trial involving 519 children (173 per arm) will be conducted to evaluate different “adherence support” strategies only, including: mobile phone reminders to CHW/ASCQ , monthly reminder visits to CHW/ASCQ by the regional social mobilisation research and support officer (CRAMS), and a control arm without any reminder intervention.
LSTM-UK will act as the legal sponsor of the trials in Kenya. The Institut de Recherche Clinique du Bénin (IRCB) will act as the sponsor for the trial in Benin.
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| Abstract of Study: |
Title: Delivery strategies for malaria chemoprevention in the post-discharge management of hospitalised children with severe anaemia or severe malaria: cluster and individually randomised controlled implementation trials with nested economic evaluation in Kenya and Benin.
Short Title: PDMC-Saves Lives (PDMC-SL)
Background and rationale: 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. 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 actual interventions to be evaluated differ between the two trials as they have been co-designed with national stakeholders during an initial formative research stage, conducted under a separate protocol (LSTM Protocol #23-053, KEMRI-SERU #480/4870).
Aim: To conduct implementation trials, co-designed with national stakeholders, to evaluate different delivery strategies to optimise health system delivery of PDMC drugs and adherence to PDMC to provide evidence-based data including acceptability, feasibility and cost-effectiveness that are useful to decision-makers.
Study Type: Kenya: A multi-centre, 2-arm, cluster-randomised trial evaluating two health system delivery strategies and a 3-arm nested individually randomised trial evaluating two new intervention strategies to enhance end-user adherence to PDMC compared to the standard of care without adherence strategies. Benin: A multi-centre, 3-arm, individually randomised trial evaluating two intervention strategies to enhance end-user adherence to PDMC compared to a control arm of PDMC without specific adherence support strategies.
Sites: Health facilities with blood transfusion services in malaria-endemic areas in Benin and western Kenya.
Study Population:
Clusters (Kenya only) inclusion criteria: health facilities with blood transfusion services offering in-patient care for children with severe anaemia and severe malaria. Exclusion criteria: primary health facilities without subservient lower-level health facilities. Individuals (Kenya and Benin) inclusion criteria: convalescent children aged <10 years, weighing ≥5 kg admitted with severe anaemia (haemoglobin<5g/dL) or severe malaria; clinically stable, able to take or switch to oral medication; post-transfusion Hb >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 4-month course of the study. HIV infection and cotrimoxazole prophylaxis are not exclusion criteria.
Study Interventions:
Cluster randomised trial (Kenya only): Hospitals will be randomised to one of two delivery platforms for PDMC (A or B). The choice of the two delivery strategies to be evaluated has been informed by formative research conducted under a separate standalone protocol (LSTM Protocol #23-053, KEMRI-SERU #480/4870) and stakeholder engagements. Strategy A comprises delivery of the initial PDMC course at the primary admitting facility two weeks after discharge during a post-discharge follow-up clinic visit. The subsequent 2 courses will be dispensed monthly at the closest health facility. Strategy B comprises delivery of all 3 PDMC courses at the primary admitting facility two weeks after discharge during a post-discharge follow-up clinic visit.
Individually randomised trial (Kenya and Benin): The final choice of the adherence support strategies to be evaluated has been informed by formative research conducted under the same separate standalone protocol. In Kenya, these include: Arm a - SMS reminders to caregivers, Arm b - Community Health Promoter (CHP) support through monthly home visits and Arm c - no reminders (control). In Benin, these include: Arm a- a telephone reminder to the community health worker (CHW)/qualified community health worker (ASCQ); Arm b - regional social mobilisation research and support officer (CRAMS) reminder through monthly visits to CHW/ASCQ; and Arm c - no reminder (control).
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 AL 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.
Endpoints: Cluster randomised trial (Kenya only): The primary endpoint will be the proportion of eligible participants who were not prescribed the full 3 courses of dpoints:PDMC. Individually randomised trial (Kenya and Benin): Primary endpoint: proportion of children with incomplete adherence to the 9 doses of PDMC (three courses of 3-day treatments 3x3=9). Secondary endpoints include 1) clinical effectiveness (all-cause and malaria-specific sick-child clinic visits, all-cause and cause-specific readmissions and all-cause mortality by the end of week 14 after discharge, 2) safety (incidence of serious adverse events), 3) cost-effectiveness, and 4) acceptability and feasibility.
Follow-up procedures: Children will be followed for 14 weeks (i.e., four weeks after the last PDMC course) through passive surveillance of clinic visits and hospitalisations. Each child will then be seen for an end-of-study visit towards the end of week 14. Children will also be visited at home for unannounced home visits one to three days from the last day of the last dose of each 3-day course of PDMC medication to assess adherence.
Sample size: Cluster randomised trial (Kenya only): Approximately 60 participants per cluster (cluster size will vary between clusters), or approximately 600 overall (300 in each of the two study arms) is estimated to provide over 80% power to detect a risk difference of 20% from 35% in the control arm to 15% in the intervention clusters (RR=0.43), using a two-sided alpha of 0.05, and assuming an intra-cluster correlation coefficient (ICC) of 0.03, a coefficient of variation of 0.39,15% loss to follow-up and small-sample correction to account for the small number of clusters. Individually randomised trial (Kenya and Benin): A sample size of 147 participants in the control arm (c) and 147 in each of the two intervention arms (a and b), totalling 441 participants, would provide 90% power to detect a 50% reduction in the primary endpoint (proportion of children with incomplete adherence to the 9 doses of PDMC) from 36.8% in the control arm to 18.4% (RR=0.50) in any of the two intervention arms using a 1:1:1 allocation after accounting for the multiple comparisons (α = 0.025). A total of 519 participants (173 per arm) will be recruited to allow for a 15% loss to follow-up.
Data Analysis: Risk ratios and corresponding 95% confidence intervals will be computed to compare treatment effects using multi-level mixed models (Kenya) or mixed models (Benin) accounting for clustering effects.
Partners institutions: IRCB, Benin; KEMRI Kisumu, Kenya; LSTM, UK; Epicentre, France; IRD, France; Centers for Disease Control and Prevention, US; TRUE, Malawi.
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