Clinical trial NCT06624631: PDMC Implementation Trial in Kenya
Official title: Delivery Strategies for Malaria Chemoprevention in the Post-discharge Management of Children Hospitalised with Severe Anaemia or Severe Malaria: Cluster and Individually Randomised Controlled Implementation Trial and Economic Evaluation in Kenya
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Severe Malaria
Severe Anemia
Keywords: Children
Antimalarial
Prevention
Chemoprevention
Caregivers
Patient discharge
Healthcare providers
Health economics
Qualitative research
Feasibility
Cost effectiveness
Kenya
Artemisinins
School age
Pre-school
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Kenya Medical Research Institute
name: Institut de Recherche Clinique du Benin (IRCB), Benin
name: Epicentre, Paris, France.
name: Institute of Research for Development, France
name: Training Research Unit of Excellence, Blantyre, Malawi
name: Makerere University
name: Centres for Disease Control and Prevention, Kenya.
First posted: 2024-10-03
Enrollment: 712
Sex: ALL
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine compared to the standard of care without adherence strategies
Primary purpose: PREVENTION

Brief summary: The goal of this implementation trial is to evaluate at least two alternative delivery strategies and adherence support for malaria chemoprevention with dihydroartemisinin-piperaquine in the post-discharge management of children hospitalised with severe anaemia or severe malaria to optimise adherence in Kenya.

The actual interventions to be evaluated will be co-designed with national stakeholders during an initial formative research stage.

Detailed description: Study design:

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 post discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine compared to the standard of care without adherence strategies.

Study sites: Health facilities with blood transfusion services in malaria-endemic areas in western Kenya.

Study Population:

Cluster 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.

Individual 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: Hospitals will be randomised to one of two delivery platforms for PDMC (A or B). The final choice of the two delivery strategies to be evaluated will be informed by formative research conducted under a separate standalone protocol (LSTM Protocol #23-053, KEMR-SERU #480/4870). For example, these could include A: Delivery of PDMC at the primary admitting facility or B: Referral to the closest peripheral facility for dispensing of PDMC two weeks after discharge.

Individually randomised trial: The final choice of the adherence support strategies to be evaluated will be informed by formative research conducted under a separate standalone protocol. For example, these could include a): CHW reminder visits at home, b) SMS/phone call reminders and c) no reminders (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.

Primary endpoints:

Cluster randomised trial: The proportion of eligible participants who were not prescribed the full 3 courses of PDMC.

Individually randomised trial: The proportion of children with incomplete adherence to the 9 doses of PDMC (three courses of 3-day treatments 3x3=9).

Secondary endpoints:

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.
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: Approximately 89 participants per cluster (cluster size will vary between clusters), or approximately 712 overall (356 in each of the two study arms) is estimated to provide over 80% power to detect a risk difference of 23% from 35% in the control arm to 12% in the intervention clusters (RR=0.45), using a two-sided alpha of 0.05, and assuming an intra-cluster correlation coefficient (ICC) of 0.03, a coefficient of variation of 0.57, 15% loss to follow-up and small-sample correction to account for the small number of clusters.

Individually randomised trial: 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 accounting for clustering effects.

Eligibility criteria: Inclusion Criteria:

CLUSTERS

* Health facilities with blood transfusion services offering in-patient care for children with severe anaemia and severe malaria.
* \>=40 children per year admitted with severe anaemia or severe malaria
* Agreement to participate by facility management
* Located in areas with moderate to high malaria transmission

INDIVIDUAL PARTICIPANTS

* Aged \<10 years of both sexes
* Hospitalised with severe anaemia or severe malaria: Initially hospitalised with haemoglobin \<5.0 g/dl or PCV \<15%, or requirement for blood transfusion for other clinical reasons on or during admission to the hospital, or severe malaria, defined as a requirement for parenteral artesunate in the opinion of the treating clinician and the presence of microscopy or RDT confirmed Plasmodium infection

Exclusion Criteria:

CLUSTERS

- Health facilities without subservient lower-level health facilities

INDIVIDUAL PARTICIPANTS

* Recognised specific other causes of severe anaemia (i.e., trauma, haematological malignancy, known bleeding disorders, such as haemophilia)
* Sickle cell anaemia/sickle cell disease
* Body weight \<5 kg
* HIV infection and cotrimoxazole prophylaxis are not exclusion criteria.

Primary outcomes:
measure: Drug delivery
timeFrame: 2, 6 and 10 weeks post discharge
measure: Adherence
timeFrame: 2, 6 and 10 weeks (days 1-3) post discharge
Secondary outcomes:
measure: Proportion of children who are readmitted with malaria
timeFrame: 0-14 weeks post discharge
measure: Proportion of children who are readmitted with any cause
timeFrame: 0-14 weeks post discharge
measure: Proportion of children who die within 14 weeks of discharge
timeFrame: 0-14 weeks post discharge
measure: Incidence of serious adverse events
timeFrame: 0-14 weeks post discharge
measure: Cost-effectiveness
timeFrame: 0-14 weeks post discharge
measure: User and provider perceptions of acceptability and feasibility
timeFrame: Trial month 6+
Other outcomes:
Locations:
Study officials:
affiliation: LSTM
name: Feiko ter Kuile, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: