Single-Use Antimalarial Monoclonal Antibodies for Post-Discharge Malaria Prevention in Children With Severe Anaemia or Severe Malaria in Kenya: A Multi-Centre, Parallel-Group, Two-Arm Randomised Placebo-Controlled Non-Inferiority Trial

Status: Recruiting
Location: See all (2) locations...
Intervention Type: Drug, Biological
Study Type: Interventional
Study Phase: Phase 3
SUMMARY

Background and rationale: Hospitalised children with severe anaemia remain at high risk of dying or requiring hospital readmission for at least 6 months after discharge. In highly malaria-endemic settings, malaria is a major contributor to these post-discharge readmissions and deaths. In 2022, the World Health Organisation (WHO) recommended post-discharge malaria chemoprevention (PDMC) for children hospitalised with severe anaemia living in malarious areas. Kenya, together with several other countries in sub-Saharan Africa, aims to expand WHO's recommendation and introduce PDMC in children hospitalised with severe anaemia or severe malaria, including children with severe malaria who do not have severe anaemia (e.g. cerebral malaria). PDMC consists of full 3-day treatment courses with long-acting antimalarials given monthly three times after discharge. PDMC is very effective in clinical trials. However, adherence to these monthly 3-day drug treatments is limited under real-life conditions. Furthermore, PDMC provides chemoprevention for about 3.5 months only, while the risk of dying or needing to be readmitted remains high for several more months. The US National Institutes of Health (NIH) has developed two monoclonal antibodies targeting Plasmodium falciparum malaria (mMAb). These proteins specifically target a highly conserved epitope found on the circumsporozoite protein-1 (CSP-1) of P. falciparum to neutralize it and prevent malaria infection. A key feature of mMAbs is that they can provide protection for up to 6 months with a single dose and thus serve as a long-acting drug. Recent placebo-controlled studies in healthy adults in Mali suggest that the first mMAb, CIS43LS, when administered at a dose of 40 mg/kg intravenously (IV), can block 88% of malaria infections for at least 6 months. More recently, studies with a newer mMAb called L9LS, which is anticipated to be more potent than CIS43LS, showed a 74% reduction in uncomplicated clinical malaria by 6 months when administered subcutaneously to healthy Malian children aged 6-10 years by a single subcutaneous (SC) dose of 10-20 mg/kg (NCT05304611). Similar studies with L9LS are ongoing in healthy children under 5 years of age in Siaya, western Kenya (NCT05400655). Young children admitted to hospitals in highly malaria-endemic areas with severe anaemia or severe malaria are an ideal target group for passive immunoprevention with mMAbs as a single infusion with mMAb while in the hospital could protect this high-risk group during the entire vulnerable post-discharge period. Overview design: investigators will conduct a 2-arm, multi-centre, individually randomised, placebo-controlled non-inferiority trial in 398 children with severe malaria or severe anaemia. Children will be randomly assigned (1:1) using minimum sufficient balance (MSB) randomisation to receive either mMAb before discharge or 3 courses of monthly PDMC after discharge, according to WHO guidelines. The study will be placebo-controlled. Children in the PDMC arm will receive a placebo infusion with normal saline before discharge; children in the mMAb arm will receive placebo-PDMC. All children will receive standard in-hospital care, including a blood transfusion and treatment for severe malaria where indicated. They will also receive a full 3-day treatment course with the antimalarial artemether-lumefantrine (AL) to clear any existing malaria infections as soon as they have recovered and can take oral medication. The primary endpoint is the incidence of clinical malaria detected by passive case detection by 6 months post-discharge (the intervention period). Key secondary endpoints include the rates of readmissions and deaths (all children). Children will be followed for another 6 months (post-intervention period) to determine the duration of protection, any long-term impact (e.g., growth) and if mMAbs result in a delayed acquisition of natural protective immunity against clinical malaria Study Interventions: All children will receive standard in-hospital care, including a blood transfusion, antibiotics, and treatment for severe malaria where indicated. All children in both arms will be empirically treated for malaria infection around discharge with a 3-day regimen with artemether-lumefantrine to ensure parasite clearance of any existing parasites. Participants in the mMAb arm will receive the study agent L9LS IV with a target dose of 30 mg/kg. The IV dose will use 1 kg step increases. During the 6-month intervention period, children in the placebo-mMAbs arm will receive three courses of monthly PDMC as per WHO guidelines with dihydroartemisinin-piperaquine (DP) at 2, 6 and 10 weeks post-discharge. Those in the mMAbs arm will receive an identical placebo PDMC

Eligibility
Participation Requirements
Sex: All
Maximum Age: 9
Healthy Volunteers: f
View:

• Aged \<10 years of both sexes

• 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

• Resident in catchment area

⁃ Eligibility criteria for enrolment

• Fulfilled the pre-study screening eligibility criteria

• Post-transfusion haemoglobin \>=5.0 g/dl or PCV \>=15%

• Clinically stable, able to take oral medication, able to feed (for breastfeeding children) or eat (for older children) and able to sit unaided (for older children who were already able to do so before hospitalisation)

• Provision of informed consent by parent or guardian Exclusion criteria for enrolment into the pre-study screening period

Locations
Other Locations
Kenya
HomaBay County Teaching and Referral Hospital
RECRUITING
Kisumu
Siaya County Referral Hospital
RECRUITING
Kisumu
Contact Information
Primary
Mary I Otiti, BSc. MBChB, MSc.
iwaret.otiti@lstmed.ac.uk
+254 724007076
Time Frame
Start Date: 2025-05-02
Estimated Completion Date: 2027-04
Participants
Target number of participants: 398
Treatments
Experimental: Antimalarial monoclonal antibodies (mMAbs) -L9LS + Placebo-PDMC
Participants in the mMAb arm will receive the study agent L9LS IV with a target dose of 30 mg/kg. The IV dose will use 1 kg step increases. They will also receive a course of PDMC-Placebo at 2, 6, and 10 weeks post-discharge
Active_comparator: Placebo-mMAB + Malaria chemoprevention- PDMC
mMAbs-placebo arm: Participants will receive a single infusion of normal saline and thereafter a course of PDMC with dihydroartemisinin-piperaquine at 2, 6, and 10 weeks post-discharge
Sponsors
Collaborators: National Institute of Allergy and Infectious Diseases (NIAID), Centers for Disease Control and Prevention
Leads: Liverpool School of Tropical Medicine

This content was sourced from clinicaltrials.gov

Similar Clinical Trials