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
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
Fulfilled the pre-study screening eligibility criteria
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 or on daily cotrimoxazole prophylaxis
Parallel
Antimalarial monoclonal antibodies
Biological/VaccineL9LS Antimalarial monoclonal antibodies (mMAbs)
Dihydroartemisinin - Piperaquine (DP)
DrugPost-Discharge Malaria Chemoprevention
Placebo mMAB
Biological/VaccinePlacebo anti malarial monoclonal antibody (placebo mMAB) which is Normal saline
Placebo PDMC
DrugPlacebo PDMC course which comprises placebo DP oral tablets
Incidence rate of clinical malaria from 3 to 26 weeks post-discharge
Assess the efficacy of a single dose of L9LS versus PDMC against microscopy or RDT-confirmed clinical malaria in hospitalised children with severe anaemia or severe malaria. Clinical malaria defined as an illness accompanied by measured fever ≥37.5°C or a history of fever (subjective or objective) in the previous 24 hours, accompanied by any level of asexual parasitaemia detected by microscopy or RDT (pLDH or HRP2-band).
Number of participants with adverse events following a dose of L9LS versus PDMC in children hospitalised with severe anaemia or severe malaria
Assess the safety and tolerability of a single dose of L9LS versus PDMC in children hospitalised with severe anaemia or severe malaria through number of participants with solicited and unsolicited adverse events following intervention product administration.
Efficacy of a single dose of L9LS versus PDMC against the first or only microscopy or RDT-confirmed clinical malaria in children hospitalised with severe anaemia or severe malaria by 6 months post-discharge
To assess the efficacy of a single dose of L9LS versus PDMC against the first or only microscopy or RDT-confirmed clinical malaria in children hospitalised with severe anaemia or severe malaria by 6 months post-discharge. the end point includes the first or only episode of clinical malaria from 3 to 26 weeks post-discharge, inclusive, by time-to-event analysis.
Efficacy of a single dose of L9LS versus PDMC against clinical malaria with parasite density >5,000/microlitre (3- 26 weeks post discharge)
To assess the efficacy of a single dose of L9LS versus PDMC against clinical malaria with parasite density \>5,000/microlitre (3-26 weeks post-discharge)
Efficacy of a single dose of L9LS versus PDMC against readmission for any reason in children hospitalised with severe anaemia or severe malaria by 6 months post-discharge
To assess the efficacy of a single dose of L9LS versus PDMC against re-admission from any cause.
The maximal observed blood concentration (Cmax) of a single dose of L9LS in children hospitalised with severe anaemia or severe malaria
The pharmacokinetics of antibody concentrations of a single dose of L9LS in children hospitalised with severe anaemia or severe malaria. This includes the pharmacokinetic parameters of antibody concentration Maximal observed blood concentration (Cmax)
Effect of a single dose of L9LS versus PDMC on biomarkers of inflammation post-discharge in children hospitalised with severe anaemia or severe malaria
To assess the effect of a single dose of L9LS versus PDMC on biomarkers of inflammation post-discharge in children hospitalised with severe anaemia or severe malaria by Inflammatory biomarkers, such as alpha-1-acid glycoprotein (AGP) and C-reactive protein (CRP).
Effect of a single dose of L9LS versus PDMC on biomarkers of naturally acquired immunity post-discharge in children hospitalised with severe anaemia or severe malaria
To asses the effect of a single dose of L9LS versus PDMC on biomarkers of naturally acquired immunity post-discharge in children hospitalised with severe anaemia or severe malaria. This will be by IgG responses to blood-stage antigens, such as antibodies to merozoite antigens, including AMA1, MSP1
Intervention costs and costs of health consequences of a single dose of post-discharge L9LS versus PDMC in children hospitalised with severe anaemia or malaria, and their caregivers' willingness to pay for it.
To determine the intervention costs and costs of health consequences of a single dose of post-discharge L9LS versus PDMC in children hospitalised with severe anaemia or malaria, and their caregivers' willingness to pay for it. this entails Costs of intervention, including costs of health consequences, that covers, Provider and patient (household) costs associated with routinely providing MmABs or PDMC and, Provider and patient (household) costs associated with primary admission and readmission or clinic visits of participating children during the follow-up period. Caregivers' willingness to pay-estimate
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Liverpool School of Tropical Medicine
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator
Centers for Disease Control and Prevention
Collaborator
