Monoclonal Antibodies in Children With Severe Anaemia or Severe Malaria to Prevent Malaria After Hospital Discharge

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

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

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.

Primary efficacy objective: To 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 by 6 months after investigational product (IP) administration.

Sites: Two hospitals in western Kenya in areas with moderate to intense malaria transmission. The number of hospitals will be expanded if recruitment rates require this.

Study Population: Inclusion criteria: convalescent children aged less than 10 years and weighing ≥5 kg hospitalised with severe anaemia (haemoglobin<5g/dL / Ht<15%) or severe malaria who have become clinically stable and can take or switch to oral medication; post-transfusion Hb >5g/dL, resident in the study area, provision of informed consent by parents or guardian. Exclusion criteria: Children eligible for any of the four doses of the RTS,S or R21 malaria vaccines, HIV-infected or HIV-exposed children on daily cotrimoxazole prophylaxis, blood loss due to trauma, malignancy, known bleeding disorders, known hypersensitivity to study drug, known heart conditions or family history of congenital QT prolongation, or taking medicinal products that are known to prolong the QTc interval, non-resident in the study area, previous participation in the study, known need at enrolment for prohibited medication and scheduled surgery during the 12-month course of the study.

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.

Follow-up procedures: Children will be followed for 12 months by passive surveillance (unscheduled sick visits) in 2 phases: a 6-month intervention period to the end of month 6 post-discharge (day 183 inclusive); a 6-month post-intervention period from month 7 to 12 inclusive (day 184 to +1 year minus 1 day following discharge).

Outcome Measures: Primary: Incidence rate of clinical malaria from 3 to 26 weeks post-discharge, 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). The HRP2-band results will only be considered when microscopy or the RDT pLDH band results are unavailable. Key secondary outcomes include the following outcomes measured during the follow-up periods (intervention and post-intervention): All-cause and cause-specific readmissions, all-cause non-severe sick-child clinic visits and those unrelated to malaria, and the pharmacokinetic parameters of L9LS. Other secondary efficacy outcomes include those measured during cross-sectional surveys conducted at the end of the intervention and post-intervention periods, including the prevalence of malaria infection, clinical malaria, anaemia, and standard anthropometric measures of malnutrition. Exploratory endpoints include immunological endpoints. Safety endpoints include solicited and unsolicited AEs (local and systemic) following mMAb administration and anti-drug antibodies (ADA) at 6 and 12 months.

Sample size: This will be a parallel, 2-arm, placebo-controlled, non-inferiority trial using a 1:1 allocation ratio. In this non-inferiority trial, investigators will compare mMAbs against monthly PDMC, assuming higher incidence rates are worse. The primary endpoint is clinical malaria during 24 weeks between 3 and 26 weeks post-discharge. The non-inferiority ratio is 1.1. To demonstrate non-inferiority with 90% power and a one-sided significance level of 0.025 and assuming a potential reduction by mMAbs relative to PDMC of 54% (IRR=0.456) from 72 to 33 per 100 person-years, the study requires approximately 398 participants (199 per arm), considering a 15% dropout rate and an overdispersion parameter of 1.18. The trial includes two interim analyses for efficacy and sample size re-estimation when 50% and 75% of participants have completed their 6-month follow-up.

Data Analysis: The primary analysis will use the modified intention-to-treat population, including all randomised participants contributing to the outcome. Incidence rates will be calculated, and incidence rate ratios will be estimated using negative binomial regression by treatment as randomised. The analysis time will be divided into a) the intervention period (first 6 months, primary analysis), b) the post-intervention period (6-12 months), c) and the cumulative effect by 12 months. If non-inferiority is demonstrated, an analysis for superiority will be conducted.

Impact: The potential application of mMAb would be routine administration to hospitalised children with severe anaemia or severe malaria in highly malarious areas. The potential benefits include the prevention of post-discharge deaths, readmissions, and malaria episodes in these vulnerable groups of children.

Inclusion Criteria:

Inclusion criteria for enrolment into the pre-study screening period

• 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

Exclusion Criteria:

Exclusion criteria for enrolment into the pre-study screening period

• 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

Exclusion criteria for enrolment

• Previous enrolment in the present study
• Children who are scheduled to receive any of the four doses of the malaria vaccine within 6 months after enrolment.
• Received any RTS,S or R21 malaria vaccine primary series or booster dose within the last 14 days inclusive
• On or eligible for cotrimoxazole prophylaxis for HIV infection or HIV exposure
• Children with sickle cell disease because they are eligible for daily proguanil
• Known hypersensitivity to artemether-lumefantrine or dihydroartemisinin-piperaquine
• Anticipated to reside for more than 1 month of the 6-month (26 weeks) intervention period outside of the catchment area (e.g. boarding school)
• Use or known need at enrolment for concomitant prohibited medication during the first 6 months post-discharge
• Ongoing or planned participation in another clinical trial involving ongoing or scheduled treatment with prohibited medicinal products or active follow-up during the first 26 weeks post-discharge
• A known need at the time of enrolment for scheduled surgery during the first 6 months post-discharge
• Suspected non-compliance with the follow-up schedule and protocol in the opinion of the investigator
• Known heart conditions or family history of congenital prolongation of the QTc interval, or taking medicinal products that are known to prolong the QTc interval