| Protocol No: | ECCT/24/09/01 | Date of Protocol: | 31-07-2024 |
| Study Title: |
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 (L9LS-pd)
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| Study Objectives: |
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
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| Laymans Summary: |
Hospitalised children with severe anaemia or severe malaria remain at high risk of dying or requiring
readmission after discharge for at least 6 months. In highly malaria-endemic settings, malaria is a
major contributor. In 2022, the World Health Organisation (WHO) recommended post-discharge
malaria prevention (PDMC) for children hospitalised with severe anaemia living in malarious areas.
Kenya and several other countries in sub-Saharan Africa aim to expand WHO’s PDMC
recommendation to children hospitalised with severe anaemia or severe malaria. PDMC consists of
full 3-day treatment courses with long-acting antimalarials given monthly, three times after hospital
discharge, providing about 14 weeks of protection. PDMC is very effective in clinical trials. However,
previous studies showed that adherence to the monthly 3-day treatment course is limited under
real-life conditions. Furthermore, PDMC only provides protection for 3.5 months, while the excess
risk of dying or needing to be readmitted remains high for the first 6 months after discharge.
The US National Institutes of Health (NIH) has developed a new intervention against malaria called
an antimalarial monoclonal antibody (mMAb). These are laboratory-made versions of a naturally
produced antibody specifically targeting the malaria parasite to neutralize and prevent 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. The first mMAb, CIS43LS, provided 88% protection against
malaria infection for at least 6 months when given intravenously (IV) by infusion in healthy adults in
Mali, West Africa. More recently, studies with a newer mMAb called L9LS showed a 74% reduction in
malaria disease by 6 months when given by injection under the skin (subcutaneously [SC]) to healthy
Malian children aged 6-10 years. Similar studies with L9LS are ongoing in healthy children under 5
years of age in Siaya, western Kenya. All studies so far have demonstrated that mMAbs are safe and
well tolerated. Hospitalised children with severe anaemia or severe malaria are an ideal target group
for protection against malaria by mMAb in highly malaria-endemic areas because a single infusion
with a mMAb, while still admitted in the hospital, could potentially protect them during the entire
vulnerable 6-month post-discharge period. Furthermore, unlike malaria vaccines, which require
three doses to provide protection, mMAbs provide immediate protection and don’t require the
children to mount their own immune response, which can be variable.
We propose a trial in 398 children hospitalised with severe anaemia or severe malaria in high
malaria transmission areas in western Kenya. We will compare the efficacy and safety of an infusion
with the mMAb L9LS provided before discharge to the standard-of-care with PDMC recommended
by WHO. PDMC will comprise three 3-day treatment courses provided at 2, 6 and 10 weeks postdischarge
with the long-acting antimalarial dihydroartemisinin-piperaquine (DP), the most effective
antimalarial used in all previous PDMC trials. The study will be placebo-controlled. Children in the
PDMC arm will receive a placebo infusion with normal saline before discharge; children in the
mMAbs arm will receive placebo-PDMC with placebo tablets that look identical to the real DP. 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.
Children will be followed for 1 year. We will compare the rates of clinical malaria between the
mMAb and the PDMC arms by 6 months post-discharge (the end of the ‘intervention period’)
(primary endpoint). We will also compare the rates of hospital readmissions and deaths. We will
then follow them for another 6 months (post-intervention period) to determine the longevity of the
protective effect and any longer-term benefits (e.g., on growth) or whether protection in the first 6
months results in delayed malaria, e.g. due to delayed acquisition of natural protective immunity
against malaria.
Written informed consent will be obtained from caregivers. The potential application of mMAb
would be routine administration to hospitalised children with severe anaemia or severe malaria in
highly malarious areas.
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| Abstract of Study: |
TITLE: 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 (L9LS-pd).
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 malariaendemic
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 postdischarge
period.
OVERVIEW DESIGN: We will conduct a 2-arm, multi-centre, individually randomised, placebocontrolled
non-inferiority trial in 398 children with severe malaria or severe anaemia. Children will
be randomly assigned (1:1) using an adaptive minimisation algorithm 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 (postintervention
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 HIVexposed
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. (Table 1, below).
Table 1: Study arms
Study arm
mMAb (L9LS) + placebo-PDMC Placebo-mMAb + PDMC
Infusion with the mMAb L9LS before
discharge
Placebo-PDMC at the end of weeks 2, 6,
10 post-discharge
Placebo-infusion with normal saline before
discharge
PDMC with DP at the end of weeks 2, 6, 10
post-discharge
mMAb=Antimalarial monoclonal Antibody (L9LS). PDMC=post-discharge malaria chemoprevention
DP=dihydroartemisinin-piperaquine.
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 postdischarge
(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): Allcause
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, we 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.
PARTNERS INSTITUTIONS: KEMRI, NIAID-NIH, LSTM, US-CDC
FUNDING: NIH and CDC
SPONSOR: LSTM
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