Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202409607254081 Date of Registration: 13/09/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Monoclonal antibodies in children with severe anaemia or severe malaria to prevent malaria after hospital discharge
Official scientific 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)
Brief summary describing the background and objectives of the trial 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. Several 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. It is very effective in clinical trials but 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. Adherence to the monthly 3-day treatment course may be limited under real-life conditions. The US National Institutes of Health (NIH) has developed antimalarial monoclonal antibodies (mMAbs). The 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. All studies so far have demonstrated that mMAbs are safe and well tolerated. 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. This trial aims to assess the efficacy of a single dose of L9LS versus PDMC against microscopy or RDT-confirmed clinical malaria in hospitalised children with severe anaema or severe malaria by 6 months after investigational product (IP) administration.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) L9LS PD
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Prevention
Anticipated trial start date 04/11/2024
Actual trial start date
Anticipated date of last follow up 04/11/2026
Actual Last follow-up date
Anticipated target sample size (number of participants) 398
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Dynamic (adaptive) random allocation such as minimization Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Antimalarial monoclonal antibodies and Placebo chemoprevention 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. PDMC-Placebo at 2, 6, and 10 weeks post-discharge Single dose of mMAb post discharge and PDMC-Placebo at 2, 6, and 10 weeks post-discharge The mMAb consists of 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. It is a sterile, aqueous, buffered solution filled into single-dose vials at 150 + 15 mg/mL to a target fill volume of 2.25 mL in a 3-mL vial. The formulation buffer is the same as the drug substance (DS). Placebo-PDMC drugs will be pre-packed in opaque sealed envelopes or boxes containing three other boxes or envelopes (one for each PDMC course). The envelopes or boxes containing active DP or placebo will look identical, and the appearance and consistency of the tablets will also be identical. 199
Control Group Placebo antimalarial monoclonal antibodies and dihydroartemisininpiperaquine Participants in the placebo-mMAb arm will receive an infusion with an identical volume of normal saline and PDMC with dihydroartemisininpiperaquine at 2, 6, and 10 weeks post-discharge. Single dose of placebo-mMAb at discharge and PDMC with dihydroartemisininpiperaquine at 2, 6, and 10 weeks post-discharge. Participants in the placebo-mMAb arm will receive an infusion or SC injection with an identical volume of normal saline. Children in the mMAbs-placebo arm will receive PDMC with dihydroartemisinin-piperaquine (DP). 199 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Aged <10 years of both sexes 2. 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 3. Resident in catchment area 4. Post-transfusion haemoglobin >=5.0 g/dl or PCV >=15% 5. 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) 6. Provision of informed consent by parent or guardian 1. Recognised specific other causes of severe anaemia (i.e., trauma, haematological malignancy, known bleeding disorders, such as haemophilia) 2. Sickle cell anaemia/sickle cell disease 3. Body weight <5 kg 4. Fever (≥37.5oC) on the day of enrolment is not an exclusion criterion as long as the child is considered clinically stable. 5. HIV infection or on daily cotrimoxazole prophylaxis. 6. Previous enrolment in the present study 7. Children who are scheduled to receive any of the four doses of the malaria vaccine within 6 months after enrolment. 8. Received any RTS,S or R21 malaria vaccine primary series or booster dose within the last 14 days inclusive 9. On or eligible for cotrimoxazole prophylaxis for HIV infection or HIV exposure 10. Children with sickle cell disease because they are eligible for daily proguanil 11. Known hypersensitivity to artemether-lumefantrine or dihydroartemisininpiperaquine 12. 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) 13. Use or known need at enrolment for concomitant prohibited medication during the first 6 months post-discharge 14. 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 15. A known need at the time of enrolment for scheduled surgery during the first 6 months post-discharge 16. Suspected non-compliance with the follow-up schedule and protocol in the opinion of the investigator 17. 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 Child: 6 Year-12 Year,Infant: 13 Month(s)-24 Month(s),Preschool Child: 2 Year-5 Year 2 Month(s) 10 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 23/07/2024 KEMRI SERU
Ethics Committee Address
Street address City Postal code Country
P.O. BOX 54840-00200 Nairobi 00200 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome 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). The HRP2-band results will only be considered when microscopy or the RDT pLDH band results are unavailable. Incidence of clinical malaria detected by passive case detection by 6 months post-discharge
Secondary Outcome First or only episode of clinical malaria from 3 to 26 weeks post-discharge, inclusive, by time-to-event analysis 3 to 26 weeks
Secondary Outcome Clinical malaria with parasite density >5,000/microlitre (3-26 weeks post-discharge) 3 to 26 weeks post discharge
Secondary Outcome Sick-child clinic visits for any reason (all-cause) (3-26 weeks post-discharge) 3-26 weeks post-discharge
Secondary Outcome Sick-child clinic visits unrelated to malaria (all-cause minus primary outcome) (3-26 weeks post-discharge) 3-26 weeks
Secondary Outcome Readmission for any reason enrollment to 12 months
Secondary Outcome Cause-specific readmissions (severe malaria, severe anaemia, severe malarial anaemia, severe non-malarial anaemia, readmissions for severe malaria or severe anaemia [composite], readmission for other reasons) (3-26 weeks post-discharge) enrollment to 12 months
Secondary Outcome Death from any cause (3-26 weeks post-discharge) 3-26 weeks post-discharge
Secondary Outcome Readmission or death from any cause (composite) (3-26 weeks post-discharge). 3-26 weeks post-discharge
Secondary Outcome Prevalence of malaria infection detected by microscopy, RDT or PCR (composite) at 6 months 6 months
Secondary Outcome Prevalence of malaria infection detected by microscopy at 6 months 6 months
Secondary Outcome Prevalence of malaria infection detected by RDT (any band) at 6 months 6 months
Secondary Outcome Prevalence of malaria infection detected by PCR at 6 months 6 months
Secondary Outcome Mean Hb at 6 months 6 months
Secondary Outcome Prevalence of any anaemia (Hb<11 g/dL), mild anaemia (Hb 10.0-10.99 g/dl), moderate anaemia (Hb 7.0-9.99 g/dL) and moderate-severe anaemia (Hb<7.0 g/dL) at 6 months 6 months
Secondary Outcome Mean Z-scores for mid-upper arm circumference (MUAC) for-age, weight-for-age, height-for-age, and height-for-weight (using the WHO child growth standards) at 6 months 6 months
Secondary Outcome Prevalence of mild (Z-score <-2) and severe (Z-score <-3) of low MUAC-for-age, low weight-for-age, low height-for-age, and low height-for-weight at 6 months 6 months
Secondary Outcome The incidence of the primary and key secondary endpoints from 27-52 weeks postdischarge and the prevalence and mean scores at 12 months of the same endpoints assessed at 6 months post-discharge 12 months
Secondary Outcome The incidence of clinical malaria and readmission due to severe malaria from 27 to 52 weeks post-discharge and the prevalence of malaria infection and parasite densities at 12 months 12 months
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Homa Bay County Teaching and Referral Hospital Homa Bay Central Homa Bay Town 40300 Kenya
Siaya County Referral Hospital Siaya Town Siaya Town 40600 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
The National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Maryland United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Liverpool School of Tropical Medicine Pembroke Place Liverpool Liverpool United Kingdom Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
Daria Nikolaeva National Institutes of Health United States of America United States of America
Daniel Neafsey Harvard T.H. Chan School of Public Health, USA Boston United States of America
Sean C. Murphy University of Washington, USA Seattle United States of America
Prof. Bjarne Robberstad University of Bergen, Norway Bergen Norway
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Feiko ter Kuile feiko.terkuile@lstmed.ac.uk +254708739228 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Professor of Tropical Epidemiology
Role Name Email Phone Street address
Public Enquiries Iwaret Otiti Iwaret.Otiti@lstmed.ac.uk +254724007076 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Research Scientist
Role Name Email Phone Street address
Scientific Enquiries Simon Kariuki skariuki1578@gmail.com +254725389246 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Senior Principal Research Scientist
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes A fully de-identified data set will be available for sharing purposes no later than 3 months after the publication of the trial. Additionally, all Individual, de-identified participant data will be made available for any individual-participant data meta-analyses, with the understanding that the results of the meta-analysis will not be published before the results of the individual trial without the prior agreement of the investigators. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol No later than 3 months after the publication of the trial The full protocol will be available on request to any interested professional and may be published in peer-reviewed journals or attached as an appendix of the main trial publication.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information