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.: PACTR202102694561794 Date of Approval: 18/02/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Phase III Trial of R21/Matrix-M
Official scientific title A Phase III randomized controlled multi-centre trial to evaluate the efficacy of the R21/Matrix-M vaccine in African children against clinical malaria
Brief summary describing the background and objectives of the trial In 2018, there were an estimated 228 million malaria cases worldwide, resulting in 405,000 deaths. 93% of these occurred in the WHO African Region. In this region, P. falciparum is the most prevalent malaria parasite causing 99.7% of the estimated malaria cases. Globally, the incidence rate of malaria declined between 2010 and 2018, the rate of change slowed considerably from 2014 to 2018. In the era of anti-malaria drug resistance, resistance to insecticide treated bed nets, and the absence of a licensed vaccine in use, there is an urgent need for a highly efficacious vaccine. This will be a double-blind, individually randomised trial, with 2:1 randomisation to R21/Matrix-M malaria vaccine or control rabies vaccine (Abhayrab). This is a multi-centre trial with sites in Burkina Faso, Kenya, Mali and Tanzania.The study groups are: i. Standard vaccination regime, 5-17 months olds (R21/Matrix-M x 3, n= 1600; Rabies vaccine x 3, n = 800) ii. Seasonal vaccination regime, 5 – 48 month olds (R21/Matrix-M x 3, n= 1600; Rabies vaccine x 3, n = 800). In each group, a booster (4th) dose of the same vaccine will be administered 12 months after the third dose. Initial follow-up will be for two years after 3rd dose, with a primary analysis at 12 months after dose 3. Objectives: To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-17 month old children living in a malaria endemic area, 12 months after completion of the primary course (standard vaccination regime). To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-48 month old children living in a malaria endemic area, 12 months after completion of the primary course (seasonal vaccination regime). To assess the safety and reactogenicity of R21/Matrix-M, employing either vaccination regime, in children living in a malaria endemic area, in the month following each vaccination, and 12 months after 3rd dose.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) VAC078
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Prevention: Vaccines
Anticipated trial start date 26/02/2021
Actual trial start date
Anticipated date of last follow up 01/12/2023
Actual Last follow-up date
Anticipated target sample size (number of participants) 4800
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
NCT04704830 clinicaltrials.gov
OXTREC Ref 8 21 Oxford Tropical Research Ethics Committee
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 Simple randomization using a randomization table created by a computer software program 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 Standard vaccination regime R21MatrixM Participants in this arm will receive 3 doses of R21/Matrix-M malaria vaccine that are four weeks apart. They will also receive a booster (4th) dose of the same vaccine will be administered 12 months after the third dose.Participants will be enrolled for the standard vaccination regime in: Dande, Burkina Faso; Kilifi, Kenya; and Bagamoyo, Tanzania Initial follow-up will be 12 months after dose 3. Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data. R21 is a virus-like particle of about 23 nm in diameter comprising a fusion protein of the central repeats and C-terminus of the CS protein to the N-terminus of the Hepatitis B surface antigen. These repeats comprise many copies of the four amino acid sequence, NANP. This fusion protein is similar to that in RTS,S, but there is a fourfold excess of unfused Hepatitis B surface antigen molecules in RTS,S to allow it to form hybrid particles. This is not the case in R21, in which unfused HBsAg molecules are absent (Figure 2), and expression and assembly in virus-like particles of the fusion protein alone for R21 proved possible due to expression in a different species of yeast (Hansenula / Pichia) with a stronger promoter, resulting in a higher intracellular concentration of the fusion protein. Matrix-M1 is used as adjuvant for Malaria R21 vaccine. It contains purified Saponin obtained from a crude extract of the plant Quillaja saponaria Molina; Cholesterol from plants and phosphatidyl choline from fresh egg yolk. Its Saponin content is a mix of 85% Matrix-A and 15% Matrix-C w/w ratio. Matrix-M1 adjuvant GMP bulk is manufactured by Novavax, AG and provided to Serum Institute of India Private Limited, at a Saponin concentration of 1 mg/mL. The bulk was released after testing, by SIIPL QC Department. 1600
Control Group Standard vaccination regime Rabies vaccine Participants to receive 3 doses of rabies vaccine four weeks a part. A booster will also be received 12 months after the third dose. Initial follow-up will be for two years after dose three. Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data. Abhayrab is a lyophilised, purified, inactivated Rabies vaccine containing inactivated rabies virus (L. Pasteur 2061 Vero Strain propagated in Vero cells). Prior to use, Abhayrab vaccine can be reconstituted with 0.5mL or 1.0mL diluent. 800 Active-Treatment of Control Group
Experimental Group Seasonal vaccination regime R21MatrixM Participants in this arm will receive 3 doses of R21/Matrix-M malaria vaccine that are four weeks apart. They will also receive a booster (4th) dose of the same vaccine will be administered 12 months after the third dose. Participants in this arm will be enrolled in Nanoro, Burkina Faso and Bougouni, Mali. Initial follow-up will be 12 months after dose 3. Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data. R21 is a virus-like particle of about 23 nm in diameter comprising a fusion protein of the central repeats and C-terminus of the CS protein to the N-terminus of the Hepatitis B surface antigen. These repeats comprise many copies of the four amino acid sequence, NANP. This fusion protein is similar to that in RTS,S, but there is a fourfold excess of unfused Hepatitis B surface antigen molecules in RTS,S to allow it to form hybrid particles. This is not the case in R21, in which unfused HBsAg molecules are absent (Figure 2), and expression and assembly in virus-like particles of the fusion protein alone for R21 proved possible due to expression in a different species of yeast (Hansenula / Pichia) with a stronger promoter, resulting in a higher intracellular concentration of the fusion protein. Matrix-M1 is used as adjuvant for Malaria R21 vaccine. It contains purified Saponin obtained from a crude extract of the plant Quillaja saponaria Molina; Cholesterol from plants and phosphatidyl choline from fresh egg yolk. Its Saponin content is a mix of 85% Matrix-A and 15% Matrix-C w/w ratio. Matrix-M1 adjuvant GMP bulk is manufactured by Novavax, AG and provided to Serum Institute of India Private Limited, at a Saponin concentration of 1 mg/mL. The bulk was released after testing, by SIIPL QC Department. 1600
Control Group Seasonal vaccination regime Rabies vaccine Participants to receive 3 doses of rabies vaccine four weeks a part. A booster will also be received 12 months after the third dose. Initial follow-up will be for two years after dose three. Extension of the trial will be considered to allow for longer follow-up as indicated by the 12-month safety and efficacy data. Abhayrab is a lyophilised, purified, inactivated Rabies vaccine containing inactivated rabies virus (L. Pasteur 2061 Vero Strain propagated in Vero cells). Prior to use, Abhayrab vaccine can be reconstituted with 0.5mL or 1.0mL diluent. 800 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
For standard vaccination regime, the child is 5-17 months of age at the time of first vaccination. For seasonal vaccination regime, the child is 5-48 months of age at the time of first vaccination. Signed informed consent/thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child to join the trial. The investigator believes that the parents/guardians can and will comply with the requirements of the protocol if the child is enrolled in the study. The child is a permanent resident of the study area and likely to remain a resident for the duration of the trial. The child has previously received a malaria vaccine. The child is enrolled in another malaria intervention trial. The child has a history of allergic disease or reactions likely to be exacerbated by any component of the malaria or control vaccine. The child has a history of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunisations. The child has major congenital defects. The child has anaemia associated with clinical signs of symptoms of decompensation, or a haemoglobin of ≤ 5.0 g/dL. The child has had a blood transfusion within one month of enrolment. The child has been administered immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate. The child has malnutrition requiring hospital admission. The child has an acute or chronic, clinically significant pulmonary, cardiovascular, gastrointestinal, endocrine, neurological, skin, hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory tests. Children currently meeting the WHO criteria for HIV disease of stage 3 or 4 severity. A previous history of stage 3 or 4 disease is not an exclusion. Note: There will be no routine testing for HIV. Positive diagnoses will be recorded at screening if known. The child has received an investigational drug or vaccine other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. The child is currently participating in another clinical trial if likely to affect data interpretation of this trial The child has any significant disease, disorder or situation which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. Infant: 13 Month(s)-24 Month(s),Preschool Child: 2 Year-5 Year 5 Month(s) 48 Month(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 12/02/2021 Oxford Tropical Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
University of Oxford Research Services, University Offices Wellington Square, Oxford OX1 2JD Oxford OX1 4BH United Kingdom
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 03/02/2021 KEMRI Scientific and Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Kenya Medical Research Institute HQ Scientific and Ethics Review Unit Off Mbagathi Road House number 8 PO Box 54840 00200 Nairobi Kenya Nairobi 00200 Kenya
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 13/01/2021 Comite dEthique pour la Recherche en Sante
Ethics Committee Address
Street address City Postal code Country
Ministere de la Sante Building Lamizana Ouagadougou Ouagadougou 09BP7009 Burkina Faso
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 18/01/2021 Comite dEthique Universite des Sciences desTechniques et des Technologies de Bamako USTTB
Ethics Committee Address
Street address City Postal code Country
Hamdalaye ACI 2000 Rue 405 Bamako Bamako BP 1805 Mali
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 12/02/2021 Ifakara Health Institute Institutional Review Board IHI IRB
Ethics Committee Address
Street address City Postal code Country
Ifakara Health Institute Dar es Salaam Dar es Salaam BOX 78373 United Republic of Tanzania
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 12/02/2021 National Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
3 Barack Obama Drive Dar es Salaam 11101 United Republic of Tanzania
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Efficacy To assess the protective efficacy of R21/Matrix-M against clinical malaria caused by Plasmodium falciparum, in 5-48 month old children living in a malaria endemic area, 12 months after completion of the primary course. [ Time Frame: 2 years ] Assessment for all efficacy outcomes will begin from 14 days after primary course of vaccination to specified time point. Clinical malaria Primary case definition: Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 5000 parasites/µL Secondary case definitions: Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 0 parasites/µL Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 2500 parasites/µL Tertiary case definitions: Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 500 parasites/µL Presence of axillary temperature ≥37.5°C and/ or history of fever within the last 24 hours AND P. falciparum asexual parasitaemia > 20,000 parasites/µL or RDT positive 12 months after dose 3
Primary Outcome Safety • To assess the safety and reactogenicity of R21/Matrix-M, in both vaccination regimes, of children living in a malaria endemic area, in the month following each vaccination, and 12 months after completion of the primary course. [ Time Frame: 2 years ] Solicited adverse events Occurrence of solicited local reactogenicity signs and symptoms for 7 days following the vaccination. Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following the vaccination. Unsolicited adverse events Occurrence of unsolicited adverse events for 28 days following the vaccination. Laboratory adverse events Change from baseline for safety laboratory measures thought to be clinically significant. Serious adverse events Occurrence of serious adverse events for the whole study duration. 2 years
Secondary Outcome Efficacy against; clinical malaria after a booster vaccination, asymptomatic infection, severe malaria, incident severe anaemia, blood transfusion requirement and malaria hospitalisation. Efficacy according to different transmission settings. [ Time Frame: 2 years ] 1. Protective efficacy following booster vaccination. All definitions of clinical malaria as mentioned previously. 2 years
Secondary Outcome Safety • Safety and reactogenicity (including Serious adverse events (SAEs) and any deaths) following the booster vaccination and for the duration of the study. [ Time Frame: 2 years ] Safety as per the primary outcome measures for safety but to be assessed post boost vaccination 2 years
Secondary Outcome Immunogenicity • Assessment of humoral immunogenicity by anti-CSP antibody concentrations measured 12 months after completion of the primary series of 3 vaccinations and 12 months after booster vaccination [ Time Frame: 2 years ] Comparison of immunogenicity (antibody responses to CSP) in the R21/Matrix-M vaccination groups with those in the rabies vaccine groups and the durability of responses ELISA to quantify antibodies to the vaccine components (regions of the CS antigen including the NANP repeat region and other elements of the protein as well as antibodies to HBsAg). 2 years
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
KEMRI Wellcome Trust Research Programme Centre for Geographic Medicine Coast KWTRP CGMRC Hospital Grounds, Off Bofa Road, PO Box 230 Kilifi Kenya 80108 Kenya
Ifakara Health Institute Bagamoyo Research and Training centre, PO Box 74, Bagamoyo, Tanzania Bagamoyo United Republic of Tanzania
Malaria Research and Training Center PO. Box 1805 Bamako, Mali Bamako Mali
Institut des Sciences et Techniques INSTech 540 Avenue de Sya Bobo Dioulasso 01 BP 277 Burkina Faso
Unite de Recherche Clinique de Nanoro URCN Institut de Recherche en Sciences de la Sante Direction Regionale du Centre Ouest IRSS DRCO 42 Avenue Kumda Yonre Ouagadougou 11 BP 218 Burkina Faso
FUNDING SOURCES
Name of source Street address City Postal code Country
Serum Institute of India Private Ltd. 212/2, Hadapsar, Off Soli Poonawalla Road, Pune 411028 India Pune India
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Oxford University of Oxford, University Offices, Wellington Square, Oxford, OX1 2JD, UK Oxford United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
University of Oxford ORCRB, Roosevelt Drive OX3 7DQ Oxford United Kingdom
Institut de Recherche en Sciences de la Sante Clinical Research Unit of Nanoro IRSS URCN 540 Avenue de Sya, 01 BP 2779 Bobo Dioulasso Burkina Faso
Institut de Recherche en Sciences de la Sante Direction Regionale de lOuest 42 Avenue Kumda-Yonre, 11 BP218 Ouagadougou Ouagadougou Burkina Faso
Malaria Research and Training Center Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako Bamako Mali
KEMRI Wellcome Trust Collaborative Research Program Hospital Road Kilifi Kenya
Ifakara Health Institute Clinical Trial Facility Bagamoyo Research and Training Centre Bagamoyo United Republic of Tanzania
London School of Hygiene and Tropical Medicine Keppel St London WC1E 7HT UK London United Kingdom
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Adrian VS Hill adrian.hill@ndm.ox.ac.uk +441865617610 The Jenner Institute Laboratories, ORCRB, Roosevelt Drive, Oxford OX3 7DQ
City Postal code Country Position/Affiliation
Oxford OX3 7DQ United Kingdom Chief Investigator
Role Name Email Phone Street address
Scientific Enquiries Mehreen Datoo mehreen.datoo@ndm.ox.ac.uk +441865611410 The Jenner Institute Laboratories, ORCRB, Roosevelt Drive, Oxford OX3 7DQ
City Postal code Country Position/Affiliation
Oxford OX3 7DQ United Kingdom Clinical Research Fellow
Role Name Email Phone Street address
Public Enquiries Rachel Roberts rachel.roberts@ndm.ox.ac.uk +441865611418 The Jenner Institute Laboratories, ORCRB, Roosevelt Drive, Oxford OX3 7DQ
City Postal code Country Position/Affiliation
Oxford OX3 7DQ United Kingdom Vaccine Programme Coordinator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes De-identified individual participant data (IPD) that underlie the published results of the trial. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Within two years of trial completion. De-identified trial data that underlies the results reported in the publication will be under managed access and data will be uploaded in an accessible repository. Requests will be reviewed by a data access committee.
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