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    Clinical Trial Results:
    A Phase I/IIa Sporozoite Challenge Study to assess the safety, immunogenicity and protective efficacy of adjuvanted R21, administered in different dose schedules in healthy UK volunteers.

    Summary
    EudraCT number
    2018-004391-34
    Trial protocol
    GB  
    Global end of trial date
    24 Aug 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Sep 2022
    First version publication date
    10 Sep 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    VAC072
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03970993
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Churchill Hospital, Old road, Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    Adrian Hill, University of Oxford, +44 01865617610, Adrian.Hill@ndm.ox.ac.uk
    Scientific contact
    Adrian Hill, University of Oxford, +44 01865617610, Adrian.Hill@ndm.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers, and the efficacy (prevention of occurrence of P. falciparum parasitemia, assessed by PCR) of adjuvanted R21 against malaria sporozoite challenge, in healthy malaria-naïve volunteers using two immunisation regimes. Secondary Objectives: To assess humoral immunogenicity generated in malaria-naïve individuals by adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers and to assess the safety and tolerability of adjuvanted R21 using different vaccination regimes and compared to R21c against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
    Protection of trial subjects
    Volunteers given at least 24 hours to read VIS before being seen and then given plenty of opportunity to ask questions prior to agreeing to take part in a study. - Screening visit including full medical history, physical examination and baseline blood tests to ensure volunteers are healthy prior to enrolment. - Vaccination carried out in clinical environment with staff trained in resuscitation in case of allergic reaction. - Safety review prior to dose escalation (LSM) - Total blood volume taken during study kept to a volume that should not compromise healthy volunteers (i.e. less than regular donation to blood transfusion service). - Volunteers observed for 1-2 hours after vaccination to monitor for any immediate adverse effects. - Volunteers seen within 3 days of vaccination for safety review and provided with 24/7 contact number for trial clinician and emergency contact card for the department. -Volunteers phoned daily by the clinic team prior to first in-person follow up after CHMI
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 76
    Worldwide total number of subjects
    76
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    76
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Volunteers were first recruited to Group 1a in June 2019. Volunteers were recruited and vaccinated at the CCVTM, Oxford and the NIHR WTCRF Southampton, Imperial College London and GSTT, London. Vaccine efficacy were assessed using Controlled Human Malaria Infection (CHMI). CHMI was conducted at Imperial College, London, and the follow up in Oxford

    Pre-assignment
    Screening details
    Screening details: Inclusion / Exclusion criteria Informed consent Medical History Physical Examination Biochemistry Haematology Urinalysis Serum Β-HCG (women only) Coagulation profile Review contraindications HBV,HCV,HIV serology Biochemistry Haematology

    Period 1
    Period 1 title
    Week 0
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Laboratory investigators processing samples for PCR analysis were blinded to group allocation. No other blinding was used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at week 0, 4, 8 and 60 (4-dose regimen) with no CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 1b
    Arm description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 2a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 2b
    Arm description
    10ug R21 in 20ug Matrix -M1 adjuvant administered at weeks 0, 4 and 24 with no CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 3a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 3b
    Arm description
    10 µg R21 in 50 µg Matrix M adjuvant administered at weeks 0, 4 and 8 with no CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 4a and b
    Arm description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50 µg R21/ Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at weeks 0 and 4 and 10 µg R21/ Matrix-M1 50 µg at week 24

    Arm title
    Group 5
    Arm description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0 and 4 followed by R21 2 µg / Matrix-M1 50 µg at week 28.

    Arm title
    Group 6 and 7
    Arm description
    Sporozoite (mosquito bite) CHMI groups serving as infectivity controls. No IMPs were administered in groups 6 and 7.
    Arm type
    CHMI

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Group 1a Group 1b Group 2a Group 2b Group 3a Group 3b Group 4a and b Group 5 Group 6 and 7
    Started
    3
    7
    13
    3
    16
    2
    11
    9
    12
    Completed
    3
    7
    13
    3
    15
    1
    10
    7
    12
    Not completed
    0
    0
    0
    0
    1
    1
    1
    2
    0
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    1
    1
    2
    -
    Period 2
    Period 2 title
    Week 4
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1a
    Arm description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60 with no CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 1b
    Arm description
    4 vaccinations with 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60. No CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 2a
    Arm description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4, 24 and 56-80 with a sporozoite CHMI at week 28 followed by a repeat CHMI at 60-84 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 2b
    Arm description
    3 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4 and 24. No CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 3a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-68.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 3b
    Arm description
    10 µg R21 in 50 µg Matrix M adjuvant administered at weeks 0, 4 and 8 with no CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 4a & b
    Arm description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 50 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Arm title
    Group 5
    Arm description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 4

    Number of subjects in period 2 [1]
    Group 1a Group 1b Group 2a Group 2b Group 3a Group 3b Group 4a & b Group 5
    Started
    3
    7
    13
    3
    15
    1
    10
    7
    Completed
    3
    7
    13
    3
    15
    1
    10
    7
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some time points at CHMI only
    Period 3
    Period 3 title
    Week 8
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1a
    Arm description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60 with no CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 1b
    Arm description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 8

    Arm title
    Group 3a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 8

    Arm title
    Group 3b
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-68.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Number of subjects in period 3 [2]
    Group 1a Group 1b Group 3a Group 3b
    Started
    3
    7
    15
    1
    Completed
    3
    7
    15
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some time points are CHMI only
    Period 4
    Period 4 title
    Week 12
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Group 3a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0, 4, 8 4--64

    Number of subjects in period 4 [3]
    Group 3a
    Started
    15
    Completed
    15
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some time points are CHMI only
    Period 5
    Period 5 title
    Week 24
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Group 2a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 24

    Arm title
    Group 2b
    Arm description
    3 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4 and 24. No CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 24

    Arm title
    Group 4a & b
    Arm description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 5
    Arm description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 24

    Number of subjects in period 5
    Group 2a Group 2b Group 4a & b Group 5
    Started
    13
    3
    10
    7
    Completed
    13
    3
    10
    7
    Period 6
    Period 6 title
    Week 28
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 4a and 4b
    Arm description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Arm title
    Group 2a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0, 4, 24 and 56-80

    Arm title
    Group 5
    Arm description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at weeks 0, 4, 24.

    Number of subjects in period 6
    Group 4a and 4b Group 2a Group 5
    Started
    10
    13
    7
    Completed
    10
    13
    7
    Period 7
    Period 7 title
    Week 60
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Group 1a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at week 0, 4, 8 and 60 (4-dose regimen) with no CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 60

    Arm title
    Group 1b
    Arm description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 60

    Number of subjects in period 7
    Group 1a Group 1b
    Started
    3
    7
    Completed
    3
    7
    Period 8
    Period 8 title
    Week 40-64
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Group 3a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64. less
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 40-64

    Number of subjects in period 8
    Group 3a
    Started
    15
    Completed
    15
    Period 9
    Period 9 title
    Week 44-68
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Group 3a
    Arm description
    Repeat CHMI at week 44-64: 10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with the repeat CHMI at week 44-64.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 44-64

    Number of subjects in period 9
    Group 3a
    Started
    15
    Completed
    15
    Period 10
    Period 10 title
    Week 56-80
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Group 2a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 0

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at week 56-80

    Number of subjects in period 10 [4]
    Group 2a
    Started
    13
    Completed
    13
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some of the time points are CHMI
    Period 11
    Period 11 title
    Week 64-84
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Group 2a
    Arm description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI.
    Arm type
    Experimental

    Investigational medicinal product name
    R21 in adjuvant Matrix-M1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Repeat CHMI for Gp 3 at week 60-84. R21 10 µg / Matrix-M1 50 µg injected intramuscularly into the deltoid muscle of the arm at weeks 0, 4, 24 and 56-80.

    Number of subjects in period 11
    Group 2a
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Week 0
    Reporting group description
    -

    Reporting group values
    Week 0 Total
    Number of subjects
    76 76
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    76 76
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    38 38
        Male
    38 38

    End points

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    End points reporting groups
    Reporting group title
    Group 1a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at week 0, 4, 8 and 60 (4-dose regimen) with no CHMI.

    Reporting group title
    Group 1b
    Reporting group description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).

    Reporting group title
    Group 2a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI

    Reporting group title
    Group 2b
    Reporting group description
    10ug R21 in 20ug Matrix -M1 adjuvant administered at weeks 0, 4 and 24 with no CHMI

    Reporting group title
    Group 3a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.

    Reporting group title
    Group 3b
    Reporting group description
    10 µg R21 in 50 µg Matrix M adjuvant administered at weeks 0, 4 and 8 with no CHMI

    Reporting group title
    Group 4a and b
    Reporting group description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.

    Reporting group title
    Group 5
    Reporting group description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.

    Reporting group title
    Group 6 and 7
    Reporting group description
    Sporozoite (mosquito bite) CHMI groups serving as infectivity controls. No IMPs were administered in groups 6 and 7.
    Reporting group title
    Group 1a
    Reporting group description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60 with no CHMI

    Reporting group title
    Group 1b
    Reporting group description
    4 vaccinations with 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60. No CHMI.

    Reporting group title
    Group 2a
    Reporting group description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4, 24 and 56-80 with a sporozoite CHMI at week 28 followed by a repeat CHMI at 60-84 weeks.

    Reporting group title
    Group 2b
    Reporting group description
    3 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4 and 24. No CHMI.

    Reporting group title
    Group 3a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-68.

    Reporting group title
    Group 3b
    Reporting group description
    10 µg R21 in 50 µg Matrix M adjuvant administered at weeks 0, 4 and 8 with no CHMI

    Reporting group title
    Group 4a & b
    Reporting group description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.

    Reporting group title
    Group 5
    Reporting group description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.
    Reporting group title
    Group 1a
    Reporting group description
    4 vaccinations of R21 10 µg / Matrix-M1 50 µg at weeks 0, 4, 8 and 60 with no CHMI

    Reporting group title
    Group 1b
    Reporting group description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).

    Reporting group title
    Group 3a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.

    Reporting group title
    Group 3b
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-68.
    Reporting group title
    Group 3a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64.
    Reporting group title
    Group 2a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI

    Reporting group title
    Group 2b
    Reporting group description
    3 vaccinations of R21 10 µg / Matrix-M1 50 µg administered at weeks 0, 4 and 24. No CHMI.

    Reporting group title
    Group 4a & b
    Reporting group description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.

    Reporting group title
    Group 5
    Reporting group description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28
    Reporting group title
    Group 4a and 4b
    Reporting group description
    50 µg of R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, and 4 followed by 10 µg R21 in 50 µg Matrix-M1 adjuvant at week 24 with a sporozoite CHMI at week 28.

    Reporting group title
    Group 2a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI

    Reporting group title
    Group 5
    Reporting group description
    10 µg R21/ Matrix-M1 50 µg administered at weeks 0 and 4 followed by receiving a dose of 2 µg R21/ Matrix-M1 50 µg at week 24. This group then underwent a sporozoite CHMI at week 28.
    Reporting group title
    Group 1a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at week 0, 4, 8 and 60 (4-dose regimen) with no CHMI.

    Reporting group title
    Group 1b
    Reporting group description
    10µg R21 in 50µg Matrix M-1 adjuvant administered at weeks 0, 4, 8 and 60 with no CHMI (4-dose regimen).
    Reporting group title
    Group 3a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with a repeat CHMI at week 44-64. less
    Reporting group title
    Group 3a
    Reporting group description
    Repeat CHMI at week 44-64: 10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 8 and 40-64. A sporozoite CHMI took place at week 12 with the repeat CHMI at week 44-64.
    Reporting group title
    Group 2a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI
    Reporting group title
    Group 2a
    Reporting group description
    10 µg R21 in 50 µg Matrix-M1 adjuvant administered at weeks 0, 4, 24 and 56-80 with sporozoite CHMI (mosquito bites) at day 28 and 60-84. 4 dose regimen with 2 CHMI.

    Primary: To assess the safety and tolerability of adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers

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    End point title
    To assess the safety and tolerability of adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers [1]
    End point description
    Due to the confidential nature of this data, we have not provided this analysis at this time. The scientific paper can be uploaded following publication, if required.
    End point type
    Primary
    End point timeframe
    All solicited local & systemic reactogenicity signs and symptoms for 7 days after vaccination. All unsolicited AEs for 28 days after vaccination. Change from day 0 (baseline) to day 28 for safety laboratory measures. SAEs were collected during whole study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the confidential nature of this information, we have not provided this analysis at this time. The scientific paper containing the final analysis can be uploaded following publication if required.
    End point values
    Group 1a Group 1b Group 2a Group 2b Group 3a Group 3b Group 4a and b Group 5 Group 6 and 7
    Number of subjects analysed
    3
    7
    13
    3
    16
    2
    11
    9
    12
    Units: number of participants
    3
    7
    13
    3
    16
    2
    11
    9
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All AEs occurring in the 28 days following each vaccination collected from diary cards, clinical review, clinical examination, laboratory results, or reported by the volunteer, whether or not attributed to study medication.
    Adverse event reporting additional description
    All AEs occurring in the 28 days following each vaccination observed by the Investigator or reported by the volunteer, whether or not attributed to study medication, are recorded. Recording and reporting of all AEs will take place as detailed in SOP VC027. SAEs are collected throughout the entire trial period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Group 3a
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Due to the confidential nature of this information, we have not provided this analysis at this time. The scientific paper containing the final analysis of all of the endpoints can be uploaded following publication if required.
    Serious adverse events
    Group 3a
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Musculoskeletal and connective tissue disorders
    Wrist fracture injury
    Additional description: There was one serious adverse event (SAE) deemed as not related to vaccination (Gp 3a). This was a left wrist fracture that occurred in a participant two months following their third vaccination after a sports injury, requiring surgical intervention
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Group 3a
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2019
    Request to extend the shelf life of R21 to 18 months
    06 Sep 2019
    Change of conduct/management of the trial: 1. Groups are now sub-divided with a new naming scheme for clarity in understanding and documentation during the trial. 2. Vaccination time point intervals have been shortened and windows have also been increased due to further scientific consideration of optimum dosing intervals. 3. Compensation amounts updated to reflect the new visit schedules. 4. Advertising materials have been updated 5. Collection of GP records has been clarified. 6. R21 storage details have been updated in the trial protocol following recommendations from the manufacturer. 7. Blood films are no longer required for diagnosis following validation of qPCR 8. Text has been added to the protocol clarifying university of oxford intellectual property terms. 9. R21 IB has been updated (reference safety information now refers exclusively to SARs, formulation and storage of R21 has been updated). 10. Consent form amended to a generic version that can be used at sites other than Oxford 11. Wording changed in PIS regarding malaria diagnosis from "two negative malaria tests" to "malaria tests showing a significant decrease in parasites" for increased clarity 12. To avoid the possibility of discrepancies: one original consent form will now be signed by volunteers and investigators, with this then being subsequently photocopied and provided to the volunteer, rather than two originals. 13. For harmonisation purposes, screening windows have now been shortened to 3 months from 6 months 14. The local safety committee chairman will be re-designated as the local safety monitor “LSM”. 15a. Various changes to visits have been made throughout the protocol. 17. Safety section of the protocol has been updated to remove reference to adverse events of special interest. We are collecting the usual AEs that we always collect in our vaccine trials at the Jenner institute and for the same duration of time.
    01 Nov 2019
    Change in conduct of trial: 1. The window of vaccination 3 for Group 2a and 2b has been increased. It now has a -35 day window. This is because from recent research presented, showing better immunogenicity and efficacy with a delayed third vaccine dose, time points used by the 2 research groups have varied between 4.5 months and 7 months after first vaccination (NCT03906474). Therefore it is unknown when exactly the best time to give the third dose is. By extending this window and reducing the time between 2nd and 3rd dose, we are giving a wider range for the time he third dose can be given and falls in to the range of 4.5-7 months. This also helps facilitate timelines with CHMI. We have not changed the PIS to reflect this as no windows on vaccinations are mentioned in the PIS and also, at the time of screening, consent and enrolment, the volunteers were informed about this research and the possibility of the window on vaccination 3 changing. 2. In the procedures table, 'diary card completed' row has been amended so that in every group, this check is done 28 days post each vaccination. 3. In section 7.1.4, a correction has been made. There has been no change to dosing regimen. The groups mentioned for vaccination were Groups 1-3 when it should have been Groups 1-5. 4. In section 9.4.9, clarification if volunteer has extra clinical review, qPCR will be performed. This will be performed instead of thick film microscopy in view of qPCR now being a validated assay and our experience in other CHMI trials where qPCR has diagnosed malaria earlier than microscopy. 5. The diary given to volunteers post CHMI has now been converted to an electronic format. While the paper diary will still be there as a back-up, in the first instance, volunteers will be asked to record these details electronically now, similar to what they do post vaccinations.
    16 Dec 2019
    Change in conduct of trial and change of PI: 1) In the last 3 CHMI trials conducted at the Jenner Institute (VAC 065a, VAC 065b and VAC 066), 1 control volunteer in each trial who underwent CHMI did not become infected with malaria. However, when looking at biting and infectivity records, these do not seem to differ from other volunteers who have undergone CHMI and have become infected. In view of this, we leave open now the option to increase the number of volunteers, should suitable volunteers be available, from 6 to 8 subjects in Groups 6 and 7 to gain more power in showing adequate malaria infection in control volunteers to be able to make suitable comparisons to vaccination groups when determining efficacy. 2) We have increased the group number sizes for Groups 4b and 5. These groups are testing the safety and immunogenicity of delayed, fractional dosing and with Group 4b, a higher dose of R21 compared to the rest of the trial. We feel it would be beneficial to have larger numbers in these groups to gain more data on these dosing regimes to help us decide if these regimes are justified to proceed into efficacy trials against CHMI. 3) The PI at NIHR Imperial College has changed from Prof David Lewis to Dr Katrina Pollock as Prof Lewis is retiring.
    17 Jun 2020
    1. Group 1: optional booster vaccine approximately 60 weeks after the first vaccination with immunology follow up. During RTS,S/AS01B efficacy trials, increased efficacy was seen following a fourth vaccine. Given this finding, we plan to assess the immunological effect of a booster vaccine. 2. Group 2a and 3a: For volunteers demonstrating sterile protection in the first challenge a) optional booster vaccine (rationale as above) AND/OR b) long term immunology follow up to assess durability of immunogenicity. As per previous protocol, all protected volunteers will be invited back for a re-challenge. The booster vaccination will be timed to occur prior to the re-challenge. Volunteers will have the choice if they want a booster vaccination or not or if they just want to have the re-challenge. 3. Group 4 and 5: optional CHMI To test efficacy (protection from P. falciparum) of delayed dose regimes and compare efficacy between regimes. The window on this third, delayed fractional dose has been increased. This is because from the unpublished studies but recent research presented, showing better immunogenicity and efficacy with a delayed third vaccine dose, time points used by the 2 research groups have varied between 4.5 months and 7 months after first vaccination (NCT03906474). Therefore, it is unknown when exactly the best time to give the third dose is. By extending this window and reducing the time between 2nd and 3rd dose, we are giving a wider range for the time the third dose can be given, and falls in to the range of 4-9 months. 4. Clarification of challenge arrangements 5.Timing of re-challenge and booster vaccinations for protected volunteers in Groups 2a and 3a
    04 Sep 2020
    1. Additional measures taking place in view of COVID-19. These include social distancing practises in clinical areas/use of PPE/adhering to PHE guidance for isolation rules and testing/what will happen in the event of a fever post vaccination or malaria challenge. 2. Windows on vaccinations for all groups have been increased. These include booster vaccinations for Groups 1/2/3, or 3rd vaccination for Groups 4/5, and all follow-up visits. This is in view of participants potentially self- isolating or if they are unable to travel to us. Telephone assessments will still take place over this period to ensure safety. • When ECGs will be performed for Groups 4/5 have been clarified in these tables also as these are needed prior to malaria challenge and can occur at any vaccination visit. • COVID-19 swab necessary at the day before the challenge to ensure that the participant does not have COVID-19 when we are giving them malaria. 3. Change of malaria diagnosis endpoint. This is to ensure diagnosis as early as possible to reduce number of clinic visits. 4. Change in follow up time post malaria challenge. This again is reduced to ensure there are less clinic visits. This will still be safe as we are diagnosing malaria at a lower parasite threshold and everyone is treated with antimalarials at the end of follow-up, regardless of if they are protected or not. 5. Clarification of treatment of malaria so Riamet and Malarone are both first-line options. 6. Compensation and blood volumes adjusted to reflect these changes. 7. Reporting of positive SARS-CoV-2 test results, as required by law.• In this case, the result and personal data (including volunteer name, contact details, and postcode) will be shared in a secure manner with Public Health England for referral to the NHS Test and Trace system.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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