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    Clinical Trial Results:
    A Phase I/IIa Sporozoite Challenge Study to Assess the Safety and Protective Efficacy of the Combination Malaria Vaccine Candidate Regimen of RTS,S/AS01B + ChAd63 and MVA encoding ME-TRAP and also RTS,S/A01B alone.

    Summary
    EudraCT number
    2013-000393-30
    Trial protocol
    GB  
    Global end of trial date
    21 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2016
    First version publication date
    15 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VAC055
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01883609
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford, CTRG
    Sponsor organisation address
    Old Road, Oxford, United Kingdom, OX3 7LE
    Public contact
    Professor Adrian Hill, University of Oxford, 01865 617610, adrian.hill@ndm.ox.ac.uk
    Scientific contact
    Professor Adrian Hill, University of Oxford, 01865 617610, 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
    21 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objectives: To assess the efficacy (occurrence of P. falciparum parasitemia, assessed by blood slide) of a combination immunization regimen with ChAd63/MVA ME-TRAP and RTS,S/AS01B, and of RTS,S/AS01B alone, against malaria sporozoite challenge, in healthy malaria-naïve volunteers. To assess the safety of a combination immunization regimen with ChAd63/MVA ME-TRAP and RTS,S/AS01B, and of RTS,S/AS01B alone, in healthy malaria-naïve volunteers. Secondary Objectives: To assess immunogenicity generated in malaria naïve individuals of a malaria vaccine schedule containing RTS,S/AS01B and ChAd63/MVA ME-TRAP, and of RTS,S/AS01B alone. To assess the efficacy (measured as time to P. falciparum parasitemia assessed by blood slide, by PCR, and parasite density dynamics assessed by PCR) of a combination immunization regimen with ChAd63/MVA ME-TRAP and RTS,S/AS01B, and of RTS,S/AS01B alone, against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
    Protection of trial subjects
    - Volunteers were given at least 24 hours to read the VIS before being seen and then given plenty of opportunity to ask questions prior to agreeing to take part in the 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. - Total blood volume taken during study kept to volume that should not compromise healthy volunteers - Volunteers observed for 30 mins after vaccination to monitor for any immediate adverse effects. - Volunteers seen within 1 day of vaccination for safety review and provided with 24/7 contact number for trial clinician and emergency contact card for the department. - ECG and cholesterol checked prior to enrolment to aid cardiac risk assessment - Age range 18 – 45 years - Volunteers given emergency contact card detailing that they have been infected with malaria. - Volunteers seen twice daily once blood stage malaria is possible with twice daily malaria films, symptom review and PCR - Malaria treated promptly when diagnosed with highly efficacious medication and at least half of doses directly observed. - Volunteers provided with symptomatic treatment (antipyretic/analgesic and antiemetic) in case of malaria symptoms. - Volunteers followed up until at least 2 consecutive negative blood films seen.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Inclusion / Exclusion criteria Informed Consent Questionnaire Informed consent Medical History Physical Examination Urinalysis Electrocardiogram β-HCG urine (women only) Review contraindications Physical Observations HBV,HCV,HIV Haematology Biochemistry

    Period 1
    Period 1 title
    Enrollment
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 3
    Arm description
    Unvaccinated controls.
    Arm type
    Unvaccinated Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls.
    Arm type
    Unvaccinated Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Group 1 Group 2 Group 3 Group 4
    Started
    20
    17
    6
    5
    Completed
    20
    17
    6
    5
    Period 2
    Period 2 title
    Day 14
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Experimental

    Investigational medicinal product name
    ChAd63 ME-TRAP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A dose of 5 x 10^10 vp.

    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Group 1 Group 2 Group 4 Group 4
    Started
    20
    17
    6
    5
    Completed
    20
    17
    6
    5
    Period 3
    Period 3 title
    Day 28
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 3
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    Group 1 Group 2 Group 3 Group 4
    Started
    20
    17
    6
    5
    Completed
    20
    17
    6
    5
    Period 4
    Period 4 title
    Day 56
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    Experimental

    Investigational medicinal product name
    RTS,S/AS01B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    50mcg of RTS,S and standard adult dose of AS01.

    Arm title
    Group 3
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    Group 1 Group 2 Group 3 Group 4
    Started
    20
    17
    6
    5
    Completed
    20
    17
    6
    5
    Period 5
    Period 5 title
    Day 70
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Experimental

    Investigational medicinal product name
    MVA ME-TRAP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 x 10^8 pfu

    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 3
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 5
    Group 1 Group 2 Group 3 Group 4
    Started
    20
    17
    6
    5
    Completed
    20
    17
    6
    5
    Period 6
    Period 6 title
    Malaria Challenge
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Malaria Challenge

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    Malaria Challenge

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 3
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 6 [1]
    Group 1 Group 2 Group 3
    Started
    17
    16
    6
    Completed
    17
    16
    6
    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: Three volunteers withdrew from Group 1 and one volunteer withdrew from Group 2 prior to the malaria challenge.
    Period 7
    Period 7 title
    Repeat Challenge/Group 4 Challenge
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.
    Arm type
    Repeat Malaria Challenge

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 2
    Arm description
    RTS,S/AS01B
    Arm type
    Repeat Malaria Challenge

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Group 4
    Arm description
    Unvaccinated controls
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 7 [2]
    Group 1 Group 2 Group 4
    Started
    8
    6
    5
    Completed
    8
    6
    5
    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: Group 2 volunteers did not take part in this stage of the study. Only sterilely protected volunteers from groups 1 and 2 took part in this stage.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls.

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls.

    Reporting group values
    Group 1 Group 2 Group 3 Group 4 Total
    Number of subjects
    20 17 6 5 48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20 17 6 5 48
    Gender categorical
    Units: Subjects
        Female
    8 8 3 3 22
        Male
    12 9 3 2 26

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls.

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls.
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 3
    Reporting group description
    Unvaccinated controls
    Reporting group title
    Group 1
    Reporting group description
    RTS,S/AS01B, ChAd63 ME-TRAP and MVA ME-TRAP.

    Reporting group title
    Group 2
    Reporting group description
    RTS,S/AS01B

    Reporting group title
    Group 4
    Reporting group description
    Unvaccinated controls

    Primary: Primary efficacy

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    End point title
    Primary efficacy [1]
    End point description
    The number of completely protected individuals will be presented between each vaccination group and controls. Completely protected individuals are those who do not, by Day 21 following sporozoite challenge, develop blood stage malaria infection.
    End point type
    Primary
    End point timeframe
    Diagnosis of malaria infection following challenge will be defined as positive thick film microscopy up to 21 days post challenge.
    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 study, we will provide additional statistical information following publication.
    End point values
    Group 1 Group 2 Group 3
    Number of subjects analysed
    17
    16
    6
    Units: Number of subjects
    17
    16
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    AEs reviewed from day of vaccination at multiple time points according to visit schedule until trial end SAEs reported within 24 hours of awareness to sponsor. SUSARs reported within 15 days of awareness (7 days for fatal or life threatening events)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Frequency threshold for reporting non-serious adverse events: 1%
    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 data at this time. The publication will be uploaded at a later date.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2013
    Amendment to IMPD to document that the shelf-life of the RTS,S purified bulk lot ARTSAPA004 has been extended to 48 months based on satisfactory real-time stability data for up to 36 months storage at -70C. In addition, the long term stability protocol applied to RTS,S drug substance was modified to introduce changes such as addition of a 42-month stability testing time point as well as addition, replacement and removal of certain tests.
    29 Aug 2013
    Correction of an error in the exclusion criteria. The previous text read: • Use of medications known to cause prolongation of the QT interval or to otherwise have a potentially clinically significant interaction with Riamet and Malarone The new text now reads: • Use of medications known to cause prolongation of the QT interval and existing contraindication to the use of Malarone • Use of medications known to have a potentially clinically significant interaction with Riamet and Malarone The protocol and GP screening letter were updated accordingly
    25 Nov 2013
    Addition of post-challenge diary card.
    27 Nov 2013
    To extend the shelf life of ChAd63 ME-TRAP (AdCh63 ME-TRAP) lot 01S11-01 to 6th January 2015.

    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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