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    Summary
    EudraCT Number:2018-004391-34
    Sponsor's Protocol Code Number:VAC072
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-04-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-004391-34
    A.3Full title of the trial
    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.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to assess the safety, immune response, and protection against infection of novel malaria vaccines.
    A.3.2Name or abbreviated title of the trial where available
    VAC 072-An efficacy study of R21/MM in different dose schedules
    A.4.1Sponsor's protocol code numberVAC072
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Oxford
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Oxford
    B.5.2Functional name of contact pointAdrian Hill
    B.5.3 Address:
    B.5.3.1Street AddressCCVTM, Churchill Hospital, Old Road
    B.5.3.2Town/ cityOxford
    B.5.3.3Post codeOX3 7LE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01865617610
    B.5.5Fax number01865857471
    B.5.6E-mailAdrian.Hill@ndm.ox.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameR21
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNR21
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2 to 50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMatrix-M
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Plasmodium falciparum infection
    E.1.1.1Medical condition in easily understood language
    Malaria
    E.1.1.2Therapeutic area Diseases [C] - Parasitic Diseases [C03]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial

    To assess humoral immunogenicity generated in malaria-naïve individuals by adjuvanted R21 using different immunisation schedules in healthy malaria-naïve volunteers.

    To further assess the efficacy using different thresholds, measured as time to P. falciparum parasitemia, assessed by PCR of adjuvanted R21 in two different vaccination regimes and compared to R21 against malaria sporozoite challenge, in healthy malaria-naïve volunteers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The volunteer must satisfy all the following criteria to be eligible for the study:
    • Healthy adults aged 18 to 45 years.
    • Able and willing (in the Investigator’s opinion) to comply with all study requirements.
    • Willing to allow the investigators to discuss the volunteer’s medical history with their General Practitioner or access this medical history electronically.
    • Women only: Must practice continuous effective contraception for the duration of the study.
    • Agreement to refrain from blood donation during the course of the study.
    • Agree to refrain from blood donation for at least 3 years after the end of their involvement in the study.*
    • Written informed consent to participate in the trial.
    • Reachable (24/7) by mobile phone during the period between CHMI and completion of antimalarial treatment. *
    • Willingness to take a curative anti-malaria regimen following CHMI. *
    • For volunteers not living close to the malaria challenge follow-up site (CCVTM, Oxford) agreement to stay in a hotel room close to the trial centre during a part of the study (from at least day 6.5 post mosquito bite until anti-malarial treatment is completed).*
    • Answer all questions on the informed consent quiz correctly.*
    Female volunteers are required to use an effective form of contraception during the course of the study as there is no information about the effect of these vaccines on a foetus.
    Acceptable forms of contraception for female volunteers include:
    • Established use of oral, injected or implanted hormonal methods of contraception.
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS).
    • Total abdominal hysterectomy
    • Barrier methods of contraception (condom or occlusive cap with spermicide)
    • Male sterilisation, if the vasectomised partner is the sole partner for the subject.
    • True abstinence, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence and withdrawal are not acceptable methods of contraception).

    * Not applicable for volunteers who do not undergo CHMI (Groups 1, 4 and 5)
    E.4Principal exclusion criteria
    The volunteer may not enter the study if any of the following apply:
    • History of clinical malaria (any species).
    • Travel to a clearly significantly malaria endemic locality planned for during the study period or within the preceding six months
    • Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin)*
    • Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period.
    • Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data as assessed by the investigator.
    • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).
    • Use of immunoglobulins or blood products within 3 months prior to enrolment.
    • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (e.g. egg products) or malaria infection.
    • Any history of anaphylaxis post vaccination.
    • History of clinically significant contact dermatitis.
    • History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection.
    • Pregnancy, lactation or intention to become pregnant during the study.
    • 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*
    • Any clinical condition known to prolong the QT interval and existing contraindication to the use of Malarone.*
    • History of cardiac arrhythmia, including clinically relevant bradycardia and existing contraindication to the use of Malarone.*
    • Clinically significant disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia
    • Family history of congenital QT prolongation or sudden death and existing contraindication to the use of Malarone.*
    • Contraindications to the use of both Riamet and Malarone*
    • History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ).
    • History of serious psychiatric condition that may affect participation in the study.
    • Any other serious chronic illness requiring hospital specialist supervision.
    • Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 25 standard UK units every week.
    • Suspected or known injecting drug abuse in the 5 years preceding enrolment.
    • Hepatitis B surface antigen (HBsAg) detected in serum.
    • Seropositive for hepatitis C virus (antibodies to HCV) at screening (unless has taken part in a prior hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study).
    • Positive family history in both 1st and 2nd degree relatives < 50 years old for cardiac disease.*
    • Volunteers unable to be closely followed for social, geographic or psychological reasons.
    • Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination. In the event of abnormal test results, confirmatory repeat tests will be requested.
    • Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

    *Not applicable for volunteers who do not undergo CHMI (Groups 1, 4 and 5)
    E.5 End points
    E.5.1Primary end point(s)
    Primary safety endpoints:
    • Occurrence of each solicited adverse event within 7-day follow-up period (day of vaccination and 6 subsequent days) after each vaccination.
    • Occurrence of unsolicited adverse events within 28 days (day of vaccination and 27 subsequent days) after each vaccination, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.
    • Occurrence of serious adverse events within 28 days (day of vaccination and 27 subsequent days) after each vaccination and over the whole study duration, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.

    Primary efficacy endpoint:
    The number of completely protected individuals will be presented for each vaccination group and controls. Completely protected individuals are those who do not, by Day 21 following sporozoite challenge, develop blood stage infection as defined in Section 9.5 in the protocol based on PCR thresholds.

    This is the first study assessing the efficacy of the novel malaria vaccine candidate, R21 in a CHMI study. Therefore, we are unable to power this study to detect a difference between vaccination groups (2 and 3). However, the proportions protected in vaccinated groups will be compared to controls by Fisher exact tests to ask if there is more protection in any of the vaccine groups than controls.

    Solicited and unsolicited AE data will be collected at each clinic visit. It will be collected from diary cards, clinical review, clinical examination (including observations) and laboratory results. This AE data will be tabulated and frequency, duration and severity of AEs compared between groups.
    Hematological (hemoglobin, WBC and platelets) and biochemical (creatinine and ALT) laboratory values will be presented according to toxicity grading scales and tabulated by group.
    SAEs, AEs of special interest and withdrawal due to AE(s)/SAE(s) will be described in detail.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation of the adverse events following vaccination will begin as soon as the first vaccine is given, and will continue throughout the remainder of the trial. It will be assessed by analysing adverse event data collected from diary cards,
    clinical review of volunteers, and laboratory measurements. Any adverse events persisting at the end of the trial will be followed up until there is a satisfactory resolution or stabilisation occurs or until a non study related causality is found.

    Evaluation for blood stage malaria infection will occur from Day 6.5 following malaria challenge to Day 21 following malaria challenge.
    E.5.2Secondary end point(s)
    The specific aims for the immunogenicity assessment are as follows:

    • To document immunogenicity measures, capturing humoral and cellular immune responses to R21 as follows: Anti-CS antibody titers.

    Further measures of vaccine efficacy will be used, as secondary endpoints, to provide more detailed quantitative assessment (such as delay to parasitaemia or parasite burden at day 7) of the dynamics of malaria infection in sporozoite-challenged volunteers. These measures enable more powerful distinction, than the use of sterile efficacy rates, between the performance of different vaccination regimens, and between individuals receiving the same vaccination regimen, as has been shown for previous efficacy trials. This maximises the yield of information from the volunteers in this study that is used to assess the primary objective. These measures of efficacy will be the same as used in the VAC055,VAC059, VAC 065 and VAC 067 clinical trials.
    Kaplan-Meier analyses will be performed for each vaccination regimen and for controls. Separate analyses will be done using various outcome measures for malaria blood stage infection including: (i) parasitaemia as defined by 10,000 or more parasites/ml in peripheral blood by quantitative PCR or composite of symptoms and PCR > 1000 p/ml, (ii) parasitaemia >1,000 p/ml on PCR, (iii) parasitaemia > 500 p/ml on PCR (iv) parasitaemia > 20 p/ml. A statistically significant difference between a vaccination regimen and controls by log rank analysis of Kaplan Meier curves any endpoint, will be considered as an indicator of likely vaccine efficacy compared to controls.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Immunology investigations will be collected on blood specimens taken from volunteers across the course of their participation in the trial.

    PCR data will be collected from Day 6.5 to day 21 (or until malaria diagnosis) to establish time to 20 parasites per ml and time to 500 parasites per ml.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Unvaccinated volunteers who undergo malaria challenge
    E.8.2.4Number of treatment arms in the trial9
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days5
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 82
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state82
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 82
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Continued provision of the intervention is not appropriate, as the intervention is an investigational vaccine. All participants are healthy volunteers.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-19
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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