E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Plasmodium falciparum infection |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This is a clinical trial in which healthy volunteers will be administered experimental malaria vaccines. One group of volunteers will receive a vaccination regimen composed of three doses of the RTS,S/AS01 vaccine, at 4 week intervals. Another group will receive a vaccination schedule composed of the same dosage and timing of RTS,S/AS01, but they will also receive a dose of the ChAd63 ME-TRAP vaccine at week 2, and a dose of the MVA ME-TRAP vaccine at week 8.
The vaccine schedule containing RTS,S alone, and ChAd63 ME-TRAP and MVA ME-TRAP have been tested independently in clinical trials, however, the vaccine schedule containing both RTS,S/AS01, ChAd63 ME-TRAP and MVA ME-TRAP has not yet been tested. The first principal research objective is to measure how well this new malaria vaccine strategy acts to prevent malaria disease. This is called efficacy. We will measure it by infecting volunteers with malaria and seeing whether the vaccines change how long it takes for malaria disease t |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the immune responses to these vaccination strategies. We will do this by taking blood from volunteers who have received the vaccines and doing tests on it, such as measuring the number of immune cells that are induced by the vaccines. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 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. • 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 and 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 in 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.
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E.4 | Principal exclusion criteria |
• History of clinical malaria (any species). • Travel to a malaria endemic region during the study period or within the preceding six months with significant risk of malaria exposure. • 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 malaria vaccine or any other investigational vaccine likely to impact on interpretation of the trial data. If any volunteers in Group 1 and 2 undergo rechallenge, this exclusion criterion does not extend to the vaccines previously received in the VAC055 trial • 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, Kathon) 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 or to otherwise have a potentially clinically significant interaction with Riamet and Malarone • Any clinical condition known to prolong the QT interval • History of cardiac arrhythmia, including clinically relevant bradycardia • Disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia • Family history of congenital QT prolongation or sudden death • Contraindications to the use of all three proposed anti-malarial medications; Riamet, Malarone and Chloroquine. • 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 42 standard UK units every week. • Suspected or known injecting drug abuse in the 5 years preceding enrolment. • Seropositive for hepatitis B surface antigen (HBsAg). • Seropositive for hepatitis C virus (antibodies to HCV) at screening. • An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system.77 • Positive family history in 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. Absolute values for exclusion for confirmed abnormal results are shown in Section 17, Appendix A • 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy of the Group 1 vaccination regimen will be assessed by comparing the number of volunteers who develop blood stage infection, and the time to blood stage infection following CHMI, between Group 1 volunteers, Group 2 volunteers and control volunteers (Group 3 and 4). Safety of the vaccination schedule in Group 1 will be assessed by comparison of frequency, severity and duration of AEs between vaccination groups.
Volunteers will be diagnosed as having blood stage malaria infection according to the criteria in the protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the AEs 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. |
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E.5.2 | Secondary end point(s) |
Interferon gamma ELISPOT and flow cytometry to measure T cell responses will be used to assess the malaria-specific immune responses induced by vaccination. Other laboratory investigations including microarray analysis may be performed. 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. |
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Unvaccinated volunteers who undergo malaria challenge |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 1 |