| 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 |
• To assess the efficacy (occurrence of P. falciparum malaria parasitemia, assessed by PCR) of intramuscular vaccination followed by intravenous boosting with ChAd63 and MVA encoding ME-TRAP, against malaria sporozoite challenge, in healthy malaria-naïve volunteers
• To assess the safety of intramuscular vaccination followed by intravenous boosting with ChAd63 and MVA encoding ME-TRAP, in healthy malaria-naïve volunteers
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| E.2.2 | Secondary objectives of the trial |
• To assess cellular immune responses generated in malaria naïve individuals of vaccination schedules incorporating intramuscular prime dose(s) followed by intravenous booster with ChAd63 and MVA encoding ME-TRAP
• To assess the efficacy as measured by time to infection and parasite growth rates, of intramuscular vaccination followed by intravenous boosting with ChAd63 and MVA encoding ME-TRAP, against malaria sporozoite challenge, in healthy malaria-naïve volunteers |
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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
• For females only, willingness to practice continuous effective contraception (see below) during the study and a negative pregnancy test on the day(s) of screening and vaccination
• Agreement to refrain from blood donation during the course of the study
• Provide written informed consent to participate in the trial.
• 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.
• 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.
• Willingness to provide a named person who may be contacted in the event it is not possible to locate the volunteer following CHMI
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| E.4 | Principal exclusion criteria |
• History of clinical malaria (any species).
• Travel to a clearly malaria endemic locality during the study period or within the preceding six months
• 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. This may include non-malaria adenovirus vectored experimental vaccine. If any volunteers undergo rechallenge, this exclusion criterion does not extend to the vaccines previously received in the VAC066 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.
• Pregnancy, lactation or intention to become pregnant during the study.
• 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.
• 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).
• Inability of the study team to contact the volunteer’s GP to confirm medical history and safety to participate
• 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 (described in section 9.6.1).
• 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.
• Clinically significant disturbances of electrolyte balance, eg, hypokalaemia or hypomagnesaemia
• Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin).
• History of sickle cell anaemia, sickle cell trait, thalassaemia or thalassaemia trait or any haematological condition that could affect susceptibility to malaria infection.
• 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.
• Contraindications to the use of both Riamet and Malarone.
• Any clinical condition known to prolong the QT interval and existing contraindication to the use of Malarone.
• Family history of congenital QT prolongation or sudden death and existing contraindication to the use of Malarone.
• History of cardiac arrhythmia, including clinically relevant bradycardia and existing contraindication to the use of Malarone.
• Positive family history in both 1st and 2nd degree relatives < 50 years old for cardiac disease.
• Volunteer unable to be closely followed for social, geographic or psychological reason
The Fine Needle Aspiration of the liver will only be arranged for willing volunteers. Eligibility to undergo the FNA liver will be reviewed by the operating physician at a separate screening. The participant may not undergo FNA liver if any of the following apply (though note, also covered by trial exclusion criteria of serious illness above):
• Withdrawal of consent to undergo FNA or inability to provide consent
• Significant comorbid medical condition(s) which may increase the risk of an FNA Liver.
• Clinically significant blood test abnormalities which would indicate increases risk of bleeding:
o INR>1.3 or PT>16 seconds.
o Platelet count <100 x 10^3/L.
• Known hepatobiliary malignancy.
• Clinical suspicion or evidence of ascites.
• Use of an oral anticoagulant or antiplatelet agent.
• Pregnancy.
• Any concern by the trial investigator or operating physician regarding the safety or appropriateness of the participant to undergo FNA liver |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome measure will be the number of individuals completely protected against malaria compared to controls. Completely protected individuals are those who do not, by Day 21 following sporozoite challenge, develop blood stage infection as defined in the protocol. The proportion protected will be compared individually to controls by Fisher exact tests to ask if there is more protection in the vaccine group than controls. This CHMI study will use a highly sensitive PCR assay for the detection malaria parasite (nucleic acids)as the diagnostic endpoint. This is emerging as standard practice across CHMI centres due to its superior sensitivity to microscopy to allow for earlier and more accurate malaria diagnosis.
The specific endpoints for safety and reactogenicity will be actively and passively collected data on adverse events. The following parameters will be assessed:
• Occurrence of solicited local reactogenicity signs and symptoms for 7 days following each vaccination
• Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following the vaccination
• Occurrence of unsolicited adverse events for 28 days following the vaccination
• Change from baseline for safety laboratory measures for 28 days following vaccination
• Occurrence of serious adverse events during the whole study duration
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The efficacy evaluation will begin at 6.5 days following challenge when the post-CHMI follow-up begins. This will continue to 21 days post challenge to determine how many vaccine recipients and controls have become infected.
Evaluation of the adverse events following vaccination will begin as soon as the vaccine is given, and will continue throughout the remainder of the trial (5-6 months from first vaccination; 4 months from final vaccine, 3 months after challenge). 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 |
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| E.5.2 | Secondary end point(s) |
Changes in immune response before and after vaccination will be assessed by immunological assays. The key measure of immunogenicity will be ELISPOT to enumerate IFN-γ producing T cells.
Secondary end points for vaccine efficacy include time to P. falciparum parasitemia assessed by PCR, and parasite density dynamics assessed by PCR 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.
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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 relevant malaria diagnostic endpoints and PCR thresholds: 20 parasites per ml; time to 500 parasites per ml; time to 1000 parasites per ml as well as time to malaria diagnosis - >10,000 parasites per ml or 1000 parasites per/ml in the presence of malaria symptoms. |
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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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| safety and immunogenicity of novel regimens |
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| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label, partially blinded, phase I/IIa, controlled human malaria infection study |
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| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 23 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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