| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Plasmodium falciparum malaria |
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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 safety of the RH5.1/AS01 vaccine in healthy volunteers at different doses.
To establish whether the RH5.1/AS01 vaccine can demonstrate a reduced parasite multiplication rate in vaccinated subjects compared to infectivity controls in a blood-stage controlled human malaria infection model.
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| E.2.2 | Secondary objectives of the trial |
To assess the humoral and cellular immunogenicity of RH5.1/AS01 when administered to healthy volunteers at different doses.
To assess immunological readouts for association with a reduced parasite multiplication rate.
To assess the durability of any reduction in parasite multiplication rate (PMR) in vaccinated Group 5 subjects by subjecting them to a re-challenge with 3D7 clone parasites approximately 4 months after the primary challenge (Group 7), and comparing the PMR with 1) that of previously challenged Group 6 controls receiving a second challenge (Group 8); and 2) that of newly recruited malaria-naïve controls (Group 9) receiving a primary challenge.assess immunological readouts for association with a reduced parasite multiplication rate. This is using the same Phase IIa blood-stage controlled human malaria infection (CHMI) model.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (GP).
•For females only, willingness to practice continuous effective contraception during the study and a negative pregnancy test on the day(s) of screening and vaccination, and on the day prior to blood-stage CHMI, and prior to the start of antimalarial treatment for Group 5-9 volunteers.
•Agreement to refrain from blood donation during the course of the study.
•Provide written informed consent.
Additional Inclusion Criteria for Groups 5 - 9
•Agreement to permanently refrain from blood donation, as per current UK Blood Transfusion and Tissue Transplantation Services guidelines.
•Reachable (24 hours a day) by mobile phone during the period between CHMI and completion of antimalarial treatment.
•Willingness to take a curative anti-malaria regimen following CHMI.
•Answer all questions on the informed consent questionnaire correctly.
•For Groups 7-8: completion of primary challenge, curative antimalarials and follow-up (up until at least the C+28 visit)
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| E.4 | Principal exclusion criteria |
The volunteer may not enter the study if any of the following apply:
•Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use 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. For Group 7 volunteers undergoing re-challenge, this exclusion criterion does not extend to the RH5.1/AS01B vaccine previously received.
•Any medical condition that in the judgment of the investigator would make intramuscular (IM) injection unsafe.
•Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate.
•Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 20 mg/day (for adult subjects), or equivalent. Inhaled and topical steroids are allowed.
•Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab).
•Chronic use of antibiotics with antimalarial effects (e.g. tetracyclines for dermatologic patients, sulfa for recurrent urinary tract infections, etc.).
•History of malaria chemoprophylaxis within 60 days prior to vaccination.
•History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
•Any history of anaphylaxis in relation to vaccination.
•History of splenectomy.
•Pregnancy, lactation or willingness/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 likely to 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 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 (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).
•History of clinical malaria (any species). (Not applicable to Groups 7 and 8).
•Travel to a malaria endemic region during the study period or within the previous six months.
•Any clinically significant abnormal finding on screening biochemistry or haematology blood tests or urinalysis.
•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.
•Inability of the study team to contact the volunteer’s GP to confirm medical history and safety to participate.
Additional exclusion criteria for groups 5 - 10
•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.
•Laboratory evidence of G6PD deficiency at screening
•Laboratory evidence of haemoglobinopathy at screening
•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.
•Family history of congenital QT prolongation or sudden death.
•Positive family history in both 1st and 2nd degree relatives < 50 years old for cardiac disease.
•History of cardiac arrhythmia, including clinically relevant bradycardia.
•Volunteer unable to be closely followed for social, geographic or psychological reasons.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The specific endpoints for safety and reactogenicity will be actively and passively collected data on adverse events.
The specific endpoints for GIA in vitro will be assessed from a titration of the purified IgG in the assay.
PCR-derived parasite multiplication rate (PMR) will be the primary efficacy endpoint for the Phase IIa stage of the trial, and comparison of the endpoint between the Groups 5 and 6 will constitute the primary analysis for efficacy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Volunteers will complete diary cards for 28 days after each vaccination and will be seen 1, 7, 14 and 28 days after each vaccination where safety and reactogenicity will be reviewed by clinical staff.
GIA will be assessed at days 42, 56, 70 and 84 for groups 1, 2 and 4 and at days 42, 56, 196 and 210 for Group 3.
For Groups 5-9 GIA will be assessed at day C-1 (i.e. day before CHMI) |
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| E.5.2 | Secondary end point(s) |
To assess the humoral and cellular immunogenicity of RH5.1/AS01 using different vaccine doses and vaccination regimens.
To assess immunological readouts for association with a reduced parasite multiplication rate.
PCR-derived parasite multiplication rate (PMR) will also be the efficacy endpoint for assessing the durability of the vaccine-reduction in PMR, and comparison of this PMR endpoint between Groups 7, 8 and 9 will constitute this secondary analysis for efficacy.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Groups 1, 2 & 4 (humoral and cellular immunogenicity):
Days 0, 1, 7, 14, 28, 29, 35, 42, 56, 57, 63, 70, 84, 140 and 240
Group 3 (humoral and cellular immunogenicity):
Days 0, 1, 7, 14, 28, 29, 35, 42, 56, 182, 183, 189, 196, 210, 266 and 366
Group 5 (humoral and cellular immunogenicity + immunological readouts for reduced PMR after malaria challenge): Days 0, 1, 7, 14, 29, 35, 42, 57, 63, 69 (C-1), day of diagnosis, C+28, C+90
where 'C' refers to malaria controlled human malaria infection (CHMI/challenge)- to take place on day 70 - 84.
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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 | 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 a malaria challenge |
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| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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