| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Ebola virus disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Prevention of Ebola virus disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014071 |
| E.1.2 | Term | Ebola disease |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of Stage 1 is:
• To evaluate the safety of a heterologous prime-boost regimen utilizing Ad26.ZEBOV and MVA-BN-Filo given at a 56-day interval.
The primary objective of Stage 2 is:
• To evaluate the safety of a heterologous prime-boost regimen utilizing Ad26.ZEBOV and MVA-BN-Filo given at a 56-day interval compared to an active control vaccine.
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| E.2.2 | Secondary objectives of the trial |
The secondary objective of Stage 1 is:
• To assess humoral immune responses to a heterologous prime-boost regimen utilizing Ad26.ZEBOV and MVA-BN-Filo as measured by an enzyme-linked immunosorbent assay (ELISA) at 21 days post-boost vaccination.
• To assess the safety and tolerability of a third vaccination using Ad26.ZEBOV administered at least 2 years post prime.
The secondary objective of Stage 2 is:
• To assess humoral immune responses to a heterologous prime-boost regimen utilizing Ad26.ZEBOV and MVA-BN-Filo as measured by an ELISA at 21 days post boost vaccination.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Stage 1
1. Documented community engagement by a community leader must be available. At the individual level, each subject must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study. In case the subject cannot read or write, the procedures must be explained and informed consent must be witnessed by a literate third party not involved in the conduct of the study.
2. Must be a male or female subject aged 18 years or older at screening.
3. Must be resident in the selected study community, with no intention to move from the study area within the next 5 months.
4. Must be healthy on the basis of physical examination and clinical laboratory tests performed at screening. Subjects must meet the following laboratory criteria within 28 days before Day 1:
• Hemoglobin: women: ≥12.5 g/dL; men ≥13.0 g/dL
• Hematocrit: ≥36%
• Red blood cell (RBC) count: ≥4,500,000/mm^3
• White blood cell (WBC) count: ≥4,000/mm^3
• Platelets: ≥150,000/mm^3
• Alanine aminotransferase (ALT): ≤69 U/L
• Aspartate aminotransferase (AST): ≤46 U/L
• Creatinine: <109 µmol/L
5. Female subjects of childbearing potential must use adequate birth control measures consistent with local regulations regarding the use of birth control for subjects participating in clinical studies from at least 14 days before the prime vaccination, with a negative urine β-hCG pregnancy test at screening and immediately prior to the prime vaccination, which shall occur no earlier than 14 days after the screening visit.
6. Male subjects who are sexually active with a woman of childbearing potential must be willing to use condoms for sexual intercourse beginning prior to enrollment.
7. Must pass the test of understanding (TOU).
Stage 2
8. Documented community engagement by a community leader must be available. At the individual level, adult subjects (aged 18 years and older at screening) must sign an ICF indicating that he or she understands the purpose of the study and the procedures required for the study and is willing to participate in the study. In case the subject cannot read or write, the procedures must be explained and informed consent must be witnessed by a literate third party not involved in the conduct of the study. In case the subject’s age is below the legal cut-off age for consent (according to local regulations), the parent/legal guardian will be asked to give consent, and the subject will be informed about the study. Subjects aged 7 years and older will be asked to give positive assent. The assent procedure must be witnessed by an adult literate parent/legal guardian/third party not involved in the conduct of the study, and documented.
9. Must be a male or female subject aged 1 year or older at screening.
10. Must be resident in the selected study community, with no intention to move from the study area during the subject's participation in the study.
11. Must be healthy on the basis of physical examination and clinical laboratory tests performed at screening. If the results of the laboratory screening tests are outside the institutional normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initialed by the investigator.
12. Sexually active female subjects of childbearing potential must use adequate birth control measures consistent with the local standards regarding the use of birth control for subjects participating in clinical studies and what is available from at least 14 days before the prime vaccination, with a negative urine β-hCG pregnancy test at screening and immediately prior to the prime vaccination, which shall occur no earlier than 14 days after the screening visit.
13. Male subjects who are sexually active with a woman of childbearing potential must be willing to use condoms for sexual intercourse beginning prior to enrollment.
14. Subjects or the parent/legal guardian (for children) must pass the TOU. |
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| E.4 | Principal exclusion criteria |
Stage 1
1. Women who are breast-feeding or known to be pregnant. A pregnancy test will be performed at screening in women of childbearing potential.
2. Subjects who have an illness prior to vaccination. This does not include acute illnesses such as diarrhea or mild upper respiratory tract infection unless accompanied by body temperature >37.5°C.
3. Subjects with any clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation. Subjects who identify themselves as being HIV-positive can be included as long as their general condition is good, ie, they are on antiretroviral treatment or have no signs or symptoms of immune incompetence.
4. Subjects with anemia (defined as hemoglobin <10 g/dL).
5. Subjects who have had a previous adverse reaction to vaccination excluding mild non-systemic adverse reactions.
6. Subjects who are being treated with an immunosuppressive drug at the time of screening.
7. Subjects who have received a blood transfusion or other blood products within 8 weeks of vaccination.
8. Subjects who have been vaccinated with a candidate Ebola vaccine or have participated in another Ebola preventative or therapeutic biomedical intervention study.
9. Subjects who have been vaccinated with live-attenuated vaccines within 30 days before the prime vaccination, and with inactivated vaccines within 15 days before the prime vaccination.
10. Subjects who are known to have received any Ad26- or MVA-based candidate vaccine in the past.
11. Subjects who have been diagnosed with EVD or are under quarantine/have been exposed to Ebola.
12. Subjects who, in the opinion of the investigator, are unlikely to adhere to the requirements of the study or are unlikely to complete the full course of vaccination and observation.
13. Fever (body temperature ≥38.0°C). Temperature will be taken according to standardized temperature monitoring as per Ebola response regulations. Subjects with a fever of ≥38.0°C will be referred to the EVD assessment services.
Stage 2
1. Women who are breast-feeding or known to be pregnant. A pregnancy test will be performed at screening in women of childbearing potential.
2. Subjects who have an illness prior to vaccination. This does not include acute illnesses such as diarrhea or mild upper respiratory tract infection unless accompanied by body temperature ≥38.0° C.
3. Subjects with any clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation. Subjects who identify themselves as being HIV positive can be included as long as their general condition is good, ie, they are on antiretroviral treatment or have no signs or symptoms of immune incompetence, diagnosed on the basis of physical examination, medical history, and the investigator’s clinical judgment.
4. Subjects with anemia (defined as hemoglobin <8 g/dL for children aged ≥1 to <5 years, <9 g/dL for children aged ≥5 to <15 years, and <10 g/dL for subjects aged ≥15 years).
5. Subjects who have had a previous adverse reaction to vaccination excluding mild nonsystemic adverse reactions.
6. Subjects who are being treated with an immunosuppressive drug at the time of screening.
7. Subjects who have received a blood transfusion or other blood products within 8 weeks of vaccination.
8. Subjects who have been vaccinated with a candidate Ebola vaccine or have participated in another Ebola preventative or therapeutic biomedical intervention study.
9. Subjects who have been vaccinated with live-attenuated vaccines within 30 days before the prime vaccination, and with inactivated vaccines within 15 days before the prime vaccination.
10. Subjects who are known to have received any Ad26- or MVA-based candidate vaccine in the past.
11. Subjects who have been diagnosed with EVD or are under quarantine/have been exposed to Ebola.
12. Subjects who, in the opinion of the investigator, are unlikely to adhere to the requirements of the study or are unlikely to complete the full course of vaccination and observation.
13. Children with weight-per-height below 10th percentile according to the WHO (1- and 2- year-olds) and Centers for Disease Control and Prevention (CDC) growth charts (3- to 11-year-olds).
14. Fever (body temperature ≥38.0° C). Temperature will be taken according to standardized temperature monitoring as per Ebola local response regulations. Subjects with a fever of ≥38.0° C will be referred to routine medical follow-up.
15. Subjects who have received a meningitis vaccine in the past. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Solicited local and systemic adverse events (reactogenicity), collected until 7 days after the prime and boost vaccination (Stage 1 and Stage 2) and the third vaccination (Stage 1) as recorded by the subjects (or, when appropriate, by a project field worker, a caregiver, surrogate, or the subject's legally acceptable representative) in a diary during daily home contacts with a project field worker.
2. Solicited local and systemic adverse events (reactogenicity), collected until 60 minutes after the prime and boost vaccination and until 30 minutes after the third vaccination in all subjects from Stage 1, and until 30 minutes after each vaccine administration in all subjects from Stage 2.
3. Unsolicited adverse events, collected by the investigator or the clinical designee from provision of informed consent onwards until 56 days after the boost vaccination in Stage 1 and then again from the day of the third vaccination until 28 days after the third vaccination, and from provision of informed consent onwards until 28 days after the prime vaccination in Stage 2 and then again until 28 days after the boost vaccination.
4. Serious adverse events, including deaths, and immediate reportable events (IREs) collected in all subjects from Stage 1 and Stage 2 from provision of informed consent onwards until the subject’s last study visit.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Until 7 days after the prime and boost vaccination (Stage 1 and Stage 2) and the third vaccination (Stage 1)
2. Until 60 minutes after the prime and boost vaccination and until 30 minutes after the third vaccination in all subjects from Stage 1, and until 30 minutes after each vaccine administration in all subjects from Stage 2
3. Until 56 days after the boost vaccination in Stage 1 and then again from the day of the third vaccination until 28 days after the third vaccination, and from provision of informed consent onwards until 28 days after the prime vaccination in Stage 2 and then again until 28 days after the boost vaccination
4. From Stage 1 and Stage 2 from provision of informed consent onwards until the subject’s last study visit |
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| E.5.2 | Secondary end point(s) |
Evaluation of antibody responses depending on assay and/or sample availability any of the following assays
• EBOV GP ELISA: to determine the binding antibody levels elicited by vaccination.
• VNA: neutralizing antibody reactivity against the EBOV GP defined as the serum titer that is able to inhibit viral infection by a certain percentage (IC50,IC80 or IC90).
• ELISA, VNA, and/or PRNT: to explore the binding and/or neutralizing antibody responses against the adenovirus and/or MVA vector. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 |
| Immunogenicity and tolerability |
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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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 |
| Staged study with an open-label uncontrolled Stage 1 and a double-blinded controlled Stage 2 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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.8.9.2 | In all countries concerned by the trial years | 4 |
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