| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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] - 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 | 10037742 |
| E.1.2 | Term | Rabies |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 demonstrate the VRVg-2 is non-inferior to Verorab and Imovax Rabies vaccines in each age group (pediatric and adult populations) when administered as a 3-dose PrEP regimen, in terms of proportion of participants achieving a RVNA titer ≥ 0.5 IU/mL at Day 42, ie. 14 days after the 3rd injection. |
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| E.2.2 | Secondary objectives of the trial |
-To describe the safety profile of VRVg-2 versus Verorab and Imovax Rabies vaccines (2 comparator vaccines) after each vaccination, per age group
-To describe the safety of a booster dose of VRVg-2 in a subset of adults at month 12 after 3-dose primary series (Cohort 1) and between 24 to 36 months after 2-dose primary series (Cohort 2)
-To demonstrate that the observed proportion of participants in the VRVg-2 group achieving an RVNA titer ≥ 0.5 IU/mL at Day 42 is at least 99%, with a lower limit of the 95% confidence interval of at least 97%
-To demonstrate that VRVg-2 is non-inferior to comparator vaccines per age group, in terms of proportion of participants achieving a RVNA titer ≥ 0.5 IU/mL at Day 28
-To describe the immune response induced by VRVg-2 versus comparator vaccines among subset of adults at Day 28 and Day 42; and 14 days after booster dose (Month 12 in cohort 1 and between 24-36 months in cohort 2) regardless of the vaccine received in primary series |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Aged ≥1 year on the day of inclusion
- Informed consent form has been signed and dated by the participant and /or and the parent(s) or Legally Acceptable Representative and by an independent witness (if required by local regulations), as necessary; and Assent form has been signed and dated by the participant, as required
- Participant (adult ≥ 18 years) or participant and parent/LAR (1 year to <18 years) are able to attend all scheduled visits and to comply with all studyprocedures.
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
- Participant is pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until 1 month after each vaccination. To be considered of non-childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, or surgically sterile.
- Participation at the time of study enrollment or, planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure.
- Receipt of any vaccine in the 4 weeks (28 days) preceding the first study vaccination or planned receipt of any vaccine prior to Visit 5 for pediatric participants and adult participants in Cohort 1, and prior to Visit 4 for adult participants in Cohort 2.
- Previous vaccination against rabies (in pre- or post-exposure regimen) with either the study vaccines or another vaccine.
- Bite by, or exposure to a potentially rabid animal in the previous 6 months with or without post-exposure prophylaxis.
- Receipt of immune globulins, blood or blood-derived products in the past 3 months.
- Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
- At high risk for rabies exposure during the study.
- Known systemic hypersensitivity to any of the study/control vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances
- Self-reported thrombocytopenia, contraindicating intramuscular vaccination.
- Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination.
- Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily.
- Current alcohol or substance abuse that, in the opinion of the investigator, might interfere with the study conduct or completion.
- Chronic illness1 that, in the opinion of the Investigator, is at a stage where it might interfere with study conduct or completion.
- Moderate or severe acute illness/infection (according to Investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.
- Personal history of Guillain-Barré syndrome.
- Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (ie, parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.
1 Chronic illness may include, but is not limited to, neurological, cardiopulmonary, gastrointestinal, renal, genitourinary, metabolic, hematologic, auto-immune, or psychiatric disorders or infection |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Participant with RVNA titer ≥ 0.5 IU/mL - Percentage of participants with RVNA titer above threshold (≥ 0.5 IU/mL). RVNA titers are measured by the rapid fluorescent focus inhibition test (RFFIT) assay |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 42 for participants in Primary Series Cohort 1 |
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| E.5.2 | Secondary end point(s) |
1) Number of participants with immediate adverse events - Percentage of participants reporting systemic unsolicited adverse events in the 30 minutes after vaccination
2) Number of participants with solicited injection site or systemic reactions - Percentage of participants reporting- injection site reactions in participants aged <=23 months: tenderness, erythema, and swelling; in participants aged 2 years and above: pain, erythema and swelling or in participants aged <=23 months: fever, vomiting, crying abnormal, drowsiness, appetite lost, and irritability; in participants aged 2 years and above: fever, headache, malaise, and myalgia
3) Number of participants with unsolicited adverse events - Percentage of subjecs with unsolicited (spontaneously reported) injection site reactions occurring within 28 days after each injection and unsolicited systemic AEs between each injection and up to 28 days after the last injection
4) Number of participants with serious adverse events (SAEs) and adverse events of special interest (AESIs) - Percentage of participants with SAEs, including AESIs, throughout the study
5) RVNA titer - RVNA titers are measured by RFFIT and expressed as geometric mean titers (GMT)
6) RVNA titer ≥ 0.5 IU/mL - Percentage of participants witth RVNA titers above threshold (≥ 0.5 IU/mL). RVNA titers are measured by RFFIT
7) RVNA titer above lower limit of quantification (LLOQ) IU/Ml - Percentage of participants with RVNA titers above LLOQ IU/ml are measured by RFFIT
8) RVNA titer ratio - Individual RVNA titer ratio
9) Participant with complete or incomplete neutralization at the starting dilution of the RFFIT assay - Percentage of participants with complete or incomplete neutralization at the dilution of 1/5 in RFFIT. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Within 30 minutes after vaccination
2) Within 7 days after vaccination
3) Within 28 days after vaccination
4) Up to 6 months after last vaccination
5) 6) 7) 9) Day 0 and Day 28 for participants in Primary Series Cohort 1 and Cohort 2
Day 42 for participants in Primary Series Cohort 1
Month 12 and Month 12+Day 14 for the Booster Phase Cohort 1
Between Month 24 up to Month36 and between Month 24 up to Month 36+Day 14 for the Booster Phase Cohort 2
8) Day 28/Day 0 on Primary Series Cohort 1 and Cohort 2, and Day 42/Day 0 in Primary Series Cohort 1 |
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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 |
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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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| blinded for primary series and booster for cohort 1 and primary series for cohort 2, open-label for |
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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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| 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 | 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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| End of the safety follow-up period, that is the last participant contact through a phone call 6 months after the last vaccine injection of primary series and 6 months after the booster dose, Cohorts 1 and 2 |
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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 | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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