Study of Purified Vero Rabies Vaccine Compared With Two Reference Rabies Vaccines, Given in a Pre-exposure Regimen to Children and Adults and as Single Booster Dose to a Subset of Adults

Rabies (Healthy Volunteers) Clinical Trial

— VRV12  

Official title:

Immunogenicity and Safety of a Purified Vero Rabies Vaccine - Serum Free in Comparison With Verorab® and Imovax® Rabies, in a Pre-exposure Regimen in Both Pediatric and Adult Populations and a Single Booster Dose of Purified Vero Rabies Vaccine - Serum Free Administered at 1 Year Post-3-dose Primary Series, and Between 2 up to 3 Years Post-One Week 2-Dose Primary Series in a Subset of Adults in Thailand

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04127786
• Other study ID #: VRV12
• Secondary ID: 2019-000973-22U1
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 21, 2019
• Est. completion date: May 12, 2025

Study information

• Verified date: February 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is:

To demonstrate the Purified Vero Rabies Vaccine - Serum Free (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 pre-exposure prophylaxis (PrEP) regimen, in terms of proportion of participants achieving a rabies virus neutralizing antibody (RVNA) titer greater than or equal to (>=) 0.5 IU/mL at Day (D) 42, i.e., 14 days after the 3rd injection (for Primary Series Cohort 1).

The secondary objectives of this study are: First 1-5 with hypotheses testing will be evaluated sequentially - only if the previous objective is achieved, will the next objective be tested.

To demonstrate that:

• the observed proportion of participants in the VRVg-2 (VRVg) group at D42 is at least 99% with a lower limit of the 95% confidence interval (CI) of at least 97%

• VRVg is non-inferior (NI) to Verorab and Imovax Rabies vaccines (Imovax) in each age group at D28

• 2-dose VRVg at D28 is NI to 3-dose Imovax at D42 in each age group

• the observed proportion of participants in the VRVg group at D28 is at least 99% with a lower limit of the 95% CI of at least 97%

• 2-dose Imovax at D28 is NI to 3-dose Imovax at D42 in overall participants (Cohort 1)

To describe:

• the immune response induced by VRVg versus Verorab and Imovax at D28 and at D42 in all age groups

• the immune response induced by VRVg at D14 after a booster dose of VRVg administered at Month (M) 12 (Cohort 1) and between M24 up to M36 (Cohort 2)

• the persistence of immune response at M6,12,18, and pre-booster between M24 up to M36 post-primary series vaccination (Cohort 2)

• safety profile of VRVg versus Verorab and Imovax in primary series and after a booster dose of VRVg.

Description:

The duration of each participant's participation in the primary series Cohort 1 of the study will be approximately 7 months (28 day-vaccination period followed by 6-month safety follow-up period). For the subset of adult participants in Booster Phase Cohort 1 who received a single booster dose of VRVg-2 (1 booster dose 365 days after primary series followed by 6-month safety follow-up period), the duration will be approximately 18 months.

For Primary Series Cohort 2, the duration of each participant's participation in the study will be approximately 7 months (one week vaccination period followed by 6-month safety follow-up period).

For the subset of adult participants in Immunogenicity Persistence and Booster Phase Cohort 2 who will be followed-up for evaluation of immunogenicity persistence after primary series (including blood samples collection at M6, M12, M18, and between 24 up to 36 months) and who will receive a single booster dose of VRVg-2 (after the blood sample collection between 24 up to 36 months), the duration will be approximately 30 to 42 months.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1708
• Est. completion date: May 12, 2025
• Est. primary completion date: March 25, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Year and older

Eligibility

Inclusion Criteria:

• Aged >=1 year on the day of inclusion

• Cohort 1 - pediatrics (>=1 to 17 years old) and adults (>=18 years old)

• Cohort 2 - all adults (>=18 years old)

• Informed consent form has been signed and dated by the participant and /or and parent(s) or legally acceptable representative (LAR) 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 less than [<]18 years) are able to attend all scheduled visits and to comply with all study procedures.

Exclusion Criteria:

• 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 illness(1) 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 (i.e., 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

Related Conditions & MeSH terms

• Rabies
• Rabies (Healthy Volunteers)

Intervention

Biological:
• Purified vero rabies vaccine - serum free - VRVg-2
Pharmaceutical form: Freeze-dried Route of administration: Intramuscular
• Purified inactivated rabies vaccine - Verorab®
Pharmaceutical form:Freeze-dried Route of administration: Intramuscular
• Purified inactivated rabies vaccine - Imovax® Rabies
Pharmaceutical form: Freeze-dried Route of administration: Intramuscular

Locations

Country	Name	City	State
Thailand	Investigational Site Number :7640001	Bangkok
Thailand	Investigational Site Number :7640003	Bangkok
Thailand	Investigational Site Number :7640004	Bangkok
Thailand	Investigational Site Number :7640002	Khon Kaen

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi Pasteur, a Sanofi Company

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody (RVNA) Titer Greater Than or Equal to (>=) 0.5 IU/mL	RVNA titer against rabies virus was assessed using the Rapid Fluorescent Focus Inhibition test (RFFIT) assay method.	Day 42 (post-vaccination)
Secondary	Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Pooled Population	RVNA titer against rabies virus was assessed using the RFFIT assay method. At Baseline, Group 1 was equivalent to Group 4 (both groups received VRVg-2), Group 2 was equivalent to Group 5 (both groups received Verorab®), and Group 3 was equivalent to Group 6 (both groups received Imovax Rabies®), therefore it was planned to collect and present pooled data of specified Groups, and separately for adults and pediatric participants in this outcome measure.	Cohort 1: Day 0 (pre-vaccination), Day 28 (post-vaccination); Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Primary Series: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Pooled Population (Groups 1 and 4) Versus Cohort 1: Group 3: Non-inferiority Analysis	RVNA titer against rabies virus was assessed using the RFFIT assay method. At Baseline, Group 1 was equivalent to Group 4 (both groups received VRVg-2), therefore it was planned to collect and present pooled data of specified Group, and separately for adults and pediatric participants in this outcome measure. Data for this outcome measure was planned to be collected at Day 28 for Pooled Groups 1 and 4 and at Day 42 for Primary Series: Cohort-1 Group 3: Imovax Rabies® and reported as overall data for the non-inferiority analysis in this outcome measure.	Pooled Groups 1 and 4: Day 28 (post-vaccination) and Primary Series: Cohort-1 Group 3: Day 42 (post-vaccination)
Secondary	Primary Series: Groups 1 and 4: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Pooled Population - Superiority Analysis	RVNA titer against rabies virus was assessed using the RFFIT assay method. At Baseline, Group 1 was equivalent to Group 4 (both groups received VRVg-2), therefore it was planned to collect and present pooled data of specified Group in this outcome measure.	Day 28 (post-vaccination)
Secondary	Primary Series Cohort 1 Group 3: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Non-Inferiority Analysis	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Cohort 1: Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series Cohort 1: Rabies Virus Neutralizing Antibody Geometric Mean Titers (GMTs) Against Rabies Virus	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series Cohort 2: Rabies Virus Neutralizing Antibody Geometric Mean Titers (GMTs) Against Rabies Virus	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Primary Series Cohort 2: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])	RVNA titer against rabies virus was assessed using the RFFIT assay method. LLOQ for the RFFIT assay was 0.2 IU/mL.	Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series Cohort 2: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])	RVNA titer against rabies virus was assessed using the RFFIT assay method. LLOQ for the RFFIT assay was 0.2 IU/mL.	Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Primary Series Cohort 1: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs post-vaccination (i.e., on Day 28 and Day 42) and pre-vaccination on Day 0.	Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series Cohort 2: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs post-vaccination (i.e., on Day 28) and pre-vaccination on Day 0.	Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Primary Series Cohort 1: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization	Virus neutralization was defined as complete (absence of fluorescent cells) and incomplete (presence of fluorescent cells) at the participant/timepoint level at the starting dilution (1/5) of RFFIT assay. Percentage of participants with determined complete and determined incomplete virus neutralization were reported.	Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
Secondary	Primary Series Cohort 2: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization	Virus neutralization was defined as complete (absence of fluorescent cells) and incomplete (presence of fluorescent cells) at the participant/timepoint level at the starting dilution (1/5) of RFFIT assay. Percentage of participants with determined complete and determined incomplete virus neutralization were reported.	Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
Secondary	Booster Phase: Rabies Virus Neutralizing Antibody (RVNA) Geometric Mean Titers (GMTs) Against Rabies Virus	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
Secondary	Booster Phase: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL	RVNA titer against rabies virus was assessed using the RFFIT assay method.	Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
Secondary	Booster Phase: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (LLOQ)	RVNA titer against rabies virus was assessed using the RFFIT assay method. LLOQ for the RFFIT assay was 0.2 IU/mL.	Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
Secondary	Booster Phase: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers	RVNA titer against rabies virus was assessed using the RFFIT assay method. GMTRs were calculated as the ratio of GMTs post vaccination (i.e., on Month 12 and Month 12 + Day 14) and pre-vaccination on Day 0, pre-booster dose on Month 12.	Day 0 (pre-vaccination), Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
Secondary	Booster Phase: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization	Virus neutralization was defined as complete (absence of fluorescent cells) and incomplete (presence of fluorescent cells) at the participant/timepoint level at the starting dilution (1/5) of RFFIT assay. Percentage of participants with determined complete and determined incomplete virus neutralization were reported.	Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
Secondary	Number of Participants With Immediate Unsolicited Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a participant who received study vaccine and does not necessarily had to have a causal relationship with the treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report book (CRB) in terms of diagnosis and/or onset post-vaccination. All participants were observed for 30 minutes after any vaccination, and any unsolicited AEs occurred during that time were recorded as immediate unsolicited AEs in the CRB.	Within 30 minutes after any vaccination
Secondary	Number of Participants With Immediate Unsolicited Adverse Events (AEs) - Booster Phase Cohort-2	An AE was defined as any untoward medical occurrence in a participant who received study vaccine and does not necessarily had to have a causal relationship with the treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report book (CRB) in terms of diagnosis and/or onset post-vaccination. All participants were observed for 30 minutes after any vaccination, and any unsolicited AEs occurred during that time were recorded as immediate unsolicited AEs in the CRB.	Within 30 minutes after any vaccination
Secondary	Number of Participants With Systemic Reactions	A SR was an expected AR observed and reported under conditions (nature and onset) pre-listed (i.e., solicited) in the protocol and CRB and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited systemic reactions included fever, vomiting, crying abnormal, drowsiness, appetite loss, irritability, headache, malaise and myalgia. Solicited systemic reactions were collected by different age groups: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability were collected for participants aged 12 to 23 months. Fever, Headache, Malaise and Myalgia were collected for participants aged >= 2 years.	Within 7 Days after any vaccination
Secondary	Number of Participants With Systemic Reactions - Booster Phase Cohort-2	A SR was an expected AR observed and reported under conditions (nature and onset) pre-listed (i.e., solicited) in the protocol and CRB and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited systemic reactions included fever, vomiting, crying abnormal, drowsiness, appetite loss, irritability, headache, malaise and myalgia. Solicited systemic reactions were collected by different age groups: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability were collected for participants aged 12 to 23 months. Fever, Headache, Malaise and Myalgia were collected for participants aged >= 2 years.	Within 7 Days after any vaccination
Secondary	Number of Participants With Solicited Injection Site Reactions	A solicited reaction (SR) was an expected AR observed and reported under conditions (nature and onset) pre-listed (i.e., solicited) in the protocol and CRB and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited injection site reactions included tenderness/pain, erythema and swelling.	Within 7 Days after any vaccination
Secondary	Number of Participants With Solicited Injection Site Reactions - Booster Phase Cohort-2	A solicited reaction (SR) was an expected AR observed and reported under conditions (nature and onset) pre-listed (i.e., solicited) in the protocol and CRB and considered as related to vaccination. An AR was all noxious and unintended responses to a medicinal product related to any dose. Solicited injection site reactions included tenderness/pain, erythema and swelling.	Within 7 Days after any vaccination
Secondary	Number of Participants With Unsolicited Adverse Events	An AE was defined as any untoward medical occurrence in a participant who received study vaccine and does not necessarily had to have a causal relationship with the treatment. An unsolicited AE was an observed AE that did not fulfill the conditions pre-listed in the CRB in terms of diagnosis and/or onset post-vaccination.	Within 28 Days after any vaccination
Secondary	Number of Participants With Unsolicited Adverse Events - Booster Phase Cohort-2	An AE was defined as any untoward medical occurrence in a participant who received study vaccine and does not necessarily had to have a causal relationship with the treatment. An unsolicited AE was an observed AE that did not fulfill the conditions pre-listed in the CRB in terms of diagnosis and/or onset post-vaccination.	Within 28 Days after any vaccination
Secondary	Number of Participants With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)	An SAEs was any untoward medical occurrence that at any dose resulted in death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or a medically important event. An AESI was defined as one of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was appropriate. All SAEs and AESIs occurring during the study that were related to the product administered were reported by the Investigator to the Independent Ethics Committee/Institutional Review Board. Relatedness to study vaccine was based on Investigator's discretion.	From Baseline (Day 0) up to 6 months after last vaccination (i.e., up to 7 months for Primary Series Cohorts 1 & 2 and up to Month 18 for Booster Phase, Cohort 1)
Secondary	Number of Participants With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) - Booster Phase Cohort-2	An SAEs was any untoward medical occurrence that at any dose resulted in death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or a medically important event. An AESI was defined as one of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was appropriate. All SAEs and AESIs occurring during the study that were related to the product administered were reported by the Investigator to the Independent Ethics Committee/Institutional Review Board. Relatedness to study vaccine was based on Investigator's discretion.	From Baseline (Day 0) up to 6 months after last vaccination (i.e., up to Month 42 for Booster Phase, Cohort 2)