Clinical trial NCT04127786: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Rabies (Healthy Volunteers)
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2019-10-16
Enrollment: 1708
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Primary series will be observer-blinded for both Cohort 1 (3-dose pre-exposure prophylaxis \[PrEP\] regimen) and Cohort 2 (one week 2-dose PrEP regimen).

Booster phase will be conducted in a blinded manner (vaccine received in the primary series) with an adult subset from Cohort 1 and hereafter referred as "Booster Phase Cohort 1" (with booster dose 1 year after the 1st primary series vaccine injection).

Evaluation of immunogenicity persistence after primary series and a booster phase will be conducted in an open label manner with an adult subset from Cohort 2 and hereafter referred as "Immunogenicity Persistence and Booster Phase Cohort 2" (including blood samples collection at Month 6, Month 12, Month 18, pre-booster between Month 24 up to Month 36, and post-booster between Month 24 up to Month 36+Day 14; and a booster dose between Month 24 up to Month 36).
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody (RVNA) Titer Greater Than or Equal to (>=) 0.5 IU/mL
timeFrame: Day 42 (post-vaccination)
Secondary outcomes:
measure: Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
measure: Primary Series: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Pooled Population
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 (post-vaccination); Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: 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
timeFrame: Pooled Groups 1 and 4: Day 28 (post-vaccination) and Primary Series: Cohort-1 Group 3: Day 42 (post-vaccination)
measure: Primary Series: Groups 1 and 4: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Pooled Population - Superiority Analysis
timeFrame: Day 28 (post-vaccination)
measure: Primary Series Cohort 1 Group 3: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL - Non-Inferiority Analysis
timeFrame: Cohort 1: Day 28 and Day 42 (post-vaccination)
measure: Primary Series Cohort 1: Rabies Virus Neutralizing Antibody Geometric Mean Titers (GMTs) Against Rabies Virus
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
measure: Primary Series Cohort 2: Rabies Virus Neutralizing Antibody Geometric Mean Titers (GMTs) Against Rabies Virus
timeFrame: Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: Primary Series Cohort 2: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL
timeFrame: Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: Primary Series Cohort 1: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
measure: Primary Series Cohort 2: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])
timeFrame: Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: Primary Series Cohort 1: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
measure: Primary Series Cohort 2: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers
timeFrame: Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: Primary Series Cohort 1: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization
timeFrame: Cohort 1: Day 0 (pre-vaccination), Day 28 and Day 42 (post-vaccination)
measure: Primary Series Cohort 2: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization
timeFrame: Cohort 2: Day 0 (pre-vaccination) and Day 28 (post-vaccination)
measure: Booster Phase: Rabies Virus Neutralizing Antibody (RVNA) Geometric Mean Titers (GMTs) Against Rabies Virus
timeFrame: Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
measure: Booster Phase: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.5 IU/mL
timeFrame: Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
measure: Booster Phase: Percentage of Participants With Rabies Virus Neutralizing Antibody Titers >=0.2 IU/mL (LLOQ)
timeFrame: Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
measure: Booster Phase: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralizing Antibody Titers
timeFrame: Day 0 (pre-vaccination), Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
measure: Booster Phase: Percentage of Participants With Determined Complete and Determined Incomplete Virus Neutralization
timeFrame: Month 12 (pre-booster dose) and Month 12 + Day 14 (post-booster dose)
measure: Number of Participants With Immediate Unsolicited Adverse Events (AEs)
timeFrame: Within 30 minutes after any vaccination
measure: Number of Participants With Immediate Unsolicited Adverse Events (AEs) - Booster Phase Cohort-2
timeFrame: Within 30 minutes after any vaccination
measure: Number of Participants With Systemic Reactions
timeFrame: Within 7 Days after any vaccination
measure: Number of Participants With Systemic Reactions - Booster Phase Cohort-2
timeFrame: Within 7 Days after any vaccination
measure: Number of Participants With Solicited Injection Site Reactions
timeFrame: Within 7 Days after any vaccination
measure: Number of Participants With Solicited Injection Site Reactions - Booster Phase Cohort-2
timeFrame: Within 7 Days after any vaccination
measure: Number of Participants With Unsolicited Adverse Events
timeFrame: Within 28 Days after any vaccination
measure: Number of Participants With Unsolicited Adverse Events - Booster Phase Cohort-2
timeFrame: Within 28 Days after any vaccination
measure: Number of Participants With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
timeFrame: 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)
measure: Number of Participants With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) - Booster Phase Cohort-2
timeFrame: From Baseline (Day 0) up to 6 months after last vaccination (i.e., up to Month 42 for Booster Phase, Cohort 2)
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Investigational Site Number :7640001
city: Bangkok
country: Thailand
facility: Investigational Site Number :7640004
city: Bangkok
country: Thailand
facility: Investigational Site Number :7640003
city: Khon Kaen
country: Thailand
facility: Investigational Site Number :7640002
Study officials:
affiliation: Sanofi Pasteur, a Sanofi Company
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: