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    Clinical Trial Results:
    Immunogenicity and Safety of a Purified Vero Rabies Vaccine - Serum Free in Comparison with Verorab® and Imovax® Rabies, in a Simulated Rabies Post-exposure Regimen in Healthy Adults in France

    Summary
    EudraCT number
    2018-004055-20
    Trial protocol
    FR  
    Global end of trial date
    01 Jul 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2022
    First version publication date
    15 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VRV13
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03965962
    WHO universal trial number (UTN)
    U1111-1216-6151
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that Purified Vero Rabies Vaccine - Serum Free Vaccine generation 2 (VRVg-2) was non-inferior to Verorab and Imovax Rabies vaccines when co-administered with human rabies immunoglobulin (HRIG), in terms of proportion of subjects achieving a rabies virus neutralising antibody (RVNA) titer greater than or equal to (>=) 0.5 international units per millilitre (IU/mL) at Day 28, i.e., 14 days after the fourth vaccine injection.
    Protection of trial subjects
    Subjects were informed of the risks of participating in the trial in accordance with international guidelines and applicable regulations. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions. Subjects were followed up for safety according to the endpoints of the trial. The safety follow-up for serious adverse events and adverse events of special interest lasted 6 months after the last vaccination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 640
    Worldwide total number of subjects
    640
    EEA total number of subjects
    640
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    552
    From 65 to 84 years
    88
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 2 active centres in France.

    Pre-assignment
    Screening details
    A total of 640 subjects were enrolled in the study. Data presented in the disposition table (all milestones) is based on randomised group, except for safety analysis set (SafAS) milestone which is presented based on the actual vaccination group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Modified double-blind (for Groups 1 to 3): the subject (or legally acceptable representative), and the Investigator remained unaware of the treatment assignments throughout the study. An unblinded qualified trial staff member administered the appropriate vaccine but was not involved in the immunogenicity and safety evaluations. Group 4 was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1 VRVg-2+HRIG
    Arm description
    Subjects received 0.5 millilitres (mL) intramuscular (IM) injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    VRVg-2: Purified Vero Rabies Vaccine- Serum Free Vaccine generation 2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM dose at Days 0, 3, 7, 14 and 28.

    Investigational medicinal product name
    IMOGAM® Rabies-HT Licensed HRIGs
    Investigational medicinal product code
    Other name
    Rabies immune globulin (human)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per body weight, IM injections in the anterolateral thigh at Day 0.

    Arm title
    Group 2 Verorab+HRIG
    Arm description
    Subjects received 0.5 mL IM injection of Verorab on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Verorab®: purified inactivated rabies vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM dose at Days 0, 3, 7, 14 and 28.

    Investigational medicinal product name
    IMOGAM® Rabies-HT Licensed HRIGs
    Investigational medicinal product code
    Other name
    Rabies immune globulin (human)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per body weight, IM injections in the anterolateral thigh at Day 0.

    Arm title
    Group 3 Imovax Rabies+HRIG
    Arm description
    Subjects received 1 mL IM injection of Imovax Rabies on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Imovax® Rabies
    Investigational medicinal product code
    Other name
    Human Diploid Cell Vaccine (HDCV)
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 mL, IM dose at Days 0, 3, 7, 14 and 28.

    Investigational medicinal product name
    IMOGAM® Rabies-HT Licensed HRIGs
    Investigational medicinal product code
    Other name
    Rabies immune globulin (human)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    As per body weight, IM injections in the anterolateral thigh at Day 0.

    Arm title
    Group 4 VRVg-2
    Arm description
    Subjects received 0.5 mL IM injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28.
    Arm type
    Experimental

    Investigational medicinal product name
    VRVg-2: Purified Vero Rabies Vaccine- Serum Free Vaccine generation 2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM dose at Days 0, 3, 7, 14 and 28.

    Number of subjects in period 1
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Started
    320
    107
    107
    106
    Vaccination 1 (Day 0)
    318
    107
    107
    106
    Vaccination 2 (Day 3)
    317
    104
    107
    106
    Vaccination 3 (Day 7)
    311
    103
    105
    105
    Vaccination 4 (Day 14)
    301
    101 [1]
    101
    103
    Vaccination 5 (Day 28)
    294 [2]
    98 [3]
    97
    98 [4]
    Safety analysis set (SafAS)
    320
    107
    107
    104
    Completed
    295
    102
    97
    100
    Not completed
    25
    5
    10
    6
         Protocol deviation
    21
    4
    10
    5
         Adverse event, non-fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    3
    -
    -
    1
         Lost to follow-up
    -
    1
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The vaccinated number of subjects in each visit is less than the number of randomised subjects as not all randomised subjects received vaccination at each visit or not all randomised subjects presented at each visit.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The vaccinated number of subjects in each visit is less than the number of randomised subjects as not all randomised subjects received vaccination at each visit or not all randomised subjects presented at each visit.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The vaccinated number of subjects in each visit is less than the number of randomised subjects as not all randomised subjects received vaccination at each visit or not all randomised subjects presented at each visit.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The vaccinated number of subjects in each visit is less than the number of randomised subjects as not all randomised subjects received vaccination at each visit or not all randomised subjects presented at each visit.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 VRVg-2+HRIG
    Reporting group description
    Subjects received 0.5 millilitres (mL) intramuscular (IM) injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 2 Verorab+HRIG
    Reporting group description
    Subjects received 0.5 mL IM injection of Verorab on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 3 Imovax Rabies+HRIG
    Reporting group description
    Subjects received 1 mL IM injection of Imovax Rabies on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 4 VRVg-2
    Reporting group description
    Subjects received 0.5 mL IM injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28.

    Reporting group values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2 Total
    Number of subjects
    320 107 107 106
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.0 ± 14.7 46.2 ± 14.8 46.3 ± 15.6 46.4 ± 15.0 -
    Gender categorical
    Units: Subjects
        Female
    196 61 65 60 382
        Male
    124 46 42 46 258
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    2 2 0 0 4
        Asian
    4 1 3 0 8
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    9 1 0 1 11
        White
    301 102 104 105 612
        More than one race
    1 1 0 0 2
        Unknown or Not Reported
    3 0 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Group 1 VRVg-2+HRIG
    Reporting group description
    Subjects received 0.5 millilitres (mL) intramuscular (IM) injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 2 Verorab+HRIG
    Reporting group description
    Subjects received 0.5 mL IM injection of Verorab on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 3 Imovax Rabies+HRIG
    Reporting group description
    Subjects received 1 mL IM injection of Imovax Rabies on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 4 VRVg-2
    Reporting group description
    Subjects received 0.5 mL IM injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28.

    Primary: Percentage of Subjects With Rabies Virus Neutralising Antibody (RVNA) Titers Greater Than or Equal to (>=) 0.5 International Units per Millilitre (IU/mL)-Non-Inferiority Analysis

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    End point title
    Percentage of Subjects With Rabies Virus Neutralising Antibody (RVNA) Titers Greater Than or Equal to (>=) 0.5 International Units per Millilitre (IU/mL)-Non-Inferiority Analysis [1]
    End point description
    RVNA titer against rabies virus was assessed using the Rapid Fluorescent Focus Inhibition test (RFFIT) assay method. Analysis was performed on the per-protocol analysis set (PPAS) that included all subjects who received at least 1 dose of the study vaccines. The subjects who presented protocol deviations, met PPAS exclusion criteria were excluded from PPAS. Data for this endpoint was planned to be collected and analysed only for Groups 1, 2, and 3.
    End point type
    Primary
    End point timeframe
    Day 28
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was planned to be collected and analysed only for Groups 1, 2, and 3.
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG
    Number of subjects analysed
    239
    77
    78
    Units: percentage of subjects
        number (confidence interval 95%)
    99.6 (97.7 to 100)
    100 (95.3 to 100)
    98.7 (93.1 to 100)
    Statistical analysis title
    Group 1: VRVg-2+HRIG, Group 2: Verorab+HRIG
    Comparison groups
    Group 1 VRVg-2+HRIG v Group 2 Verorab+HRIG
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.33
         upper limit
    4.35
    Notes
    [2] - The two-sided 95 percent (%) confidence interval (CI) was calculated based on the Wilson score method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 95% CI of the difference of the percentages between the test group (Group 1) and control group (Group 2) was greater than (>) -5% at Day 28.
    Statistical analysis title
    Group 1: VRVg-2+HRIG, Group 3: Imovax Rabies+HRIG
    Comparison groups
    Group 1 VRVg-2+HRIG v Group 3 Imovax Rabies+HRIG
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    6.5
    Notes
    [3] - The two-sided 95 % CI was calculated based on the Wilson score method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 95% CI of the difference of the percentages between the test group (Group 1) and control group (Group 3) was > -5% at Day 28.

    Secondary: Percentage of Subjects With Rabies Virus Neutralising Antibody Titers >=0.5 IU/mL

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    End point title
    Percentage of Subjects With Rabies Virus Neutralising Antibody Titers >=0.5 IU/mL
    End point description
    RVNA titer against rabies virus was assessed using the RFFIT assay method. Immune response of VRVg-2 was considered sufficient if the lower limit of the 95% CI for percentage of subjects in Group 1 with RVNA titers >=0.5 IU/mL was not less than 95% at Day 28, when the primary non-inferiority objective was achieved at Day 28. Analysis was performed on the PPAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 14, Day 28 and Day 42
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    239
    77
    78
    77
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 0 (n=239,77,78,77)
    0 (0 to 1.5)
    0 (0 to 4.7)
    0 (0 to 4.6)
    0 (0 to 4.7)
        Day 14 (n=213,75,68,69)
    92.5 (88.1 to 95.6)
    88.0 (78.4 to 94.4)
    94.1 (85.6 to 98.4)
    97.1 (89.9 to 99.6)
        Day 28 (n=239,77,78,77)
    99.6 (97.7 to 100)
    100 (95.3 to 100)
    98.7 (93.1 to 100)
    100 (95.3 to 100)
        Day 42 (n=226,74,76,76)
    100 (98.4 to 100)
    100 (95.1 to 100)
    98.7 (92.9 to 100)
    100 (95.3 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Rabies Virus Neutralising Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])

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    End point title
    Percentage of Subjects With Rabies Virus Neutralising Antibody Titers >=0.2 IU/mL (Lower Limit of Quantification [LLOQ])
    End point description
    RVNA titer against rabies virus was assessed using the RFFIT assay method. Lower limit of quantitation (LLOQ) for the RFFIT assay was 0.2 IU/mL. Analysis was performed on the PPAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 14, Day 28 and Day 42
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    239
    77
    78
    77
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 0 (n=239,77,78,77)
    0 (0 to 1.5)
    0 (0 to 4.7)
    0 (0 to 4.6)
    0 (0 to 4.7)
        Day 14 (n=213,75,68,69)
    99.5 (97.4 to 100)
    100 (95.2 to 100)
    98.5 (92.1 to 100)
    100 (94.8 to 100)
        Day 28 (n=239,77,78,77)
    100 (98.5 to 100)
    100 (95.3 to 100)
    98.7 (93.1 to 100)
    100 (95.3 to 100)
        Day 42 (n=226,74,76,76)
    100 (98.4 to 100)
    100 (95.1 to 100)
    100 (95.3 to 100)
    100 (95.3 to 100)
    No statistical analyses for this end point

    Secondary: Rabies Virus Neutralising Antibody (RVNA) Geometric Mean Titers (GMTs) Against Rabies Virus

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    End point title
    Rabies Virus Neutralising Antibody (RVNA) Geometric Mean Titers (GMTs) Against Rabies Virus
    End point description
    RVNA GMT against rabies virus was assessed using the RFFIT assay method. Analysis was performed on the PPAS. Here, 'n' = subjects with available data for each specified category and '99999' is used as space filler which signifies that upper and lower limits of 95% CI were not estimable because all the subjects had same value and no variability was observed.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 14, Day 28 and Day 42
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    239
    77
    78
    77
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Day 0 (n=239,77,78,77)
    0.100 (0.100 to 0.101)
    0.100 (-99999 to 99999)
    0.100 (-99999 to 99999)
    0.101 (0.099 to 0.102)
        Day 14 (n=213,75,68,69)
    2.40 (2.09 to 2.76)
    1.86 (1.44 to 2.41)
    1.83 (1.46 to 2.28)
    5.41 (4.24 to 6.90)
        Day 28 (n=239,77,78,77)
    6.49 (5.75 to 7.34)
    5.03 (3.94 to 6.44)
    5.51 (4.35 to 6.96)
    12.4 (10.5 to 14.5)
        Day 42 (n=226,74,76,76)
    13.6 (12.3 to 15.0)
    9.47 (7.96 to 11.3)
    10.7 (8.97 to 12.7)
    19.8 (17.5 to 22.5)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralising Antibody Titers

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    End point title
    Geometric Mean Titer Ratio (GMTR) of Rabies Virus Neutralising Antibody Titers
    End point description
    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 14, 28 and Day 42) and pre-vaccination on Day 0. Analysis was performed on the PPAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 14, Day 28 and Day 42
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    239
    77
    78
    77
    Units: ratio
    geometric mean (confidence interval 95%)
        Day 14/Day 0 (n=213,75,68,69)
    24.0 (20.8 to 27.6)
    18.6 (14.4 to 24.1)
    18.3 (14.6 to 22.8)
    53.7 (42.1 to 68.4)
        Day 28/Day 0 (n=239,77,78,77)
    64.8 (57.3 to 73.2)
    50.3 (39.4 to 64.4)
    55.1 (43.5 to 69.6)
    123 (105 to 144)
        Day 42/Day 0 (n=226,74,76,76)
    135 (122 to 149)
    94.7 (79.6 to 113)
    107 (89.7 to 127)
    197 (173 to 224)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Determined Complete and Determined Incomplete Virus Neutralisation

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    End point title
    Percentage of Subjects with Determined Complete and Determined Incomplete Virus Neutralisation
    End point description
    Virus neutralisation was defined as complete (absence of fluorescent cells) and incomplete (presence of fluorescent cells) at the subject/timepoint level at the starting dilution (1/5) of RFFIT assay. Percentage of subjects with determined complete and determined incomplete virus neutralisation were reported. Analysis was performed on PPAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 14, Day 28 and Day 42
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    239
    77
    78
    77
    Units: percentage of subjects
    number (confidence interval 95%)
        Day 0: Complete Neutralisation (n=231,74,72,74)
    0.4 (0 to 2.4)
    0 (0 to 4.9)
    0 (0 to 5.0)
    1.4 (0 to 7.3)
        Day 0: Incomplete Neutralisation (n=231,74,72,74)
    99.6 (97.6 to 100)
    100 (95.1 to 100)
    100 (95.0 to 100)
    98.6 (92.7 to 100)
        Day 14: Complete Neutralisation (n=229,75,75,77)
    98.7 (96.2 to 99.7)
    100 (95.2 to 100)
    98.7 (92.8 to 100)
    98.7 (93.0 to 100)
        Day 14: Incomplete Neutralisation (n=229,75,75,77)
    1.3 (0.3 to 3.8)
    0 (0 to 4.8)
    1.3 (0 to 7.2)
    1.3 (0 to 7.0)
        Day 28: Complete Neutralisation (n=237,77,78,77)
    100 (98.5 to 100)
    100 (95.3 to 100)
    98.7 (93.1 to 100)
    100 (95.3 to 100)
        Day 28: Incomplete Neutralisation (n=237,77,78,77)
    0 (0 to 1.5)
    0 (0 to 4.7)
    1.3 (0 to 6.9)
    0 (0 to 4.7)
        Day 42: Complete Neutralisation (n=236,77,78,77)
    100 (98.4 to 100)
    100 (95.3 to 100)
    100 (95.4 to 100)
    100 (95.3 to 100)
        Day 42: Incomplete Neutralisation (n=236,77,78,77)
    0 (0 to 1.6)
    0 (0 to 4.7)
    0 (0 to 4.6)
    0 (0 to 4.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Immediate Unsolicited Adverse Events (AEs)

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    End point title
    Percentage of Subjects With Immediate Unsolicited Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study vaccine and does not necessary had to have a causal relationship with 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 subjects 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. Immediate AEs considered as related to vaccination were recorded as immediate unsolicited adverse reactions (ARs). Analysis was performed on the safety analysis set (SafAS) that included subject who had received at least one dose of the study vaccine and were analysed according to the actual treatment received. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after any and each vaccination (Vaccinations 1, 2, 3, 4 and 5)
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    320
    107
    107
    104
    Units: percentage of subjects
    number (not applicable)
        Post-any vaccination (n=320, 107, 107, 104)
    0.9
    0
    0
    1.0
        Post-vaccination 1 (n=320, 107, 107, 104)
    0.9
    0
    0
    1.0
        Post-vaccination 2 (n=319, 104, 107, 104)
    0
    0
    0
    0
        Post-vaccination 3 (n=313, 103, 105, 103)
    0
    0
    0
    0
        Post-vaccination 4 (n=303, 101, 101, 101)
    0
    0
    0
    0
        Post-vaccination 5 (n=296, 98, 97, 96)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Injection Site Reactions

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    End point title
    Percentage of Subjects With Solicited Injection Site Reactions
    End point description
    A solicited reaction (SR) was an expected AR observed and reported under conditions (nature and onset) prelisted (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 pain, erythema and swelling at and around the injection site. Analysis was performed on the SafAS. Here, 'n'= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 7 days after any and each vaccination (Vaccinations 1, 2, 3, 4 and 5)
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    320
    107
    107
    104
    Units: percentage of subjects
    number (not applicable)
        Pain Post-any vaccination (n=320,107,107,104)
    44.4
    34.6
    45.8
    42.3
        Pain Post-vaccination 1 (n=320,107,107,104)
    22.2
    17.8
    23.4
    22.1
        Pain Post-vaccination 2 (n=319,104,107,104)
    26.3
    16.3
    15.9
    19.2
        Pain Post-vaccination 3 (n=312,103,105,103)
    23.4
    13.6
    21.9
    22.3
        Pain Post-vaccination 4 (n=300,101,100,100)
    23.0
    11.9
    29.0
    27.0
        Pain Post-vaccination 5 (n=295,98,97,96)
    13.6
    12.2
    24.7
    21.9
        Erythema Post-any vaccination (n=320,107,107,104)
    1.6
    4.7
    2.8
    1.0
        Erythema Post-vaccination 1 (n=320,107,107,104)
    0
    0.9
    0.9
    0
        Erythema Post-vaccination 2 (n=319,104,107,104)
    0
    0
    0
    0
        Erythema Post-vaccination 3 (n=312,103,105,103)
    0
    1.0
    1.0
    0
        Erythema Post-vaccination 4 (n=300,101,100,100)
    1.0
    3.0
    1.0
    1.0
        Erythema Post-vaccination 5 (n=295,98,97,96)
    0.7
    1.0
    1.0
    0
        Swelling Post-any vaccination (n=320,107,107,104)
    1.6
    0.9
    0.9
    0
        Swelling Post-vaccination 1 (n=320,107,107,104)
    0.3
    0
    0
    0
        Swelling Post-vaccination 2 (n=319,104,106,104)
    0
    0
    0
    0
        Swelling Post-vaccination 3 (n=312,103,105,103)
    0.6
    0
    1.0
    0
        Swelling Post-vaccination 4 (n=300,101,100,100)
    0.7
    0
    0
    0
        Swelling Post-vaccination 5 (n=295,98,97,96)
    0.3
    1.0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Systemic Reactions

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    End point title
    Percentage of Subjects With Solicited Systemic Reactions
    End point description
    SR was an expected AR observed and reported under conditions (nature and onset) prelisted (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, headache, malaise and myalgia. Analysis was performed on the SafAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Up to 7 days after any and each vaccination (Vaccinations 1, 2, 3, 4 and 5)
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    320
    107
    107
    104
    Units: percentage of subjects
    number (not applicable)
        Fever Post-any vaccination (n=319,107,107,104)
    1.3
    1.9
    3.7
    1.0
        Fever Post-vaccination 1 (n=319,107,107,104)
    0
    0
    0.9
    0
        Fever Post-vaccination 2 (n=318,104,107,104)
    0
    0
    0.9
    0
        Fever Post-vaccination 3 (n=311,103,105,103)
    0.6
    1.0
    1.0
    0
        Fever Post-vaccination 4 (n=300,101,100,100)
    0
    0
    2.0
    1.0
        Fever Post-vaccination 5 (n=295,97,97,95)
    0.7
    1.0
    1.0
    0
        Headache Post-any vaccination (n=320,107,107,104)
    33.4
    32.7
    35.5
    34.6
        Headache Post-vaccination 1 (n=320,107,107,104)
    13.8
    18.7
    16.8
    16.3
        Headache Post-vaccination 2 (n=319,104,107,104)
    8.2
    9.6
    9.3
    5.8
        Headache Post-vaccination 3 (n=312,103,105,103)
    12.2
    12.6
    15.2
    13.6
        Headache Post-vaccination 4 (n=300,101,100,100)
    9.7
    9.9
    5.0
    14.0
        Headache Post-vaccination 5 (n=295,98,97,96)
    7.8
    7.1
    5.2
    13.5
        Malaise Post-any vaccination (n=320,107,107,104)
    10.6
    12.1
    13.1
    12.5
        Malaise Post-vaccination 1 (n=320,107,107,104)
    6.3
    6.5
    4.7
    3.8
        Malaise Post-vaccination 2 (n=319,104,107,104)
    2.2
    2.9
    4.7
    1.0
        Malaise Post-vaccination 3 (n=312,103,105,103)
    2.9
    3.9
    3.8
    5.8
        Malaise Post-vaccination 4 (n=300,101,100,100)
    2.7
    1.0
    1.0
    6.0
        Malaise Post-vaccination 5 (n=295,98,97,96)
    2.0
    0
    2.1
    2.1
        Myalgia Post-any vaccination (n=320,107,107,104)
    36.9
    34.6
    35.5
    31.7
        Myalgia Post-vaccination 1 (n=320,107,107,104)
    18.1
    15.9
    21.5
    19.2
        Myalgia Post-vaccination 2 (n=319,104,107,104)
    15.7
    10.6
    8.4
    13.5
        Myalgia Post-vaccination 3 (n=312,103,105,103)
    16.0
    12.6
    14.3
    11.7
        Myalgia Post-vaccination 4 (n=300,101,100,100)
    11.7
    7.9
    14.0
    17.0
        Myalgia Post-vaccination 5 (n=295,98,97,96)
    8.8
    8.2
    10.3
    11.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Unsolicited Adverse Events

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    End point title
    Percentage of Subjects With Unsolicited Adverse Events
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study vaccine and does not necessary had to have a causal relationship with treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRB in terms of diagnosis and/or onset post-vaccination. Analysis was performed on the SafAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after any and each vaccination (Vaccinations 1, 2, 3, 4 and 5)
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    320
    107
    107
    104
    Units: percentage of subjects
    number (not applicable)
        Post-any vaccination (n=320, 107, 107, 104)
    45.3
    43.0
    36.4
    40.4
        Post-vaccination 1 (n=320, 107, 107, 104)
    14.7
    20.6
    11.2
    9.6
        Post-vaccination 2 (n=319, 104, 107, 104)
    8.5
    4.8
    10.3
    4.8
        Post-vaccination 3 (n=313, 103, 105, 103)
    9.9
    8.7
    6.7
    7.8
        Post-vaccination 4 (n=303, 101, 101, 101)
    12.2
    8.9
    13.9
    10.9
        Post-vaccination 5 (n=296, 98, 97, 96)
    20.3
    11.2
    12.4
    21.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

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    End point title
    Percentage of Subjects With Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study vaccine and does not necessary had to have a causal relationship with treatment. An SAE was any untoward medical occurrence that at any dose resulted in death, life-threatening, initial or prolonged inpatient hospitalisation, 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. Analysis was performed on the SafAS.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 0) up to 6 months after last vaccination (i.e., up to Month 7)
    End point values
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Number of subjects analysed
    320
    107
    107
    104
    Units: percentage of subjects
    number (not applicable)
        SAE
    1.3
    3.7
    0
    2.9
        SAE related to study vaccine
    0
    1.9
    0
    0
        AESI
    0
    0
    0
    0
        AESI related to study vaccine
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Unsolicited AE data collected from Day 0 (post-vaccination 1) up to 28 days post any vaccination. SR data collected within 7 days post any vaccination. SAE were collected from Baseline (Day 0) up to 6 months after last vaccination (i.e., up to Month 7)
    Adverse event reporting additional description
    Analysis performed on SafAS. SR: an expected AR observed and reported under conditions (nature and onset) prelisted (i.e., solicited) in protocol and CRB and considered as related to vaccination. An unsolicited AE: an observed AE that did not fulfill conditions prelisted (i.e., solicited) in CRB in terms of diagnosis and/or onset post-vaccination.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Group 1 VRVg-2+HRIG
    Reporting group description
    Subjects received 0.5 millilitres (mL) intramuscular (IM) injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 2 Verorab+HRIG
    Reporting group description
    Subjects received 0.5 mL IM injection of Verorab on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 3 Imovax Rabies+HRIG
    Reporting group description
    Subjects received 1 mL IM injection of Imovax Rabies on Days 0, 3, 7, 14 and 28 along with HRIG injection at Day 0.

    Reporting group title
    Group 4 VRVg-2
    Reporting group description
    Subjects received 0.5 mL IM injection of VRVg-2 formulation on Days 0, 3, 7, 14 and 28.

    Serious adverse events
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 320 (1.25%)
    4 / 107 (3.74%)
    0 / 107 (0.00%)
    3 / 104 (2.88%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ligament Injury
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma Benign
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cervical Radiculopathy
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General Physical Health Deterioration
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Eating Disorder
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1 VRVg-2+HRIG Group 2 Verorab+HRIG Group 3 Imovax Rabies+HRIG Group 4 VRVg-2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    204 / 320 (63.75%)
    59 / 107 (55.14%)
    66 / 107 (61.68%)
    67 / 104 (64.42%)
    Nervous system disorders
    Headache
    Additional description: Headache events that occurred after 7 days post-vaccination were considered as unsolicited AE.
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    113 / 320 (35.31%)
    35 / 107 (32.71%)
    41 / 107 (38.32%)
    40 / 104 (38.46%)
         occurrences all number
    173
    62
    59
    73
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 320 (0.94%)
    6 / 107 (5.61%)
    1 / 107 (0.93%)
    1 / 104 (0.96%)
         occurrences all number
    3
    6
    1
    1
    Injection Site Pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    142 / 320 (44.38%)
    37 / 107 (34.58%)
    49 / 107 (45.79%)
    44 / 104 (42.31%)
         occurrences all number
    337
    74
    118
    115
    Malaise
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    34 / 320 (10.63%)
    13 / 107 (12.15%)
    14 / 107 (13.08%)
    13 / 104 (12.50%)
         occurrences all number
    50
    15
    17
    19
    Musculoskeletal and connective tissue disorders
    Myalgia
    Additional description: Myalgia events that occurred after 7 days post-vaccination were considered as unsolicited AE.
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    118 / 320 (36.88%)
    37 / 107 (34.58%)
    38 / 107 (35.51%)
    34 / 104 (32.69%)
         occurrences all number
    221
    58
    71
    75

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2019
    Following changes were made: Any study conducted in healthy volunteers could be put on hold by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) due to any SAE. Consequently, the SAE “multiple crises of abnormal movements in both arms and legs” led to the temporary halt of the study from 06 September 2019 to 10 September 2019. That SAE was considered as related to the vaccine by the Investigator and unrelated by the Sponsor. As per the recommendations of the ANSM, all subjects who were participating in the study had to be informed about the related SAEs in the informed consent form (ICF) or through an addendum to the ICF. The subjects were also informed about the temporary halt and the increase in sample size. The Investigators were notified and the Investigator’s Brochure was updated with this information. Due to the temporary halt, the Sponsor increased the sample size to replace subjects who were to be excluded from the PPAS due to inability to perform the vaccination within allowed time windows for the first 4 dose and adjusted the attrition rate of the study from 15% to 20% to ensure the adequate power to fulfill the primary and key secondary objectives.
    27 Apr 2020
    Following changes were made: Due to coronavirus disease 2019 (COVID 19) pandemic, enrollment of subjects was paused on 12 March 2020 due to increased number of cases in France. Ongoing vaccinations were stopped on 16 March 2020 due to the confinement established in the country and consequent impossibility to follow study visits within requested time window. As the study vaccine was administered in healthy individuals in simulated schedule, there was no safety issue in case of incomplete vaccination. Different measures were taken according to the stage of vaccination:• For 3 subjects who had finished their vaccination scheme, follow-up was monitored by phone. The 2 due visits (Visit [V] 06 [Day 42] and V07 [Day 56]) were replaced by phone call to monitor safety (no blood sample was taken). • For 29 subjects who had not finished their vaccination scheme, they were withdrawn from the study due to protocol deviation (ie, inability to attend vaccination visit within allowed time windows), but they continued to be followed for safety. The follow-up of these subjects was monitored by phone. •The 6-month follow-up was done by phone as planned in protocol. These measures were taken by Sponsor to ensure the well-being of subjects (ie, to limit exposure to COVID-19) and were implemented without IRB/IEC approval, as per national and international guidance’s. However, IRB/IEC and health authorities were informed promptly about measures reported in the amendment. The enrollment resumed as soon as subjects’ safety was ensured, and national health authorities and Ethic Committee approved. The Sponsor increased sample size of the study to replace subjects who were to be excluded from PPAS due to inability to attend vaccination visit within allowed time windows for the first 4 dose or inability to take blood samples during the confinement and to ensure adequate statistical power to fulfill the primary and key secondary objectives and allowed further replacement of withdrawn subjects.
    09 Mar 2021
    Following changes were made: Most of the subjects were expected to have reached RVNA titers >= 0.5 IU/mL after 4 or 5 doses of any rabies vaccine. If this did not occurred (i.e., RVNA titers < 0.5 IU/mL at Day 42) or occurred lately (i.e., RVNA titers < 0.5 IU/mL up to Day 28 and RVNA titers >= 0.5 IU/mL from Day 42), the absence or delayed immune response to the rabies vaccination might suggested an undiagnosed comorbidity that causes immunosuppression. Therefore, any subject in this situation was to be offered additional blood tests to evaluate a potential immunosuppression, the assessment of the RVNA titer in case of non-response to the rabies vaccine before and after a vaccination with a licensed vaccine in the country might be offered, as applicable and according to the pre-exposure prophylaxis recommendations in national guidelines.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Sep 2019
    The SAE “multiple crises of abnormal movements in both arms and legs” led to the temporary halt of the study from 06 September 2019 to 10 September 2019 as precautionary measurement. That SAE was considered as related to the vaccine by the Investigator and unrelated by the Sponsor. As per the recommendations of the ANSM, all subjects who were participating in the study had to be informed about the related SAEs in the ICF or through an addendum to the ICF. The subjects were also informed about the temporary halt and the increase in sample size. The Investigators were notified and the Investigator’s Brochure was updated with this information.
    11 Sep 2019
    12 Mar 2020
    Due to the coronavirus disease 2019 (COVID 19) pandemic, the enrollment of subjects was paused on 12 March 2020 due to the increased number of cases in France. The ongoing vaccinations were stopped on 16 March 2020 due to the confinement established in the country and the consequent impossibility to follow study visits within requested time window. As the study vaccine was administered in healthy individuals in a simulated schedule, there was no safety issue in case of incomplete vaccination.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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