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    Clinical Trial Results:
    Immunogenicity and Safety of the Purified Vero Rabies Vaccine- Serum Free (VRVg) in Comparison with the Human Diploid Cell Vaccine, IMOVAX® Rabies in a Pre-exposure Prophylaxis Regimen in Healthy Children and Adolescents Aged 2 to 17 Years

    Summary
    EudraCT number
    2015-003203-30
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    14 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jan 2018
    First version publication date
    31 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VRV06
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01930357
    WHO universal trial number (UTN)
    U1111-1127-7340
    Other trial identifiers
    The Philippine Health Research Registry: PHRR130822-000107
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, F-69367
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 37 54 76, ada-maria.minutello@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 37 54 76, ada-maria.minutello@sanofipasteur.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2014
    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 (VRVg) is non-inferior to Imovax Rabies in terms of proportion of subjects achieving a rabies virus neutralizing antibody (RVNA) titer >=0.5 international units (IU)/mL at Day 42 (D42), i.e. 14 days after the last vaccination. • To describe if at least 99% of subjects achieve an RVNA titer >=0.5 IU/mL at D42 with a lower bound of the 95% confidence interval (CI) of at least 97%, in the VRVg group.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. 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 kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was available on site in case of any immediate allergic reactions.
    Background therapy
    Not applicable
    Evidence for comparator
    Human diploid cell vaccine (HDCV), licensed since 1975 and also marketed worldwide as Imovax® Rabies, was used as a reference vaccine.
    Actual start date of recruitment
    03 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Philippines: 342
    Worldwide total number of subjects
    342
    EEA total number of subjects
    0
    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)
    171
    Adolescents (12-17 years)
    171
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study subjects were enrolled in 2 main centers in the Philippines from 03 September 2013 to 16 October 2013.

    Pre-assignment
    Screening details
    A total of 342 subjects who met all of the inclusion and none of the exclusion criteria were randomized and vaccinated in this study.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    This was an observer-blind study. Subjects were blinded to which vaccine was administered. Only the person who prepared and administered the vaccine remained unblinded. To maintain the blind, the person who administered the vaccine was different from the person who assessed safety to avoid bias in safety collection. In the event of an emergency (i.e., serious adverse event) the code could be broken as explained in the code-breaking procedures by the Investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Purified Vero Rabies Vaccine - Serum Free (VRVg)
    Arm description
    Subjects received a total of 3 VRVg vaccine injections.
    Arm type
    Experimental

    Investigational medicinal product name
    VRVg
    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, intramuscular (alternating between the left and right deltoid for each injection, starting with the left deltoid for the first injection), 1 injection each on Day 0, 7, and 28 (for a total of 3 injections).

    Arm title
    Imovax Rabies
    Arm description
    Subjects received a total of 3 Imovax Rabies vaccine injections.
    Arm type
    Active comparator

    Investigational medicinal product name
    Human Diploid Cell Vaccine (Imovax Rabies)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 mL, intramuscular (alternating between the left and right deltoid for each injection, starting with the left deltoid for the first injection), 1 injection each on Day 0, 7, and 28 (for a total of 3 injections).

    Number of subjects in period 1
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies
    Started
    229
    113
    Completed
    224
    110
    Not completed
    5
    3
         Protocol deviation
             2
             2
         Adverse event, serious fatal
             -
             1
         Consent withdrawn by subject
             2
             -
         Adverse Event
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Purified Vero Rabies Vaccine - Serum Free (VRVg)
    Reporting group description
    Subjects received a total of 3 VRVg vaccine injections.

    Reporting group title
    Imovax Rabies
    Reporting group description
    Subjects received a total of 3 Imovax Rabies vaccine injections.

    Reporting group values
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies Total
    Number of subjects
    229 113 342
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    115 56 171
        Adolescents (12-17 years)
    114 57 171
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.0 ± 4.3 10.7 ± 4.5 -
    Gender categorical
    Units: Subjects
        Female
    110 63 173
        Male
    119 50 169

    End points

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    End points reporting groups
    Reporting group title
    Purified Vero Rabies Vaccine - Serum Free (VRVg)
    Reporting group description
    Subjects received a total of 3 VRVg vaccine injections.

    Reporting group title
    Imovax Rabies
    Reporting group description
    Subjects received a total of 3 Imovax Rabies vaccine injections.

    Primary: Percentage of Subjects Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer >=0.5 IU/mL at Day 42

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    End point title
    Percentage of Subjects Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer >=0.5 IU/mL at Day 42
    End point description
    Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers >=0.5 IU/mL. The analysis was performed using per-protocol analysis set (PPAS) which was a subset of full analysis set (FAS defined as: all randomized subjects who received at least one dose of the study vaccine).
    End point type
    Primary
    End point timeframe
    Day 42
    End point values
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies
    Number of subjects analysed
    221
    112
    Units: Percentage of subjects
    number (not applicable)
        Subjects with RVNA titers >=0.5 IU/mL
    100
    100
    Statistical analysis title
    Non-inferiority (VRVg-Imovax Rabies; Day 42)
    Statistical analysis description
    This was a non-inferiority analysis of the immunogenicity of VRVg vs Imovax Rabies, in terms of proportion of subjects with an RVNA titer >=0.5 IU/mL.
    Comparison groups
    Purified Vero Rabies Vaccine - Serum Free (VRVg) v Imovax Rabies
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Difference in proportions
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.71
         upper limit
    3.32
    Notes
    [1] - Non-inferiority was demonstrated if the lower limit of the 95% confidence interval of the difference VRVg - Imovax Rabies for proportion of subjects with RVNA titer >=0.5 IU/mL was >-5.0%.

    Secondary: Percentage of Subjects Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer >=0.5 IU/mL at Days 0, 42 and Month 6

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    End point title
    Percentage of Subjects Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer >=0.5 IU/mL at Days 0, 42 and Month 6
    End point description
    Antibody titers to each vaccine were assessed using the RFFIT method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers >=0.5 IU/mL. Analysis was performed using FAS which included randomized subjects who received at least one dose of the study vaccine. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 42 and Month 6
    End point values
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies
    Number of subjects analysed
    229
    113
    Units: Percentage of subjects
    number (not applicable)
        Day 0 (pre-vaccination) (n = 229, 113)
    1.7
    0.9
        Day 42 (n = 226, 113)
    100
    100
        Month 6 (n = 224, 110)
    91.1
    97.3
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of Rabies Virus Neutralizing Antibodies (RVNA)

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    End point title
    Geometric Mean Titers (GMTs) of Rabies Virus Neutralizing Antibodies (RVNA)
    End point description
    Antibody titers to each vaccine were assessed using the RFFIT method. Analysis was performed using FAS which included randomized subjects who received at least one dose of the study vaccine. Here 'n' signifies evaluable subjects in each specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination), Day 42 and Month 6
    End point values
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies
    Number of subjects analysed
    229
    113
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Day 0 (pre-vaccination) (n = 229, 113)
    0.105 (0.100 to 0.110)
    0.102 (0.098 to 0.107)
        Day 42 (n = 226, 113)
    14.3 (13.0 to 15.7)
    17.2 (15.2 to 19.4)
        Month 6 (n = 224, 110)
    1.22 (1.08 to 1.38)
    1.54 (1.34 to 1.77)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, and Swelling) and Systemic Reactions (Fever, Headache, Malaise, Myalgia)

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    End point title
    Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, and Swelling) and Systemic Reactions (Fever, Headache, Malaise, Myalgia)
    End point description
    Solicited reaction: AE prelisted in eCRF and considered to be related to vaccination. A solicited reaction: an adverse drug reaction (ADR) observed and reported under conditions (nature and time to onset) prelisted (i.e., solicited) in the eCRF. Unsolicited AE: an observed AE not fulfill the conditions prelisted in eCRF in terms of symptom and/or time to onset post-vaccination. Solicited injection site reactions: Pain, Erythema, swelling. Solicited systemic reactions: Fever, Headache, Malaise, and Myalgia. Grade 3 Solicited injection site reactions: Pain, significant; prevents daily activity; Erythema and Swelling >100 mm. Grade 3 Solicited systemic reactions: Fever >=39.0°C; headache, malaise, and myalgia, significant: prevents daily activity. Number of subjects with any of Grade 1, 2 or 3 solicited injection-site, systemic reactions and Grade 3 solicited injection-site and systemic reactions were reported. Safety analysis set: subjects who had received the study or control vaccine.
    End point type
    Secondary
    End point timeframe
    Within 7 days after any vaccine injection
    End point values
    Purified Vero Rabies Vaccine - Serum Free (VRVg) Imovax Rabies
    Number of subjects analysed
    229
    113
    Units: Percentage of subjects
    number (not applicable)
        Any Injection site pain: After-Any Injection
    27.9
    39.8
        Grade 3 Injection site pain: After-Any Injection
    0.4
    0.0
        Any Injection site erythema: After-Any Injection
    3.5
    6.2
        Grade 3 Injection site erythema: After-Any Injecti
    0.0
    0.0
        Any Injection site swelling: After-Any Injection
    3.5
    5.3
        Grade 3 Injection site swelling: After-Any Injecti
    0.0
    0.0
        Any Fever: After-Any Injection
    10.9
    7.1
        Grade 3 Fever: After-Any Injection
    1.7
    0.0
        Any Headache: After-Any Injection
    21.8
    28.3
        Grade 3 Headache: After-Any Injection
    0.0
    0.0
        Any Malaise: After-Any Injection
    15.7
    20.4
        Grade 3 Malaise: After-Any Injection
    0.0
    0.0
        Any Myalgia: After-Any Injection
    10.9
    13.3
        Grade 3 Myalgia: After-Any Injection
    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
    Adverse event (AE) data were collected from Day 0 (pre-vaccination) up to 7 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    VRVg
    Reporting group description
    Subjects received a total of 3 VRVg vaccine injections.

    Reporting group title
    Imovax® Rabies
    Reporting group description
    Subjects received a total of 3 Imovax Rabies vaccine injections.

    Serious adverse events
    VRVg Imovax® Rabies
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 229 (3.93%)
    4 / 113 (3.54%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Animal Bite
         subjects affected / exposed
    2 / 229 (0.87%)
    2 / 113 (1.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal Scratch
         subjects affected / exposed
    4 / 229 (1.75%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Complete
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion Incomplete
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis Tuberculous
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    VRVg Imovax® Rabies
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 229 (56.33%)
    70 / 113 (61.95%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    50 / 229 (21.83%)
    33 / 113 (29.20%)
         occurrences all number
    71
    41
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    8 / 229 (3.49%)
    7 / 113 (6.19%)
         occurrences all number
    11
    12
    Injection Site Pain
         subjects affected / exposed
    64 / 229 (27.95%)
    45 / 113 (39.82%)
         occurrences all number
    88
    73
    Injection Site Swelling
         subjects affected / exposed
    8 / 229 (3.49%)
    6 / 113 (5.31%)
         occurrences all number
    10
    10
    Malaise
         subjects affected / exposed
    36 / 229 (15.72%)
    23 / 113 (20.35%)
         occurrences all number
    41
    31
    Pyrexia
         subjects affected / exposed
    32 / 229 (13.97%)
    10 / 113 (8.85%)
         occurrences all number
    33
    11
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    25 / 229 (10.92%)
    15 / 113 (13.27%)
         occurrences all number
    27
    18
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    8 / 229 (3.49%)
    11 / 113 (9.73%)
         occurrences all number
    8
    13
    Upper Respiratory Tract Infection
         subjects affected / exposed
    39 / 229 (17.03%)
    15 / 113 (13.27%)
         occurrences all number
    42
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2013
    Clarification on the post-exposure management of subjects in case of rabies exposure.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    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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