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    Clinical Trial Results:
    Verorab® immunogenicity and safety after a one week, 4-site, intradermal (ID) post-exposure prophylaxis regimen (4-4-4-0-0) followed by a one visit, 4-site, ID booster at five years.

    Summary
    EudraCT number
    		 2018-004707-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    14 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2019
    First version publication date
    24 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAB40
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01622062
    WHO universal trial number (UTN)
    		 U1111-1117-7193
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that post-exposure prophylaxis (PEP) using the "one-week, 4-site" (4-4-4-0-0) intradermal (ID) vaccination regimen is non-inferior to PEP using the updated Thai Red Cross (TRC) (2-2-2-0-2) ID vaccination regimen in terms of seroconversion rate at Day 14 (Group 1 versus Group 3, and Group 2 versus Group 3).
    Protection of trial subjects
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 2012
    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: 600
    Worldwide total number of subjects
    600
    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)
    17
    Children (2-11 years)
    237
    Adolescents (12-17 years)
    65
    Adults (18-64 years)
    281
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at Philippines from 29 June 2012 to 14 November 2018.

    Pre-assignment
    Screening details
    		 A total of 600 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomised in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Purified Vero cell Rabies Vaccine
    Investigational medicinal product code
    Other name
    VERORAB®
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Subjects received 0.1 milliliter (mL) of vaccine administered intradermally in 4 site 'one week' (4-4-4-0-0) regimen at both deltoids and both anterior thighs.

    Arm title
    		 Group 2
    Arm description
    		 Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Purified Vero cell Rabies Vaccine
    Investigational medicinal product code
    Other name
    VERORAB®
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Subjects received 0.1 mL of vaccine administered intradermally in 4 site 'one week' (4-4-4-0-0) regimen at both deltoids and both anterior thighs.

    Investigational medicinal product name
    Purified Equine Rabies Immunoglobulin
    Investigational medicinal product code
    Other name
    FAVIRAB®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    The dose was calculated according to the weight of the subject. The recommended dose was same for children and adults: 40 international units per kilogram (IU/kg) of body weight.

    Arm title
    		 Group 3
    Arm description
    		 Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Purified Vero cell Rabies Vaccine
    Investigational medicinal product code
    Other name
    VERORAB®
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Subjects received 0.1 mL of vaccine administered intradermally in 2-site TRC (2-2-2-0-2) regimen at both deltoids.

    Investigational medicinal product name
    Purified Equine Rabies Immunoglobulin
    Investigational medicinal product code
    Other name
    FAVIRAB®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    The dose was calculated according to the weight of the subject. The recommended dose was same for children and adults: 40 IU/kg of body weight.

    Number of subjects in period 1
    		Group 1 Group 2 Group 3
    Started
    200
    201
    199
    Completed
    133
    139
    134
    Not completed
    67
    62
    65
         Adverse event, serious fatal
    -
    2
    -
         Consent withdrawn by subject
    7
    3
    3
         Lost to follow-up
    7
    6
    9
         Protocol deviation
    53
    51
    53

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group values
    		 Group 1 Group 2 Group 3 Total
    Number of subjects
    		 200 201 199 600
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 17.5 ( 14.0 ) 19.2 ( 13.8 ) 19.5 ( 14.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 102 95 96 293
        Male
    		 98 106 103 307

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Primary: Percentage of Subjects With Seroconversion on Day 14

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    End point title
    		 Percentage of Subjects With Seroconversion on Day 14
    End point description
    Seroconversion was defined as a rabies virus-neutralizing antibody titer >= 0.5 IU/mL. Analysis was performed on Per Protocol Analysis Set (PPAS) which included all subjects who received at least one dose of the study vaccine during the Primary Vaccination Phase, and had a post-vaccination blood sample at Day 14 or Day 90. Subjects with following protocol deviations were excluded from PPAS: subject did not meet all protocol-specified inclusion criteria or met at least one of the protocol specified exclusion criteria, subject did not complete the vaccination schedule at visits (V) 01, V02, and V03, subject received a vaccine other than the one that he / she was randomised to receive, subjects received a protocol-restricted therapy / medication / vaccine between V01 and V04, subjects with rabies virus-neutralizing antibodies (≥ 0.2 IU/mL or missing value) at baseline; sample collection not done at Day 14 or sample at V04 did not produced a valid test result.
    End point type
    Primary
    End point timeframe
    Day 14 (post vaccination)
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    175
    162
    172
    Units: Percentage of subjects
        number (not applicable)
    100.0
    99.4
    98.8
    Statistical analysis title
    		 Group 1 versus (vs) Group 3
    Comparison groups
    Group 1 v Group 3
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Percentage difference
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.145
         upper limit
    		 4.14
    Notes
    [1] - Non-inferiority was concluded if the limit of the two-sided 95% Confidence Interval (CI) of the difference is above delta.
    Statistical analysis title
    		 Group 2 vs Group 3
    Comparison groups
    Group 2 v Group 3
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Percentage difference
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.375
         upper limit
    		 3.566
    Notes
    [2] - Non-inferiority was concluded if the limit of the two-sided 95% CI of the difference is above delta.

    Secondary: Percentage of Subjects With Seroconversion Before and After Primary Vaccination

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    End point title
    		 Percentage of Subjects With Seroconversion Before and After Primary Vaccination
    End point description
    Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on PPAS. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 14, Day 90
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    175
    162
    172
    Units: Percentage of subjects
    number (not applicable)
        Day 0 (n=175, 162, 172)
    0.0
    0.0
    0.0
        Day 14 (n=175, 162, 172)
    100.0
    99.4
    98.8
        Day 90 (n=166, 157, 165)
    98.2
    94.9
    98.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seroconversion After Primary Vaccination (Antibody Persistence)

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    End point title
    		 Percentage of Subjects With Seroconversion After Primary Vaccination (Antibody Persistence)
    End point description
    Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on Full analysis set which included all randomised subjects who received at least one dose of the study vaccine during the Primary Vaccination Phase, and had a post-vaccination blood sample at Day 14 or Day 90. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Year 1 to Year 4
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    198
    Units: Percentage of subjects
    number (not applicable)
        Year 1 (n = 169, 182, 178)
    97.6
    89.0
    79.8
        Year 2 (n= 150, 174, 153)
    98.0
    88.5
    79.1
        Year 3 (n= 139, 151, 142)
    95.7
    89.4
    71.8
        Year 4 (n= 130, 141, 130)
    96.2
    80.1
    60.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seroconversion After Booster Vaccination

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    End point title
    		 Percentage of Subjects With Seroconversion After Booster Vaccination
    End point description
    Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on booster full analysis set which included randomised subjects who received the booster vaccine at V13, and had a post-vaccination blood sample at Day 11 post-V13.
    End point type
    Secondary
    End point timeframe
    Year 5 and Year 5 + 11 days
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    128
    136
    130
    Units: Percentage of subjects
    number (not applicable)
        Year 5 (n=126, 132, 128)
    97.6
    84.8
    64.1
        Year 5 + 11 days (n=124, 135, 130)
    100.0
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) Ratio Against Rabies Virus Antibodies Before and After Primary Vaccination

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    End point title
    		 Geometric Mean Titers (GMTs) Ratio Against Rabies Virus Antibodies Before and After Primary Vaccination
    End point description
    GMTs of rabies virus-neutralizing antibodies were assessed by the rapid fluorescent focus inhibition test. Analysis was performed on PPAS. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 14, Day 90
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    175
    162
    172
    Units: titer ratio
    geometric mean (confidence interval 95%)
        Day 14/Day 0 (n=175, 162, 172)
    108 (95.0 to 123)
    97.7 (83.1 to 115)
    58.9 (50.8 to 68.4)
        Day 90/Day 0 (n=166, 157, 165)
    31.5 (27.8 to 35.8)
    17.6 (15.6 to 19.9)
    25.3 (22.8 to 28.1)
    No statistical analyses for this end point

    Secondary: GMT Ratio Against Rabies Virus Antibodies After Primary Vaccination (Antibody Persistence)

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    End point title
    		 GMT Ratio Against Rabies Virus Antibodies After Primary Vaccination (Antibody Persistence)
    End point description
    GMT ratio of rabies virus-neutralizing antibodies was assessed by the rapid fluorescent focus inhibition test. Analysis was performed on Full analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Year 1, 2, 3, 4 and Day 90
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    198
    Units: titer ratio
    geometric mean (confidence interval 95%)
        Year 1/Day 90 (n=168, 180, 176)
    0.894 (0.818 to 0.978)
    0.750 (0.695 to 0.810)
    0.362 (0.331 to 0.397)
        Year 2/Day 90 (n=148, 172, 152)
    0.941 (0.859 to 1.03)
    0.818 (0.738 to 0.905)
    0.383 (0.342 to 0.429)
        Year 3/Day 90 (n=138, 149, 141)
    0.773 (0.694 to 0.860)
    0.733 (0.653 to 0.823)
    0.336 (0.298 to 0.379)
        Year 4/Day 90 (n=129, 139, 129)
    0.725 (0.647 to 0.812)
    0.527 (0.466 to 0.596)
    0.248 (0.213 to 0.289)
    No statistical analyses for this end point

    Secondary: GMTs Against Rabies Virus Antibodies After Booster Vaccination

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    End point title
    		 GMTs Against Rabies Virus Antibodies After Booster Vaccination
    End point description
    GMTs of rabies virus-neutralizing antibodies was assessed by the rapid fluorescent focus inhibition test. Analysis was performed on booster full analysis set.
    End point type
    Secondary
    End point timeframe
    Year 5, Year 5 + 11 days
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    128
    136
    130
    Units: titer (1/dilution)
    geometric mean (confidence interval 95%)
        Year 5 (n=126, 132, 128)
    2.22 (1.90 to 2.60)
    1.05 (0.918 to 1.21)
    0.762 (0.649 to 0.896)
        Year 5 + 11 days (n=124, 135, 130)
    193 (170 to 218)
    137 (120 to 157)
    138 (120 to 160)
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Immediate Unsolicited Adverse Events Following Primary and Booster Vaccination

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    End point title
    		 Number of Subjects Reporting Immediate Unsolicited Adverse Events Following Primary and Booster Vaccination
    End point description
    An unsolicited Adverse Event (AE) is an observed AE that does not fulfill the conditions prelisted in the case report form in terms of symptom and / or onset post-vaccination. Analysis was performed on safety analysis set which included subjects who received a dose of study or control vaccine. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after vaccination
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        Immediate AE: Primary Phase (n=199,201,199)
    0
    2
    5
        Immediate AE: Booster Phase (n=129,137, 130)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Injection Site Reactions Following Primary and Booster Vaccination

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    End point title
    		 Number of Subjects Reporting Solicited Injection Site Reactions Following Primary and Booster Vaccination
    End point description
    Solicited Injection (Inj.) site reactions were tenderness (for subjects aged <= 23 months), pain (for subjects aged >= 2 years), erythema and swelling. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 7 days after vaccination
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        Inj. site tenderness/pain: Primary (n=199,201,199)
    109
    140
    126
        Inj. site erythema: Primary (n=199,201,199)
    85
    78
    56
        Inj. site swelling: Primary (n=199, 201,199)
    33
    37
    33
        Inj. site tenderness/pain: Booster (n=129,137,130)
    64
    72
    67
        Inj. site erythema: Booster (n=129, 137, 130)
    53
    62
    53
        Inj. site swelling: Booster (n=129, 137, 130)
    34
    40
    33
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Systemic Reactions Following Primary and Booster Vaccination

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    End point title
    		 Number of Subjects Reporting Solicited Systemic Reactions Following Primary and Booster Vaccination
    End point description
    Solicited systemic reactions are Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability for subjects aged ≤ 23 months and Fever (Temperature), Headache, Malaise, and Myalgia for subjects aged ≥ 2 years. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 7 days after injection 1, 2 and 3, and 7 days after subsequent injections
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        Fever: Primary (n=199, 201, 199)
    19
    14
    15
        Vomiting: Primary (n= 11, 3, 3)
    2
    0
    0
        Crying Abnormal: Primary (n= 11, 3, 3)
    3
    0
    1
        Drowsiness: Primary (n= 11, 3, 3)
    2
    0
    1
        Appetite loss: Primary (n= 11, 3, 3)
    5
    0
    0
        Irritability: Primary (n= 11, 3, 3)
    5
    0
    1
        Headache: Primary (n= 188, 198, 196)
    76
    88
    89
        Malaise: Primary (n=188,198,196)
    78
    83
    103
        Myalgia: Primary (n=188, 198, 196)
    66
    83
    92
        Fever: Booster (n= 129, 137, 130)
    4
    3
    1
        Headache: Booster (n= 129,137, 130)
    37
    39
    31
        Malaise: Booster (n=129, 137, 130)
    32
    34
    30
        Myalgia: Booster (n=129, 137, 130)
    28
    29
    32
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited Injection Site Reactions (Reac.)

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    End point title
    		 Number of Subjects Reporting Unsolicited Injection Site Reactions (Reac.)
    End point description
    Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Within 21 days after vaccination
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        Unsolicited inj. site reac.:Primary(n=199,201,199)
    2
    6
    2
        Unsolicited inj. site reac.:Booster(n=129,137,130)
    16
    20
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited Systemic Adverse Events

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    End point title
    		 Number of Subjects Reporting Unsolicited Systemic Adverse Events
    End point description
    Unsolicited systemic adverse events were defined as any unfavorable and unintended sign, symptom or disease not meeting the definition of solicited event and not occurring at the injection site of the investigational medicinal product, whether or not considered related to the investigational medicinal product. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Between the first and the second vaccination, between the second and the third vaccination, between the third and the fourth vaccination (for Group 3), and up to 28 days after the remaining vaccination
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        Unsolicited systemic AE: Primary (n=199, 201,199)
    102
    89
    110
        Unsolicited systemic AE: Booster (n=129, 137,130)
    20
    13
    11
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAE)

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    End point title
    		 Number of Subjects Reporting Serious Adverse Events (SAE)
    End point description
    An SAE is any untoward medical occurrence that at any dose (including overdose): results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect, is an important medical event, whether or not considered related to the investigational medical product. Only related or fatal serious adverse events were reported during the period ranging from Day 28 post primary vaccination to the booster vaccination at Year 5. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after primary vaccination and booster vaccination, during full study duration
    End point values
    		 Group 1 Group 2 Group 3
    Number of subjects analysed
    199
    201
    199
    Units: subjects
    number (not applicable)
        SAE: Primary (n=199, 201, 199)
    5
    3
    9
        SAE: Booster (n= 129, 137, 130)
    0
    0
    0
        SAE: Full study (n=199, 201, 199)
    5
    5
    9
        Related SAE: Full study (n=199, 201, 199)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited reaction (SR) within 7 days after vaccination, unsolicited injection site reaction within 21 days after vaccination, unsolicited AEs between vaccinations up to fourth vaccination, then up to 28 days after remaining vaccinations,SAEs during study
    Adverse event reporting additional description
    Safety Analysis Set. SR: AE prelisted(PL) in electronic case report form (eCRF),considered related to vaccination(adverse drug reaction). Unsolicited AE:observed AE not fulfilling conditions PL in eCRF in terms of symptom &/or onset post-vaccination. Only related/fatal SAEs reported from D28 post primary vaccination to booster vaccination at Year 5
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects with WHO Category II exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 3
    Reporting group description
    		 Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later.

    Serious adverse events
    		 Group 1 Group 3 Group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 199 (2.51%)
    9 / 199 (4.52%)
    5 / 201 (2.49%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Electrocution
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type I Hypersensitivity
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 199 (2.01%)
    5 / 199 (2.51%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Rash
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 199 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1 Group 3 Group 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    183 / 199 (91.96%)
    184 / 199 (92.46%)
    188 / 201 (93.53%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    95 / 199 (47.74%)
    105 / 199 (52.76%)
    103 / 201 (51.24%)
         occurrences all number
    166
    188
    184
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    13 / 199 (6.53%)
    15 / 199 (7.54%)
    9 / 201 (4.48%)
         occurrences all number
    14
    16
    9
    Injection Site Erythema
         subjects affected / exposed
    109 / 199 (54.77%)
    87 / 199 (43.72%)
    101 / 201 (50.25%)
         occurrences all number
    705
    386
    668
    Injection Site Pain
         subjects affected / exposed
    134 / 199 (67.34%)
    145 / 199 (72.86%)
    161 / 201 (80.10%)
         occurrences all number
    799
    625
    890
    Injection Site Pruritus
         subjects affected / exposed
    13 / 199 (6.53%)
    11 / 199 (5.53%)
    21 / 201 (10.45%)
         occurrences all number
    28
    22
    45
    Injection Site Swelling
         subjects affected / exposed
    58 / 199 (29.15%)
    63 / 199 (31.66%)
    71 / 201 (35.32%)
         occurrences all number
    213
    192
    264
    Malaise
         subjects affected / exposed
    97 / 199 (48.74%)
    115 / 199 (57.79%)
    101 / 201 (50.25%)
         occurrences all number
    149
    210
    169
    Pyrexia
         subjects affected / exposed
    29 / 199 (14.57%)
    27 / 199 (13.57%)
    21 / 201 (10.45%)
         occurrences all number
    32
    29
    26
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 199 (1.51%)
    27 / 199 (13.57%)
    20 / 201 (9.95%)
         occurrences all number
    3
    29
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 199 (10.05%)
    15 / 199 (7.54%)
    10 / 201 (4.98%)
         occurrences all number
    21
    15
    10
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    75 / 199 (37.69%)
    105 / 199 (52.76%)
    103 / 201 (51.24%)
         occurrences all number
    129
    191
    164
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    36 / 199 (18.09%)
    31 / 199 (15.58%)
    26 / 201 (12.94%)
         occurrences all number
    37
    34
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2012
    Following amendment changes were made: The wording in the primary objective, primary endpoint and secondary endpoints and other parts of the protocol was modified; mainly “seroprotection” was changed to “seroconversion”; women of childbearing potential and sexually active were required to use a medically acceptable and effective method of birth control during 1 month following booster vaccination. The wording was updated to reflect this; Favirab® was deleted from the primary study objective. Also it was clarified that Favirab® was a commercial product and not an investigational product; sentences were added to the primary objective to define the comparison between groups at Day 14.
    01 Jul 2013
    Following amendment changes were made: Originally, the countries planned to participate in the study were India, Pakistan and The Philippines. Due to organizational difficulties, India and Pakistan did not participate in the study. Therefore, all parts of the protocol related to the involvement of these 2 countries were deleted from the protocol; in order to avoid the drop out of the subjects in-between yearly visits, phone calls were given on a quarterly basis to the subjects to remind them to come back to the site for the next visits. The wording in the protocol was added to reflect this; clarification on the process to follow if re-exposure of subjects occurred during the study; clarification on collection of all SAEs during the study.
    10 Apr 2014
    Following amendment changes were made: Originally, two interim analyses (Day 90, Year 1) and corresponding interim reports were planned. The testing of the Day 90 blood samples at the laboratory was unexpectedly delayed and all Year 1 follow-up blood samples would be available before the Day 90 samples could be tested. Therefore it was decided by the Sponsor to test all Day 90 and Year 1 blood samples at the same time and delete the D90 interim analysis and interim report. The wording throughout the protocol was adapted accordingly; the timelines for different milestones of the study (eg, first visit of first patient) were updated.

    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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