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    Clinical Trial Results:
    A Phase III, Multicenter, Observer-blind, Safety and Immunogenicity Study of Rabies Vaccine and Japanese Encephalitis Vaccine Administered Concomitantly and/or Separately According to 1 of 2 Different Pre-exposure Prophylaxis Schedules to Healthy Adult Subjects

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-005173-23
    Trial protocol
    		 AT  
    Global end of trial date
    28 Oct 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Jun 2016
    First version publication date
    28 Dec 2014
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    re-QC of the study needed because of EudraCT system glitch and updates are required.

    Trial information

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    Trial identification
    Sponsor protocol code
    V49_23
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01662440
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics SRL
    Sponsor organisation address
    Via Fiorentina 1 , Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics SRL, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director , Novartis Vaccines and Diagnostics SRL, RegistryContactVaccinesUS@novartis.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 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of Rabies and JE vaccines given concomitantly or alone and according to either of 2 schedules for pre-exposure prophylaxis Immunogenicity: Primary: 1. To establish non-inferiority of the immune response of Rabies vaccine (administered concomitantly with JE vaccine) accelerated schedule as compared to Rabies vaccine administered alone following the conventional schedule. 2. To establish non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine), accelerated schedule as compared to JE vaccine administered alone following the conventional schedule.
    Protection of trial subjects
    This trial was performed with the ethical principles that have their origin in the Declaration of Helsinki that are consistent with GCP according to International Conference on Harmonization (ICH) guidelines, the applicable regulatory requirements(s) for the country in which the study is conducted, and applicable standard operating procedures (SOPs). Specifically, this trial was based on adequately performed laboratory and animal experimentation; it was conducted under a protocol reviewed and approved by the EC and by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the trial did not find the hazards to outweigh the potential benefits; each subject, or where applicable, each subject's legally acceptable representative(s) gave his or her written informed consent before any protocol-driven tests or evaluations were performed. A copy of the ICH GCP guidelines and the Declaration of Helsinki were included in the investigator's study file.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Aug 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 10 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 100
    Country: Number of subjects enrolled
    Germany: 479
    Country: Number of subjects enrolled
    Switzerland: 82
    Worldwide total number of subjects
    661
    EEA total number of subjects
    579
    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)
    654
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled from five sites in Germany, one site in Austria, and one site in Switzerland.

    Pre-assignment
    Screening details
    		 All subjects were included in the trial.

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    Subjects were not informed which injections were active and which were placebo. All vaccines were assembled away from the view of the subject and blinded site staff members. All injections were administered by a designated unblinded staff member who was not involved in the evaluation of safety or in immunogenicity analyses. All other site personnel remained blinded to study vaccine group. Laboratory personnel determining antibody titers were not aware of vaccine group assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R/JE – Conv
    Arm description
    		 Subjects received Rabies (R) and Japanese Encephalitis (JE) vaccines, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and JE vaccination on day 1 and 29, and placebo on day 8 in the left arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rabies, whole virus vaccine (inactivated, Germany)
    Investigational medicinal product code
    SUB25746
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received three injections (days 1, 8, and 29) of 1 mL.

    Investigational medicinal product name
    Japanese encephalitis vaccine (inactivated, adsorbed)
    Investigational medicinal product code
    SUB30399
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received two injections (days 1 and 29) of 0.5 mL.

    Arm title
    		 R/JE – Acc
    Arm description
    		 Subjects received Rabies and JE vaccines, accelerated schedule, ie, Rabies vaccination on days 1, 4, and 8, and placebo on day 29 in the right arm or leg; and JE vaccination on days 1 and 8, and placebo on day 29 in the left arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rabies, whole virus vaccine (inactivated, Germany)
    Investigational medicinal product code
    SUB25746
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received three injections (days 1, 4, and 8) of 1 mL containing ≥ 2.5 IU of antigen.

    Investigational medicinal product name
    Japanese encephalitis vaccine (inactivated, adsorbed)
    Investigational medicinal product code
    SUB30399
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received two injections (days 1 and 8) of 0.5 mL containing 6 μg of antigen.

    Arm title
    		 R – Conv
    Arm description
    		 Subjects received Rabies vaccine, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and placebo on days 1, 8 and 29 in the left arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rabies, whole virus vaccine (inactivated, Germany)
    Investigational medicinal product code
    SUB25746
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received three injections (days 1, 8, and 29) of 1 mL.

    Arm title
    		 JE – Conv
    Arm description
    		 Subjects received JE vaccine, conventional schedule, ie, placebo on days 1, 4, 8 and 29 in the right arm or leg; and JE vaccination on days 1 and 29 and placebo injection on day 8 in the left arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Japanese encephalitis vaccine (inactivated, adsorbed)
    Investigational medicinal product code
    SUB30399
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received two injections (days 1 and 29) of 0.5 mL.

    Number of subjects in period 1
    		R/JE – Conv R/JE – Acc R – Conv JE – Conv
    Started
    167
    217
    221
    56
    Completed
    158
    211
    215
    52
    Not completed
    9
    6
    6
    4
         Consent withdrawn by subject
    5
    2
    2
    2
         Adverse event, non-fatal
    1
    -
    -
    1
         Subject moved to another country
    -
    1
    -
    -
         Death
    -
    1
    -
    -
         Lost to follow-up
    2
    2
    4
    1
         Protocol deviation
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R/JE – Conv
    Reporting group description
    		 Subjects received Rabies (R) and Japanese Encephalitis (JE) vaccines, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and JE vaccination on day 1 and 29, and placebo on day 8 in the left arm.

    Reporting group title
    R/JE – Acc
    Reporting group description
    		 Subjects received Rabies and JE vaccines, accelerated schedule, ie, Rabies vaccination on days 1, 4, and 8, and placebo on day 29 in the right arm or leg; and JE vaccination on days 1 and 8, and placebo on day 29 in the left arm.

    Reporting group title
    R – Conv
    Reporting group description
    		 Subjects received Rabies vaccine, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and placebo on days 1, 8 and 29 in the left arm.

    Reporting group title
    JE – Conv
    Reporting group description
    		 Subjects received JE vaccine, conventional schedule, ie, placebo on days 1, 4, 8 and 29 in the right arm or leg; and JE vaccination on days 1 and 29 and placebo injection on day 8 in the left arm.

    Reporting group values
    		 R/JE – Conv R/JE – Acc R – Conv JE – Conv Total
    Number of subjects
    		 167 217 221 56 661
    Age categorical
    Units: Subjects
    Age continuous
    Analysis was done on the All Enrolled Set, ie, all subjects who have signed an informed consent, undergone screening procedure(s) and were randomized.
    Units: years
        arithmetic mean (standard deviation)
    		 37.3 ( 13.4 ) 36.8 ( 12.7 ) 35.7 ( 12.6 ) 38.8 ( 13.3 ) -
    Gender categorical
    Analysis was done on the all enrolled set, ie, all subjects who have signed an informed consent, undergone screening procedure(s) and were randomized.
    Units: Subjects
        Female
    		 76 128 125 30 359
        Male
    		 91 89 96 26 302

    End points

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    End points reporting groups
    Reporting group title
    R/JE – Conv
    Reporting group description
    		 Subjects received Rabies (R) and Japanese Encephalitis (JE) vaccines, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and JE vaccination on day 1 and 29, and placebo on day 8 in the left arm.

    Reporting group title
    R/JE – Acc
    Reporting group description
    		 Subjects received Rabies and JE vaccines, accelerated schedule, ie, Rabies vaccination on days 1, 4, and 8, and placebo on day 29 in the right arm or leg; and JE vaccination on days 1 and 8, and placebo on day 29 in the left arm.

    Reporting group title
    R – Conv
    Reporting group description
    		 Subjects received Rabies vaccine, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and placebo on days 1, 8 and 29 in the left arm.

    Reporting group title
    JE – Conv
    Reporting group description
    		 Subjects received JE vaccine, conventional schedule, ie, placebo on days 1, 4, 8 and 29 in the right arm or leg; and JE vaccination on days 1 and 29 and placebo injection on day 8 in the left arm.

    Primary: 1) Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 7 Days After Last Active Vaccination

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    End point title
    		 1) Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 7 Days After Last Active Vaccination [1]
    End point description
    Immune response was measured as the percentage of subjects with rabies virus neutralizing antibody (RVNA) concentrations ≥0.5 IU/mL, evaluated using the rapid fluorescent focus inhibition test, before vaccination (day 1) and 7 days after last active vaccination, i.e. the third out of four vaccinations given in the accelerated Rabies vaccine schedule and the fourth out of four vaccinations given in the conventional Rabies vaccine schedule. As per study design, this primary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs R - Conv. Analysis was done on the per-protocol (PP) dataset, ie, the subjects who received the vaccine correctly, provided evaluable serum samples at the relevant time points, and had no major protocol violations as defined prior to unblinding.
    End point type
    Primary
    End point timeframe
    Day 7 after last active vaccination (day 15 – group received accelerated schedule, day 36 – group received conventional schedule)
    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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc R – Conv
    Number of subjects analysed
    209
    207
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 7 after last active vaccination
    100 (97 to 100)
    100 (97 to 100)
    Statistical analysis title
    		 non-inferiority of the immune response
    Statistical analysis description
    To establish non-inferiority of the immune response of Rabies vaccine (administered concomitantly with JE vaccine) accelerated schedule as compared to Rabies vaccine administered alone following the conventional schedule at 7 days after last active vaccination.
    Comparison groups
    R/JE – Acc v R – Conv
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    0
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 2.8
    Notes
    [2] - The immune response of accelerated schedule of the Rabies vaccine considered non-inferior to the conventional schedule if the lower bound of the two-sided 97.5% Confidence Intervals (CI) of the difference in the percentages of subjects with RVNA titer ≥0.5 IU/mL measured 7 days after last active vaccination is greater than -5.

    Primary: 2) Percentages of Subjects With PRNT50 Titer ≥1:10 At 28 Days After Last Active Vaccination

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    End point title
    		 2) Percentages of Subjects With PRNT50 Titer ≥1:10 At 28 Days After Last Active Vaccination [3]
    End point description
    Immune response was measured as the percentages of subjects with a titer of ≥1:10 in a 50% plaque reduction neutralization test (PRNT50) 28 days after last active vaccination, ie, the second out of three vaccinations given in the accelerated JE vaccine schedule and the third out of three vaccinations given in the conventional JE vaccine schedule. As per study design, this primary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs JE - Conv.
    End point type
    Primary
    End point timeframe
    Day 28 after last active vaccination (day 36 – group received accelerated schedule, day 57 – group received conventional schedule)
    Notes
    [3] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc JE – Conv
    Number of subjects analysed
    206
    49
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 28 after last active vaccination
    99 (96 to 100)
    100 (93 to 100)
    Statistical analysis title
    		 Non-inferiority of the immune response
    Statistical analysis description
    Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) accelerated schedule as compared to JE vaccine administered alone following the conventional schedule at 28 day after last active vaccination
    Comparison groups
    R/JE – Acc v JE – Conv
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    -1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 7.9
    Notes
    [4] - The immune response of accelerated schedule of the JE vaccine is considered non-inferior to the conventional schedule if the lower bound of the two-sided 97.5% CI of the difference in the percentages of subjects with PRNT50 titer ≥1:10 measured 28 days after last active vaccination is greater than -10.

    Secondary: 3) RVNA Geometric Mean Concentrations (GMCs) At 28Days After Last Active Vaccination

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    End point title
    		 3) RVNA Geometric Mean Concentrations (GMCs) At 28Days After Last Active Vaccination [5]
    End point description
    Immune response was measured as the RVNA GMCs), 28 days after last active vaccination, i.e. day 57 for all groups that received the conventional schedule. Data were adjusted using ANOVA model, as per protocol specification. Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    28 days after last active vaccination (day 57)
    Notes
    [5] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv R – Conv
    Number of subjects analysed
    157
    204
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Day 28 after last active vaccination
    11 (9 to 12)
    9.9 (8.57 to 11)
    Statistical analysis title
    		 Non-inferiority of the immune response
    Statistical analysis description
    Non-inferiority of the immune response of Rabies vaccine (administered concomitantly with JE vaccine) as compared to Rabies vaccines (administered alone) as given according to conventional schedule at 28day after last active vaccination
    Comparison groups
    R – Conv v R/JE – Conv
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Between groups ratio of GMCs]
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.32
    Notes
    [6] - The conventional schedule of Rabies vaccine co-administered with JE vaccine considered non inferior to the conventional schedule of Rabies vaccine administered alone if the lower bound of the two-sided 95% CI of the ratio of GMCs measured 28 days after last active vaccination is greater than 0.667.

    Secondary: 4) PRNT50 GMTs At 28 Days After Last Active Vaccination

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    End point title
    		 4) PRNT50 GMTs At 28 Days After Last Active Vaccination [7]
    End point description
    Immune response was measured as the PRNT50 GMTs 28 days after last active vaccination, ie, day 57 for all groups that received the conventional schedule. Data were adjusted using ANOVA model, as per protocol specifications. Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    28 days after last active vaccination (day 57)
    Notes
    [7] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv JE – Conv
    Number of subjects analysed
    157
    49
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 28 after last active vaccination
    291 (256 to 331)
    331 (265 to 415)
    Statistical analysis title
    		 Non-inferiority of the immune response
    Statistical analysis description
    Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) as compared to JE vaccine (administered alone) as given according to conventional schedule at day 28 after last active vaccination.
    Comparison groups
    R/JE – Conv v JE – Conv
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.13
    Notes
    [8] - The conventional schedule of JE vaccine co-administered with Rabies vaccine considered non inferior to the conventional schedule of JE vaccine administered alone if the lower bound of the two-sided 95% CI of the ratio of GMTs measured 28 days after last active vaccination is greater than 0.5.

    Secondary: 5) Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 28Days After Last Active Vaccination

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    End point title
    		 5) Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 28Days After Last Active Vaccination [9]
    End point description
    Immune response was measured as the percentage of subjects with RVNA concentrations ≥0.5 IU/mL, 28 days after last active vaccination, i.e. day 36 for the group that received the accelerated schedule and day 57 for the group that received the conventional schedule. As per study design, this secondary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs R - Conv. Analysis was done on the PP set.
    End point type
    Secondary
    End point timeframe
    Day 36 and day 57 (28 days after last active vaccination)
    Notes
    [9] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc R – Conv
    Number of subjects analysed
    206
    204
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 28 after last active vaccination
    99 (96 to 100)
    100 (97 to 100)
    Statistical analysis title
    		 Non-inferiority of the Rabies immune response
    Statistical analysis description
    Non-inferiority of the Rabies immune response (administered concomitantly with JE vaccine) as given according to an accelerated schedule as compared Rabies vaccine (administered alone) as given to a conventional schedule at day 28 after last active vaccination.
    Comparison groups
    R/JE – Acc v R – Conv
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 1.4
    Notes
    [10] - The immune response of accelerated schedule of the Rabies vaccine is considered non-inferior to the Rabies vaccine conventional schedule if the lower bound of the two-sided 95% CI of the difference in the percentages of subjects with RVNA concentrations ≥0.5 IU/mL measured 28 days after last active vaccine administration is greater than -5.

    Secondary: 6) Percentage of Subjects With PRNT50 Titer ≥1:10 At 7 Days After Last Active Vaccination

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    End point title
    		 6) Percentage of Subjects With PRNT50 Titer ≥1:10 At 7 Days After Last Active Vaccination [11]
    End point description
    Immune response was measured as the percentage of subjects with PRNT50 titer of ≥1:10, 7 days after last active vaccination, ie, day 15 for the group that received the accelerated schedule and day 36 for the group that received the conventional schedule. As per study design, this secondary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs JE - Conv. Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 15 and day 36 (28 after last active vaccination)
    Notes
    [11] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc JE – Conv
    Number of subjects analysed
    209
    47
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 7 after last active vaccination
    99 (96 to 100)
    100 (92 to 100)
    Statistical analysis title
    		 Non-inferiority of the immune response
    Statistical analysis description
    Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) as given according to an accelerated schedule as compared to JE vaccine (administered alone) as given according to a conventional schedule at 7day after last active vaccine administration.
    Comparison groups
    R/JE – Acc v JE – Conv
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 6.2
    Notes
    [12] - The immune response of accelerated schedule of the JE vaccine considered non-inferior to the conventional schedule if the lower bound of the two-sided 95% CI of the difference in the percentages of subjects with PRNT50 titer ≥1:10 measured 7 days after last active vaccine administration is greater than -10.

    Secondary: 7) Kinetics of Rabies Immune Response Measured as Percentage of Subjects With RVNA Concentrations ≥0.5 IU/mL

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    End point title
    		 7) Kinetics of Rabies Immune Response Measured as Percentage of Subjects With RVNA Concentrations ≥0.5 IU/mL [13]
    End point description
    To evaluate the kinetics of antibody response to Rabies vaccine, the immunogenicity was measured as the percentage of subjects with RVNA concentrations ≥0.5 IU/mL on days 1, 8, 15, 36, 57, 91, 181, and 366.
    End point type
    Secondary
    End point timeframe
    Day 1, 15, 36, 57, 91, 181 and Day 366
    Notes
    [13] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv R/JE – Acc R – Conv
    Number of subjects analysed
    166
    215
    218
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 1
    1 (0.015 to 3)
    1 (0 to 3)
    1 (0 to 4)
        Day 8 (N=161, 210, 213)
    4 (2 to 9)
    16 (11 to 21)
    4 (2 to 8)
        Day 15 (N=161, 209, 210)
    99 (96 to 100)
    100 (97 to 100)
    99 (97 to 100)
        Day 36 (N=157, 206, 207)
    100 (98 to 100)
    99 (96 to 100)
    100 (97 to 100)
        Day 57 (157, 204, 204)
    100 (98 to 100)
    97 (93 to 99)
    100 (97 to 100)
        Day 91 (N=152, 206, 204)
    99 (95 to 100)
    85 (79 to 90)
    98 (95 to 99)
        Day 181 (N= 155, 200, 202)
    88 (82 to 92)
    75 (68 to 81)
    89 (84 to 93)
        Day 366 (154, 199, 204)
    76 (68 to 82)
    68 (61 to 74)
    80 (74 to 85)
    No statistical analyses for this end point

    Secondary: 8) Kinetics of Rabies Immune Response Measured as the RVNA GMCs

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    End point title
    		 8) Kinetics of Rabies Immune Response Measured as the RVNA GMCs [14]
    End point description
    To evaluate the kinetics of antibody response to Rabies vaccine, the immunogenicity was measured as the RVNA GMCs on days 1, 8, 15, 36, 57, 91, 181, and 366. Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 1, 8, 15, 36, 57, 91, 181, and 366
    Notes
    [14] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv R/JE – Acc R – Conv
    Number of subjects analysed
    166
    215
    218
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Day 1
    0.052 (0.048 to 0.056)
    0.053 (0.049 to 0.056)
    0.054 (0.05 to 0.057)
        Day 8 (N=161, 210, 213)
    0.071 (0.061 to 0.084)
    0.13 (0.12 to 0.16)
    0.076 (0.066 to 0.088)
        Day 15 (N=161, 209, 210)
    21 (17 to 25)
    26 (22 to 30)
    24 (20 to 28)
        Day 36 (N=157, 206, 207)
    14 (12 to 17)
    5.75 (4.95 to 6.67)
    13 (11 to 15)
        Day 57 (N=157, 204, 204)
    10 (8.72 to 12)
    3.01 (2.59 to 3.51)
    9.66 (8.31 to 11)
        Day 91 (N=152, 206, 204)
    4.79 (3.98 to 5.76)
    1.63 (1.39 to 1.91)
    5.04 (4.29 to 5.91)
        Day 181 (N= 155, 200, 202)
    1.86 (1.51 to 2.3)
    1 (0.83 to 1.21)
    2.04 (1.69 to 2.46)
        Day 366 (N=154, 199, 204)
    0.93 (0.75 to 1.16)
    0.82 (0.67 to 1)
    1.14 (0.94 to 1.38)
    No statistical analyses for this end point

    Secondary: 9) Kinetics of JE Immune Response Measured as Percentages of Subjects With PRNT50 ≥1:10 IU/mL

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    End point title
    		 9) Kinetics of JE Immune Response Measured as Percentages of Subjects With PRNT50 ≥1:10 IU/mL [15]
    End point description
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the percentages of subjects with PRNT50 titer ≥1:10 on days 1, 36, 57, 181, and 366 (group that received JE vaccine as a conventional schedule). Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    Days 1, 36, 57, 181 and 366
    Notes
    [15] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv JE – Conv
    Number of subjects analysed
    165
    55
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 1
    1 (0 to 4)
    9 (3 to 20)
        Day 36 (157, 47)
    99 (97 to 100)
    100 (92 to 100)
        Day 57 (N=157, 49)
    100 (98 to 100)
    100 (93 to 100)
        Day 181 (N=155, 49)
    94 (88 to 97)
    92 (80 to 98)
        Day 366 (N=154, 48)
    86 (79 to 91)
    88 (75 to 95)
    No statistical analyses for this end point

    Secondary: 10) Kinetics of JE Immune Response Measured as Percentage of Subjects With PRNT50 Titers ≥1:10

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    End point title
    		 10) Kinetics of JE Immune Response Measured as Percentage of Subjects With PRNT50 Titers ≥1:10 [16]
    End point description
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the percentage of subjects with PRNT50 titer ≥1:10 on days 1, 15, 22, 36, 57, 91, 181, and 366 (group that received JE vaccine as an accelerated schedule). Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 1, 15, 22, 36, 57, 91, 181, and 366
    Notes
    [16] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc
    Number of subjects analysed
    215
    Units: Percentage of Subjects
    geometric mean (confidence interval 95%)
        Day 1
    6 (3 to 10)
        Day 15 (N= 209)
    99 (96 to 100)
        Day 22 (N= 208)
    100 (97 to 100)
        Day 36 (N= 206)
    99 (96 to 100)
        Day 57 (N= 204)
    98 (95 to 100)
        Day 91 (N= 206)
    98 (95 to 99)
        Day 181 (N= 200)
    98 (94 to 99)
        Day 366 (N= 199)
    94 (90 to 97)
    No statistical analyses for this end point

    Secondary: 11) Kinetics of JE Immune Response Measured as PRNT50 GMTs

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    End point title
    		 11) Kinetics of JE Immune Response Measured as PRNT50 GMTs [17]
    End point description
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the PRNT50 GMTs on days 1, 36, 57, 181, and 366 (groups that received JE vaccine as a conventional schedule). Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    day 1, 36, 57, 181, and 366
    Notes
    [17] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv JE – Conv
    Number of subjects analysed
    165
    55
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 1
    5.13 (4.84 to 5.43)
    5.73 (5.2 to 6.33)
        Day 36 (N=157, 47)
    292 (247 to 346)
    376 (277 to 510)
        Day 57 (N= 157, 49)
    299 (254 to 352)
    337 (252 to 451)
        Day 181 (N=155, 49)
    63 (53 to 75)
    64 (47 to 87)
        Day 366 (N=154, 48)
    39 (33 to 47)
    39 (28 to 54)
    No statistical analyses for this end point

    Secondary: 12) Kinetics of JE Immune Response Measured as PRNT50 GMTs

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    End point title
    		 12) Kinetics of JE Immune Response Measured as PRNT50 GMTs [18]
    End point description
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the PRNT50 GMTs on days 1, 15, 22, 36, 57, 91, 181, and 366 (group that received JE vaccine as an accelerated schedule). Analysis was done on the PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 1, 15, 22, 36, 57, 91, 181, and 366
    Notes
    [18] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc
    Number of subjects analysed
    215
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 1
    5.63 (5.35 to 5.92)
        Day 15 (N= 209)
    715 (608 to 842)
        Day 22 (N= 208)
    1255 (1068 to 1475)
        Day 36 (N= 206)
    690 (595 to 801)
        Day 57 (N= 204)
    372 (322 to 430)
        Day 91 (N= 206)
    228 (192 to 272)
        Day 181 (N= 200)
    151 (130 to 176)
        Day 366 (N= 199)
    117 (100 to 137)
    No statistical analyses for this end point

    Secondary: 13) Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination, conventional schedule

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    End point title
    		 13) Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination, conventional schedule [19]
    End point description
    Safety was assessed as the number of subjects who reported solicited local adverse events (AEs) after each rabies vaccination given according to the conventional schedule as follows: from day 1 through day 7 (vaccination on day 1), day 8 through day 14 (vaccination on day 8), or day 29 through day 35 (vaccination on day 29). Analysis was done on the solicited safety set, i.e. the subjects in the exposed population who provided postvaccination solicited safety data.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each vaccination (day 1, 8 and 29)
    Notes
    [19] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv R – Conv
    Number of subjects analysed
    166
    220
    Units: Number of Subjects
        Erythema (day 1 to 7)
    13
    28
        Induration (day 1 to 7)
    3
    11
        Pain (day 1 to 7)
    43
    72
        Erythema (day 8 to 14)
    8
    29
        Induration (day 8 to 14)
    10
    17
        Pain (day 8 to 14)
    57
    90
        Erythema (day 29 to 35)
    23
    45
        Induration (day 29 to 35)
    18
    32
        Pain (day 29 to 35)
    52
    87
    No statistical analyses for this end point

    Secondary: 14) Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination, accelerated schedule

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    End point title
    		 14) Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination, accelerated schedule [20]
    End point description
    Safety was assessed as the number of subjects who reported solicited local adverse events (AEs) after each rabies vaccination given according to accelerated schedule as follows: from day 1 through day 7 (vaccination on day 1), day 4 through day 10 (vaccination on day 4), day 8 through day 14 (vaccination on day 8). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each vaccination (on day 1, 4, 8 and 29)
    Notes
    [20] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc
    Number of subjects analysed
    217
    Units: Number of Subjects
        Erythema (day 1 to 7)
    31
        Induration (day 1 to 7)
    16
        Pain (day 1 to 7)
    69
        Erythema (day 4 to 10)
    17
        Induration (day 4 to 10)
    9
        Pain (day 4 to 10)
    55
        Erythema (day 8 to 14)
    31
        Induration (day 8 to 14)
    15
        Pain (day 8 to 14)
    87
    No statistical analyses for this end point

    Secondary: 15) Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination, conventional schedule

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    End point title
    		 15) Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination, conventional schedule [21]
    End point description
    Safety was assessed as the number of subjects who reported solicited local AEs after each JE vaccination given according to conventional schedule as follow: from day 1 through day 7 (vaccination on day 1) and day 29 through day 35 (vaccination on day 29). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each vaccination (on day 1 and 29)
    Notes
    [21] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv JE – Conv
    Number of subjects analysed
    166
    56
    Units: Number of Subjects
        Erythema (day 1 to 7)
    20
    6
        Induration (day 1 to 7)
    13
    5
        Pain (day 1 to 7)
    82
    26
        Erythema (day 29 to 35)
    12
    5
        Induration (day 29 to 35)
    5
    4
        Pain (day 29 to 35)
    46
    12
    No statistical analyses for this end point

    Secondary: 16) Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination, accelerated schedule

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    End point title
    		 16) Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination, accelerated schedule [22]
    End point description
    Safety was assessed as the number of subjects who reported solicited local AEs after each JE vaccination given according to accelerated or conventional schedule as follow: from day 1 through day 7 (vaccination on day 1), day 8 through day 14 (vaccination on day 8). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each vaccination (on day 1 and 8)
    Notes
    [22] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc
    Number of subjects analysed
    217
    Units: Number of Subjects
        Erythema (day 1 to 7)
    30
        Induration (day 1 to 7)
    19
        Pain (day 1 to 7)
    102
        Erythema (day 8 to 14)
    18
        Induration (day 8 to 14)
    12
        Pain (day 8 to 14)
    60
    No statistical analyses for this end point

    Secondary: 17) Number of Subjects in the R/JE – Conv group Who Reported Solicited Local AEs After Each Placebo Injection

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    End point title
    		 17) Number of Subjects in the R/JE – Conv group Who Reported Solicited Local AEs After Each Placebo Injection [23]
    End point description
    Safety was assessed as the number of subjects in the R/JE – Conv group who reported solicited local AEs after each placebo injection given according to conventional schedule as follow: from day 4 through day 10 (injection on day 4) and day 8 through day 14 (injection on day 8). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each injection (day 4 and 8)
    Notes
    [23] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Conv
    Number of subjects analysed
    166
    Units: Number of Subjects
        Erythema (day 4 to 10)
    8
        Induration (day 4 to 10)
    1
        Pain (day 4 to 10)
    7
        Erythema (day 8 to 14)
    1
        Induration (day 8 to 14)
    0
        Pain (day 8 to 14)
    19
    No statistical analyses for this end point

    Secondary: 18) Number of Subjects in the R/JE – Accccelerated schedule group Who Reported Solicited Local AEs After Each Placebo Injection

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    End point title
    		 18) Number of Subjects in the R/JE – Accccelerated schedule group Who Reported Solicited Local AEs After Each Placebo Injection [24]
    End point description
    Safety was assessed as the number of subjects who reported solicited local AEs after each placebo injection given according to accelerated schedule as follow: from day 29 through day 35 (injection on day 29). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each injection (day 1, 4, 8 and 29)
    Notes
    [24] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R/JE – Acc
    Number of subjects analysed
    213
    Units: Number of Subjects
        Erythema (day 29 to 35)
    15
        Erythema (day 29 to 35 after 2nd Placebo dose)
    14
        Induration (day 29 to 35)
    6
        Induration (day 29 to 35 after 2nd Placebo dose)
    4
        Pain (day 29 to 35)
    15
        Pain (day 29 to 35 after 2nd Placebo dose)
    19
    No statistical analyses for this end point

    Secondary: 19) Number of Subjects in the R – Conventional schedule group Who Reported Solicited Local AEs After Each Placebo Injection

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    End point title
    		 19) Number of Subjects in the R – Conventional schedule group Who Reported Solicited Local AEs After Each Placebo Injection [25]
    End point description
    Safety was assessed as the number of subjects in the R – Conventional schedule group who reported solicited local AEs after each placebo injection given according to conventional schedule as follow: from day 1 through day 7 (injection on day 1), day 4 through day 10 (injection on day 4), day 8 through day 14 (injection on day 8), and day 29 through day 35 (injection on day 29). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each injection (day 1, 4, 8 and 29)
    Notes
    [25] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 R – Conv
    Number of subjects analysed
    220
    Units: Number of Subjects
        Erythema (day 1 to 7)
    20
        Induration (day 1 to 7)
    4
        Pain (day 1 to 7)
    26
        Erythema (day 4 to 10)
    13
        Induration (day 4 to 10)
    4
        Pain (day 4 to 10)
    15
        Erythema (day 8 to 14)
    11
        Induration (day 8 to 14)
    5
        Pain (day 8 to 14)
    20
        Erythema (day 29 to 35)
    15
        Induration (day 29 to 35)
    4
        Pain (day 29 to 35)
    28
    No statistical analyses for this end point

    Secondary: 20) Number of Subjects in the JE – Conventional schedule group Who Reported Solicited Local AEs After Each Placebo Injection

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    End point title
    		 20) Number of Subjects in the JE – Conventional schedule group Who Reported Solicited Local AEs After Each Placebo Injection [26]
    End point description
    Safety was assessed as the number of subjects in the JE – Conventional schedule group who reported solicited local AEs after each placebo injection given according to conventional schedule as follow: from day 1 through day 7 (injection on day 1), day 4 through day 10 (injection on day 4), day 8 through day 14 (injection on day 8), and day 29 through day 35 (injection on day 29). Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each injection (day 1, 4, 8 and 29)
    Notes
    [26] - 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: There was no statistical analysis done for this endpoint.
    End point values
    		 JE – Conv
    Number of subjects analysed
    56
    Units: Number of Subjects
        Erythema (day 1 to 7)
    3
        Induration (day 1 to 7)
    5
        Pain (day 1 to 7)
    7
        Erythema (day 4 to 10)
    3
        Induration (day 4 to 10)
    2
        Pain (day 4 to 10)
    3
        Erythema (day 8 to 14)
    4
        Erythema (day 8 to 14 after 2nd Placebo dose)
    3
        Induration (day 8 to 14)
    1
        Induration (day 8 to 14 after 2nd Placebo dose)
    1
        Pain (day 8 to 14)
    3
        Pain (day 8 to 14 after 2nd Placebo dose)
    5
        Erythema (day 29 to 35)
    3
        Induration (day 29 to 35)
    1
        Pain (day 29 to 35)
    3
    No statistical analyses for this end point

    Secondary: 21) Number of Subjects Who Reported Solicited Systemic AEs and Other Indicators of Reactogenicity After Each Vaccination

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    End point title
    		 21) Number of Subjects Who Reported Solicited Systemic AEs and Other Indicators of Reactogenicity After Each Vaccination
    End point description
    Safety was assessed as the number of subjects who reported solicited systemic AEs and other indicators of reactogenicity after each vaccination given according to accelerated and conventional schedule. Analysis was done on the solicited safety set.
    End point type
    Secondary
    End point timeframe
    Day 1 through day 7 after each vaccination (day 1, 4, 8 and 29)
    End point values
    		 R/JE – Conv R/JE – Acc R – Conv JE – Conv
    Number of subjects analysed
    166
    217
    220
    56
    Units: Number of Subjects
        Fatigue (day 1 to 7)
    39
    56
    46
    16
        Headache (day 1 to 7)
    35
    46
    38
    14
        Myalgia (day 1 to 7)
    27
    55
    31
    7
        Arthralgia (day 1 to 7)
    8
    13
    7
    1
        Loss of Appetite (day1 to day 7)
    10
    8
    12
    6
        Nausea (day1 to day 7)
    8
    7
    13
    4
        Body temperature (≥38 °C, day 1 to day 7)
    1
    2
    2
    0
        Analgesic/Antipyretic used (day 1 to day 7)
    11
    11
    8
    3
        Fatigue (day 4 to 10)
    14
    30
    33
    5
        Headache (day 4 to 10)
    17
    28
    29
    3
        Myalgia (day 4 to 10)
    11
    19
    14
    1
        Arthralgia (day 4 to 10)
    1
    9
    9
    0
        Loss of Appetite (day4 to day 10)
    4
    8
    9
    2
        Nausea (day4 to day 10)
    4
    5
    8
    0
        Body temperature (≥38 °C, day 4 to day 10)
    1
    1
    2
    0
        Analgesic/Antipyretic used (day 4 to 10)
    8
    10
    15
    2
        Fatigue (day 8 to 14)
    24
    47
    47
    6
        Headache (day 8 to 14)
    33
    43
    41
    3
        Myalgia (day 8 to 14)
    22
    41
    38
    1
        Arthralgia (day 8 to 14)
    6
    9
    13
    1
        Loss of Appetite (day8 to day 14)
    10
    14
    13
    2
        Nausea (day8 to day 14)
    5
    14
    16
    2
        Body temperature (≥38 °C, day 8 to 14)
    2
    1
    5
    0
        Analgesic/Antipyretic used (day 8 to 14)
    10
    17
    20
    2
        Fatigue (day 29 to 35)
    21
    29
    36
    3
        Headache (day 29 to 35)
    27
    22
    40
    4
        Myalgia (day 29 to 35)
    23
    15
    28
    2
        Arthralgia (day 29 to 35)
    5
    6
    14
    1
        Body temperature (≥38 °C, day 29 to day 35)
    1
    2
    1
    0
        Analgesic/Antipyretic used (day 29 to day 35)
    9
    10
    11
    3
        Loss if appetite (day 29 to day 25)
    2
    8
    9
    2
        nausea (day29 to day 25)
    7
    12
    9
    2
    No statistical analyses for this end point

    Secondary: 22) Numbers of Subjects Reporting Unsolicited AEs After Any Vaccination From Day 1 Through Day 57

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    End point title
    		 22) Numbers of Subjects Reporting Unsolicited AEs After Any Vaccination From Day 1 Through Day 57
    End point description
    Safety was assessed as the number of subjects who reported unsolicited AEs after any vaccination given according to accelerated and conventional schedule.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 57
    End point values
    		 R/JE – Conv R/JE – Acc R – Conv JE – Conv
    Number of subjects analysed
    166
    217
    220
    56
    Units: Numbers of Subjects
        Any AE
    69
    108
    110
    29
        SAE
    2
    3
    2
    3
        AEs leading to premature withdrawal
    1
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs were collected for 7 days after each vaccination. All unsolicited AEs, serious adverse events (SAEs), AEs leading to study and/or treatment withdrawal were collected through day 57. From day 57 to day 366 vaccine-related SAEs were collected.
    Adverse event reporting additional description
    Solicited adverse events were collected by systematic assessment, unsolicited AEs by non-systematic assessment. SAEs analysis was done one the unsolicited safety set, other AEs analysis was done on the overall safety set.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    R/JE – Conv
    Reporting group description
    		 Subjects received Rabies (R) and Japanese Encephalitis (JE) vaccines, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and JE vaccination on day 1 and 29, and placebo on day 8 in the left arm.

    Reporting group title
    R – Conv
    Reporting group description
    		 Subjects received Rabies vaccine, conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and placebo on days 1, 8 and 29 in the left arm.

    Reporting group title
    JE – Conv
    Reporting group description
    		 Subjects received JE vaccine, conventional schedule, ie, placebo on days 1, 4, 8 and 29 in the right arm or leg; and JE vaccination on days 1 and 29 and placebo injection on day 8 in the left arm.

    Reporting group title
    R/JE – Acc
    Reporting group description
    		 Subjects received Rabies and JE vaccines, accelerated schedule, ie, Rabies vaccination on days 1, 4, and 8, and placebo on day 29 in the right arm or leg; and JE vaccination on days 1 and 8, and placebo on day 29 in the left arm.

    Serious adverse events
    		 R/JE – Conv R – Conv JE – Conv R/JE – Acc
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 166 (1.20%)
    2 / 220 (0.91%)
    3 / 56 (5.36%)
    3 / 217 (1.38%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    0 / 56 (0.00%)
    1 / 217 (0.46%)
         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
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 220 (0.00%)
    0 / 56 (0.00%)
    0 / 217 (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
    Meniscus injury
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    0 / 56 (0.00%)
    1 / 217 (0.46%)
         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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 220 (0.45%)
    0 / 56 (0.00%)
    0 / 217 (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
    Tachycardia
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 220 (0.45%)
    0 / 56 (0.00%)
    0 / 217 (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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 220 (0.45%)
    0 / 56 (0.00%)
    0 / 217 (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
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    1 / 56 (1.79%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    0 / 56 (0.00%)
    1 / 217 (0.46%)
         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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    1 / 56 (1.79%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    1 / 56 (1.79%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    1 / 56 (1.79%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 166 (0.00%)
    0 / 220 (0.00%)
    1 / 56 (1.79%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 220 (0.00%)
    0 / 56 (0.00%)
    0 / 217 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 R/JE – Conv R – Conv JE – Conv R/JE – Acc
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 166 (83.13%)
    185 / 220 (84.09%)
    45 / 56 (80.36%)
    186 / 217 (85.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    63 / 166 (37.95%)
    95 / 220 (43.18%)
    19 / 56 (33.93%)
    94 / 217 (43.32%)
         occurrences all number
    139
    189
    30
    185
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    54 / 166 (32.53%)
    84 / 220 (38.18%)
    19 / 56 (33.93%)
    93 / 217 (42.86%)
         occurrences all number
    107
    189
    33
    182
    Injection site erythema
         subjects affected / exposed
    48 / 166 (28.92%)
    85 / 220 (38.64%)
    13 / 56 (23.21%)
    73 / 217 (33.64%)
         occurrences all number
    90
    163
    28
    160
    Injection site induration
         subjects affected / exposed
    29 / 166 (17.47%)
    48 / 220 (21.82%)
    10 / 56 (17.86%)
    43 / 217 (19.82%)
         occurrences all number
    54
    77
    19
    81
    Injection site pain
         subjects affected / exposed
    115 / 166 (69.28%)
    131 / 220 (59.55%)
    31 / 56 (55.36%)
    146 / 217 (67.28%)
         occurrences all number
    314
    342
    62
    418
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    19 / 166 (11.45%)
    35 / 220 (15.91%)
    9 / 56 (16.07%)
    31 / 217 (14.29%)
         occurrences all number
    29
    52
    10
    44
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 166 (7.83%)
    31 / 220 (14.09%)
    3 / 56 (5.36%)
    29 / 217 (13.36%)
         occurrences all number
    21
    48
    3
    37
    Myalgia
         subjects affected / exposed
    50 / 166 (30.12%)
    60 / 220 (27.27%)
    10 / 56 (17.86%)
    75 / 217 (34.56%)
         occurrences all number
    86
    115
    13
    137
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 166 (13.25%)
    32 / 220 (14.55%)
    7 / 56 (12.50%)
    33 / 217 (15.21%)
         occurrences all number
    25
    36
    7
    37
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 166 (11.45%)
    27 / 220 (12.27%)
    9 / 56 (16.07%)
    24 / 217 (11.06%)
         occurrences all number
    31
    50
    12
    43

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2012
    Protocol Number V49_23, Version 2.0, Amendment 1 – Date: 06 APR 12, (revised from Version 1.0, Date: 05 DEC 11)

    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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