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    Clinical Trial Results:
    A Phase 3, Open-label, Multicenter Study to Evaluate Long-term Immunogenicity and Boostability of Immune Responses in Adults who Received Different Primary Vaccination Regimens of Pre-exposure Prophylaxis with Purified Chick-Embryo Cell Rabies Vaccine Administered Concomitantly or Separately from a Japanese Encephalitis Vaccine

    Summary
    EudraCT number
    		 2015-000382-31
    Trial protocol
    		 DE   AT  
    Global end of trial date
    15 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2024
    First version publication date
    06 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    205214
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02545517
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    GSK Response Center, GlaxoSmithKline, 44 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 44 8664357343, GSKClinicalSupportHD@gsk.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
    24 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is an extension study aimed: • To evaluate the safety of a booster dose of PCEC rabies vaccine following a primary series of accelerated or conventional rabies PrEP IM regimen in the parent study (V49_23). • To compare the long-term (up to approx.10 years) persistence of antibody responses (i.e. time until antibody concentrations drop below 0.5 IU/mL) in participants who received a primary series of accelerated or conventional rabies PrEP intramuscular (IM) regimen in the parent study (V49_23). • To evaluate the antibody responses to a booster dose of PCEC rabies vaccine administered to participants with RVNA concentrations <0.5 IU/mL following a primary series of accelerated or conventional rabies PrEP IM regimen in the parent study (V49_23).
    Protection of trial subjects
    Study participants receiving a booster vaccination were observed at the site for at least 30 minutes after immunization for any immediate reactions. Appropriate medical treatment was readily available during the observation period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2015
    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
    Austria: 67
    Country: Number of subjects enrolled
    Germany: 327
    Country: Number of subjects enrolled
    Switzerland: 65
    Worldwide total number of subjects
    459
    EEA total number of subjects
    394
    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)
    451
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Up to 459 participants, who successfully completed rabies pre-exposure prophylaxis (PrEP) regimens in parent study (V49_23) (NCT01662440, EudraCT ID- 2011-005173-23) and did not have protocol deviations which could impact the immunogenicity response (e.g., wrong vaccination) were enrolled in this extension study.

    Pre-assignment
    Screening details
    		 As prespecified in protocol, Visit 1 in the extension study corresponds to Year 3, i.e. approximately 3 years after completion of rabies primary series in the parent study. Subsequent visits (2,3,4,5,6,7 and 8) occurred at yearly intervals applied after completion of parent study (Year 4, 5, 6, 7, 8, 9 and 10).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Conv-R/JE Group
    Arm description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29, and Japanese Encephalitis (JE) primary series regimen on days 1 and 29 in the parent study (V49_23) and who received at least one booster dose of purified chick embryo cell culture (PCEC) rabies vaccine in this extension study, if Rabies Virus Neutralizing Antibody (RNVA) concentrations were less than (<)0.5 IU/mL at scheduled visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Purified chick-embryo cell derived (PCEC) rabies vaccine
    Investigational medicinal product code
    Other name
    Rabipur
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single dose of 1.0 mL of the PCEC rabies vaccine was administered intramuscularly in the deltoid of the non-dominant arm for participants with RVNA concentrations <0.5 IU/mL.

    Arm title
    		 Acc-R/JE Group
    Arm description
    		 Participants who completed the Rabies PrEP regimen on days 1, 4 and 8 and JE primary series regimen on days 1 and 8 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PCEC rabies vaccine
    Investigational medicinal product code
    Other name
    Rabipur
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single dose of 1.0 mL of the PCEC rabies vaccine was administered intramuscularly in the deltoid of the non-dominant arm for participants with RVNA concentrations <0.5 IU/mL.

    Arm title
    		 Conv-R Group
    Arm description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PCEC rabies vaccine
    Investigational medicinal product code
    Other name
    Rabipur
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single dose of 1.0 mL of the PCEC rabies vaccine was administered intramuscularly in the deltoid of the non-dominant arm for participants with RVNA concentrations <0.5 IU/mL.

    Number of subjects in period 1
    		Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Started
    126
    157
    176
    Completed
    98
    123
    135
    Not completed
    28
    34
    41
         Adverse event, serious fatal
    2
    2
    1
         Consent withdrawn by subject
    5
    8
    9
         Unspecified
    2
    4
    3
         Lost to follow-up
    14
    13
    17
         Administrative reason
    5
    6
    10
         Protocol deviation
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Conv-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29, and Japanese Encephalitis (JE) primary series regimen on days 1 and 29 in the parent study (V49_23) and who received at least one booster dose of purified chick embryo cell culture (PCEC) rabies vaccine in this extension study, if Rabies Virus Neutralizing Antibody (RNVA) concentrations were less than (<)0.5 IU/mL at scheduled visits.

    Reporting group title
    Acc-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 4 and 8 and JE primary series regimen on days 1 and 8 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.

    Reporting group title
    Conv-R Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.

    Reporting group values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group Total
    Number of subjects
    		 126 157 176 459
    Age categorical
    Units: Participants
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 122 155 174 451
        From 65-84 years
    		 4 2 2 8
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.9 ± 13.2 38.7 ± 13.0 36.6 ± 12.8 -
    Sex: Female, Male
    Units: Participants
        Male
    		 65 63 75 203
        Female
    		 61 94 101 256
    Race/Ethnicity, Customized
    Units: Subjects
        ASIAN
    		 1 0 1 2
        BLACK OR AFRICAN AMERICAN
    		 0 2 0 2
        OTHER UNSPECIFIED
    		 0 1 2 3
        WHITE
    		 125 154 173 452

    End points

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    End points reporting groups
    Reporting group title
    Conv-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29, and Japanese Encephalitis (JE) primary series regimen on days 1 and 29 in the parent study (V49_23) and who received at least one booster dose of purified chick embryo cell culture (PCEC) rabies vaccine in this extension study, if Rabies Virus Neutralizing Antibody (RNVA) concentrations were less than (<)0.5 IU/mL at scheduled visits.

    Reporting group title
    Acc-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 4 and 8 and JE primary series regimen on days 1 and 8 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.

    Reporting group title
    Conv-R Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29 in the parent study (V49_23) and who received at least one booster dose of PCEC rabies vaccine in this extension study, if RNVA concentrations were <0.5 IU/mL at scheduled visits.

    Primary: Number of participants reporting serious adverse events (SAEs) after a booster dose of purified chick embryo cell culture (PCEC) rabies vaccine

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    End point title
    		 Number of participants reporting serious adverse events (SAEs) after a booster dose of purified chick embryo cell culture (PCEC) rabies vaccine [1]
    End point description
    A SAE is defined as any untoward medical occurrence that at any dose results in one or more of the following: death, is life-threatening, required/prolonged hospitalization, persistent or significant disability/incapacity, congenital anomaly/or birth defect, an important and significant medical event that may not be immediately life threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the participants or may require intervention to prevent one of the other outcomes listed. Safety is assessed as the number of participants reporting SAEs after a booster dose of PCEC rabies vaccine administered in this extension study, if RNVA concentrations were <0.5 IU/mL, following a primary series of accelerated or conventional rabies pre-exposure (PrEP) intramuscular (IM) regimen in the parent study. The analysis was performed on the Safety Set which included all enrolled participants who received a booster dose and reported safety data.
    End point type
    Primary
    End point timeframe
    From booster vaccination [6 to 9 months after Year 3 (3 years after primary series of vaccination)] up until completion of the safety follow-up period (10 years after primary series of vaccination)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    44
    47
    53
    Units: Participants
    2
    0
    3
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 3 and Year 4

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 3 and Year 4 [2]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 3 to Year 4 (after primary series of vaccination)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    93
    92
    133
    Units: Participants
    5
    5
    7
    No statistical analyses for this end point

    Primary: Number of participants who had their Rabies Virus Neutralizing Antibody (RNVA) concentrations drop below 0.5 international units (IU) per milliliter (mL) between Day 366 and Year 3

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    End point title
    		 Number of participants who had their Rabies Virus Neutralizing Antibody (RNVA) concentrations drop below 0.5 international units (IU) per milliliter (mL) between Day 366 and Year 3 [3]
    End point description
    The analysis was performed on the Full Analysis Set-2 (FAS-2): long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Day 366 to Year 3 (after primary series of vaccination)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    96
    98
    133
    Units: Participants
    1
    1
    2
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 4 and Year 5

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 4 and Year 5 [4]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 4 to Year 5 (after primary series of vaccination)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    85
    84
    117
    Units: Participants
    7
    0
    4
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 9 and Year 10

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 9 and Year 10 [5]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 9 to Year 10 (after primary series of vaccination)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    61
    69
    85
    Units: Participants
    2
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 8 and Year 9

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 8 and Year 9 [6]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 8 to Year 9 (after primary series of vaccination)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    66
    72
    93
    Units: Participants
    1
    0
    2
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 5 and Year 6

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 5 and Year 6 [7]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 5 to Year 6 (after primary series of vaccination)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    72
    83
    112
    Units: Participants
    3
    2
    10
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 6 and Year 7

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 6 and Year 7 [8]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 6 to Year 7 (after primary series of vaccination)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    67
    78
    101
    Units: Participants
    0
    2
    0
    No statistical analyses for this end point

    Primary: Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 7 and Year 8

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    End point title
    		 Number of participants who had their RNVA concentrations drop below 0.5 IU/mL between Year 7 and Year 8 [9]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Year 7 to Year 8 (after primary series of vaccination)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    67
    74
    97
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: RVNA antibody concentrations 7 days after the booster dose

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    End point title
    		 RVNA antibody concentrations 7 days after the booster dose [10]
    End point description
    RVNA antibody concentrations were measured in terms of Geometric Mean Concentrations (GMCs) and expressed in IU/mL. Analysis was performed on the Full Analysis Set-1 (FAS-1): booster immunogenicity analysis, which included all eligible participants from the V49_23 study enrolled in this extension study, whom received booster dose (booster dose was administered only when participants reached RVNA concentrations <0.5 IU/mL) and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Day 7 after booster dose
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    43
    46
    52
    Units: IU/mL
        geometric mean (confidence interval 95%)
    4.2 (2.8 to 6.4)
    4.2 (2.8 to 6.2)
    4.4 (3.0 to 6.4)
    No statistical analyses for this end point

    Primary: RVNA Geometric Mean Ratios (GMRs) 7 days after the booster dose versus antibody concentrations before the booster dose

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    End point title
    		 RVNA Geometric Mean Ratios (GMRs) 7 days after the booster dose versus antibody concentrations before the booster dose [11]
    End point description
    GMR was calculated as ratio of post booster dose RVNA GMCs (7-day post booster dose) to the baseline RVNA GMCs (7 days before booster dose). Analysis was performed on the FAS-1: booster immunogenicity analysis, which included all eligible participants from the V49_23 study enrolled in this extension study, whom received booster dose (booster dose was administered only when participants reached RVNA concentrations <0.5 IU/mL) and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    Day 7 after booster dose compared to baseline (7 days before booster dose)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    43
    46
    52
    Units: Ratio
        geometric mean (confidence interval 95%)
    23.6 (16.1 to 34.4)
    23.4 (16.2 to 33.8)
    19.3 (13.7 to 27.3)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations greater than or equal to (>=) 0.5 IU/mL, 7 days after booster dose

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    End point title
    		 Percentage of participants with RVNA concentrations greater than or equal to (>=) 0.5 IU/mL, 7 days after booster dose [12]
    End point description
    Analysis was performed on the FAS-1: booster immunogenicity analysis, which included all eligible participants from the V49_23 study enrolled in this extension study, whom received booster dose (booster dose was administered only when participants reached RVNA concentrations <0.5 IU/mL) and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Day 7 after booster dose
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    43
    46
    52
    Units: Percentage of participants
        number (confidence interval 95%)
    95.3 (84.2 to 99.4)
    89.1 (76.4 to 96.4)
    98.1 (89.7 to 100.0)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 6

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 6 [13]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 6 after primary series of vaccine administration
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    110
    139
    158
    Units: Percentage of participants
        number (confidence interval 95%)
    60.9 (51.1 to 70.1)
    66.2 (57.7 to 74.0)
    66.5 (58.5 to 73.8)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 5

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 5 [14]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 5 after primary series of vaccine administration
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    118
    139
    160
    Units: Percentage of participants
        number (confidence interval 95%)
    66.1 (56.8 to 74.6)
    69.1 (60.7 to 76.6)
    73.1 (65.6 to 79.8)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 4

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 4 [15]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
     At Year 4 after primary series of vaccine administration
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    121
    144
    166
    Units: Percentage of participants
        number (confidence interval 95%)
    74.4 (65.6 to 81.9)
    70.8 (62.7 to 78.1)
    76.5 (69.3 to 82.7)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 3

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 3 [16]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 3 after primary series of vaccine administration
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    125
    151
    172
    Units: Percentage of participants
        number (confidence interval 95%)
    81.6 (73.7 to 88.0)
    78.8 (71.4 to 85.0)
    84.9 (78.6 to 89.9)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 9

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 9 [17]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 9 after primary series of vaccine administration
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    108
    132
    150
    Units: Percentage of participants
        number (confidence interval 95%)
    59.3 (49.4 to 68.6)
    63.6 (54.8 to 71.8)
    64.0 (55.8 to 71.7)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 8

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 8 [18]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
     At Year 8 after primary series of vaccine administration
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    107
    131
    144
    Units: Percentage of participants
        number (confidence interval 95%)
    59.8 (49.9 to 69.2)
    64.1 (55.3 to 72.3)
    64.6 (56.2 to 72.4)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 7

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 7 [19]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 7 after primary series of vaccine administration
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    108
    135
    156
    Units: Percentage of participants
        number (confidence interval 95%)
    60.2 (50.3 to 69.5)
    64.4 (55.8 to 72.5)
    67.3 (59.3 to 74.6)
    No statistical analyses for this end point

    Primary: Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 10

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    End point title
    		 Percentage of participants with RVNA concentrations >= 0.5 IU/mL at Year 10 [20]
    End point description
    The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoint.
    End point type
    Primary
    End point timeframe
    At Year 10 after primary series of vaccine administration
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of this endpoint was descriptive (no statistical hypothesis test was performed).
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    105
    130
    142
    Units: Percentage of participants
        number (confidence interval 95%)
    56.2 (46.2 to 65.9)
    62.3 (53.4 to 70.7)
    62.7 (54.2 to 70.6)
    No statistical analyses for this end point

    Secondary: Rabies Virus Neutralizing Antibody concentrations

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    End point title
    		 Rabies Virus Neutralizing Antibody concentrations
    End point description
    Antibody concentrations were measured in terms of GMCs and expressed in IU/mL. The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoints.
    End point type
    Secondary
    End point timeframe
    At Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and Year 10 after primary series of vaccine administration
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    126
    157
    176
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Year 3
    1.21 (0.88 to 1.65)
    1.16 (0.87 to 1.55)
    1.3 (0.99 to 1.7)
        Year 4
    0.69 (0.5 to 0.94)
    0.73 (0.55 to 0.97)
    0.82 (0.63 to 1.07)
        Year 5
    0.66 (0.48 to 0.9)
    0.7 (0.53 to 0.94)
    0.74 (0.56 to 0.96)
        Year 6
    0.5 (0.37 to 0.69)
    0.6 (0.45 to 0.8)
    0.58 (0.44 to 0.76)
        Year 7
    0.49 (0.36 to 0.67)
    0.6 (0.45 to 0.79)
    0.61 (0.47 to 0.8)
        Year 8
    0.56 (0.41 to 0.77)
    0.76 (0.57 to 1.01)
    0.68 (0.52 to 0.89)
        Year 9
    0.53 (0.39 to 0.73)
    0.7 (0.53 to 0.94)
    0.62 (0.47 to 0.81)
        Year 10
    0.59 (0.43 to 0.81)
    0.72 (0.54 to 0.96)
    0.68 (0.52 to 0.89)
    No statistical analyses for this end point

    Secondary: Reverse Cumulative percentage for participants with RVNA concentrations >=0.5 IU/mL

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    End point title
    		 Reverse Cumulative percentage for participants with RVNA concentrations >=0.5 IU/mL
    End point description
    As specified in the statistical analysis plan, a graphical presentation of the Reverse Cumulative Distribution Plots for participants with RVNA concentrations >=0.5 IU/mL was analyzed for this outcome measure. Due to system constrains, only the reverse cumulative percentage values were reported, to depict the Reverse Cumulative Distribution Plots. The analysis was performed on the FAS-2: long term immunogenicity analysis which included all eligible participants from the V49_23 study enrolled in this extension study and provided immunogenicity data for the specific analysis at the specific timepoints.
    End point type
    Secondary
    End point timeframe
    At Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and Year 10 after primary series of vaccine administration
    End point values
    		 Conv-R/JE Group Acc-R/JE Group Conv-R Group
    Number of subjects analysed
    102
    119
    146
    Units: Cumulative percentage of participants
        Year 3
    100
    100
    100
        Year 4
    83
    84
    83
        Year 5
    67
    70
    69
        Year 6
    54
    57
    56
        Year 7
    43
    45
    44
        Year 8
    32
    33
    32
        Year 9
    21
    22
    21
        Year 10
    10
    11
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All Cause Mortality: from Year 3 (3 years after primary series of vaccination) until completion of safety follow-up at Year 10 (10 years after primary series of vaccination); SAEs: from booster vaccination (6 to 9 months after Year 3) until Year 10
    Adverse event reporting additional description
    SAEs were collected only from participants who received booster dose. Five deaths were recorded during this extension study but only one of them was reported as SAE as this was the only one that occurred in a participant who received a booster dose. Solicited and non-serious unsolicited AEs were not collected in this study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Conv-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29, and Japanese Encephalitis (JE) primary series regimen on days 1 and 29 in the parent study (V49_23) and, if Rabies Virus Neutralizing Antibody (RNVA) concentrations were less than (<)0.5 IU/mL, they received at least one booster dose of purified chick embryo cell culture (PCEC) rabies vaccine in this extension study.

    Reporting group title
    Conv-R Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 8 and 29 in the parent study (V49_23) and, if RVNA concentrations were <0.5 IU/mL, they received at least one booster dose of the PCEC rabies vaccine in this extension study.

    Reporting group title
    Acc-R/JE Group
    Reporting group description
    		 Participants who completed the Rabies PrEP regimen on days 1, 4 and 8 and JE primary series regimen on days 1 and 8 in the parent study (V49_23) and, if RVNA concentrations were <0.5 IU/mL, they received at least one booster dose of the PCEC rabies vaccine in this extension study.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Solicited and non-serious unsolicited AEs were not collected in this study as the objective was to evaluate long term immunogenicity in participants who received a primary series of accelerated or conventional rabies PrEP regimens in the parent study.
    Serious adverse events
    		 Conv-R/JE Group Conv-R Group Acc-R/JE Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 53 (5.66%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    2
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leiomyoma
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 53 (0.00%)
    0 / 47 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 53 (0.00%)
    0 / 47 (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
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 53 (1.89%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Conv-R/JE Group Conv-R Group Acc-R/JE Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 53 (0.00%)
    0 / 47 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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