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    Clinical Trial Results:
    A Phase IV, Uncontrolled, Open-Label, Single-Center Study in Adolescents and Adults: Evaluation of Immunogenicity and Safety of the First Booster Vaccination With Novartis Vaccines and Diagnostics (Ex Chiron’s) TBE Vaccine for Adults in Participants of Study V48P7 and Long-Term Evaluation of Immunogenicity up to 5 Years After First Booster Vaccination.

    Summary
    EudraCT number
    		 2006-001676-21
    Trial protocol
    		 CZ  
    Global end of trial date
    07 Oct 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Dec 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V48P7E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00387634
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics GmbH & Co. KG
    Sponsor organisation address
    Postfach 1630, Marburg, Germany, 35006
    Public contact
    Posting Director, Novartis Vaccines , RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines , 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
    13 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Descriptive evaluation of subjects with respect to antibody titers and percentage of subjects with neutralizing antibodies on day 0 in study V48P7E1 (ie, day of first booster vaccination after primary vaccination in study V48P7 for subjects who did not get a booster vaccination, or first blood draw for those who did receive a booster dose), on day 21 in study V48P7E1 (7 days) and year 1, 2, 3, 4, and 5 (±30 days each) after booster vaccination with Novartis Vaccines and Diagnostics (ex Chiron’s) tick borne encephalitis (TBE) vaccine for adults as measured by neutralization test ([NT]; in-house, Novartis Vaccines and Diagnostics).
    Protection of trial subjects
    This study 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 Harmonisation (ICH) guidelines, the applicable regulatory requirements(s) for the country in which the study was conducted, and applicable standard operating procedures (SOPs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Sep 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 323
    Worldwide total number of subjects
    323
    EEA total number of subjects
    323
    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)
    20
    Adults (18-64 years)
    293
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled in 1 site in Czech Republic.

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TBE_R
    Arm description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TBE vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml

    Arm title
    		 TBE_R_B
    Arm description
    		 Subjects received the first booster between study V48P7 and V48P7E1 at 12 to 18 months after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7). Subjects in the arm did not receive any intervention (only blood draw).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 TBE_C
    Arm description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Conventional schedule group-consisted of 3 vaccinations with an interval of 1 month between the first and second vaccination and an interval of 10 months to 12 months between the second and third vaccination (ie, on day 0, day 28, day 300 of study V48P7).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TBE vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml

    Arm title
    		 TBE_MC
    Arm description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Modified conventional (MC) schedule group-TBE vaccine was given with a reduced interval between first and second vaccination; ie, from 28 days to 21 days (ie, vaccinations on day 0, day 21, day 300 of study V48P7).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TBE vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml

    Arm title
    		 TBE_AC
    Arm description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Accelerated conventional (AC) schedule group-TBE vaccine was given by means of an even more reduced interval between the first and second vaccination; ie, from 28 days to 14 days (ie, vaccinations on day 0, day 14, and day 300 of study V48P7).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TBE vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml

    Number of subjects in period 1
    		TBE_R TBE_R_B TBE_C TBE_MC TBE_AC
    Started
    9
    40
    55
    110
    109
    Completed
    9
    39
    52
    107
    106
    Not completed
    0
    1
    3
    3
    3
         Death
    -
    1
    1
    -
    2
         Lost to follow-up
    -
    -
    1
    1
    -
         Protocol deviation
    -
    -
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TBE_R
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7).

    Reporting group title
    TBE_R_B
    Reporting group description
    		 Subjects received the first booster between study V48P7 and V48P7E1 at 12 to 18 months after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7). Subjects in the arm did not receive any intervention (only blood draw).

    Reporting group title
    TBE_C
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Conventional schedule group-consisted of 3 vaccinations with an interval of 1 month between the first and second vaccination and an interval of 10 months to 12 months between the second and third vaccination (ie, on day 0, day 28, day 300 of study V48P7).

    Reporting group title
    TBE_MC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Modified conventional (MC) schedule group-TBE vaccine was given with a reduced interval between first and second vaccination; ie, from 28 days to 21 days (ie, vaccinations on day 0, day 21, day 300 of study V48P7).

    Reporting group title
    TBE_AC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Accelerated conventional (AC) schedule group-TBE vaccine was given by means of an even more reduced interval between the first and second vaccination; ie, from 28 days to 14 days (ie, vaccinations on day 0, day 14, and day 300 of study V48P7).

    Reporting group values
    		 TBE_R TBE_R_B TBE_C TBE_MC TBE_AC Total
    Number of subjects
    		 9 40 55 110 109 323
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.6 ( 9.2 ) 38.1 ( 16.4 ) 36.3 ( 14.5 ) 37.5 ( 14.3 ) 37.1 ( 14.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 19 35 63 58 180
        Male
    		 4 21 20 47 51 143
    Subject analysis sets

    Subject analysis set title
    All enrolled set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The enrolled population contained all subjects enrolled in the study, ie, with a record in DEMOG panel. This population was used for the analysis of demographics, concomitant medications, medical history and all subject listings.

    Subject analysis set title
    Full Analysis Set (FAS) Immunogenecity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who: ▫ were admitted to the study, irrespective whether they received study vaccination or not; ▫ provided at least one evaluable serum sample

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received a booster vaccination on day 0 (V48P7E1) excluding TBE_R_B group and provided postvaccination safety data.

    Subject analysis set title
    Per-Protocol (PP) Population, Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS comprised all subjects who: ▫ received the relevant booster vaccination correctly or had completed the rapid schedule and had already received a booster vaccination prior to admission into the present study; ▫ provided evaluable serum samples at the relevant time points; ▫ presented no major violations regarding concomitant medication/concomitant disease; ▫ had no major violations of inclusion/exclusion criteria. Specifically, subjects meeting the following criteria were excluded from the PPS: ▫ subjects who received another vaccine within 4 weeks after the administration of the study vaccine*; ▫ subjects treated with immunoglobulins, whole blood or plasma derivates up to 4 weeks after administration of study vaccine subjects treated with immunosuppressants or systemic corticosteroids during the study period, except short term use of topic corticosteroids or low-dose systemic use (e.g.,up to 10 mg of prednisolone for up to 14 days). Subjects meeting the following crite

    Subject analysis sets values
    		 All enrolled set Full Analysis Set (FAS) Immunogenecity Safety Population Per-Protocol (PP) Population, Immunogenicity
    Number of subjects
    323
    323
    278
    289
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.1 ( 14.5 )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    180
        Male
    143

    End points

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    End points reporting groups
    Reporting group title
    TBE_R
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7).

    Reporting group title
    TBE_R_B
    Reporting group description
    		 Subjects received the first booster between study V48P7 and V48P7E1 at 12 to 18 months after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7). Subjects in the arm did not receive any intervention (only blood draw).

    Reporting group title
    TBE_C
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Conventional schedule group-consisted of 3 vaccinations with an interval of 1 month between the first and second vaccination and an interval of 10 months to 12 months between the second and third vaccination (ie, on day 0, day 28, day 300 of study V48P7).

    Reporting group title
    TBE_MC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Modified conventional (MC) schedule group-TBE vaccine was given with a reduced interval between first and second vaccination; ie, from 28 days to 21 days (ie, vaccinations on day 0, day 21, day 300 of study V48P7).

    Reporting group title
    TBE_AC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Accelerated conventional (AC) schedule group-TBE vaccine was given by means of an even more reduced interval between the first and second vaccination; ie, from 28 days to 14 days (ie, vaccinations on day 0, day 14, and day 300 of study V48P7).

    Subject analysis set title
    All enrolled set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The enrolled population contained all subjects enrolled in the study, ie, with a record in DEMOG panel. This population was used for the analysis of demographics, concomitant medications, medical history and all subject listings.

    Subject analysis set title
    Full Analysis Set (FAS) Immunogenecity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who: ▫ were admitted to the study, irrespective whether they received study vaccination or not; ▫ provided at least one evaluable serum sample

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who received a booster vaccination on day 0 (V48P7E1) excluding TBE_R_B group and provided postvaccination safety data.

    Subject analysis set title
    Per-Protocol (PP) Population, Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS comprised all subjects who: ▫ received the relevant booster vaccination correctly or had completed the rapid schedule and had already received a booster vaccination prior to admission into the present study; ▫ provided evaluable serum samples at the relevant time points; ▫ presented no major violations regarding concomitant medication/concomitant disease; ▫ had no major violations of inclusion/exclusion criteria. Specifically, subjects meeting the following criteria were excluded from the PPS: ▫ subjects who received another vaccine within 4 weeks after the administration of the study vaccine*; ▫ subjects treated with immunoglobulins, whole blood or plasma derivates up to 4 weeks after administration of study vaccine subjects treated with immunosuppressants or systemic corticosteroids during the study period, except short term use of topic corticosteroids or low-dose systemic use (e.g.,up to 10 mg of prednisolone for up to 14 days). Subjects meeting the following crite

    Primary: 1. Percentage of Subjects With Antibody Titers ≥2 as Measured by NT.

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    End point title
    		 1. Percentage of Subjects With Antibody Titers ≥2 as Measured by NT. [1]
    End point description
    Immunogenicity was measured in terms of the Percentage of Subjects With Antibody Titers ≥2 as Measured by Neutralization-test (NT). Data are reported based on the Per Protocol Set (PPS).
    End point type
    Primary
    End point timeframe
    Year 5
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    8
    37
    51
    101
    101
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 0
    88 (47 to 100)
    100 (91 to 100)
    100 (93 to 100)
    99 (95 to 100)
    100 (96 to 100)
        Day 21 (N=8,0,51,101,100)
    100 (63 to 100)
    0 (0 to 0)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 1 (N=8,35,50,100,101)
    100 (63 to 100)
    100 (90 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 2 (N=8,35,51,99,100)
    100 (63 to 100)
    100 (90 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 3 (N=8,35,49,100,100)
    100 (63 to 100)
    97 (85 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 4 (N=7,34,48,99,100)
    100 (59 to 100)
    100 (90 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 5 (N=8,36,48,98,99)
    100 (63 to 100)
    100 (90 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
    No statistical analyses for this end point

    Primary: 2. Percentage of Subjects With Antibody Titers ≥10 as Measured by NT.

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    End point title
    		 2. Percentage of Subjects With Antibody Titers ≥10 as Measured by NT. [2]
    End point description
    Immunogenicity was measured in terms of the Percentage of Subjects With Antibody Titers ≥10 as Measured by NT. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    Year 5
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    8
    37
    51
    101
    101
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 0
    75 (35 to 97)
    97 (86 to 100)
    98 (90 to 100)
    97 (92 to 99)
    99 (95 to 100)
        Day 21 (N=8,0,51,101,100)
    100 (63 to 100)
    0 (0 to 0)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 1 (N=8,35,50,100,101)
    100 (63 to 100)
    97 (85 to 100)
    100 (93 to 100)
    100 (96 to 100)
    100 (96 to 100)
        Year 2 (N=8,35,51,99,100)
    100 (63 to 100)
    97 (85 to 100)
    100 (93 to 100)
    99 (95 to 100)
    100 (96 to 100)
        Year 3 (N=8,35,49,100,100)
    100 (63 to 100)
    97 (85 to 100)
    100 (93 to 100)
    95 (89 to 98)
    100 (96 to 100)
        Year 4 (N=7,34,48,99,100)
    100 (59 to 100)
    94 (80 to 99)
    100 (93 to 100)
    97 (91 to 99)
    100 (96 to 100)
        Year 5 (N=8,36,48,98,99)
    100 (63 to 100)
    97 (85 to 100)
    100 (93 to 100)
    98 (93 to 100)
    100 (96 to 100)
    No statistical analyses for this end point

    Primary: 3. Geometric Mean Antibody Titers (GMT) as Measured by NT.

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    End point title
    		 3. Geometric Mean Antibody Titers (GMT) as Measured by NT. [3]
    End point description
    Immunogenicity was measured in terms of the Geometric Mean Antibody Titers (GMT) as Measured by NT. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    Year 5
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    8
    37
    51
    101
    101
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 0
    67 (22 to 201)
    395 (236 to 658)
    232 (150 to 359)
    206 (151 to 281)
    237 (174 to 323)
        Day 21 (N=8,0,51,101,100)
    1476 (646 to 3373)
    0 (0 to 0)
    1182 (852 to 1640)
    1024 (812 to 1293)
    1059 (838 to 1338)
        Year 1 (N=8,35,50,100,101)
    378 (152 to 936)
    234 (152 to 362)
    240 (167 to 345)
    249 (193 to 322)
    246 (190 to 317)
        Year 2 (N=8,35,51,99,100)
    370 (150 to 913)
    235 (152 to 362)
    229 (160 to 237)
    211 (163 to 272)
    232 (180 to 300)
        Year 3 (N=8,35,49,100,100)
    331 (121 to 910)
    235 (145 to 380)
    230 (153 to 346)
    211 (159 to 281)
    228 (171 to 303)
        Year 4 (N=7,34,48,99,100)
    137 (50 to 379)
    192 (121 to 304)
    250 (169 to 368)
    208 (159 to 273)
    253 (193 to 331)
        Year 5 (N=8,36,48,98,99)
    429 (151 to 1217)
    358 (219 to 586)
    300 (196 to 460)
    281 (208 to 378)
    305 (227 to 410)
    No statistical analyses for this end point

    Primary: 4. Ratios of Geometric Mean Antibody Titers (GMT) as Measured by NT.

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    End point title
    		 4. Ratios of Geometric Mean Antibody Titers (GMT) as Measured by NT. [4]
    End point description
    Immunogenicity was measured in terms of the Ratios of Geometric Mean Antibody Titers (GMT) as Measured by NT. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    Year 5
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    8
    37
    51
    101
    101
    Units: Ratio of GMTs
    number (confidence interval 95%)
        Day 21/Day 0 (N=8,0,51,101,100)
    22 (11 to 45)
    0 (0 to 0)
    5.1 (3.85 to 6.75)
    4.97 (4.07 to 6.07)
    4.5 (3.68 to 5.49)
        year 1/day 0 (N=8,35,50,100,101)
    5.66 (2.83 to 11)
    0.57 (0.41 to 0.79)
    1.04 (0.79 to 1.37)
    1.21 (1 to 1.48)
    1.04 (0.85 to 1.26)
        Year2/day 0 (N=8,35,51,99,100)
    5.55 (3.09 to 9.96)
    0.57 (0.43 to 0.75)
    0.99 (0.78 to 1.24)
    1.03 (0.87 to 1.21)
    0.96 (0.82 to 1.14)
        Year 3/day 0 (N=8,35,49,100,100)
    4.97 (2.8 to 8.8)
    0.57 (0.43 to 0.75)
    1.04 (0.82 to 1.31)
    1.05 (0.89 to 1.23)
    0.95 (0.81 to 1.12)
        Year 4/day 0 (N=7,34,48,99,100)
    2.15 (0.92 to 5)
    0.47 (0.32 to 0.69)
    1.06 (0.77 to 1.46)
    1.04 (0.83 to 1.31)
    1.05 (0.84 to 1.32)
        Year 5/day 0 (N=8,36,48,98,99)
    6.44 (3.56 to 12)
    0.88 (0.67 to 1.16)
    1.28 (1 to 1.63)
    1.38 (1.16 to 1.63)
    1.28 (1.08 to 1.51)
    No statistical analyses for this end point

    Primary: 5. Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only.

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    End point title
    		 5. Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only. [5] [6]
    End point description
    Immunogenicity was measured in terms of the Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    Visit 6 up to visit 10 (Day 0)
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    [6] - 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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B
    Number of subjects analysed
    8
    37
    Units: Titers
    geometric mean (confidence interval 95%)
        Visit 6
    64 (27 to 152)
    42 (28 to 63)
        Visit 7
    19 (7.76 to 45)
    33 (22 to 49)
        Visit 8
    14 (6.29 to 30)
    24 (17 to 34)
        Visit 10
    67 (21 to 208)
    395 (232 to 670)
    No statistical analyses for this end point

    Primary: 6. Ratios of Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only.

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    End point title
    		 6. Ratios of Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only. [7] [8]
    End point description
    Immunogenicity was measured in terms of the ratios of the Geometric Mean Antibody Titers as Measured by NT for Rapid Schedule Only. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    up to Visit 10 (Day 0)
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    [8] - 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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_R_B
    Number of subjects analysed
    8
    37
    Units: Ratio of GMTs
    number (confidence interval 95%)
        Visit 10: Visit 6
    1.04 (0.3 to 3.57)
    9.4 (5.3 to 17)
        Visit 10: Visit 7
    3.56 (1.26 to 10)
    12 (7.46 to 20)
        Visit 10: Visit 8
    4.87 (1.82 to 13)
    16 (10 to 26)
    No statistical analyses for this end point

    Primary: 7. Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules.

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    End point title
    		 7. Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules. [9] [10]
    End point description
    Immunogenicity was measured in terms of the Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    up to visit 10 (Day 0)
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    [10] - 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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    51
    101
    101
    Units: Titers
    geometric mean (confidence interval 95%)
        Visit 9
    1131 (770 to 1660)
    1133 (862 to 1489)
    1143 (870 to 1501)
        Visit 10
    232 (150 to 359)
    206 (151 to 281)
    237 (174 to 323)
    No statistical analyses for this end point

    Primary: 8. Ratios of the Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules.

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    End point title
    		 8. Ratios of the Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules. [11] [12]
    End point description
    Immunogenicity was measured in terms of the ratios of the Geometric Mean Antibody Titers as Measured by NT for Conventional Schedules. Data are reported based on the PPS.
    End point type
    Primary
    End point timeframe
    up to Visit 10 (Day 0)
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    [12] - 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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    51
    101
    101
    Units: Ratio of GMTs
    number (confidence interval 95%)
        Visit 10/visit 9
    0.21 (0.16 to 0.26)
    0.18 (0.15 to 0.21)
    0.21 (0.18 to 0.24)
    No statistical analyses for this end point

    Secondary: 9. Number of subjects with solicited local and solicited systemic AEs

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    End point title
    		 9. Number of subjects with solicited local and solicited systemic AEs [13]
    End point description
    Safety was assessed in terms of the Number of subjects with solicited local and solicited systemic AEs up to 3 days after booster vaccination.
    End point type
    Secondary
    End point timeframe
    4 days (up to day 3)
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    9
    55
    108
    106
    Units: Subjects
        Pain_Classification A
    7
    35
    59
    52
        Erythema (mm)_Classification A
    1
    3
    9
    9
        Swelling (mm)_Classification A
    0
    4
    7
    6
        Pain_Classification B
    7
    35
    59
    52
        Erythema (mm)_Classification B
    0
    1
    4
    1
        Swelling (mm)_Classification B
    0
    3
    6
    1
        Nausea
    1
    2
    3
    4
        Malaise
    1
    3
    8
    7
        Myalgia
    3
    12
    18
    13
        Arthralgia
    1
    3
    7
    3
        Headache
    2
    8
    12
    17
    No statistical analyses for this end point

    Secondary: 10. Number of Subjects with unsolicited AEs.

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    End point title
    		 10. Number of Subjects with unsolicited AEs. [14]
    End point description
    Safety was assessed in terms of the number of subjects with unsolicited Adverse Events from Day 0 up to Day 21.
    End point type
    Secondary
    End point timeframe
    Day 0 up to day 21.
    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: No statistical analysis is associated to this endpoint. The analyses were run descriptively.
    End point values
    		 TBE_R TBE_C TBE_MC TBE_AC
    Number of subjects analysed
    9
    55
    108
    106
    Units: Partecipants
        Any Adverse Events
    1
    9
    12
    14
        At least possibly related AEs
    1
    3
    5
    3
        Serious AEs
    0
    3
    5
    7
        At least possibly related SAEs
    0
    0
    0
    0
        Deaths
    0
    1
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 0 through year 5.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    TBE_R
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination: Rapid (R) schedule group- all 3 vaccinations were given within 3 weeks, with an interval of 1 week between the first and second vaccination and an interval of 2 weeks between the second and third vaccination (ie, on day 0, day 7, day 21 of study V48P7).

    Reporting group title
    TBE_C
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Conventional schedule group-consisted of 3 vaccinations with an interval of 1 month between the first and second vaccination and an interval of 10 months to 12 months between the second and third vaccination (ie, on day 0, day 28, day 300 of study V48P7).

    Reporting group title
    TBE_MC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Modified conventional (MC) schedule group-TBE vaccine was given with a reduced interval between first and second vaccination; ie, from 28 days to 21 days (ie, vaccinations on day 0, day 21, day 300 of study V48P7).

    Reporting group title
    TBE_AC
    Reporting group description
    		 Subjects received First booster vaccine at 3 years after the completion of the primary vaccination series of study V48P7. Primary vaccination Accelerated conventional (AC) schedule group-TBE vaccine was given by means of an even more reduced interval between the first and second vaccination; ie, from 28 days to 14 days (ie, vaccinations on day 0, day 14, and day 300 of study V48P7).

    Serious adverse events
    		 TBE_R TBE_C TBE_MC TBE_AC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 55 (5.45%)
    5 / 108 (4.63%)
    7 / 106 (6.60%)
         number of deaths (all causes)
    0
    1
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 55 (1.82%)
    0 / 108 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 55 (1.82%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Malignant melanoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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
    Ankle Fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Patella Fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 55 (1.82%)
    0 / 108 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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
    Congenital, familial and genetic disorders
    Trisomy 21
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Myocardial Infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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
    1 / 1
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Nervous system disorders
    Peroneal Nerve Palsy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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 / 9 (0.00%)
    0 / 55 (0.00%)
    1 / 108 (0.93%)
    0 / 106 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 55 (0.00%)
    0 / 108 (0.00%)
    1 / 106 (0.94%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TBE_R TBE_C TBE_MC TBE_AC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    40 / 55 (72.73%)
    69 / 108 (63.89%)
    62 / 106 (58.49%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    8 / 55 (14.55%)
    12 / 108 (11.11%)
    17 / 106 (16.04%)
         occurrences all number
    3
    10
    14
    19
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 55 (5.45%)
    9 / 108 (8.33%)
    9 / 106 (8.49%)
         occurrences all number
    1
    3
    9
    9
    Injectino site pain
         subjects affected / exposed
    7 / 9 (77.78%)
    35 / 55 (63.64%)
    59 / 108 (54.63%)
    52 / 106 (49.06%)
         occurrences all number
    7
    35
    60
    53
    Injection site swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 55 (7.27%)
    7 / 108 (6.48%)
    6 / 106 (5.66%)
         occurrences all number
    0
    4
    7
    6
    Malaise
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 55 (5.45%)
    8 / 108 (7.41%)
    7 / 106 (6.60%)
         occurrences all number
    1
    4
    8
    8
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 55 (3.64%)
    3 / 108 (2.78%)
    1 / 106 (0.94%)
         occurrences all number
    1
    2
    3
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 55 (3.64%)
    3 / 108 (2.78%)
    4 / 106 (3.77%)
         occurrences all number
    1
    3
    3
    5
    Musculoskeletal and connective tissue disorders
    Athralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 55 (5.45%)
    7 / 108 (6.48%)
    3 / 106 (2.83%)
         occurrences all number
    1
    3
    9
    3
    Myalgia
         subjects affected / exposed
    3 / 9 (33.33%)
    12 / 55 (21.82%)
    18 / 108 (16.67%)
    13 / 106 (12.26%)
         occurrences all number
    3
    14
    19
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2008
    slight revision of wording regarding points of time of blood withdrawal; adjustment related to ELISA tests (ie, TBE antibody titers were to be determined by Neutralization Test only).Specification of SAE reporting procedure

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24950352
    For support, Contact us.
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