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    Clinical Trial Results:
    Open-label follow-up study to investigate the seropersistence of TBE antibodies and the booster response to a tick-borne encephalitis vaccine in children and adolescents aged 3 - 18 years.

    Summary
    EudraCT number
    2005-000767-26
    Trial protocol
    AT   DE  
    Global end of trial date
    25 Jul 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    700401
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00161967
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias: B9371020
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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?
    Yes
    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
    23 Jul 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess Tick-Borne Encephalitis (TBE) antibody persistence 24 months and 34 months after the third TBE vaccination with FSME-IMMUN 0.25 milliliter (mL), by means of Enzyme-Linked immunosorbent Assay (ELISA) (IMMUNOZYM FSME immunoglobulin G [IgG]) and neutralization test (NT). To assess TBE antibody response to a booster vaccination with FSME-IMMUN 0.25 mL or FSME-IMMUN 0.5 mL administered 36 months after the third vaccination, by means of ELISA and NT.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 160
    Country: Number of subjects enrolled
    Austria: 79
    Country: Number of subjects enrolled
    Poland: 119
    Worldwide total number of subjects
    358
    EEA total number of subjects
    358
    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)
    59
    Children (2-11 years)
    220
    Adolescents (12-17 years)
    79
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was carried out at 4 study sites in 3 European countries (Austria, Germany and Poland). It started on 09 May 2005 and completed on 25 Jul 2008.

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

    Arms
    Arm title
    3 or 4 Doses FSME-IMMUN
    Arm description
    Subjects received primary immunization (3 vaccinations at 0, 1 and 6 Month with FSME-IMMUN 0.25 milliliter [mL]) in study 209 [NCT00161863] were offered a booster dose (4th dose) 3-, 4-, or 5-year after the third vaccination, depending on their TBE titers. Subjects with high TBE antibody levels (ELISA greater than [>] 1000 Vienna Units per milliliter [VIE U/ml] and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination were not to receive the 4th dose.
    Arm type
    Experimental

    Investigational medicinal product name
    FSME-IMMUN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received a booster dose (4th dose) of FSME-IMMUN 0.25 mL (age less than [<] 16 years) or 0.5 mL (age greater than or equal to [>=] 16 years old) 3-, 4-, or 5-years after the third vaccination in study 209 if the TBE antibody level was ELISA <= 1000 VIE U/mL or negative NT results at 24, 34, 46, and/or 58 months after the third vaccination from study 209.

    Number of subjects in period 1
    3 or 4 Doses FSME-IMMUN
    Started
    358
    36-Month Booster Dose
    175 [1]
    48-Month Booster Dose
    29 [2]
    60-Month Booster Dose
    1 [3]
    Completed
    324
    Not completed
    34
         'Already vaccinated by mistake '
             2
         Decision of Medical Director
             8
         Subject dropped out due to desensitization
             1
         Not given study vaccination
             5
         No return
             4
         Not possible to withdraw blood from the volunteer
             1
         'Remove of wire of the ulna and radius in hospital '
             1
         Refused the blood draw
             5
         Consent withdrawn by subject
             4
         Subject changed to/went to family doctor
             2
         Lost to follow-up
             1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not all subjects who enrolled in this study, received a booster vaccination. Subjects with high TBE antibody levels (ELISA >1000 VIE U/ml and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination did not received the 4th dose.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not all subjects who enrolled in this study, received a booster vaccination. Subjects with high TBE antibody levels (ELISA >1000 VIE U/ml and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination did not received the 4th dose.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not all subjects who enrolled in this study, received a booster vaccination. Subjects with high TBE antibody levels (ELISA >1000 VIE U/ml and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination did not received the 4th dose.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    3 or 4 Doses FSME-IMMUN
    Reporting group description
    Subjects received primary immunization (3 vaccinations at 0, 1 and 6 Month with FSME-IMMUN 0.25 milliliter [mL]) in study 209 [NCT00161863] were offered a booster dose (4th dose) 3-, 4-, or 5-year after the third vaccination, depending on their TBE titers. Subjects with high TBE antibody levels (ELISA greater than [>] 1000 Vienna Units per milliliter [VIE U/ml] and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination were not to receive the 4th dose.

    Reporting group values
    3 or 4 Doses FSME-IMMUN Total
    Number of subjects
    358 358
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.519553 ± 4.391666 -
    Gender categorical
    Units: Subjects
        Female
    178 178
        Male
    180 180

    End points

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    End points reporting groups
    Reporting group title
    3 or 4 Doses FSME-IMMUN
    Reporting group description
    Subjects received primary immunization (3 vaccinations at 0, 1 and 6 Month with FSME-IMMUN 0.25 milliliter [mL]) in study 209 [NCT00161863] were offered a booster dose (4th dose) 3-, 4-, or 5-year after the third vaccination, depending on their TBE titers. Subjects with high TBE antibody levels (ELISA greater than [>] 1000 Vienna Units per milliliter [VIE U/ml] and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination were not to receive the 4th dose.

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 1 Month After the Third Vaccination in Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 1 Month After the Third Vaccination in Study 209 by First Dose Age Group [1]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or NT >=10. Here, 'N' signifies those subjects who were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    1 month after the third vaccination in study 209
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1-2 years (N= 75)
    100 (95.2 to 100)
        3-6 years (N= 70)
    100 (94.9 to 100)
        7-15 years (N= 213)
    100 (98.3 to 100)
        12-15 years (N= 79)
    100 (95.4 to 100)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 24 Months After the Third Vaccination in Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 24 Months After the Third Vaccination in Study 209 by First Dose Age Group [2]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or NT >=10. Here, 'N' signifies those subjects who were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    24 months after the third vaccination in study 209
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1-2 years (N= 75)
    100 (95.2 to 100)
        3-6 years (N= 70)
    98.6 (92.3 to 100)
        7-15 years (N= 213)
    97.7 (94.6 to 99.2)
        12-15 years (N= 79)
    98.7 (93.1 to 100)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 34 Months After the Third Vaccination in Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 34 Months After the Third Vaccination in Study 209 by First Dose Age Group [3]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or NT >=10. Here, 'N' signifies those subjects who evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    34 months after the third vaccination in study 209
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1-2 years (N= 73)
    100 (95.1 to 100)
        3-6 years (N= 68)
    98.5 (92.1 to 100)
        7-15 years (N= 212)
    97.2 (93.9 to 99)
        12-15 years (N= 78)
    97.4 (91 to 99.7)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 46 Months After the Third Vaccination in Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 46 Months After the Third Vaccination in Study 209 by First Dose Age Group [4]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or NT >=10. Here, 'N' signifies those subjects who were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    46 months after the third vaccination in study 209
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1-2 years (N= 73)
    98.6 (92.6 to 100)
        3-6 years (N= 68)
    97.1 (89.8 to 99.6)
        7-15 years (N= 212)
    92.9 (88.6 to 96)
        12-15 years (N= 78)
    91 (82.4 to 96.3)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 58 Months After the Third Vaccination in Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 at 58 Months After the Third Vaccination in Study 209 by First Dose Age Group [5]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or NT >=10. Here, 'N' signifies those subjects who were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    58 months after the third vaccination in study 209
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1-2 years (N= 73)
    87.7 (77.9 to 94.2)
        3-6 years (N= 68)
    95.6 (87.6 to 99.1)
        7-15 years (N= 212)
    84 (78.3 to 88.6)
        12-15 years (N= 78)
    79.5 (68.8 to 87.8)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 36 Month Booster Vaccination in this Study by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 36 Month Booster Vaccination in this Study by First Dose Age Group [6]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or with NT >=10 among subjects who received Booster Vaccination at Month 36. Full analysis dataset included subjects who received a booster vaccination at 36 Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies those subjects who received the corresponding booster vaccination at Month 36 and were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    21-35 days after 36-month booster dose
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    174
    Units: Percentage of Subjects
    number (confidence interval 95%)
        FSME-IMMUN 0.25mL: 1-2 years (N= 25)
    100 (86.3 to 100)
        FSME-IMMUN 0.25mL: 3-6 years (N= 24)
    100 (85.8 to 100)
        FSME-IMMUN 0.25mL: 7-15 years (N= 89)
    100 (95.9 to 100)
        FSME-IMMUN 0.5mL: 7-15 years (N= 36)
    100 (90.3 to 100)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 48 Month Booster Vaccination in this Study by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 48 Month Booster Vaccination in this Study by First Dose Age Group [7]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or with NT >=10 among subjects who received Booster Vaccination at Month 48. Full analysis dataset included subjects who received a booster vaccination at 48 Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies those subjects who received the corresponding booster vaccination at Month 48 and were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    21-35 days after 48-month booster dose
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    29
    Units: Percentage of Subjects
    number (confidence interval 95%)
        FSME-IMMUN 0.25mL: 1-2 years (N= 6)
    100 (54.1 to 100)
        FSME-IMMUN 0.25mL: 3-6 years (N= 6)
    100 (54.1 to 100)
        FSME-IMMUN 0.25mL: 7-15 years (N= 6)
    100 (54.1 to 100)
        FSME-IMMUN 0.5mL: 7-15 years (N= 11)
    100 (71.5 to 100)
    No statistical analyses for this end point

    Primary: Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 60 Month Booster Vaccination in this Study by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA and/or NT According to Adner et al., 2001 After the 60 Month Booster Vaccination in this Study by First Dose Age Group [8]
    End point description
    Proportion of subjects with ELISA >126 VIE U/mL or with NT >=10 among subjects who received Booster Vaccination at Month 60. Full analysis dataset included subjects who received a booster vaccination at 60 Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies the subjects who received the corresponding booster vaccination at Month 60 and were evaluable within the specified age group in study 209.
    End point type
    Primary
    End point timeframe
    21-35 days after 60-month booster dose
    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: Only descriptive statistics (95% CI) were planned, no formal hypothesis testing analysis performed. 
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    1
    Units: Percentage of Subjects
    number (confidence interval 95%)
        FSME-IMMUN 0.5mL: 7-15 years
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Seropositivity Rate Measured by ELISA at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by ELISA at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    Proportion of subjects with ELISA concentrations >126 VIE U/mL and 95% confidence interval (CI) were presented. Results were summarized for the applicable categories based on the time point of assessment, dose of FSME-IMMUN received in current study (0.25 mL and 0.5 mL) and age of the subject at first vaccination in study 209: 1-2 years, 3-6 years, 7-15 years, and 12-15 years. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    1, 24, 34, 46, 58 months after the third vaccination in study 209; 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1 month after third dose:1-2years (N= 75)
    100 (95.2 to 100)
        1 month after third dose:3-6years (N= 70)
    100 (94.9 to 100)
        1 month after third dose:7-15years (N= 213)
    99.5 (97.4 to 100)
        1 month after third dose:12-15years (N= 79)
    98.7 (93.1 to 100)
        24 months after third dose:1-2years (N= 75)
    100 (95.2 to 100)
        24 months after third dose:3-6years (N= 70)
    98.6 (92.3 to 100)
        24 months after third dose:7-15years (N= 213)
    93 (88.7 to 96)
        24 months after third dose:12-15years(N= 79)
    92.4 (84.2 to 97.2)
        34 months after third dose:1-2years (N= 73)
    100 (95.1 to 100)
        34 months after third dose:3-6years (N= 68)
    98.5 (92.1 to 100)
        34 months after third dose:7-15years (N= 212)
    94.8 (90.9 to 97.4)
        34 months after third dose:12-15years(N= 78)
    93.6 (85.7 to 97.9)
        46 month after third dose:1-2years (N= 73)
    97.3 (90.5 to 99.7)
        46 months after third dose:3-6years (N= 68)
    95.6 (87.6 to 99.1)
        46 months after third dose:7-15years (N= 210)
    86.2 (80.8 to 90.6)
        46 months after third dose:12-15years (N= 78)
    83.3 (73.2 to 90.8)
        58 months after third dose:1-2years (N= 73)
    75.3 (63.9 to 84.7)
        58 months after third dose:3-6years (N= 68)
    83.8 (72.9 to 91.6)
        58 months after third dose:7-15years (N= 210)
    69.5 (62.8 to 75.7)
        58 months after third dose:12-15years(N= 78)
    69.2 (57.8 to 79.2)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    100 (86.3 to 100)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    95.8 (78.9 to 99.9)
        After 36 month booster dose 0.25mL:7-15years(N=89)
    97.8 (92.1 to 99.7)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    100 (90.3 to 100)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    100 (71.5 to 100)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Seropositivity Rate Measured by NT According to Adner et al., 2001 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by NT According to Adner et al., 2001 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    Proportion of subjects with NT titer >=10 and 95% CI were presented. Results were summarized for the applicable categories based on the time point of assessment, dose of FSME-IMMUN received in current study (0.25 mL and 0.5 mL) and age of the subject at first vaccination in study 209: 1-2 years, 3-6 years, 7-15 years, and 12-15 years. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    1, 24, 34, 46, 58 months after the third vaccination in study 209; 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        1 month after third dose:1-2years (N= 75)
    100 (95.2 to 100)
        1 month after third dose:3-6years (N= 70)
    98.6 (92.3 to 100)
        1 month after third dose:7-15years (N= 213)
    99.5 (97.4 to 100)
        1 month after third dose:12-15years (N= 79)
    98.7 (93.1 to 100)
        24 months after third dose:1-2years (N= 75)
    100 (95.2 to 100)
        24 months after third dose:3-6years (N= 70)
    98.6 (92.3 to 100)
        24 months after third dose:7-15years (N= 213)
    97.7 (94.6 to 99.2)
        24 months after third dose:12-15years(N= 79)
    98.7 (93.1 to 100)
        34 months after third dose:1-2years (N= 73)
    100 (95.1 to 100)
        34 months after third dose:3-6years (N= 68)
    98.5 (92.1 to 100)
        34 months after third dose:7-15years (N= 212)
    97.2 (93.9 to 99)
        34 months after third dose:12-15years(N= 78)
    97.4 (91 to 99.7)
        46 month after third dose:1-2years (N= 73)
    94.5 (86.6 to 98.5)
        46 months after third dose:3-6years (N= 68)
    97.1 (89.8 to 99.6)
        46 months after third dose:7-15years (N= 211)
    91.9 (87.4 to 95.2)
        46 months after third dose:12-15years(N= 77)
    88.3 (79 to 94.5)
        58 months after third dose:1-2years (N= 73)
    86.3 (76.2 to 93.2)
        58 months after third dose:3-6years (N= 68)
    95.6 (87.6 to 99.1)
        58 months after third dose:7-15years (N= 210)
    81.9 (76 to 86.9)
        58 months after third dose:12-15years(N= 76)
    75 (63.7 to 84.2)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    100 (86.3 to 100)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    100 (85.8 to 100)
        After 36 month booster dose 0.25mL:7-15years(N=88)
    100 (95.9 to 100)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    100 (90.3 to 100)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    100 (54.1 to 100)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    100 (71.5 to 100)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Geometric Mean Antibody Concentration (GMC) as Measured by ELISA at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Geometric Mean Antibody Concentration (GMC) as Measured by ELISA at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    Antibody GMC for TBE as measured by ELISA for subjects presented. GMC and corresponding 2-sided 95% CIs were evaluated. Results were summarized for the applicable categories based on the time point of assessment, dose of FSME-IMMUN received in current study (0.25 mL and 0.5 mL) and age of the subject at first vaccination in study 209: 1-2 years, 3-6 years, 7-15 years, and 12-15 years. Here -99999 and 99999 indicates lower and upper limit of CI. CI was not estimable as number of subjects evaluable for 60-Month booster dose was 1. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    1, 24, 34, 46, 58 months after the third vaccination in study 209; 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Vienna Units per milliliter(VIE U/mL)
    geometric mean (confidence interval 95%)
        1 month after third dose:1-2years (N= 75)
    9320.9 (8137 to 10677.1)
        1 month after third dose:3-6years (N= 70)
    7999.5 (6614.2 to 9674.9)
        1 month after third dose:7-15years (N= 213)
    4159.9 (3665.3 to 4721.2)
        1 month after third dose:12-15years (N= 79)
    2908.9 (2308 to 3666.4)
        24 months after third dose:1-2years (N= 75)
    1836 (1526.7 to 2207.8)
        24 months after third dose:3-6years (N= 70)
    1626.1 (1332.8 to 1984)
        24 months after third dose:7-15years (N= 213)
    838.2 (731.4 to 960.7)
        24 months after third dose:12-15years(N= 79)
    697.3 (559.8 to 868.5)
        34 months after third dose:1-2years (N= 73)
    1420.5 (1187.6 to 1699.2)
        34 months after third dose:3-6years (N= 68)
    1388.5 (1135 to 1698.6)
        34 months after third dose:7-15years (N= 212)
    793.9 (694 to 908.2)
        34 months after third dose:12-15years(N= 78)
    688.7 (538.6 to 880.7)
        46 month after third dose:1-2years (N= 73)
    863 (666.9 to 1116.9)
        46 months after third dose:3-6years (N= 68)
    858.7 (662.5 to 1113)
        46 months after third dose:7-15years (N= 210)
    404.3 (340.2 to 480.4)
        46 months after third dose:12-15years(N= 78)
    367.3 (273.3 to 493.7)
        58 month after third dose:1-2years (N= 73)
    568.9 (401.6 to 805.7)
        58 months after third dose:3-6years (N= 68)
    631.6 (443.2 to 900.1)
        58 months after third dose:7-15years (N= 210)
    245.6 (195.6 to 308.4)
        58 months after third dose:12-15years(N= 78)
    219.5 (150.7 to 319.6)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    8686.5 (6077.6 to 12415.4)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    5867.5 (3195.4 to 10774.2)
        After 36 month booster dose 0.25mL:7-15years(N=89
    3805 (2837.3 to 5102.6)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    2737.6 (1886.4 to 3972.9)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    7636.3 (6165.7 to 9457.6)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    5373.8 (2600.9 to 11103.2)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    8400.8 (3862.1 to 18273.3)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    5483.4 (3389.6 to 8870.7)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    1001 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Geometric Mean Antibody Titer (GMT) as Measured by NT According to Adner et al., 2001 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Geometric Mean Antibody Titer (GMT) as Measured by NT According to Adner et al., 2001 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    GMT for NT and corresponding 2-sided 95% CIs were evaluated. Results were summarized for the applicable categories based on the time point of assessment, dose of FSME-IMMUN received in current study (0.25 mL and 0.5 mL) and age of the subject at first vaccination in study 209: 1-2 years, 3-6 years, 7-15 years, and 12-15 years. Here, -99999 and 99999 indicates lower and upper limit of CI. CI was not estimable as number of subjects evaluable for 60-Month booster dose was 1. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    1, 24, 34, 46, 58 months after the third vaccination in study 209; 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Titer
    geometric mean (confidence interval 95%)
        1 month after third dose:1-2years (N= 75)
    567.6 (526.6 to 611.8)
        1 month after third dose:3-6years (N= 70)
    461.5 (387.4 to 549.8)
        1 month after third dose:7-15years (N= 213)
    303.1 (267.5 to 343.3)
        1 month after third dose:12-15years (N= 79)
    227.8 (182 to 285.1)
        24 months after third dose:1-2years (N= 75)
    153.5 (124.9 to 188.7)
        24 months after third dose:3-6years (N= 70)
    204 (165.1 to 252.1)
        24 months after third dose:7-15years (N= 213)
    110.8 (95.3 to 128.7)
        24 months after third dose:12-15years(N= 79)
    94 (73.2 to 120.7)
        34 months after third dose:1-2years (N= 73)
    166.3 (134.9 to 204.9)
        34 months after third dose:3-6years (N= 68)
    188.4 (150.2 to 236.3)
        34 months after third dose:7-15years (N= 212)
    97.1 (83.2 to 113.3)
        34 months after third dose:12-15years(N= 78)
    74.6 (57.1 to 97.5)
        46 months after third dose:1-2years (N= 73)
    74.1 (58.1 to 94.5)
        46 months after third dose:3-6years (N= 68)
    95.1 (76.5 to 118.2)
        46 months after third dose:7-15years (N= 211)
    50.6 (43 to 59.6)
        46 months after third dose:12-15years(N= 77)
    42.5 (31.8 to 56.9)
        58 month after third dose:1-2years (N= 73)
    57.1 (41.2 to 79.1)
        58 months after third dose:3-6years (N= 68)
    81.9 (62.5 to 107.3)
        58 months after third dose:7-15years (N= 210)
    36.4 (29.5 to 44.9)
        58 months after third dose:12-15years(N= 76)
    29.3 (20.3 to 42.1)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    564.9 (490.7 to 650.4)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    349.1 (234.5 to 519.8)
        After 36 month booster dose 0.25mL:7-15years(N=88)
    330.3 (272.9 to 399.8)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    332.8 (245.4 to 451.2)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    570.2 (423.7 to 767.3)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    522.7 (310.7 to 879.5)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    553.9 (382.1 to 803)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    489.6 (337.1 to 711.1)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    80 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Fold Increase in Antibody Concentrations After the Booster Vaccination as Compared to Before the Booster Vaccination as Measured by ELISA by First Dose Age Group

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    End point title
    Geometric Mean of Fold Increase in Antibody Concentrations After the Booster Vaccination as Compared to Before the Booster Vaccination as Measured by ELISA by First Dose Age Group
    End point description
    Geometric mean of fold increase in TBE antibody concentrations as measured by ELISA and 95% CIs were evaluated. Results were summarized for the applicable categories based on the dose and timepoint of FSME-IMMUN received and age of the subject at first vaccination: 1-2 years, 3-6 years, 7-15 years. Here, -99999 and 99999 indicates lower and upper limit of CI. It was not estimable as the number of subjects evaluable for 60 Month booster dose was 1. Full analysis dataset included subjects who received a booster vaccination at 36-, 48- or 60-Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    From before booster dose to 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    204
    Units: Fold Increase
    geometric mean (confidence interval 95%)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    13.5 (9.8 to 18.5)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    8.2 (5.3 to 12.6)
        After 36 month booster dose 0.25mL:7-15years(N=89)
    7.7 (6.2 to 9.5)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    7.4 (5.5 to 10)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    9.1 (6.7 to 12.3)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    7.1 (3.1 to 16.1)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    12.6 (7.4 to 21.2)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    7 (4 to 12.1)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    3.7 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Fold Increase in Antibody Titer After the Booster Vaccination as Compared to Before the Booster Vaccination Measured by NT According to Adner et al., 2001 by First Dose Age Group

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    End point title
    Geometric Mean of Fold Increase in Antibody Titer After the Booster Vaccination as Compared to Before the Booster Vaccination Measured by NT According to Adner et al., 2001 by First Dose Age Group
    End point description
    Geometric mean of fold increase in TBE antibody titer as measured by NT and 95% CIs were evaluated. Results were summarized for the applicable categories based on the dose and timepoint of FSME-IMMUN received and age of the subject at first vaccination: 1-2 years, 3-6 years, 7-15 years. Here, -99999 and 99999 indicates lower and upper limit of CI. It was not estimable as the number of subjects evaluable for 60-Month booster dose was 1. Full analysis dataset included subjects who received a booster vaccination at 36-, 48- or 60-Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    From before booster dose to 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    204
    Units: Fold Increase
    geometric mean (confidence interval 95%)
        After 36 month booster dose 0.25mL:1-2years(N=25)
    8.2 (6.2 to 10.7)
        After 36 month booster dose 0.25mL:3-6years(N=24)
    3.8 (2.5 to 5.9)
        After 36 month booster dose 0.25mL:7-15years(N=88)
    5.7 (4.8 to 6.7)
        After 36 month booster dose 0.5mL:7-15years(N=36)
    8.2 (6.3 to 10.8)
        After 48 month booster dose 0.25mL:1-2years(N=6)
    10.1 (7 to 14.4)
        After 48 month booster dose 0.25mL:3-6years(N=6)
    7.3 (3.2 to 16.9)
        After 48 month booster dose 0.25mL:7-15years(N=6)
    11 (6 to 20.2)
        After 48 month booster dose 0.5mL:7-15years(N=11)
    9.8 (5.2 to 18.4)
        After 60 month booster dose 0.5mL:7-15years(N=1)
    11.4 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Seropositivity Rate Measured by NT according to Holzmann et al., 1996 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Seropositivity Rate Measured by NT according to Holzmann et al., 1996 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    Proportion of subjects with NT100 titers >=10 and NT50 titers >10 and 95% CIs were presented. Results were summarized for the applicable categories based on the time point of assessment, dose of FSME-IMMUN received in current study (0.25 mL and 0.5 mL) and age of the subject at first vaccination in study 209: 1-2 years, 3-6 years, 7-15 years, and 12-15 years. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    24, 34 month after the third vaccination in study 209; 21-35 days after the 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Percentage of Subjects
    number (confidence interval 95%)
        NT50:24 months after third dose:1-2years (N= 75)
    84 (73.7 to 91.4)
        NT100:24 months after third dose:1-2years (N= 75)
    72 (60.4 to 81.8)
        NT50:24 months after third dose:3-6years (N= 70)
    91.4 (82.3 to 96.8)
        NT100:24 months after third dose:3-6years (N= 70)
    81.4 (70.3 to 89.7)
        NT50:24 months after third dose:7-15years (N= 212)
    73.6 (67.1 to 79.4)
        NT100:24 months after third dose:7-15years(N= 212)
    57.1 (50.1 to 63.8)
        NT50:24 months after third dose:12-15years(N= 79)
    62 (50.4 to 72.7)
        NT100:24 months after third dose:12-15years(N= 79)
    46.8 (35.5 to 58.4)
        NT50:34 months after third dose:1-2years(N= 73)
    86.3 (76.2 to 93.2)
        NT100:34 months after third dose:1-2years(N= 73)
    75.3 (63.9 to 84.7)
        NT50:34 months after third dose:3-6years(N= 68)
    80.9 (69.5 to 89.4)
        NT100:34 months after third dose:3-6years(N= 68)
    64.7 (52.2 to 75.9)
        NT50:34 months after third dose:7-15years(N= 211)
    55.5 (48.5 to 62.3)
        NT100:34 months after third dose:7-15years(N= 211)
    38.9 (32.2 to 45.8)
        NT50:34 months after third dose:12-15years(N= 79)
    53.8 (42.2 to 65.2)
        NT100:34 months after third dose:12-15years(N= 79)
    30.8 (20.8 to 42.2)
        NT50:36 month booster dose 0.25mL:1-2years(N=25)
    100 (86.3 to 100)
        NT100:36 month booster dose 0.25mL:1-2years(N=25)
    100 (86.3 to 100)
        NT50:36 month booster dose 0.25mL:3-6years(N=24)
    91.7 (73 to 99)
        NT100:36 month booster dose 0.25mL:3-6years(N=24)
    91.7 (73 to 99)
        NT50:36 month booster dose 0.25mL:7-15years(N=88)
    90.9 (82.9 to 96)
        NT100:36 month booster dose 0.25mL:7-15years(N=88)
    87.5 (78.7 to 93.6)
        NT50:36 month booster dose 0.5mL:7-15years(N=36)
    88.9 (73.9 to 96.9)
        NT100:36 month booster dose 0.5mL:7-15years(N=36)
    86.1 (70.5 to 95.3)
        NT50:48 month booster dose 0.25mL:1-2years(N=6)
    100 (54.1 to 100)
        NT100:48 month booster dose 0.25mL:1-2years(N=6)
    100 (54.1 to 100)
        NT50:48 month booster dose 0.25mL:3-6years(N=6)
    100 (54.1 to 100)
        NT100:48 month booster dose 0.25mL:3-6years(N=6)
    100 (54.1 to 100)
        NT50:48 month booster dose 0.25mL:7-15years(N=6)
    100 (54.1 to 100)
        NT100:48 month booster dose 0.25mL:7-15years(N=6)
    100 (54.1 to 100)
        NT50:48 month booster dose 0.5mL:7-15years(N=11)
    100 (71.5 to 100)
        NT100:48 month booster dose 0.5mL:7-15years(N=11)
    100 (71.5 to 100)
        NT50:60 month booster dose 0.5mL:7-15years(N=1)
    100 (2.5 to 100)
        NT100:60 month booster dose 0.5mL:7-15years(N=1)
    0 (0 to 97.5)
    No statistical analyses for this end point

    Secondary: Geometric Mean Antibody Titer (GMT) as Measured by NT According to Holzmann et al., 1996 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group

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    End point title
    Geometric Mean Antibody Titer (GMT) as Measured by NT According to Holzmann et al., 1996 at Each Available Time Point After the Third Vaccination in the Study 209 by First Dose Age Group
    End point description
    GMT for NT and corresponding 2-sided 95% CIs were evaluated. NT100 titers and NT50 titers were presented. Results were summarized for the applicable categories based on the dose and timepoint of FSME-IMMUN received and age of the subject at first vaccination: 1-2 years, 3-6 years, 7-15 years and 12-15 years. Here, -99999 and 99999 indicates lower and upper limit of CI. It was not estimable as number of subjects evaluable for 60-Month booster dose was 1. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    24, 34 months after the third vaccination in study 209; 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    358
    Units: Titer
    geometric mean (confidence interval 95%)
        NT50:24 month after third dose:1-2years (N= 75)
    21.7 (17.5 to 26.8)
        NT100:24 months after third dose:1-2years (N= 75)
    14 (11.6 to 16.9)
        NT50:24 months after third dose:3-6years (N= 70)
    33.4 (27.2 to 41.1)
        NT100:24 months after third dose:3-6years (N= 70)
    17.7 (14.7 to 21.3)
        NT50:24 months after third dose:7-15years(N= 212)
    18.7 (16.3 to 21.5)
        NT100:24 months after third dose:7-15years(N=212)
    11 (9.9 to 12.2)
        NT50:24 months after third dose:12-15years(N= 79)
    14.2 (11.4 to 17.7)
        NT100:24 months after third dose:12-15years(N=79)
    9.5 (8 to 11.3)
        NT50:34 months after third dose:1-2years (N= 73)
    30.7 (24.3 to 38.8)
        NT100:34 months after third dose:1-2years (N= 73)
    14.1 (11.7 to 17)
        NT50:34 months after third dose:3-6years (N= 68)
    23.8 (18.1 to 31.3)
        NT100:34 months after third dose:3-6years (N= 68)
    12.6 (10.3 to 15.5)
        NT50:34 months after third dose:7-15years(N=211)
    13.2 (11.5 to 15.3)
        NT100:34 months after third dose:7-15years(N=211)
    8.4 (7.5 to 9.3)
        NT50:34 months after third dose:12-15years(N=78)
    12.4 (9.8 to 15.6)
        NT100:34 months after third dose:12-15years(N=78)
    7.6 (6.5 to 9)
        NT50:36 month booster dose 0.25mL:1-2years(N=25)
    103.6 (76.2 to 141)
        NT100:36month booster dose 0.25mL:1-2years(N=25)
    65.9 (48.4 to 89.9)
        NT50:36month booster dose 0.25mL:3-6years(N=24)
    70.6 (42.6 to 117.1)
        NT100:36month booster dose 0.25mL:3-6years(N=24)
    44.7 (27.4 to 73)
        NT50:36month booster dose 0.25mL:7-15years(N=88)
    53.2 (42 to 67.4)
        NT100:36month booster dose 0.25mL:7-15years(N=88)
    32.3 (25.9 to 40.4)
        NT50:36month booster dose 0.5mL:7-15years(N=36)
    39.8 (27.5 to 57.5)
        NT100:36month booster dose 0.5mL:7-15years(N=36)
    25 (18.5 to 33.9)
        NT50:48month booster dose 0.25mL:1-2years(N=6)
    209.7 (116.3 to 378.1)
        NT100:48month booster dose 0.25mL:1-2years(N=6)
    115.4 (83.2 to 160)
        NT50:48month booster dose 0.25mL:3-6years(N=6)
    166.4 (80.3 to 344.7)
        NT100:48month booster dose 0.25mL:3-6years(N=6)
    64.8 (25.9 to 162.1)
        NT50:48month booster dose 0.25mL:7-15years(N=6)
    163.2 (84 to 317.1)
        NT100:48month booster dose 0.25mL:7-15years(N=6)
    55 (27 to 111.8)
        NT50:48month booster dose 0.5mL:7-15years(N=11)
    140.4 (81.5 to 241.8)
        NT100:48month booster dose 0.5mL:7-15years(N=11)
    46.4 (27.5 to 78.1)
        NT50:60month booster dose 0.5mL:7-15years(N=1)
    30 (-99999 to 99999)
        NT100:60month booster dose 0.5mL:7-15years(N=1)
    5 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Fold Increase in Antibody Titer After the Booster Vaccination as Compared to Before the Booster Vaccination Measured by NT According to Holzmann et al., 1996 by First Dose Age Group

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    End point title
    Geometric Mean of Fold Increase in Antibody Titer After the Booster Vaccination as Compared to Before the Booster Vaccination Measured by NT According to Holzmann et al., 1996 by First Dose Age Group
    End point description
    Geometric mean of fold increase in TBE antibody titer after the booster vaccination as compared to before the booster vaccination as measured by NT according to Holzmann et al., 1996 and 95% CIs were evaluated. Results were summarized for the applicable categories based on the dose and timepoint of FSME-IMMUN received and age of the subject at first vaccination: 1-2 years, 3-6 years, 7-15 years. Here, -99999 and 99999 indicates lower and upper limit of CI. It was not estimable as the number of subjects evaluable for 60-Month booster dose was 1. Full analysis dataset included subjects who received a booster vaccination at 36-, 48- or 60-Month after the third vaccination in the study 209, and with assay results 21-35 days after the booster vaccination. Here, 'N' signifies subjects of the mentioned combination of timepoint/age group in study 209/booster dose.
    End point type
    Secondary
    End point timeframe
    From before booster dose to 21-35 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    204
    Units: Fold Increase
    geometric mean (confidence interval 95%)
        NT50:36 month booster dose 0.25mL:1-2years(N=25)
    8.7 (5.6 to 13.3)
        NT100:36month booster dose 0.25mL:1-2years(N=25)
    10.2 (7.5 to 13.9)
        NT50:36month booster dose 0.25mL:3-6years(N=24)
    5.6 (3.1 to 10.2)
        NT100:36month booster dose 0.25mL:3-6years(N=24)
    6 (3.9 to 9.5)
        NT50:36month booster dose 0.25mL:7-15years(N=88)
    6.7 (5.3 to 8.4)
        NT100:36month booster dose 0.25mL:7-15years(N=88)
    5.5 (4.4 to 6.8)
        NT50:36month booster dose 0.5mL:7-15years(N=36)
    4.7 (3.1 to 7.2)
        NT100:36month booster dose 0.5mL:7-15years(N=36)
    4.6 (3.3 to 6.3)
        NT50:48month booster dose 0.25mL:1-2years(N=6)
    13 (4.3 to 39.2)
        NT100:48month booster dose 0.25mL:1-2years(N=6)
    13.6 (9.1 to 20.3)
        NT50:48month booster dose 0.25mL:3-6years(N=6)
    6.8 (1.9 to 24.1)
        NT100:48month booster dose 0.25mL:3-6years(N=6)
    5.1 (1.8 to 14.4)
        NT50:48month booster dose 0.25mL:7-15years(N=6)
    17.1 (5.5 to 53.5)
        NT100:48month booster dose 0.25mL:7-15years(N=6)
    7.8 (2.6 to 23.4)
        NT50:48month booster dose 0.5mL:7-15years(N=11)
    13.9 (6.9 to 27.9)
        NT100:48month booster dose 0.5mL:7-15years(N=11)
    6.7 (3.2 to 13.8)
        NT50:60month booster dose 0.5mL:7-15years(N=1)
    6 (-99999 to 99999)
        NT100:60month booster dose 0.5mL:7-15years(N=1)
    1 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Fever After 36 Month, 48 Month and 60 Month Booster Vaccination

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    End point title
    Percentage of Subjects with Fever After 36 Month, 48 Month and 60 Month Booster Vaccination
    End point description
    Proportion of subjects with fever >=38.0 degrees Celsius (C) and their 95% CIs were presented according to the booster dose. Subject his/her parent/legal guardian were asked to carefully monitor for fever and therefore, to measure the body temperature orally or rectally (optional for small children) in the evening of the vaccination day, on the following morning, and in the evening each day for 3 days following the booster vaccination (altogether 4 days). All measured temperatures, including the first day without fever and the method used (oral or rectal), were to be documented in the subject diary. Full analysis dataset included subjects who received a booster vaccination at 36-, 48- or 60-Month after the third vaccination in study 209. Here, 'N' signifies subjects of the mentioned combination of timepoint and booster dose in this study.
    End point type
    Secondary
    End point timeframe
    Within 4 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    205
    Units: Percentage of Subjects
    number (confidence interval 95%)
        After 36 month booster dose 0.25mL (N=136)
    0 (0 to 2.7)
        After 36 month booster dose 0.5mL (N=37)
    0 (0 to 9.5)
        After 48 month booster dose 0.25mL (N=18)
    0 (0 to 18.5)
        After 48 month booster dose 0.5mL (N=11)
    0 (0 to 28.5)
        After 60 month booster dose 0.5mL (N=1)
    0 (0 to 97.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Local and Systemic Reactions After 36 Month, 48 Month and 60 Month Booster Vaccination

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    End point title
    Percentage of Subjects with Local and Systemic Reactions After 36 Month, 48 Month and 60 Month Booster Vaccination
    End point description
    Proportion of subjects with local reactions (LR) and systemic reactions (SR) (other than fever) after the 36 Month, 48 Month or 60 Month booster dose and 95% CIs were presented according to the booster dose. Local reactions included: swelling, induration, redness, injection site pain and tenderness, ecchymosis and hematoma. Systemic symptoms including headache, nausea, vomiting, muscle pain, joint pain, swelling of the lymph nodes, loss of appetite, changes in sleeping behavior, fatigue and malaise were to be monitored and documented in the subject diary. Full analysis dataset included subjects who received a booster vaccination at 36 Month, 48 Month, or 60 Month after the third vaccination in study 209. Here, 'N' signifies subjects of the mentioned combination of 4th vaccination dose level, timepoint, and endpoints.
    End point type
    Secondary
    End point timeframe
    Within 4 days after 36-, 48- or 60-month booster dose
    End point values
    3 or 4 Doses FSME-IMMUN
    Number of subjects analysed
    205
    Units: Percentage of Subjects
    number (confidence interval 95%)
        LR: After 36 month booster dose 0.25mL (N=138)
    17.4 (11.5 to 24.8)
        LR: After 36 month booster dose 0.5mL (N=37)
    18.9 (8 to 35.2)
        SR: After 36 month booster dose 0.25mL (N=138)
    5.8 (2.5 to 11.1)
        SR: After 36 month booster dose 0.5mL (N=37)
    2.7 (0.1 to 14.2)
        LR: After 48 month booster dose 0.25mL (N=18)
    22.2 (6.4 to 47.6)
        LR: After 48 month booster dose 0.5mL (N=11)
    9.1 (0.2 to 41.3)
        SR: After 48 month booster dose 0.25mL (N=18)
    16.7 (3.6 to 41.4)
        SR: After 48 month booster dose 0.5mL (N=11)
    0 (0 to 28.5)
        LR: After 60 month booster dose 0.5mL (N=1)
    0 (0 to 97.5)
        SR: After 60 month booster dose 0.5mL (N=1)
    0 (0 to 97.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs)/serious AEs recorded through 21 to 35 days after the booster dose. LR and SR were recorded within 4 days after the booster vaccination in a subject diary.
    Adverse event reporting additional description
    SAEs and AEs were grouped by system organ class and summarized. AEs included AEs collected in subject diary (local and systemic reactions for FSME-IMMUN) and AEs collected on case report form at each visit (non-systematic assessment).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    8.1
    Reporting groups
    Reporting group title
    3 or 4 Doses FSME­-IMMUN
    Reporting group description
    Subjects received primary immunization (3 vaccinations at 0, 1 and 6 Month with FSME-IMMUN 0.25 mL) in study 209 [NCT00161863] were offered a booster dose (4th dose) 3-, 4-, or 5-year after the third vaccination, depending on their TBE titers. Subjects with high TBE antibody levels (ELISA > 1000 VIE U/ml and positive NT result) at 24, 34, 46, and/or 58 months after the third vaccination were not to receive the 4th dose.

    Serious adverse events
    3 or 4 Doses FSME­-IMMUN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 358 (0.56%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Chest injury; Spinal cord injury cervical
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture; Skull fractured base; Spinal cord injury
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    3 or 4 Doses FSME­-IMMUN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 358 (9.22%)
    Vascular disorders
    Haematoma; Road traffic accident
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Surgical and medical procedures
    Dental operation
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Nail operation
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Immune system disorders
    Allergy to animal; Seasonal allergy
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Injection site erythema
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Injection site induration
         subjects affected / exposed
    5 / 358 (1.40%)
         occurrences all number
    5
    Injection site pain
         subjects affected / exposed
    29 / 358 (8.10%)
         occurrences all number
    40
    Injection site swelling
         subjects affected / exposed
    4 / 358 (1.12%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Laceration
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Headache (SR)
         subjects affected / exposed
    5 / 358 (1.40%)
         occurrences all number
    5
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Enteritis
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Dermatitis allergic
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Arthralgia (SR)
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Laryngotracheo bronchitis
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Mycoplasma infection
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    2
    Paronychia
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 358 (0.28%)
         occurrences all number
    1
    Tonsillitis streptococcal
         subjects affected / exposed
    2 / 358 (0.56%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    12 / 358 (3.35%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2006
    The clinical study was prolonged for children and adolescents who still showed highly positive TBE virus antibody concentrations as determined by ELISA (>1000 VIE U/mL) and positive NT titers (>=10) at approximately 3 years after the third vaccination. The protocol was amended to include further follow-up of TBE antibody persistence at 46 and 58 months after the third vaccination, as well as a booster vaccination offered at either Month 48 or Month 60 after the third vaccination in study 209, depending on individual TBE antibody levels. A total of 172 subjects who had not received the first booster vaccination at Month 36 after the third vaccination in study 209 were invited for this study prolongation. The extension was introduced to investigate seropersistence beyond 3 years and consequently to obtain clinical data to identify the optimal booster interval for FSME-IMMUN 0.25 mL.

    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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