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    Clinical Trial Results:
    A Phase 3, Single-arm, Open-label Study to Evaluate the Immunogenicity, Safety, and Tolerability of a Tick-borne Encephalitis Vaccine in Healthy Japanese Participants 1 Year Of Age and Older

    Summary
    EudraCT number
    		 2022-004181-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    21 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2023
    First version publication date
    03 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B9371039
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04648241
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, 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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the immunogenicity of Tick-borne Encephalitis (TBE) vaccine 0.5 mL and 0.25 mL by 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 Harmonisation (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
    18 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 165
    Worldwide total number of subjects
    165
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    2
    Children (2-11 years)
    52
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    80
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted as part of the Phase 3 clinical development plan to support the use of TBE vaccine 0.5 milliliter (mL) in healthy Japanese adults (greater than or equal to [>=] 16 years old) and 0.25 mL in pediatric subjects (>=1 and less than [<] 16 years old) at investigator sites in Japan.

    Pre-assignment
    Screening details
    		 The study was conducted in single country from 18 January 2021 to 21 February 2022. A total of 165 subjects were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adults (>=16 years old)
    Arm description
    		 Subjects aged >=16 years old received three doses of 0.5 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tick-borne encephalitis vaccine
    Investigational medicinal product code
    PF-06830414
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received three doses of 0.5 mL TBE vaccine intramuscularly.

    Arm title
    		 Pediatric (1 to <16 Years Old)
    Arm description
    		 Subjects aged 1 to <16 years old received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tick-borne encephalitis vaccine
    Investigational medicinal product code
    PF-06830414
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received three doses of 0.25 mL TBE vaccine intramuscularly.

    Number of subjects in period 1
    		Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Started
    100
    65
    Completed
    99
    65
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adults (>=16 years old)
    Reporting group description
    		 Subjects aged >=16 years old received three doses of 0.5 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Reporting group title
    Pediatric (1 to <16 Years Old)
    Reporting group description
    		 Subjects aged 1 to <16 years old received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Reporting group values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old) Total
    Number of subjects
    		 100 65 165
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 2 2
        Children (2-11 years)
    		 0 52 52
        Adolescents (12-17 years)
    		 5 11 16
        Adults (18-64 years)
    		 80 0 80
        From 65-84 years
    		 15 0 15
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 44.3 ± 16.02 6.9 ± 3.89 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 55 19 74
        Male
    		 45 46 91
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 100 65 165
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 0 0 0
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 100 65 165
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Adults (>=16 years old)
    Reporting group description
    		 Subjects aged >=16 years old received three doses of 0.5 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Reporting group title
    Pediatric (1 to <16 Years Old)
    Reporting group description
    		 Subjects aged 1 to <16 years old received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Subject analysis set title
    Pediatric (3 to 15 Years Old)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects aged 3 to 15 years old received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 in between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Subject analysis set title
    Pediatric (1 to 2 Years Old)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects aged 1 to 2 years received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 in between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Primary: Percentage of Seropositive Subjects at 4 Weeks After Dose 3

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    End point title
    		 Percentage of Seropositive Subjects at 4 Weeks After Dose 3 [1]
    End point description
    Seropositivity rate based on the immune response was determined by neutralization test (NT). Subjects who achieved tick-borne encephalitis virus (TBEV) NT titers greater than or equal to (>=) 1:10 were considered as seropositive. Exact 2-sided 95% confidence interval (CI) based on the Clopper and Pearson method was presented. Evaluable immunogenicity (EI) population: Subjects who received all 3 doses of the investigational product(IP), had blood drawn for assay testing within the specified time frame for baseline and 4 weeks after the third vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the third vaccination visit, were NT seronegative at baseline, and had no major protocol violations. Number of subjects analysed=subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    4 weeks after Dose 3
    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 data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    98.0 (92.9 to 99.8)
    100 (94.5 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Local Reactions (LR) Within 7 Days After Dose 1

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    End point title
    		 Percentage of Subjects With Local Reactions (LR) Within 7 Days After Dose 1 [2]
    End point description
    LR:subject or legally acceptable representative/parent/legal guardian using an electronic diary (e-diary).LR:redness, swelling & pain at injection site.Redness & swelling measured using measuring device units.1 measuring device unit=0.5 centimeter(cm).Redness & swelling were graded as: for subjects >=12 years of age, mild(greater than[>] 2.0 to 5.0 cm), moderate(>5.0 to 10.0 cm) and severe (>10.0 cm); for subjects less than (<)12 years of age, mild(>0 to 2.0 cm), moderate(>2.0 to7.0 cm) and severe(>7.0 cm). Pain at injection site was graded as: for subjects >2 years of age, mild(does not interfere with activity),moderate(interferes with activity) and severe(prevents daily activity); for subjects less than or equal to(<=)2 years of age, mild(hurts if gently touched) moderate(hurts if gently touched with crying)and severe(causes limitation of limb movement). Safety analysis included all enrolled subjects who received at least 1 dose of IP.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 1
    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 data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
    number (confidence interval 95%)
        Redness: Mild
    2.0 (0.2 to 7.0)
    3.1 (0.4 to 10.7)
        Redness: Moderate
    0 (0.0 to 3.6)
    1.5 (0.0 to 8.3)
        Redness: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Swelling: Mild
    3.0 (0.6 to 8.5)
    3.1 (0.4 to 10.7)
        Swelling: Moderate
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Swelling: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Pain at the injection site: Mild
    52.0 (41.8 to 62.1)
    36.9 (25.3 to 49.8)
        Pain at the injection site: Moderate
    7.0 (2.9 to 13.9)
    6.2 (1.7 to 15.0)
        Pain at the injection site: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Local Reactions Within 7 Days After Dose 2

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    End point title
    		 Percentage of Subjects With Local Reactions Within 7 Days After Dose 2 [3]
    End point description
    LR:subject or legally acceptable representative/parent/legal guardian using an e-diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were measured using measuring device units. 1 measuring device unit =0.5 cm. Redness and swelling were graded as: for subjects >=12 years of age, mild (>2.0 to 5.0 cm), moderate(>5.0 to 10.0 cm) and severe (>10.0 cm); for subjects <12 years of age, mild(>0 to 2.0 cm), moderate(>2.0 to7.0 cm) and severe(>7.0 cm). Pain at the injection site was graded as: for subjects >2 years of age, mild(does not interfere with activity), moderate(interferes with activity) and severe(prevents daily activity); for subjects <=2 years of age, mild(hurts if gently touched) moderate(hurts if gently touched with crying) and severe(causes limitation of limb movement). Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety set analysed.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 2
    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 data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
    number (confidence interval 95%)
        Redness: Mild
    0.0 (0.0 to 3.6)
    3.1 (0.4 to 10.7)
        Redness: Moderate
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Redness: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Swelling: Mild
    0 (0.0 to 3.6)
    1.5 (0.0 to 8.3)
        Swelling: Moderate
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Swelling: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
        Pain at the injection site: Mild
    40.0 (30.3 to 50.3)
    24.6 (14.8 to 36.9)
        Pain at the injection site: Moderate
    4.0 (1.1 to 9.9)
    1.5 (0.0 to 8.3)
        Pain at the injection site: Severe
    0 (0.0 to 3.6)
    0 (0.0 to 5.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Local Reactions Within 7 Days After Dose 3

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    End point title
    		 Percentage of Subjects With Local Reactions Within 7 Days After Dose 3 [4]
    End point description
    LR:subject or legally acceptable representative/parent/legal guardian using an e-diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were measured using measuring device units. 1 measuring device unit =0.5 cm. Redness and swelling were graded as: for subjects >=12 years of age, mild (>2.0 to 5.0 cm), moderate(>5.0 to 10.0 cm) and severe (>10.0 cm); for subjects <12 years of age, mild(>0 to 2.0 cm), moderate(>2.0 to7.0 cm) and severe(>7.0 cm). Pain at the injection site was graded as: for subjects >2 years of age, mild(does not interfere with activity), moderate(interferes with activity) and severe(prevents daily activity); for subjects <=2 years of age, mild(hurts if gently touched) moderate(hurts if gently touched with crying) and severe(causes limitation of limb movement). Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety set analyzed.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 3
    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 data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Percentage of subjects
    number (confidence interval 95%)
        Redness: Mild
    2.0 (0.2 to 7.1)
    7.7 (2.5 to 17.0)
        Redness: Moderate
    0 (0.0 to 3.7)
    0 (0.0 to 5.5)
        Redness: Severe
    0 (0.0 to 3.7)
    0 (0.0 to 5.5)
        Swelling: Mild
    1.0 (0.0 to 5.5)
    6.2 (1.7 to 15.0)
        Swelling: Moderate
    1.0 (0.0 to 5.5)
    3.1 (0.4 to 10.7)
        Swelling: Severe
    0 (0.0 to 3.7)
    0 (0.0 to 5.5)
        Pain at the injection site: Mild
    33.3 (24.2 to 43.5)
    30.8 (19.9 to 43.4)
        Pain at the injection site: Moderate
    3.0 (0.6 to 8.6)
    4.6 (1.0 to 12.9)
        Pain at the injection site: Severe
    0 (0.0 to 3.7)
    0 (0.0 to 5.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Systemic Events (SE) Within 7 Days After Dose 1

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    End point title
    		 Percentage of Subjects With Systemic Events (SE) Within 7 Days After Dose 1 [5] [6]
    End point description
    SE:subjects/legally acceptable representative/parent/legal guardian using e-diary,fever:temperature >=37.5 degree(deg)Celsius (C),categorized:37.5to38.4, 38.5to38.9, 39.0to40.0, >40.0degC.Fatigue, headache, muscle pain, joint pain: mild(didn’t interfere with activity),moderate(mod)(some interference with activity),severe(prevented daily activity).Vomiting: mild(1-2 times in 24 hours[hrs]),mod(>2 times in 24hrs),severe(required IV hydration).Diarrhea: mild(2-3 loose stools in 24hrs),mod(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite: mild(decreased interest in eating), mod(decreased oral intake), severe(refusal to feed).Drowsiness: mild(Increased sleeping bouts), mod(slightly subdued interfering with daily activity), severe(disabling not interested in usual daily activity). Irritability: mild(easily consolable),mod(required increased attention), severe(inconsolable).Safety set . 99999=not applicable.n=subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 1
    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 data was planned to be analyzed for this endpoint.
    [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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (3 to 15 Years Old) Pediatric (1 to 2 Years Old)
    Number of subjects analysed
    100
    57
    8
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever: >=37.5 degree C(n=100,57,8)
    2.0 (0.2 to 7.0)
    5.3 (1.1 to 14.6)
    25.0 (3.2 to 65.1)
        Fever: 37.5 to 38.4 degree C(n=100,57,8)
    2.0 (0.2 to 7.0)
    3.5 (0.4 to 12.1)
    25.0 (3.2 to 65.1)
        Fever: 38.5 to 38.9 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    1.8 (0.0 to 9.4)
    0 (0.0 to 36.9)
        Fever: 39.0 to 40.0 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fever: >40.0 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fatigue: Mild(n=100,57,0)
    11.0 (5.6 to 18.8)
    8.8 (2.9 to 19.3)
    99999 (99999 to 99999)
        Fatigue: Moderate(n=100,57,0)
    5.0 (1.6 to 11.3)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Fatigue: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Headache: Mild(n=100,57,0)
    7.0 (2.9 to 13.9)
    7.0 (1.9 to 17.0)
    99999 (99999 to 99999)
        Headache: Moderate(n=100,57,0)
    6.0 (2.2 to 12.6)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Headache: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Vomiting: Mild(n=100,57,0)
    1.0 (0.0 to 5.4)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Moderate(n=100,57,0)
    1.0 (0.0 to 5.4)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Diarrhea: Mild(n=100,57,0)
    7.0 (2.9 to 13.9)
    8.8 (2.9 to 19.3)
    99999 (99999 to 99999)
        Diarrhea: Moderate(n=100,57,0)
    2.0 (0.2 to 7.0)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Diarrhea: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Mild(n=100,57,0)
    16.0 (9.4 to 24.7)
    5.3 (1.1 to 14.6)
    99999 (99999 to 99999)
        Muscle pain: Moderate(n=100,57,0)
    3.0 (0.6 to 8.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Mild(n=100,57,0)
    4.0 (1.1 to 9.9)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Moderate(n=100,57,0)
    3.0 (0.6 to 8.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Decreased appetite: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Decreased appetite: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
        Decreased appetite: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    25.0 (3.2 to 65.1)
        Drowsiness: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
        Irritability: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
        Irritability: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Systemic Events Within 7 Days After Dose 2

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    End point title
    		 Percentage of Subjects With Systemic Events Within 7 Days After Dose 2 [7] [8]
    End point description
    SE: subjects/legally acceptable representative/parent/legal guardian using e-diary. It included fever: temperature >=37.5 deg C and categorised as 37.5 to 38.4, 38.5 to 38.9, 39.0 to 40.0, >40.0 deg C. Fatigue, headache, muscle pain, joint pain: mild(didn’t interfere with activity),mod(some interference with activity),severe(prevented daily activity). Vomiting: mild(1-2 times in 24 hours[hrs]),mod(>2 times in 24hrs), severe(required intravenous hydration).Diarrhea: mild(2-3 loose stools in 24hrs),moderate(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite: mild(decreased interest in eating), moderate(decreased oral intake),severe(refusal to feed) .Safety set .99999=not applicable.n=subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 2
    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 data was planned to be analyzed for this endpoint.
    [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: The endpoint was planned to be analyzed for Overall Study Adults (>=16 years old), Pediatric (3 to 15 Years Old) and Pediatric (1 to 2 Years Old) arms.
    End point values
    		 Adults (>=16 years old) Pediatric (3 to 15 Years Old) Pediatric (1 to 2 Years Old)
    Number of subjects analysed
    100
    57
    8
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever: >=37.5 degree C(n=100,57,8)
    1.0 (0.0 to 5.4)
    7.0 (1.9 to 17.0)
    0 (0.0 to 36.9)
        Fever: 37.5 to 38.4 degree C(n=100,57,8)
    1.0 (0.0 to 5.4)
    3.5 (0.4 to 12.1)
    0 (0.0 to 36.9)
        Fever: 38.5 to 38.9 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    3.5 (0.4 to 12.1)
    0 (0.0 to 36.9)
        Fever: 39.0 to 40.0 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fever: >40.0 degree C(n=100,57,8)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fatigue: Mild(n=100,57,0)
    7.0 (2.9 to 13.9)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Fatigue: Moderate(n=100,57,0)
    1.0 (0.0 to 5.4)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Fatigue: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Headache: Mild(n=100,57,0)
    10.0 (4.9 to 17.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Headache: Moderate(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Headache: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Mild(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Moderate(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Diarrhea: Mild(n=100,57,0)
    4.0 (1.1 to 9.9)
    7.0 (1.9 to 17.0)
    99999 (99999 to 99999)
        Diarrhea: Moderate(n=100,57,0)
    1.0 (0.0 to 5.4)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Diarrhea: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Mild(n=100,57,0)
    2.0 (0.2 to 7.0)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Muscle pain: Moderate(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Mild(n=100,57,0)
    1.0 (0.0 to 5.4)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Moderate(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Severe(n=100,57,0)
    0 (0.0 to 3.6)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Decreased appetite: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Decreased appetite: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Decreased appetite: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
        Drowsiness: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Systemic Events Within 7 Days After Dose 3

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    End point title
    		 Percentage of Subjects With Systemic Events Within 7 Days After Dose 3 [9] [10]
    End point description
    SE: subjects/legally acceptable representative/parent/legal guardian using e-diary. It included fever: temperature >=37.5 deg C and categorised as 37.5 to 38.4, 38.5 to 38.9, 39.0 to 40.0, >40.0 deg C. Fatigue, headache, muscle pain, joint pain: mild(didn’t interfere with activity),mod(some interference with activity),severe(prevented daily activity). Vomiting: mild(1-2 times in 24 hours[hrs]),mod(>2 times in 24hrs), severe(required intravenous hydration).Diarrhea: mild(2-3 loose stools in 24hrs),moderate(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite: mild(decreased interest in eating), moderate(decreased oral intake),severe(refusal to feed) .Safety set .99999=not applicable.n=subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 7 days after Dose 3
    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: Only descriptive data was planned to be analyzed for this endpoint.
    [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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (3 to 15 Years Old) Pediatric (1 to 2 Years Old)
    Number of subjects analysed
    99
    57
    8
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever: >=37.5 degree C(n=99,57,8)
    1.0 (0.0 to 5.5)
    10.5 (4.0 to 21.5)
    12.5 (0.3 to 52.7)
        Fever: 37.5 to 38.4 degree C(n=99,57,8)
    0 (0.0 to 3.7)
    8.8 (2.9 to 19.3)
    12.5 (0.3 to 52.7)
        Fever: 38.5 to 38.9 degree C(n=99,57,8)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fever: 39.0 to 40.0 degree C(n=99,57,8)
    0 (0.0 to 3.7)
    1.8 (0.0 to 9.4)
    0 (0.0 to 36.9)
        Fever: >40.0 degree C(n=99,57,8)
    0 (0.0 to 3.7)
    0 (0.0 to 6.3)
    0 (0.0 to 36.9)
        Fatigue: Mild(n=99,57,0)
    9.1 (4.2 to 16.6)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Fatigue: Moderate(n=99,57,0)
    2.0 (0.2 to 7.1)
    5.3 (1.1 to 14.6)
    99999 (99999 to 99999)
        Fatigue: Severe(n=99,57,0)
    0 (0.0 to 3.7)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Headache: Mild(n=99,57,0)
    9.1 (4.2 to 16.6)
    5.3 (1.1 to 14.6)
    99999 (99999 to 99999)
        Headache: Moderate(n=99,57,0)
    1.0 (0.0 to 5.5)
    3.5 (0.4 to 12.1)
    99999 (99999 to 99999)
        Headache: Severe(n=99,57,0)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Vomiting: Mild(n=99,57,0)
    2.0 (0.2 to 7.1)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Vomiting: Moderate(n=99,57,0)
    0 (0.0 to 3.7)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Vomiting: Severe(n=99,57,0)
    0 (0.0 to 3.7)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Diarrhea: Mild(n=99,57,0)
    5.1 (1.7 to 11.4)
    5.3 (1.1 to 14.6)
    99999 (99999 to 99999)
        Diarrhea: Moderate(n=99,57,0)
    0 (0.0 to 3.7)
    3.5 (0.4 to 12.1)
    99999 (99999 to 99999)
        Diarrhea: Severe(n=99,57,0)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Mild(n=99,57,0)
    3.0 (0.6 to 8.6)
    1.8 (0.0 to 9.4)
    99999 (99999 to 99999)
        Muscle pain: Moderate(n=99,57,0)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Muscle pain: Severe(n=99,57,0)
    0 (0.0 to 3.7)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Mild(n=99,57,0)
    0 (0.0 to 3.7)
    5.3 (1.1 to 14.6)
    99999 (99999 to 99999)
        Joint pain: Moderate(n=99,57,0)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Joint pain: Severe(n=99,57,0)
    1.0 (0.0 to 5.5)
    0 (0.0 to 6.3)
    99999 (99999 to 99999)
        Decreased appetite: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.5 (0.3 to 52.7)
        Decreased appetite: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Decreased appetite: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    25.0 (3.2 to 65.1)
        Drowsiness: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Drowsiness: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Mild(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Moderate(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
        Irritability: Severe(n=0,0,8)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0 (0.0 to 36.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 1

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 1 [11]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety analysis population included all enrolled subjects who received at least 1 dose of the investigational product.
    End point type
    Primary
    End point timeframe
    Within 1 month after Dose 1
    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: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    6.0 (2.2 to 12.6)
    21.5 (12.3 to 33.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 2

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 2 [12]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety analysis population included all enrolled subjects who received at least 1 dose of the investigational product. Number of subjects analysed= subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Within 1 month after Dose 2
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The endpoint was planned to be analyzed for Overall Study Adults (>=16 years old), Pediatric (3 to 15 Years Old) and Pediatric (1 to 2 Years Old) arms.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    2.0 (0.2 to 7.0)
    10.8 (4.4 to 20.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events (AEs) Within 1 Month After any Dose

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) Within 1 Month After any Dose [13]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety analysis population included all enrolled subjects who received at least 1 dose of the investigational product.
    End point type
    Primary
    End point timeframe
    Within 1 month after any Dose
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    14.0 (7.9 to 22.4)
    41.5 (29.4 to 54.4)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 3

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) Within 1 Month After Dose 3 [14]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety analysis population included all enrolled subjects who received at least 1 dose of the investigational product.
    End point type
    Primary
    End point timeframe
    Within 1 month after Dose 3
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The endpoint was planned to be analyzed for Overall Study Adults (>=16 years old), Pediatric (3 to 15 Years Old) and Pediatric (1 to 2 Years Old) arms.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    6.1 (2.3 to 12.7)
    29.2 (18.6 to 41.8)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Serious Adverse Events (SAEs) Throughout the Study

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    End point title
    		 Percentage of Subjects With Serious Adverse Events (SAEs) Throughout the Study [15]
    End point description
    An SAE was defined as any untoward medical occurrence that, at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect or that is considered to be an important medical event. Percentage of subjects with SAEs and the exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Safety analysis population included all enrolled subjects who received at least 1 dose of the investigational product.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 35 days after Dose 3 (up to approximately 15 months)
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    2.0 (0.2 to 7.0)
    1.5 (0.0 to 8.3)
    No statistical analyses for this end point

    Secondary: Percentage of Seropositive Subjects at 4 Weeks After Dose 2

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    End point title
    		 Percentage of Seropositive Subjects at 4 Weeks After Dose 2
    End point description
    Seropositivity rate based on the immune response was determined by NT. Subjects who achieved TBEV NT titers >=1:10 were considered as seropositive. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. Evaluable immunogenicity population for the second dose: Subjects who received the first 2 doses of the investigational product, had blood drawn for assay testing within the specified time frame for baseline and 4 weeks after the second vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the second vaccination visit, were NT seronegative at baseline, and had no major protocol violations.
    End point type
    Secondary
    End point timeframe
    4 weeks after Dose 2
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Percentage of subjects
        number (confidence interval 95%)
    93.0 (86.1 to 97.1)
    92.3 (83.0 to 97.5)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 and Dose 3

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    End point title
    		 Geometric Mean Titers (GMTs) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 and Dose 3
    End point description
    GMTs and associated 2-sided 95% CIs were calculated as the mean of the assay results on the natural logarithmic scale based on Student’s t distribution and then exponentiating the results. The lower limit of quantitation (LLOQ) value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. EI population: Subjects who received all 3 doses of the investigational product, had blood drawn for assay testing within specified time frame for baseline and 4 weeks after the third vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the third vaccination visit, were NT seronegative at baseline, and had no major protocol violations. Here, “Number of Subjects Analysed” signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    4 weeks after Dose 2 and Dose 3
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Titer
    geometric mean (confidence interval 95%)
        4 Weeks after Dose 2
    28.2 (23.5 to 33.8)
    29.4 (23.3 to 37.0)
        4 Weeks after Dose 3
    80.1 (65.1 to 98.5)
    233.1 (187.9 to 289.1)
    No statistical analyses for this end point

    Secondary: Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to Baseline

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    End point title
    		 Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to Baseline
    End point description
    GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. EI population: Subjects who received all 3 doses of the investigational product, had blood drawn for assay testing within specified time frame for baseline and 4 weeks after the third vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the third vaccination visit, were NT seronegative at baseline, and had no major protocol violations. Here, “Number of subjects analysed” signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 weeks after Dose 3
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Fold rise
        geometric mean (confidence interval 95%)
    32.0 (26.0 to 39.4)
    93.2 (75.2 to 115.6)
    No statistical analyses for this end point

    Secondary: Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 as Compared to Baseline

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    End point title
    		 Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 as Compared to Baseline
    End point description
    GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. Evaluable immunogenicity population for the second dose: Subjects who received the first 2 doses of the investigational product, had blood drawn for assay testing within the specified time frame for baseline and 4 weeks after the second vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the second vaccination visit, were NT seronegative at baseline, and had no major protocol violations.
    End point type
    Secondary
    End point timeframe
    From Baseline to 4 weeks after Dose 2
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    100
    65
    Units: Fold rise
        geometric mean (confidence interval 95%)
    11.2 (9.3 to 13.4)
    11.8 (9.3 to 14.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Neutralizing Antibody Titers >= Lower Limit of Quantification (LLOQ)

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    End point title
    		 Percentage of Subjects with Neutralizing Antibody Titers >= Lower Limit of Quantification (LLOQ)
    End point description
    The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. Percentage of subjects with NT>=LLOQ and exact 2-sided 95% CI based on the Clopper and Pearson method was presented. EI population: Subjects who received all 3 doses of the investigational product, had blood drawn for assay testing within specified time frame for baseline and 4 weeks after the third vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the third vaccination visit, were NT seronegative at baseline, and had no major protocol violations. Here, “Number of subjects analysed” signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Before Dose 1, 4 weeks after Dose 2, Before Dose 3 and 4 weeks after Dose 3
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Before Dose 1
    0 (0.0 to 3.7)
    0 (0.0 to 5.5)
        4 Weeks after Dose 2
    96.0 (90.0 to 98.9)
    98.5 (91.7 to 100.0)
        Before Dose 3
    63.6 (53.4 to 73.1)
    86.2 (75.3 to 93.5)
        4 Weeks after Dose 3
    99.0 (94.5 to 100.0)
    100.0 (94.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to 4 Weeks After Dose 2

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    End point title
    		 Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to 4 Weeks After Dose 2
    End point description
    GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. EI population: Subjects who received all 3 doses of the investigational product, had blood drawn for assay testing within specified time frame for baseline and 4 weeks after the third vaccination, had valid and determinate assay result (NT titer) at baseline and 4 weeks after the third vaccination visit, were NT seronegative at baseline, and had no major protocol violations. Here, “Number of subjects analysed” signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From 4 weeks after Dose 2 to 4 weeks after Dose 3
    End point values
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Number of subjects analysed
    99
    65
    Units: Fold rise
        geometric mean (confidence interval 95%)
    2.8 (2.3 to 3.5)
    7.9 (6.2 to 10.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause mortality: from Day(D)1 up to 35D after Dose3(up to approximately 15months([M]); SAEs:from D1 up to 35D after Dose3(up to approx.15M);Other AEs(non-systematic assessment[SA]):up to 1M after each Dose;LR&SE(SA,other AEs):within 7Dafter each Dose)
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorised as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v 24.1
    Reporting groups
    Reporting group title
    Adults (>=16 years old)
    Reporting group description
    		 Subjects aged >=16 years old received three doses of 0.5 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Reporting group title
    Pediatric (1 to <16 Years Old)
    Reporting group description
    		 Subjects aged 1 to <16 years old received three doses of 0.25 mL TBE vaccine intramuscularly as Dose 1 on Day 1, Dose 2 between 21 to 35 days after Dose 1 and Dose 3 between 150-365 days after Dose 2. Subjects were followed up for safety for 21-35 days after Dose 3.

    Serious adverse events
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 65 (1.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adults (>=16 years old) Pediatric (1 to <16 Years Old)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 100 (76.00%)
    59 / 65 (90.77%)
    Injury, poisoning and procedural complications
    Cartilage injury
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Arthropod sting
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Ankle fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 65 (1.54%)
         occurrences all number
    2
    1
    Joint injury
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache (HEADACHE)
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 100 (23.00%)
    9 / 65 (13.85%)
         occurrences all number
    39
    12
    Hypersomnia (INCREASED SLEEP)
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    5
    General disorders and administration site conditions
    Fatigue (FATIGUE)
    alternative assessment type: Systematic
         subjects affected / exposed
    27 / 100 (27.00%)
    9 / 65 (13.85%)
         occurrences all number
    42
    11
    Injection site erythema (REDNESS)
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 100 (3.00%)
    7 / 65 (10.77%)
         occurrences all number
    4
    12
    Injection site swelling (SWELLING)
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 100 (4.00%)
    9 / 65 (13.85%)
         occurrences all number
    5
    10
    Injection site pain (PAIN)
    alternative assessment type: Systematic
         subjects affected / exposed
    68 / 100 (68.00%)
    43 / 65 (66.15%)
         occurrences all number
    141
    71
    Pyrexia (FEVER)
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 100 (3.00%)
    13 / 65 (20.00%)
         occurrences all number
    6
    20
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Myopia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Vomiting (VOMITING)
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 65 (3.08%)
         occurrences all number
    4
    2
    Diarrhoea (DIARRHEA)
    alternative assessment type: Systematic
         subjects affected / exposed
    15 / 100 (15.00%)
    12 / 65 (18.46%)
         occurrences all number
    22
    16
    Dental caries
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Asthma
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Dermatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Irritability (IRRITABILITY)
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia (JOINT PAIN)
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 100 (10.00%)
    3 / 65 (4.62%)
         occurrences all number
    10
    3
    Myalgia (MUSCLE PAIN)
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 100 (22.00%)
    4 / 65 (6.15%)
         occurrences all number
    26
    6
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    8 / 65 (12.31%)
         occurrences all number
    1
    8
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2
    Parotitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Otitis externa
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 100 (3.00%)
    11 / 65 (16.92%)
         occurrences all number
    3
    13
    Gastroenteritis viral
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2
    Empyema
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite (DECREASED APPETITE)
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2020
    Added fever to prespecified systemic events in primary safety endpoints for subjects 1 to <=2 years of age.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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