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    Clinical Trial Results:
    A Study in Healthy, Young Adults and Healthy Infants of the Safety, Tolerability, and Immunogenicity of a Recombinant Hepatitis B Vaccine Manufactured by an Investigational Process

    Summary
    EudraCT number
    		 2005-005939-10
    Trial protocol
    		 FI  
    Global end of trial date
    10 May 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Dec 2016
    First version publication date
    07 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V232-055
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    10 May 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were: Stage 1 assessed the safety and tolerability of glutathione (GSH)/2X phosphate process hepatitis B vaccine in healthy adults and Stage 2 evaluated the immunogenicity of the GSH/2X phosphate hepatitis B vaccine compared with the 2X phosphate hepatitis B vaccine in healthy infants who received the vaccine on a 0-, 1-, and 6-month schedule.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. Stage 2 was conducted in healthy infants, conditional upon satisfactory review of all vaccine-related serious adverse experiences (SAEs) that may have occurred after the first vaccine dose in participants from Stage 1 over the 14-day safety follow-up period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2006
    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
    Finland: 300
    Worldwide total number of subjects
    300
    EEA total number of subjects
    300
    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)
    240
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    60
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 6 clinical sites in Finland. Sixty adult participants were enrolled in Stage 1 and 240 healthy infant participants, 2 to 4 months of age, were enrolled in Stage 2 of this study.

    Pre-assignment
    Screening details
    		 Stage 1: participants 20 to 35 years of age in good health based on a medical history. Stage 2: healthy infants 2 to 4 months old.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Arm description
    		 Participants received a 3 x 10-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSH/2X Phosphate Hepatitis B Vaccine
    Investigational medicinal product code
    Other name
    V232
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received a 3 x 10-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 1.0-mL intramuscular injection

    Arm title
    		 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Arm description
    		 Participants received a 3 x 10-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection
    Arm type
    		 Active comparator

    Investigational medicinal product name
    2X Phosphate Hepatitis B Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received a 3 x 10-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 1.0-mL intramuscular injection

    Arm title
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Arm description
    		 Participants received a 3 x 5-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSH/2X Phosphate Hepatitis B Vaccine
    Investigational medicinal product code
    Other name
    V232
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received a 3 x 5-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 0.5-mL intramuscular injection

    Arm title
    		 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Arm description
    		 Participants received a 3 x 5-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    2X Phosphate Hepatitis B Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received a 3 x 5-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 0.5-mL intramuscular injection.

    Number of subjects in period 1
    		GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Started
    50
    10
    120
    120
    Received all 3 Vaccinations
    47
    9
    119
    118
    Completed
    47
    8
    118
    118
    Not completed
    3
    2
    2
    2
         Consent withdrawn by subject
    1
    -
    1
    -
         Adverse event, non-fatal
    1
    1
    -
    -
         Lost to follow-up
    -
    1
    1
    1
         Protocol deviation
    1
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants received a 3 x 10-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection.

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants received a 3 x 10-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection

    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants received a 3 x 5-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants received a 3 x 5-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection.

    Reporting group values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants Total
    Number of subjects
    		 50 10 120 120 300
    Age Categorical
    Units: Subjects
        2 to 4 months
    		 0 0 120 120 240
        20 to 35 years
    		 50 10 0 0 60
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.1 ± 4.3 25.5 ± 2.9 0.3 ± 0 0.2 ± 0.1 -
    Gender Categorical
    Units: Subjects
        Male
    		 16 4 71 56 147
        Female
    		 34 6 49 64 153

    End points

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    End points reporting groups
    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants received a 3 x 10-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection.

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants received a 3 x 10-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 1.0-mL intramuscular injection

    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants received a 3 x 5-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants received a 3 x 5-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6- month schedule, as a 0.5-mL intramuscular injection.

    Primary: Percentage of Participants Who Experienced One or More Adverse Events (AEs, Stage 1 Adults)

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events (AEs, Stage 1 Adults) [1] [2]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all adult participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine.
    End point type
    Primary
    End point timeframe
    Up to 7 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    50
    10
    Units: Percentage of Participants
        number (not applicable)
    94
    90
    No statistical analyses for this end point

    Primary: Percentage of Participants Discontinuing Study Drug Due to AEs (Stage 1 Adults)

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    End point title
    		 Percentage of Participants Discontinuing Study Drug Due to AEs (Stage 1 Adults) [3] [4]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all adult participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine.
    End point type
    Primary
    End point timeframe
    Up to Month 6
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this end point.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    50
    10
    Units: Percentage of Participants
        number (not applicable)
    2
    0
    No statistical analyses for this end point

    Primary: Seroprotection rate (SPR, Percentage of Participants with Anti-HBs Titer ≥10 mIU/mL) (Stage 2 Infants)

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    End point title
    		 Seroprotection rate (SPR, Percentage of Participants with Anti-HBs Titer ≥10 mIU/mL) (Stage 2 Infants) [5] [6]
    End point description
    SPR is defined as the percentage of participants who demonstrate antibodies to hepatitis B surface antigen ≥10 mIU/mL. A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. The statistical criterion for an adequate SPR required the lower bound of the 2-sided multiplicity adjusted 95.0% confidence interval have a lower bound that exceeds 90.0%. Per protocol population was defined as the infant participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this end point.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    110
    112
    Units: Percentage of Participants
        number (confidence interval 95%)
    100 (99.5 to 100)
    100 (99.6 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants with Any Quantifiable Anti-HBs (anti-HBs titers ≥ 5 mIU/mL) (Stage 2 Infants)

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    End point title
    		 Percentage of Participants with Any Quantifiable Anti-HBs (anti-HBs titers ≥ 5 mIU/mL) (Stage 2 Infants) [7] [8]
    End point description
    A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. Per protocol population was defined as the infant participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges
    End point type
    Primary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this end point.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    110
    112
    Units: Percentage of Participants
        number (confidence interval 95%)
    100 (99.5 to 100)
    100 (99.6 to 100)
    No statistical analyses for this end point

    Primary: Anti-Hepatitis B Antibodies Geometric Mean Titer (GMT) at Month 7 (1 month post-dose 3, Stage 2 Infants)

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    End point title
    		 Anti-Hepatitis B Antibodies Geometric Mean Titer (GMT) at Month 7 (1 month post-dose 3, Stage 2 Infants) [9]
    End point description
    GMT is in milli-international units per milliliter [mIU/mL]). A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. Per protocol population was defined as the infant participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    110
    112
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    6187.7 (5068 to 7554)
    4286.1 (3545 to 5182)
    Statistical analysis title
    		 Superiority of Anti-HBs GMT Response at Month 7
    Statistical analysis description
    Statistical Analysis of Superiority of Anti-HBs GMT Response at Month 7 (1 Month Postdose 3) Between the GSH/2X Phosphate Hepatitis B Vaccine and the 2X Phosphate Hepatitis B Vaccine (Per-Protocol Analysis) – Stage 2
    Comparison groups
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants v 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.9
    Notes
    [10] - The lower bound of the 95% confidence interval on the GMT ratio greater than the prespecified clinically relevant value of 1.00 (identity) allows for a conclusion of superiority.

    Secondary: Percentage of Participants Who Experienced One or More Adverse Events (AEs, Stage 2 Infants)

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events (AEs, Stage 2 Infants) [11]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Up to 7 months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    120
    119
    Units: Percentage of Participants
        number (not applicable)
    76.7
    79.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants Discontinuing Study Drug Due to AEs (Stage 2 Infants)

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    End point title
    		 Percentage of Participants Discontinuing Study Drug Due to AEs (Stage 2 Infants) [12]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Up to Month 6
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    120
    119
    Units: Percentage of Participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Anti-Hepatitis B Antibodies Geometric Mean Titer (GMT) at Month 7 (1 Month Post-dose 3, Stage 1 Adults)

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    End point title
    		 Anti-Hepatitis B Antibodies Geometric Mean Titer (GMT) at Month 7 (1 Month Post-dose 3, Stage 1 Adults) [13]
    End point description
    GMT is in milli-international units per milliliter [mIU/mL]). A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. Per protocol population was defined as the adult participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    46
    8
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    2127.5 (1177 to 3846)
    684.5 (119.2 to 3932)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Elevated Temperatures (Stage 2 Infants)

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    End point title
    		 Percentage of Participants with Elevated Temperatures (Stage 2 Infants) [14]
    End point description
    After each of the 3 vaccinations, participants or the parent/legal guardian (in Stage 2) were to record the participant’s temperature in the evening on the day of vaccination and daily at the same time for the next 4 days. An elevated temperature is defined as a rectal temperature of >= 38.1 C (100.6 F) in Stage 2 was considered an adverse experience. The report of a "feverish feeling" was also considered an adverse experience. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5 following any vaccination (Up to approximately 6 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    120
    119
    Units: Percentage of Participants
        number (not applicable)
    21.7
    13.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants with One or More Injection-Site AEs (Stage 2 Infants)

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    End point title
    		 Percentage of Participants with One or More Injection-Site AEs (Stage 2 Infants) [15]
    End point description
    Injection-site adverse experiences were observed and recorded for Days 1 through 5 following any vaccination visit for Stage 2. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5 following any vaccination (Up to approximately 6 months)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Number of subjects analysed
    120
    119
    Units: Percentage of Participants
        number (not applicable)
    35
    40.3
    No statistical analyses for this end point

    Secondary: SPR, Percentage of Participants with Anti-HBs Titer ≥10 mIU/mL (Stage 1 Adults)

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    End point title
    		 SPR, Percentage of Participants with Anti-HBs Titer ≥10 mIU/mL (Stage 1 Adults) [16]
    End point description
    SPR is defined as the percentage of participants who demonstrate antibodies to hepatitis B surface antigen ≥10 mIU/mL. A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. The statistical criterion for an adequate SPR required the lower bound of the 2-sided multiplicity adjusted 95.0% confidence interval have a lower bound that exceeds 90.0%. Per protocol population was defined as the adult participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    46
    8
    Units: Percentage of Participants
        number (confidence interval 95%)
    95.7 (88.6 to 100)
    87.5 (58.2 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Quantifiable Anti-HBs (anti-HBs titers ≥ 5 mIU/mL) (Stage 1 Adults)

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    End point title
    		 Percentage of Participants with Any Quantifiable Anti-HBs (anti-HBs titers ≥ 5 mIU/mL) (Stage 1 Adults) [17]
    End point description
    A Hepatitis B enhanced chemiluminescence assay was used in this antibody analysis. Per protocol population was defined as the adult participants who met the inclusion criteria, were not protocol violators, were seronegative at baseline (prevaccination anti-HBs titer <5 mIU/mL), and had serology and vaccinations within the specified day ranges.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month post-dose 3)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    46
    8
    Units: Percentage of Participants
        number (confidence interval 95%)
    97.8 (92.5 to 100)
    87.5 (58.2 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with One or More Injection-Site AEs (Stage 1 Adults)

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    End point title
    		 Percentage of Participants with One or More Injection-Site AEs (Stage 1 Adults) [18]
    End point description
    Injection-site adverse experiences were observed and recorded for Days 1 through 5 following any vaccination visit for Stage 2. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5 following any vaccination (Up to approximately 6 months)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    50
    10
    Units: Percentage of Participants
        number (not applicable)
    86
    90
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Elevated Temperatures (Stage 1 Adults)

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    End point title
    		 Percentage of Participants with Elevated Temperatures (Stage 1 Adults) [19]
    End point description
    After each of the 3 vaccinations, participants or the parent/legal guardian (in Stage 2) were to record the participant’s temperature in the evening on the day of vaccination and daily at the same time for the next 4 days. An elevated temperature is defined as a rectal temperature of >= 38.1 C (100.6 F) in Stage 2 was considered an adverse experience. The report of a "feverish feeling" was also considered an adverse experience. The safety population consisted of all infant participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine and had follow-up data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5 following any vaccination (Up to approximately 6 months)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned or performed for this end point.
    End point values
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Number of subjects analysed
    50
    10
    Units: Percentage of Participants
        number (not applicable)
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 7 months
    Adverse event reporting additional description
    The safety population consisted of all participants who received at least one dose of GSH/2X Phosphate Hepatitis B Vaccine or 2X Phosphate Hepatitis B Vaccine. Serious adverse events were reported for the entire study period; non-serious adverse events were reported for Days 1 through 14 following any vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants will receive a 3 x 10-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 1.0-mL intramuscular injection

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 1 Adults
    Reporting group description
    		 Participants will receive a 3 x 10-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 1.0-mL intramuscular injection

    Reporting group title
    GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants will receive a 3 x 5-μg regimen of GSH/2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 0.5-mL intramuscular injection

    Reporting group title
    2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Reporting group description
    		 Participants will receive a 3 x 5-μg regimen of 2X Phosphate Hepatitis B Vaccine on a 0-, 1-, and 6-month schedule, as a 0.5-mL intramuscular injection.

    Serious adverse events
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 10 (10.00%)
    1 / 120 (0.83%)
    1 / 119 (0.84%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Facial paresis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 10 (10.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign intracranial hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 10 (10.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic arthritis staphylococcal
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GSH/2X Phosphate Hepatitis B Vaccine - Stage 1 Adults 2X Phosphate Hepatitis B Vaccine - Stage 1 Adults GSH/2X Phosphate Hepatitis B Vaccine - Stage 2 Infants 2X Phosphate Hepatitis B Vaccine - Stage 2 Infants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 50 (94.00%)
    9 / 10 (90.00%)
    92 / 120 (76.67%)
    95 / 119 (79.83%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 10 (0.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Headache
         subjects affected / exposed
    22 / 50 (44.00%)
    3 / 10 (30.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    42
    3
    0
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 10 (10.00%)
    20 / 120 (16.67%)
    20 / 119 (16.81%)
         occurrences all number
    4
    2
    29
    25
    Injection site pain
         subjects affected / exposed
    43 / 50 (86.00%)
    9 / 10 (90.00%)
    17 / 120 (14.17%)
    18 / 119 (15.13%)
         occurrences all number
    110
    25
    22
    29
    Injection site paraesthesia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 10 (10.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site swelling
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 10 (10.00%)
    15 / 120 (12.50%)
    19 / 119 (15.97%)
         occurrences all number
    3
    2
    18
    27
    Irritability
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    30 / 120 (25.00%)
    39 / 119 (32.77%)
         occurrences all number
    0
    0
    42
    58
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 10 (0.00%)
    36 / 120 (30.00%)
    27 / 119 (22.69%)
         occurrences all number
    4
    0
    43
    30
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 10 (0.00%)
    8 / 120 (6.67%)
    7 / 119 (5.88%)
         occurrences all number
    2
    0
    10
    8
    Nausea
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 10 (0.00%)
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences all number
    3
    0
    0
    1
    Teething
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    8 / 120 (6.67%)
    9 / 119 (7.56%)
         occurrences all number
    0
    0
    10
    14
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 10 (0.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 10 (0.00%)
    5 / 120 (4.17%)
    9 / 119 (7.56%)
         occurrences all number
    2
    0
    6
    9
    Pharyngolaryngeal pain
         subjects affected / exposed
    6 / 50 (12.00%)
    1 / 10 (10.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Psychiatric disorders
    Crying
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    10 / 120 (8.33%)
    10 / 119 (8.40%)
         occurrences all number
    0
    0
    15
    12
    Restlessness
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    4 / 120 (3.33%)
    7 / 119 (5.88%)
         occurrences all number
    0
    0
    6
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 10 (0.00%)
    0 / 120 (0.00%)
    0 / 119 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    7 / 120 (5.83%)
    5 / 119 (4.20%)
         occurrences all number
    0
    0
    7
    5
    Rhinitis
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 10 (0.00%)
    16 / 120 (13.33%)
    30 / 119 (25.21%)
         occurrences all number
    4
    0
    17
    32
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 10 (10.00%)
    10 / 120 (8.33%)
    17 / 119 (14.29%)
         occurrences all number
    3
    1
    12
    18

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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