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    Clinical Trial Results:
    A Study in Healthy Neonates of Safety, Tolerability, and Immunogenicity of Recombinant Hepatitis B Vaccine Manufactured Using a Modified Process

    Summary
    EudraCT number
    2016-003981-15
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    20 Jul 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Feb 2017
    First version publication date
    03 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V232-056
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00322361
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck Registration Number: 2006_007
    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
    20 Jul 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Hepatitis B Vaccine [Recombinant] is a well established vaccine which has been used extensively, worldwide since its initial licensure in 1986. Hepatitis B vaccines: [1] induce protection against the morbidity and mortality of acute hepatitis B virus infection, [2] reduce the incidence of chronic infection in vaccinated populations, and [3] thereby, reduce the incidence of hepatocellular carcinoma. The purpose of the trial was to assess if the new manufacturing process of the Hepatitis B Vaccine [Recombinant] vaccine showed the same or better level of hepatitis B antibody response than does the currently licensed Hepatitis B Vaccine [Recombinant] vaccine. This study was also to confirm that the new process vaccine is as well tolerated as the current vaccine in neonates.
    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. The following additional measure defined for this individual study was in place for the protection of trial participants: participants who did not develop seroprotective levels of anti-HBs, 1 month after the third dose, may have been offered additional vaccination, outside of the protocol, at the discretion of the investigator.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    United States: 531
    Worldwide total number of subjects
    566
    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)
    566
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Healthy male and female full-term (37-42 weeks gestation) neonates (birth to 10 days of age) born to mothers with documented negative test for hepatitis B surface antigen (HBsAg) within 9 months prior to delivery.

    Pre-assignment
    Screening details
    No pre-screening for antibody to hepatitis B surface antigen (anti-HBs) or hepatitis B core antigen (anti-HBc) was conducted.

    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
    Modified Process Hepatitis B Vaccine
    Arm description
    Modified Process Hepatitis B three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Modified Process Hepatitis B Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    5 mcg (0.5 mL) per dose

    Arm title
    RECOMBIVAX HB™ Vaccine
    Arm description
    RECOMBIVAX HB™ three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.
    Arm type
    Active comparator

    Investigational medicinal product name
    RECOMBIVAX HB™ Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    5 mcg (0.5 mL) per dose

    Number of subjects in period 1
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine
    Started
    283
    283
    Vaccine 1
    282
    283
    Vaccine 2
    267
    263
    Vaccine 3
    214
    215
    Completed
    194
    193
    Not completed
    89
    90
         Participant moved
    6
    9
         Consent withdrawn by subject
    22
    20
         Other reason not specified
    22
    22
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    18
    13
         Protocol deviation
    20
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Modified Process Hepatitis B Vaccine
    Reporting group description
    Modified Process Hepatitis B three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.

    Reporting group title
    RECOMBIVAX HB™ Vaccine
    Reporting group description
    RECOMBIVAX HB™ three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.

    Reporting group values
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine Total
    Number of subjects
    283 283 566
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: days
        arithmetic mean (standard deviation)
    6.5 ± 2.29 6.6 ± 2.4 -
    Gender Categorical
    Units: Subjects
        Female
    156 138 294
        Male
    127 145 272

    End points

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    End points reporting groups
    Reporting group title
    Modified Process Hepatitis B Vaccine
    Reporting group description
    Modified Process Hepatitis B three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.

    Reporting group title
    RECOMBIVAX HB™ Vaccine
    Reporting group description
    RECOMBIVAX HB™ three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1.

    Primary: Geometric mean titer (GMT) to anti-HBs at Month 7

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    End point title
    Geometric mean titer (GMT) to anti-HBs at Month 7
    End point description
    Geometric mean antibody titers to hepatitis B surface antigen (milli international units/milliliter [mIU/mL]) were measured 4 weeks after the third vaccination. Analysis population: per-protocol population included all participants who met the inclusion criteria, were not protocol violators and had serology and vaccinations within the specified day ranges.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month post vaccination 3)
    End point values
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine
    Number of subjects analysed
    191
    187
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    843.7 (680.8 to 1045.5)
    670.1 (549.2 to 817.5)
    Statistical analysis title
    GMT ratio
    Statistical analysis description
    The lower bound of the 95% confidence interval (CI) on the GMT ratio greater than the pre-specified clinically relevant values of 0.67 (i.e., a 1.5-fold decrease) and 1.00 (identity) allows for a conclusion of non-inferiority or superiority, respectively.
    Comparison groups
    Modified Process Hepatitis B Vaccine v RECOMBIVAX HB™ Vaccine
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    GMT ratio
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.94
         upper limit
    1.69

    Secondary: Percentage of participants who experienced an adverse event

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    End point title
    Percentage of participants who experienced an adverse event
    End point description
    Adverse experience means any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a Merck product whether or not considered related to the use of the product. Participant's parents/legal guardians recorded in the Vaccination Report Card (VRC) systemic and injection-site adverse experiences, temperatures, and any other vaccines or medications administered during Day 1 through Day 14. Analysis population: all participants who received at least 1 injection of vaccine in this study and had safety follow-up data for at least 1 day following an injection.
    End point type
    Secondary
    End point timeframe
    Up to 42 days (including follow-up 14 days post vaccination 1, 2, & 3)
    End point values
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine
    Number of subjects analysed
    273
    272
    Units: Percentage of participants
        number (not applicable)
    72.2
    72.4
    Statistical analysis title
    Difference in risk
    Statistical analysis description
    Risk differences in percentage points (Modified Process Hepatitis B Vaccine - RECOMBIVAX HB™ Vaccine) and confidence intervals are based on pooled incidence rates across all study centers.
    Comparison groups
    Modified Process Hepatitis B Vaccine v RECOMBIVAX HB™ Vaccine
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.8
         upper limit
    7.3

    Secondary: Percentage of participants who discontinued from study therapy due to an adverse event

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    End point title
    Percentage of participants who discontinued from study therapy due to an adverse event
    End point description
    Adverse experience means any unfavorable and unintended change in the structure (signs), function (symptoms), or chemistry (laboratory data) of the body temporally associated with any use of a Merck product whether or not considered related to the use of the product. Participant's parents/legal guardians recorded in the Vaccination Report Card (VRC) systemic and injection-site adverse experiences, temperatures, and any other vaccines or medications administered during Day 1 through Day 14. Analysis population: all participants who received at least 1 injection of vaccine in this study and had safety follow-up data for at least 1 day following an injection.
    End point type
    Secondary
    End point timeframe
    Up to 28 days (including follow-up 14 days post vaccination 1 & 2)
    End point values
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine
    Number of subjects analysed
    273
    272
    Units: Percentage of participants
        number (not applicable)
    0.4
    0
    Statistical analysis title
    Difference in risk
    Statistical analysis description
    Risk differences in percentage points (Modified Process Hepatitis B Vaccine - RECOMBIVAX HB™ Vaccine) and confidence intervals are based on pooled incidence rates across all study centers.
    Comparison groups
    Modified Process Hepatitis B Vaccine v RECOMBIVAX HB™ Vaccine
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    2.1

    Secondary: Percentage of Participants with Seroprotection (anti-HBsAg >=10 mIU/mL) at Month 7

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    End point title
    Percentage of Participants with Seroprotection (anti-HBsAg >=10 mIU/mL) at Month 7
    End point description
    Seroprotection rate was measured as the percentage of participants with anti-HBsAg ≥ 10 mIU/mL at Month 7. Anti-hepatitis B surface antigen titers were measured 4 weeks after the third vaccination. Analysis population: per-protocol population included all participants who met the inclusion criteria, were not protocol violators and had serology and vaccinations within the specified day ranges.
    End point type
    Secondary
    End point timeframe
    Month 7 (1 month post vaccination 3)
    End point values
    Modified Process Hepatitis B Vaccine RECOMBIVAX HB™ Vaccine
    Number of subjects analysed
    191
    187
    Units: Percentage of participants
        number (confidence interval 95%)
    97.9 (95.6 to 100)
    98.9 (97.2 to 100)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events: Up to 7 months (entire study); Non-serious systemic adverse events: Days 1-14 following any vaccination visit; Non-serious injection-site adverse events: Days 1-5 following any vaccination visit
    Adverse event reporting additional description
    Population included all randomized participants who received at least 1 injection of vaccine in this study and had safety follow-up data for at least 1 day following an injection.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    RECOMBIVAX HB™ Vaccine
    Reporting group description
    RECOMBIVAX HB™ three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1 schedule.

    Reporting group title
    Modified Process Hepatitis B Vaccine
    Reporting group description
    Modified Process Hepatitis B three 5 mcg dose regimen administered via intramuscular injection at birth (up to 10 days of age), 1 month after Dose 1, and 6 months after Dose 1 schedule.

    Serious adverse events
    RECOMBIVAX HB™ Vaccine Modified Process Hepatitis B Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 272 (1.47%)
    3 / 273 (1.10%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Blindness congenital
         subjects affected / exposed
    1 / 272 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal anomaly congenital
         subjects affected / exposed
    1 / 272 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 272 (0.74%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 272 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 272 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RECOMBIVAX HB™ Vaccine Modified Process Hepatitis B Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 272 (61.40%)
    168 / 273 (61.54%)
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    27 / 272 (9.93%)
    22 / 273 (8.06%)
         occurrences all number
    35
    24
    Pyrexia
         subjects affected / exposed
    21 / 272 (7.72%)
    30 / 273 (10.99%)
         occurrences all number
    25
    35
    Injection site erythema
         subjects affected / exposed
    97 / 272 (35.66%)
    103 / 273 (37.73%)
         occurrences all number
    148
    155
    Injection site pain
         subjects affected / exposed
    87 / 272 (31.99%)
    103 / 273 (37.73%)
         occurrences all number
    133
    165
    Injection site swelling
         subjects affected / exposed
    66 / 272 (24.26%)
    59 / 273 (21.61%)
         occurrences all number
    96
    85
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    24 / 272 (8.82%)
    26 / 273 (9.52%)
         occurrences all number
    35
    33
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 272 (5.88%)
    8 / 273 (2.93%)
         occurrences all number
    16
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2006
    Amendment 1: protocol was amended to change the age of the participant at study entry, clarify the time of scheduled study visits, change the time the informed consent will be obtained from the parent/guardian, clarify information in the Study Flow Chart, incorporate some infant immunogenicity data into the Background and Rationale, and clarify the phosphate/aluminum content in the adjuvant.
    14 Apr 2006
    Amendment 2: protocol was amended to add safety evaluation committee, capture additional information on the vaccination report card, and revise study window visits, inclusion/exclusion criteria, special handling requirements, prior and concomitant medication(s)/treatment(s).
    23 Aug 2006
    Amendment 3: protocol was amended to change from U.S. IND. US Study to Worldwide, and revise primary Packaging and Labeling Information

    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
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