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    Clinical Trial Results:
    A Phase III Observer blind Single-Coordinating Center Pediatric Study in China Comparing a Booster Dose of Vaxem™ Hib to HIBERIX® When Given as Part of a Local Dosing Regimen in Infants

    Summary
    EudraCT number
    		 2014-005135-13
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    21 Dec 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2016
    First version publication date
    09 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V37_07E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01226953
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics
    Sponsor organisation address
    Via Fiorentina, 1, Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the immune response of Vaxem™ Hib booster is non-inferior to the immune response of comparator vaccine HIBERIX® booster as assessed by the percentage of subjects with anti-PRP (polyribosyl-ribitol-phosphate) antibody levels ≥1.0μg/mL 30 days after booster vaccination.
    Protection of trial subjects
    This clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, Novartis codes on the protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2010
    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
    China: 660
    Worldwide total number of subjects
    660
    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)
    660
    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
    		 Subjects were recruited from 1 site in China.

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VaxemHib
    Arm description
    		 Subjects who received the VaxemHib vaccine in the parent study and received one booster dose of the same vaccine in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Haemophilus influenzae type b conjugate vaccine (CRM197 Conjugate)
    Investigational medicinal product code
    Other name
    VaxemHib
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single dose of 0.5 mL VaxemHib was to be administered intramuscularly into the deltoid muscle.

    Arm title
    		 HIBERIX
    Arm description
    		 Subjects who received the HIBERIX vaccine in the parent study and received one booster dose of the same vaccine in this study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Haemophilus influenzae type b Conjugate Vaccine (Tetanus Toxoid Conjugate)
    Investigational medicinal product code
    Other name
    HIBERIX
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single dose of 0.5 mL HIBERIX was to be administered intramuscularly into the deltoid muscle.

    Number of subjects in period 1
    		VaxemHib HIBERIX
    Started
    327
    333
    Completed
    327
    333

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received the VaxemHib vaccine in the parent study and received one booster dose of the same vaccine in this study.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received the HIBERIX vaccine in the parent study and received one booster dose of the same vaccine in this study.

    Reporting group values
    		 VaxemHib HIBERIX Total
    Number of subjects
    		 327 333 660
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 448 ( 49.7 ) 446.8 ( 49 ) -
    Gender categorical
    Units: Subjects
        Female
    		 150 161 311
        Male
    		 177 172 349

    End points

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    End points reporting groups
    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received the VaxemHib vaccine in the parent study and received one booster dose of the same vaccine in this study.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received the HIBERIX vaccine in the parent study and received one booster dose of the same vaccine in this study.

    Subject analysis set title
    All Enrolled Population, Demography
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who have signed an informed consent.

    Subject analysis set title
    Per protocol (PP) population, Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the Full Analysis Set (FAS)/Modified Intention-to-treat (MITT) Immunogenicity population who: - correctly receive the vaccine, and - provide evaluable serum samples at the relevant time points, and - have no major protocol violation as defined prior to analysis. A major deviation is defined as a protocol deviation that is considered to have a significant impact on the immunogenicity result of the subject.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the exposed population who provide post vaccination safety data.

    Primary: 1. Percentage of subjects achieving an anti-PRP concentration ≥1.0 μg/mL 30 days after booster vaccination.

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    End point title
    		 1. Percentage of subjects achieving an anti-PRP concentration ≥1.0 μg/mL 30 days after booster vaccination.
    End point description
    The immune response of VaxemHib booster was assessed by the percentage of subjects with anti-PRP (polyribosyl-ribitol-phosphate) antibody levels ≥1.0μg/mL 30 days after booster vaccination. Analysis was performed on the per protocol population.
    End point type
    Primary
    End point timeframe
    30 days after booster vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    301
    302
    Units: Percentages Of Subjects
    number (confidence interval 95%)
        Baseline
    98 (96 to 99)
    98 (96 to 99)
        One month post vaccination
    100 (98 to 100)
    100 (99 to 100)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of VaxemHib immune response following booster vaccination as compared to the immune response of comparator vaccine HIBERIX booster 30 days after vaccination.
    Comparison groups
    VaxemHib v HIBERIX
    Number of subjects included in analysis
    603
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1
    Notes
    [1] - Non-inferiority was assessed using a non-inferiority margin of -5% for the vaccine group difference in proportions of subjects achieving an anti-PRP concentration ≥1.0 μg/mL.

    Secondary: 2. Percentage of subjects achieving an anti-PRP concentration ≥0.15 μg/mL 30 days after booster vaccination

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    End point title
    		 2. Percentage of subjects achieving an anti-PRP concentration ≥0.15 μg/mL 30 days after booster vaccination
    End point description
    The immune response of VaxemHib booster was assessed by the percentage of subjects with anti-PRP antibody levels ≥0.15 μg/mL, 30 days after booster vaccination. Analysis was performed on the per protocol population.
    End point type
    Secondary
    End point timeframe
    30 days after booster vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    301
    302
    Units: Percentages of subjects
    number (confidence interval 95%)
        Baseline
    98 (96 to 99)
    99 (97 to 100)
        One month post vaccination
    100 (98 to 100)
    100 (99 to 100)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of VaxemHib immune response following booster vaccination as compared to the immune response of comparator vaccine HIBERIX booster 30 days after vaccination.
    Comparison groups
    HIBERIX v VaxemHib
    Number of subjects included in analysis
    603
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1
    Notes
    [2] - Non-inferiority was assessed using a non-inferiority margin of -5% for the vaccine group difference in proportions of subjects achieving an anti-PRP concentration ≥0.15 μg/mL.

    Secondary: 3. Geometric mean of anti-PRP antibody concentration 30 days after booster vaccination

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    End point title
    		 3. Geometric mean of anti-PRP antibody concentration 30 days after booster vaccination
    End point description
    The immune response of VaxemHib booster was assessed by anti-PRP antibody geometric mean concentrations (GMCs), 30 days after booster vaccination. Analysis was performed on the per protocol population.
    End point type
    Secondary
    End point timeframe
    30 days after booster vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    301
    302
    Units: Ab concentrations (μg/mL)
    geometric mean (confidence interval 95%)
        Visit 1/Baseline
    8.16 (7.23 to 9.2)
    10 (9.05 to 12)
        Visit 2/One month post vaccination
    57 (50 to 64)
    68 (60 to 77)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of VaxemHib immune response following booster vaccination as compared to the immune response of comparator vaccine HIBERIX booster
    Comparison groups
    VaxemHib v HIBERIX
    Number of subjects included in analysis
    603
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1
    Notes
    [3] - Non-inferiority was assessed using a non-inferiority margin of non-inferiority of 0.67 for the ratio of vaccine group anti-PRP GMCs

    Secondary: 4. Numbers of subjects with reported solicited local and systemic adverse events (AEs) recorded for 7 days (day 1-7) after the vaccination.

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    End point title
    		 4. Numbers of subjects with reported solicited local and systemic adverse events (AEs) recorded for 7 days (day 1-7) after the vaccination.
    End point description
    The numbers of subjects with reported solicited local and systemic adverse events (AEs) were recorded for 7 days after the vaccination. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    day 1-7 after the vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    327
    333
    Units: Number of subjects
        Any solicited local AE
    127
    83
        Tenderness
    51
    32
        Erythema (N=325, 333)
    87
    56
        Induration (N=326, 333)
    68
    39
        Any solicited systemic AE
    52
    54
        Change Eat. Habits
    15
    15
        Sleepiness
    11
    14
        Unusual Crying
    20
    24
        Irritability
    17
    17
        Rash
    4
    1
        Fever ( >= 37.5C )
    32
    30
        Analg. Antipyr. Med. Used
    20
    20
    No statistical analyses for this end point

    Secondary: 5. Numbers of subjects with reported unsolicited adverse events (AEs) recorded for 7 days (day 1-7) after the vaccination.

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    End point title
    		 5. Numbers of subjects with reported unsolicited adverse events (AEs) recorded for 7 days (day 1-7) after the vaccination.
    End point description
    The numbers of subjects with reported unsolicited adverse events (AEs) were recorded for 7 days after the vaccination. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    day 1-7 after the vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    327
    333
    Units: Number of subjects
        Any unsolicited AE
    69
    67
        Abdominal distension
    2
    0
        Diarrhoea
    33
    26
        Dyspepsia
    1
    0
        Enteritis
    0
    1
        Mouth ulceration
    0
    1
        Vomiting
    1
    0
        Induration
    1
    1
        Irritability
    0
    2
        Pyrexia
    3
    2
        Bronchitis
    2
    2
        Nasopharyngitis
    24
    20
        Upper respiratory tract infection
    21
    23
        Thermal burn
    1
    0
        Crying
    0
    2
        Somnolence
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were collected from day 1 to 30. Solicited local and systemic reactions were collected from day 1 to 7.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received the VaxemHib vaccine in the parent study and received one booster dose of the same vaccine.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received the HIBERIX vaccine in the parent study and received one booster dose of the same vaccine.

    Serious adverse events
    		 VaxemHib HIBERIX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 327 (0.00%)
    0 / 333 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VaxemHib HIBERIX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 327 (51.07%)
    135 / 333 (40.54%)
    General disorders and administration site conditions
    Crying
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    20 / 327 (6.12%)
    24 / 333 (7.21%)
         occurrences all number
    21
    27
    Injection site erythema
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    89 / 327 (27.22%)
    56 / 333 (16.82%)
         occurrences all number
    89
    56
    Injection site induration
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    69 / 327 (21.10%)
    39 / 333 (11.71%)
         occurrences all number
    69
    39
    Injection site pain
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    51 / 327 (15.60%)
    32 / 333 (9.61%)
         occurrences all number
    52
    32
    Pyrexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    33 / 327 (10.09%)
    31 / 333 (9.31%)
         occurrences all number
    37
    35
    Gastrointestinal disorders
    Diarrhoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    33 / 327 (10.09%)
    26 / 333 (7.81%)
         occurrences all number
    33
    27
    Psychiatric disorders
    Irritability
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    17 / 327 (5.20%)
    17 / 333 (5.11%)
         occurrences all number
    18
    19
    Infections and infestations
    Nasopharyngitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    24 / 327 (7.34%)
    20 / 333 (6.01%)
         occurrences all number
    24
    21
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    21 / 327 (6.42%)
    23 / 333 (6.91%)
         occurrences all number
    21
    24

    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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