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    Clinical Trial Results:
    A Phase III, Observer-Blind, Randomized, Controlled, Single Center Study To Investigate Immunogenicity And Safety Of Vaxem Hib In 13 - 59 Months Old Healthy Children In China, According To The Recommended Regimen Of 1 Dose.

    Summary
    EudraCT number
    		 2014-005246-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Oct 2009

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

    Trial information

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    Trial identification
    Sponsor protocol code
    V37_06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01125527
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics S.r.l.
    Sponsor organisation address
    Via Fiorentina 1, Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics S.r.l., RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics S.r.l., 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
    08 Apr 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that Vaxem Hib given to children aged 13-59 months at study entry is non-inferior to comparator vaccine HIBERIX with regard to percentage of subjects with antibody levels of ≥ 0.15μg/mL one month after vaccination as measured by anti- PRP ELISA.
    Protection of trial subjects
    This clinical trial was carried out in accordance with relevant requirements of Regulation on Drug Registration and Good Clinical Practice (GCP) as well as Technical Guideline on Clinical Trial of Vaccine that were issued by the State Food and Drug Administration (SFDA), and was conducted in compliance with principles of Declaration of Helsinki.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    23 Aug 2009
    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: 729
    Worldwide total number of subjects
    729
    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)
    287
    Children (2-11 years)
    442
    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 enrolled at 1 center in China.

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

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was designed as an observer-blind trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vaxem Hib Group
    Arm description
    		 Subjects received a single 0.5mL dose of Vaxem Hib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Haemophilus influenzae type b conjugate vaccine (CRM197 Conjugate)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0.5 mL.

    Arm title
    		 HIBERIX Group
    Arm description
    		 Subjects received a single 0.5 mL dose of HIBERIX.
    Arm type
    		 Control

    Investigational medicinal product name
    Haemophilus influenzae type b Conjugate Vaccine (Tetanus Toxoid Conjugate)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0.5 mL.

    Number of subjects in period 1
    		Vaxem Hib Group HIBERIX Group
    Started
    365
    364
    Completed
    348
    352
    Not completed
    17
    12
         Consent withdrawn by subject
    5
    5
         Adverse event
    1
    -
         Lost to follow-up
    11
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vaxem Hib Group
    Reporting group description
    		 Subjects received a single 0.5mL dose of Vaxem Hib.

    Reporting group title
    HIBERIX Group
    Reporting group description
    		 Subjects received a single 0.5 mL dose of HIBERIX.

    Reporting group values
    		 Vaxem Hib Group HIBERIX Group Total
    Number of subjects
    		 365 364 729
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 29.4 ± 10.5 29.5 ± 10.7 -
    Gender categorical
    Units: Subjects
        Female
    		 186 169 355
        Male
    		 179 195 374
    Subject analysis sets

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who signed an informed consent and were enrolled.

    Subject analysis set title
    Exposed Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects in the enrolled population who received vaccination.

    Subject analysis set title
    Per Protocol Set (PPS, Immunogenicity)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All enrolled subjects who correctly received the vaccine, provided evaluable serum samples at the relevant time points (for subjects in the immunogenicity subset), and had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the exposed population who provided safety data after baseline.

    Subject analysis sets values
    		 All Enrolled Population Exposed Population Per Protocol Set (PPS, Immunogenicity) Safety Population
    Number of subjects
    729
    728
    695
    728
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    29.5 ± 10.6
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    355
        Male
    374

    End points

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    End points reporting groups
    Reporting group title
    Vaxem Hib Group
    Reporting group description
    		 Subjects received a single 0.5mL dose of Vaxem Hib.

    Reporting group title
    HIBERIX Group
    Reporting group description
    		 Subjects received a single 0.5 mL dose of HIBERIX.

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who signed an informed consent and were enrolled.

    Subject analysis set title
    Exposed Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects in the enrolled population who received vaccination.

    Subject analysis set title
    Per Protocol Set (PPS, Immunogenicity)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All enrolled subjects who correctly received the vaccine, provided evaluable serum samples at the relevant time points (for subjects in the immunogenicity subset), and had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the exposed population who provided safety data after baseline.

    Primary: Percentages of subjects with an antibody level ≥ 0.15μg/mL one month after the vaccination

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    End point title
    		 Percentages of subjects with an antibody level ≥ 0.15μg/mL one month after the vaccination
    End point description
    Immunogenicity was assessed as the percentages of subjects with an antibody level ≥ 0.15μg/mL one month after the vaccination. The analysis was performed on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    One month after the vaccination.
    End point values
    		 Vaxem Hib Group HIBERIX Group
    Number of subjects analysed
    346
    349
    Units: Percentages of subjects
    number (confidence interval 95%)
        ≥ 0.15μg/mL
    98.84 (97.07 to 99.68)
    100 (98.95 to 100)
    Statistical analysis title
    		 Non-inferiority of immune response to Vaxem Hib
    Statistical analysis description
    Null hypothesis (H0) for the target value of the primary immunogenicity is that the protection rate of anti-PRP antibodies in subjects vaccinated with Vaxem Hib was not lower than that in subjects vaccinated with HIBERIX, non-inferiority threshold 5% and using one-sided 0.025. Therefore, study vaccine Vaxem Hib is not inferior to vaccine HIBERIX if the lower two-sided 95% confidence limit of difference in the long-term protection rates of antibodies is not beyond -5%.
    Comparison groups
    Vaxem Hib Group v HIBERIX Group
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 95% Confidence Intervals
    Parameter type
    		 Percentage group difference
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.28
         upper limit
    		 -0.03

    Secondary: Percentages of subjects with an antibody level ≥ 1.0 μg/mL one month after the vaccination

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    End point title
    		 Percentages of subjects with an antibody level ≥ 1.0 μg/mL one month after the vaccination
    End point description
    Immunogenicity was assessed as the percentages of subjects with an antibody level ≥ 1.0μg/mL one month after the vaccination. Analysis performed on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    One month after the vaccination.
    End point values
    		 Vaxem Hib Group HIBERIX Group
    Number of subjects analysed
    346
    349
    Units: Percentages of subjects
    number (confidence interval 95%)
        ≥ 1.0μg/mL
    98.84 (97.07 to 99.68)
    100 (98.95 to 100)
    No statistical analyses for this end point

    Secondary: Geometric mean of serum antibody concentrations one month after the vaccination

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    End point title
    		 Geometric mean of serum antibody concentrations one month after the vaccination
    End point description
    Immunogenicity was assessed as the geometric mean of serum antibody concentrations (GMC) one month after the vaccination. Analysis performed on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    One month after the vaccination.
    End point values
    		 Vaxem Hib Group HIBERIX Group
    Number of subjects analysed
    346
    349
    Units: μg/mL
    geometric mean (confidence interval 95%)
        GMC
    93.13 (79.01 to 109.76)
    115.31 (102.71 to 129.46)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following the vaccination

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    End point title
    		 Number of subjects reporting solicited local and systemic reactions during the 7 days following the vaccination
    End point description
    Safety was assessed as the number of subjects who reported solicited local and systemic reactions from day 1 through day 7 after the vaccination. Analysis performed on the safety set.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 7 after vaccination.
    End point values
    		 Vaxem Hib Group HIBERIX Group
    Number of subjects analysed
    365
    363
    Units: Number of subjects
        Any local
    40
    36
        Any systemic
    136
    143
        Erythema 1-15mm
    21
    17
        Erythema 15-30mm
    5
    2
        Erythema >30mm
    1
    0
        Tenderness mild
    20
    20
        Tenderness moderate
    1
    1
        Induration 1-15mm
    23
    18
        Induration 15-30mm
    3
    2
        Induration >30mm
    1
    1
        Fever mild
    84
    88
        Fever moderate
    43
    47
        Fever severe
    5
    4
        Rash
    8
    2
        Sleepiness
    8
    4
        Irritability
    3
    6
        Unusual crying
    7
    10
        Change in eating habits
    10
    11
        Analgesic/antipyretic medication use
    48
    56
    No statistical analyses for this end point

    Secondary: Incidence of subjects reporting any unsolicited adverse event (AE) and serious adverse event (SAE) after the vaccination.

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    End point title
    		 Incidence of subjects reporting any unsolicited adverse event (AE) and serious adverse event (SAE) after the vaccination.
    End point description
    Safety was assessed as the incidence of subjects who reported unsolicited AEs and SAEs up to one month after the vaccination. Analysis performed on the safety set.
    End point type
    Secondary
    End point timeframe
    One month after vaccination.
    End point values
    		 Vaxem Hib Group HIBERIX Group
    Number of subjects analysed
    365
    363
    Units: Number of subjects
        Total incidence rate of AEs
    128
    128
        Incidence rate of vaccine-related AEs
    11
    11
        SAE Incidence rate
    1
    0
        Withdrawal due to AE
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All solicited AEs and unsolicited AEs were collected from Day 1 to Day 7; all other serious and non-serious AEs were collected for approximately one month after the vaccination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Vaxem Hib Group
    Reporting group description
    		 Subjects received a single 0.5mL dose of Vaxem™Hib.

    Reporting group title
    HIBERIX Group
    Reporting group description
    		 Subjects received a single 0.5mL dose of HIBERIX

    Serious adverse events
    		 Vaxem Hib Group HIBERIX Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 363 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Encephalitis viral
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vaxem Hib Group HIBERIX Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    203 / 365 (55.62%)
    207 / 363 (57.02%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    27 / 365 (7.40%)
    19 / 363 (5.23%)
         occurrences all number
    27
    19
    Injection site induration
         subjects affected / exposed
    27 / 365 (7.40%)
    21 / 363 (5.79%)
         occurrences all number
    27
    21
    Injection site pain
         subjects affected / exposed
    21 / 365 (5.75%)
    21 / 363 (5.79%)
         occurrences all number
    21
    21
    Pyrexia
         subjects affected / exposed
    145 / 365 (39.73%)
    153 / 363 (42.15%)
         occurrences all number
    171
    174
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 365 (3.01%)
    21 / 363 (5.79%)
         occurrences all number
    11
    21
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    65 / 365 (17.81%)
    70 / 363 (19.28%)
         occurrences all number
    66
    71

    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.
    N/A
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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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