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    Clinical Trial Results:
    A Phase III Open Label, Multi-Center Pediatric Study in China Comparing a Booster Dose of Vaxem™ Hib to HIBERIX®

    Summary
    EudraCT number
    		 2014-005013-23
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    14 Dec 2009

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

    Trial information

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    Trial identification
    Sponsor protocol code
    M37P2E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01025544
    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 , RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines , 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
    10 Apr 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that a Vaxem™ Hib booster given to children aged 12–18 months is non-inferior to the comparator vaccine HIBERIX®. Non-inferiority was assessed as the percentage of subjects with anti-Polyribosyl-Ribitol-Phosphate (PRP) antibody levels ≥ 1.0 μg/mL one month after booster vaccination (i.e. long-term seroprotection rate). To compare safety and tolerability of the booster dose of Vaxem™ Hib with the control booster dose of HIBERIX® when given to toddlers aged 12-18 months.
    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. The trial was organised by Hebei Center for Disease Control (CDC). The study protocol and relevant documents were approved upon review by the Ethics Committee (EC) of Hebei CDC on August 18, 2008, and the study was conducted by qualified scientists and medical experts; the legal guardian of each subject signed a written Informed Consent Form (ICF) before initiation of the clinical trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Sep 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: 846
    Worldwide total number of subjects
    846
    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)
    846
    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 enrolled from 2 sites 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
    		 Not blinded
    Blinding implementation details
    This was an open label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vaxem Hib
    Arm description
    		 Subjects who received primary vaccination with Vaxem Hib in the parent study (M37P2), received a booster dose of Vaxem Hib in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capsular oligosaccharide of Haemophilus influenzae type b conjugated to CRM 197
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received one injection of 0.5 mL in the deltoid region.

    Arm title
    		 HIBERIX
    Arm description
    		 Subjects who received primary vaccination with HIBERIX in the parent study (M37P2), received a booster dose of HIBERIX in this study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capsular oligosaccharide of Haemophilus influenzae type b conjugated to tetanus toxoid.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received one injection of 0.5 mL in the deltoid region.

    Number of subjects in period 1
    		Vaxem Hib HIBERIX
    Started
    566
    280
    Completed
    566
    278
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vaxem Hib
    Reporting group description
    		 Subjects who received primary vaccination with Vaxem Hib in the parent study (M37P2), received a booster dose of Vaxem Hib in this study.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received primary vaccination with HIBERIX in the parent study (M37P2), received a booster dose of HIBERIX in this study.

    Reporting group values
    		 Vaxem Hib HIBERIX Total
    Number of subjects
    		 566 280 846
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 566 280 846
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 460 ( 35.5 ) 456.9 ( 32.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 275 135 410
        Male
    		 291 145 436

    End points

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    End points reporting groups
    Reporting group title
    Vaxem Hib
    Reporting group description
    		 Subjects who received primary vaccination with Vaxem Hib in the parent study (M37P2), received a booster dose of Vaxem Hib in this study.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received primary vaccination with HIBERIX in the parent study (M37P2), received a booster dose of HIBERIX in this study.

    Subject analysis set title
    Exposed Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the enrolled population who received vaccination

    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. Baseline is defined as the time immediately before vaccination.

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who have signed an informed consent and have been enrolled (eg, data collection).

    Subject analysis set title
    Full Analysis Set (FAS-Immunogenicity)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the enrolled population who actually received a study vaccination and provided at least one evaluable serum sample before or after baseline. Baseline is defined as the time immediately before vaccination.

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

    Primary: 1. Percentages of subjects achieving an anti-Polyribosil-Ribitol-Phosphate (PRP) concentration ≥ 1.0 μg/mL

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    End point title
    		 1. Percentages of subjects achieving an anti-Polyribosil-Ribitol-Phosphate (PRP) concentration ≥ 1.0 μg/mL
    End point description
    Non-inferiority of immune response of Vaxem Hib when compared to HIBERIX was assessed in terms of percentages of subjects achieving an anti-PRP concentration ≥ 1.0 μg/mL approximately one month post booster vaccination. Analysis was done on the Per Protocol (PP) dataset.
    End point type
    Primary
    End point timeframe
    Day 31
    End point values
    		 Vaxem Hib HIBERIX
    Number of subjects analysed
    271
    272
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PRP ≥ 1μg/mL
    100 (98.65 to 100)
    100 (98.65 to 100)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of immune response of Vaxem Hib when compared to HIBERIX was assessed as the between group difference in percentages of subjects achieving an anti-PRP concentration ≥ 1.0 μg/mL.
    Comparison groups
    HIBERIX v Vaxem Hib
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 t-test, 1-sided
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Success criterion: immune response of Vaxem Hib when compared to HIBERIX was to be considered non inferior if the lower two-sided 95% confidence limit of difference in the long-term protection rates of antibodies between the VaxemTM Hib group and the HIBERIX® group is not beyond -5% The approximation method used by the CRO in charge of the statistical analysis of the study, was not able to compute the 95% CI for the difference in proportions when values in both groups were equal to 100%.

    Secondary: 2. Percentages of subjects achieving an anti- Polyribosil-Ribitol-Phosphate (PRP) concentration ≥ 0.15 μg/mL

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    End point title
    		 2. Percentages of subjects achieving an anti- Polyribosil-Ribitol-Phosphate (PRP) concentration ≥ 0.15 μg/mL
    End point description
    Immune response of Vaxem Hib when compared to HIBERIX was assessed in terms of percentages of subjects achieving an anti-PRP concentration ≥ 0.15 μg/mL approximately one month post booster vaccination. Analysis was done on PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 31
    End point values
    		 Vaxem Hib HIBERIX
    Number of subjects analysed
    271
    272
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PRP ≥ 0.15 μg/mL
    100 (98.65 to 100)
    100 (98.65 to 100)
    No statistical analyses for this end point

    Secondary: 3. Anti-PRP geometric mean concentration (GMC)

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    End point title
    		 3. Anti-PRP geometric mean concentration (GMC)
    End point description
    Immune response of Vaxem Hib when compared to HIBERIX was assessed in terms of Anti-PRP GMC approximately one month post booster vaccination. Analysis was done on PP dataset.
    End point type
    Secondary
    End point timeframe
    Day 31
    End point values
    		 Vaxem Hib HIBERIX
    Number of subjects analysed
    271
    272
    Units: μg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP GMC
    245.9 (219.6 to 275.5)
    184.2 (162.7 to 208.5)
    No statistical analyses for this end point

    Secondary: 4. Number of subjects reporting selected indicators of reactogenicity local and/or systemic reactions.

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    End point title
    		 4. Number of subjects reporting selected indicators of reactogenicity local and/or systemic reactions.
    End point description
    Safety and tolerability of the booster dose of Vaxem Hib when compared with the control booster dose of HIBERIX are assessed in terms of number of subjects reporting selected indicators of reactogenicity, ie, local and systemic reactions. Analysis was done on Safety dataset.
    End point type
    Secondary
    End point timeframe
    From day 1 through 7 after vaccination.
    End point values
    		 Vaxem Hib HIBERIX
    Number of subjects analysed
    566
    280
    Units: Number of subjetcs
        Any local
    46
    16
        Eryhtema (< 15mm)
    5
    4
        Erythema (15-30mm)
    7
    0
        Erythema (> 30mm)
    1
    0
        Tenderness
    36
    14
        Induration (< 15mm)
    10
    3
        Induration (15-30mm)
    6
    1
        Any systemic
    153
    60
        Rash
    0
    0
        Sleepiness
    4
    2
        Irritability
    8
    1
        Unusual crying
    15
    2
        Change in eating habits
    22
    7
        Fever (37.1°C-37.5°C)
    109
    44
        Fever (37.6°C-39.0°C)
    30
    10
        Fever (> 39.0°C)
    0
    1
        Analgesic/antipyretic medication use
    34
    13
    No statistical analyses for this end point

    Secondary: 5. Number of subjects reporting unsolicited adverse events (AEs) and/or serious adverse events (SAEs)

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    End point title
    		 5. Number of subjects reporting unsolicited adverse events (AEs) and/or serious adverse events (SAEs)
    End point description
    Safety and tolerability of the booster dose of Vaxem Hib when compared with the control booster dose of HIBERIX are assessed in terms of number of subjects reporting unsolicited adverse events (AEs), vaccine-related AEs and/or serious AEs (SAEs). Analysis was done on the Safety dataset.
    End point type
    Secondary
    End point timeframe
    Throughout the entire study period.
    End point values
    		 Vaxem Hib HIBERIX
    Number of subjects analysed
    566
    280
    Units: Number of subjects
        Any unsolicited AEs
    122
    58
        Vaccine-related AEs
    6
    3
        Any SAEs
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Selected indicators of reactogenicity were recorded from day 1 to 7 after vaccination; unsolicited AEs and SAEs were recorded throughout the entire study period.
    Adverse event reporting additional description
    Selected indicators of reactogenicity were collected by systematic assessment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received primary vaccination with HIBERIX in the parent study (M37P2), received a booster dose of HIBERIX in this study.

    Reporting group title
    Vaxem Hib
    Reporting group description
    		 Subjects who received primary vaccination with Vaxem Hib in the parent study (M37P2), received a booster dose of Vaxem Hib in this study.

    Serious adverse events
    		 HIBERIX Vaxem Hib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 566 (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
    		 HIBERIX Vaxem Hib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 280 (33.93%)
    225 / 566 (39.75%)
    General disorders and administration site conditions
    Injection site pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    14 / 280 (5.00%)
    36 / 566 (6.36%)
         occurrences all number
    14
    36
    Pyrexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    55 / 280 (19.64%)
    143 / 566 (25.27%)
         occurrences all number
    64
    177
    Infections and infestations
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    40 / 280 (14.29%)
    84 / 566 (14.84%)
         occurrences all number
    41
    87

    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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    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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