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    Clinical Trial Results:
    A Phase III Observer-Blind, Randomized, Controlled, Single-Coordinating Center Pediatric Study in China Comparing Vaxem Hib to HIBERIX® Using a Local Dosing Regimen in Infants

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2014-005136-33
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    17 Jul 2010

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Jun 2016
    First version publication date
    06 Jun 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    e-QC of the study needed because of EudraCT system glitch and updates are required.

    Trial information

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    Trial identification
    Sponsor protocol code
    V37_07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01044316
    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
    31 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that 2 doses of Vaxem Hib given to children between the ages of 180 to 364 days are non-inferior to 2 doses of a comparator vaccine HIBERIX®.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Apr 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: 670
    Worldwide total number of subjects
    670
    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)
    670
    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
    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 one dose of the VaxemHib vaccine at day 1 and day 31.
    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 one dose of the HIBERIX vaccine at day 1 and day 31.
    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
    335
    335
    Completed
    314
    308
    Not completed
    21
    27
         Consent withdrawn by subject
    21
    27

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received one dose of the VaxemHib vaccine at day 1 and day 31.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received one dose of the HIBERIX vaccine at day 1 and day 31.

    Reporting group values
    		 VaxemHib HIBERIX Total
    Number of subjects
    		 335 335 670
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 264.5 ( 49.4 ) 262.2 ( 49 ) -
    Gender categorical
    Units: Subjects
        Female
    		 153 161 314
        Male
    		 182 174 356

    End points

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    End points reporting groups
    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received one dose of the VaxemHib vaccine at day 1 and day 31.

    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received one dose of the HIBERIX vaccine at day 1 and day 31.

    Subject analysis set title
    All Enrolled Population, Demography
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects whose parents or legal guardians had signed an informed consent.

    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 (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the FAS population who: - correctly received the vaccine, and - provided evaluable serum samples at the relevant time points, 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 post-vaccination safety data.

    Primary: 1. Proportion of Subjects with Serum Anti-PRP Antibody Concentrations ≥ 0.15 μg/mL

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    End point title
    		 1. Proportion of Subjects with Serum Anti-PRP Antibody Concentrations ≥ 0.15 μg/mL
    End point description
    The immunogenicity was assessed based on the percentage of subjects with anti-PRP (Polyribosyl-ribitol-phosphate capsular polysaccharide) antibody concentrations ≥ 0.15 µg/mL one month after the second vaccination. Analysis was performed on the per protocol set.
    End point type
    Primary
    End point timeframe
    one month after the second vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    314
    308
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 0.15μg/mL
    96.5 (93.82 to 98.24)
    97.73 (95.37 to 99.08)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The non-inferiority of VaxemHib vaccine relative to HIBERIX was considered as the difference in proportion between the two groups.
    Comparison groups
    VaxemHib v HIBERIX
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 difference in proportions
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.86
         upper limit
    		 1.4
    Notes
    [1] - Margin of non-inferiority (-5.00%)

    Secondary: 2. Proportion of Subjects with Anti-PRP Antibody Concentration ≥ 1.0 µg/mL

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    End point title
    		 2. Proportion of Subjects with Anti-PRP Antibody Concentration ≥ 1.0 µg/mL
    End point description
    The proportion was assessed based on the percentage of subjects with anti-PRP antibody concentrations ≥ 1.0 µg/mL one month after the second vaccination. Analysis was performed on the per protocol set.
    End point type
    Secondary
    End point timeframe
    one month after the second vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    314
    308
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 1.0 µg/mL
    96.5 (93.82 to 98.24)
    97.73 (95.37 to 99.08)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The non-inferiority of VaxemHib vaccine relative to HIBERIX was considered as the difference in proportion between the two groups.
    Comparison groups
    VaxemHib v HIBERIX
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 difference in proportions
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.86
         upper limit
    		 1.4
    Notes
    [2] - Margin of non-inferiority (-5.00%)

    Secondary: 3. Geometric mean of anti-PRP antibody concentrations

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    End point title
    		 3. Geometric mean of anti-PRP antibody concentrations
    End point description
    The geometric mean of anti-PRP antibody concentrations one month after the second vaccination was assessed for both groups. Analysis was performed on the per protocol set.
    End point type
    Secondary
    End point timeframe
    one month after the second vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    314
    308
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Antibodies concentration
    20.39 (17.16 to 24.24)
    27.02 (23.15 to 31.54)
    No statistical analyses for this end point

    Secondary: 4. Numbers of subjects with local or systemic adverse reactions within 7 days of either vaccination.

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    End point title
    		 4. Numbers of subjects with local or systemic adverse reactions within 7 days of either vaccination.
    End point description
    The numbers of subjects with solicited local or systemic adverse reactions were recorded within 7 days of either vaccination. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    day 1-7 after either vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    335
    335
    Units: Number of Subjects
        Any local reaction
    197
    160
        Any systemic reaction
    259
    244
    No statistical analyses for this end point

    Secondary: 5. Numbers of subjects with local or systemic adverse reactions within 7 days of first vaccination.

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    End point title
    		 5. Numbers of subjects with local or systemic adverse reactions within 7 days of first vaccination.
    End point description
    The numbers of subjects with local or systemic adverse reactions were recorded within 7 days of first vaccination. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    day 1-7 after the first vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    335
    335
    Units: Number of Subjects
        Any local reaction
    134
    107
        Erythema (1-15mm)
    29
    30
        Erythema (15-30mm)
    61
    42
        Erythema >30 mm
    11
    5
        Tenderness (mild)
    45
    36
        Tenderness (moderate)
    9
    5
        Induration (1-15mm)
    29
    24
        Induration (15-30mm)
    26
    25
        Induration >30 mm
    7
    4
        Any systemic reaction
    202
    191
        Fever (mild)
    125
    116
        Fever (moderate)
    40
    47
        Fever (severe)
    6
    2
        Rash
    25
    15
        Sleepiness
    30
    27
        Irritability
    49
    27
        Unusual crying
    57
    36
        Change in eating habits
    23
    16
        Other (Analgesic/antipyretic medication use)
    47
    42
    No statistical analyses for this end point

    Secondary: 6. Numbers of subjects with local or systemic adverse reactions within 7 days of second vaccination.

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    End point title
    		 6. Numbers of subjects with local or systemic adverse reactions within 7 days of second vaccination.
    End point description
    The numbers of subjects with local or systemic adverse reactions were recorded within 7 days of second vaccination. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    day 1-7 after the second vaccination
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    335
    335
    Units: Number of Subjects
        Any local reaction
    133
    112
        Erythema (1-15mm)
    16
    25
        Erythema (15-30mm)
    67
    59
        Erythema >30 mm
    35
    14
        Tenderness (mild)
    36
    27
        Tenderness (moderate)
    4
    7
        Tenderness (severe)
    1
    0
        Induration (1-15mm)
    20
    23
        Induration (15-30mm)
    33
    21
        Induration >30 mm
    7
    6
        Any systemic reaction
    165
    154
        Fever (mild)
    99
    105
        Fever (moderate)
    42
    37
        Fever (severe)
    4
    0
        Rash
    15
    16
        Sleepiness
    11
    8
        Irritability
    18
    10
        Unusual crying
    24
    24
        Change in eating habits
    7
    8
        Other (Analgesic/antipyretic medication use)
    34
    40
    No statistical analyses for this end point

    Secondary: 7. Numbers of subjects with unsolicited adverse reactions during the study

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    End point title
    		 7. Numbers of subjects with unsolicited adverse reactions during the study
    End point description
    The numbers of subjects with unsolicited adverse reactions were recorded for day 1 to day 61. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Day 1 – Day 61
    End point values
    		 VaxemHib HIBERIX
    Number of subjects analysed
    226
    197
    Units: Number of Subjects
        Not Related Adverse Events (AEs)
    199
    180
        Possibly Related AEs
    17
    11
        Probably Related AEs
    10
    6
        AEs leading to withdrawal
    0
    0
        Seariuos Adverse Events (SAEs)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited adverse events were collected within 7 days after each vaccination. Unsolicited adverse events were collected through the entire period of the study (day 1 - day 61)
    Adverse event reporting additional description
    For reporting the Adverse Events, MedDRA version 17.1 was used.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    HIBERIX
    Reporting group description
    		 Subjects who received one dose of the HIBERIX vaccine at day 1 and day 31.

    Reporting group title
    VaxemHib
    Reporting group description
    		 Subjects who received one dose of the VaxemHib vaccine at day 1 and day 31.

    Serious adverse events
    		 HIBERIX VaxemHib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 323 (0.00%)
    0 / 327 (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 VaxemHib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    291 / 323 (90.09%)
    304 / 327 (92.97%)
    Nervous system disorders
    Somnolence
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    33 / 323 (10.22%)
    38 / 327 (11.62%)
         occurrences all number
    39
    43
    General disorders and administration site conditions
    Crying
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    53 / 323 (16.41%)
    71 / 327 (21.71%)
         occurrences all number
    64
    87
    Injection site erythema
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    136 / 323 (42.11%)
    173 / 327 (52.91%)
         occurrences all number
    176
    219
    Injection site induration
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    82 / 323 (25.39%)
    103 / 327 (31.50%)
         occurrences all number
    103
    122
    Injection site pain
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    60 / 323 (18.58%)
    78 / 327 (23.85%)
         occurrences all number
    75
    95
    Pyrexia
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    230 / 323 (71.21%)
    237 / 327 (72.48%)
         occurrences all number
    624
    677
    Gastrointestinal disorders
    Diarrhoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    31 / 323 (9.60%)
    34 / 327 (10.40%)
         occurrences all number
    34
    38
    Skin and subcutaneous tissue disorders
    Rash
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    32 / 323 (9.91%)
    43 / 327 (13.15%)
         occurrences all number
    39
    53
    Psychiatric disorders
    Eating disorder
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    23 / 323 (7.12%)
    27 / 327 (8.26%)
         occurrences all number
    27
    36
    Irritability
    alternative dictionary used: MedDRA 17.1
    alternative assessment type: Systematic
         subjects affected / exposed
    33 / 323 (10.22%)
    61 / 327 (18.65%)
         occurrences all number
    43
    74
    Infections and infestations
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    87 / 323 (26.93%)
    82 / 327 (25.08%)
         occurrences all number
    104
    98

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23964690
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