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    Clinical Trial Results:
    A Phase III, Single Arm, Multi-Center, Open-Label Study to Assess the Immunogenicity, Safety and Tolerability of a Fully Liquid Pentavalent Vaccine Quinvaxem® (DTwP-Hib-HepB Vaccine) when Administered to Indian Infants at 6, 10, and 14 Weeks of Age

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2014-005309-18
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    23 Apr 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Jun 2016
    First version publication date
    02 Apr 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    V66_05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01470287
    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
    25 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess one month after third study injection, the percentage of subjects who develop: •Seroprotective antibody concentrations to diphtheria, tetanus and Hepatitis B (HepB) •Antibody concentrations ≥20 EIU/mL or a 4 fold increase from baseline for Bordetella pertussis, •Anti polyribosyl phosphate (PRP) Enzyme-Linked Immunosorbent Assay (ELISA) antibody concentrations > 0.15 ug/mL for Haemophilus influenzae type b (Hib) (short term protection).
    Protection of trial subjects
    This clinical study was designed, implemented and reported in accordance with the International Conference of Harmonization (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations guidelines issued by the Central Drugs Standard Control Organization (CDSCO) and Ethical Guidelines for Biomedical Research on Human Subjects issued by the Indian Council of Medical Research (ICMR), (and also European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki. Informed consent was obtained from parents or legal guardians of infants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Nov 2011
    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
    India: 175
    Worldwide total number of subjects
    175
    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)
    175
    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 3 study centres in India.

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

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial was designed as single arm and open label.

    Arms
    Arm title
    		 Quinvaxem
    Arm description
    		 Infants, ≥42 to ≤64 days of age, receiving three doses of vaccine at approximately 6, 10, and 14 weeks of age (study days 1, 29 and 57).
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTwP-Hib-HepB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Vaccination consisted of one 0.5 mL dose administered three times, IM into the antero-lateral area of the thigh, at day 1, 29 and 57.

    Number of subjects in period 1
    		Quinvaxem
    Started
    175
    Completed
    165
    Not completed
    10
         Adverse event
    1
         Lost to follow-up
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 175 175
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 175 175
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 48.3 ± 5.2 -
    Gender categorical
    Units: Subjects
        Female
    		 87 87
        Male
    		 88 88

    End points

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    End points reporting groups
    Reporting group title
    Quinvaxem
    Reporting group description
    		 Infants, ≥42 to ≤64 days of age, receiving three doses of vaccine at approximately 6, 10, and 14 weeks of age (study days 1, 29 and 57).

    Subject analysis set title
    All population enrolled
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who signed an informed consent. All subjects that underwent screening procedures.

    Subject analysis set title
    Immunogenicity – Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the Full Analysis Set (FAS) who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the enrolled population who received at least one dose of vaccine and provide post vaccination safety data.

    Primary: 1.Percentage of subjects with seroprotective antibody concentration to diphtheria.

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    End point title
    		 1.Percentage of subjects with seroprotective antibody concentration to diphtheria. [1]
    End point description
    Seroprotective activity of Quinvaxem against diphtheria was defined as anti-diphtheria antibody concentration ≥0.1 IU/mL. The percentage of subjects with seroprotective antibody concentration was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity – PPS population, ie. all subjects in the FAS who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Primary
    End point timeframe
    One month after the third vaccination (day 85).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: statistical analyses not applicable for this endpoint.
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Seroprotection (Day 1)
    18 (12 to 25)
        Seroprotection (Day 85)
    99 (97 to 100)
    No statistical analyses for this end point

    Primary: 2.Percentage of subjects with seroprotective antibody concentration to tetanus.

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    End point title
    		 2.Percentage of subjects with seroprotective antibody concentration to tetanus. [2]
    End point description
    Seroprotective activity of Quinvaxem against tetanus was defined as anti-tetanus antibody concentration ≥0.1 IU/mL. The percentage of subjects with seroprotective antibody concentration was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity-PPS population, ie. all subjects in the FAS who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Primary
    End point timeframe
    One month after the third vaccination (day 85).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: statistical analyses not applicable for this endpoint.
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Seroprotection (Day 1)
    100 (98 to 100)
        Seroprotection (Day 85)
    100 (98 to 100)
    No statistical analyses for this end point

    Primary: 3.Percentage of subjects with seroprotective antibody concentration to Hepatitis B.

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    End point title
    		 3.Percentage of subjects with seroprotective antibody concentration to Hepatitis B. [3]
    End point description
    Seroprotective activity of Quinvaxem against Hepatitis B was defined as anti-Hepatitis B antibody concentration ≥10 IU/mL. The percentage of subjects with seroprotective antibody concentration was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity-PPS population, ie. all subjects in the FAS who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Primary
    End point timeframe
    One month after the third vaccination (day 85).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: statistical analyses not applicable for this endpoint.
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Seroprotection (Day 1) (N=160)
    11 (6 to 16)
        Seroprotection (Day 85)
    98 (94 to 99)
    No statistical analyses for this end point

    Primary: 4.Percentage of subjects who developed antibody concentration to pertussis above pre-specified threshold.

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    End point title
    		 4.Percentage of subjects who developed antibody concentration to pertussis above pre-specified threshold. [4]
    End point description
    Seroprotective activity of Quinvaxem against pertussis was defined as anti-pertussis antibody concentration ≥20 EIU/mL or a 4-fold increase from baseline The percentage of subjects with antibody concentration above the pre-specified threshold was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity-PPS population, ie. all subjects in the FAS who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Primary
    End point timeframe
    One month after the third vaccination (day 85).
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: statistical analyses not applicable for this endpoint.
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pre-specified threshold (Day 1)
    2 (1 to 6)
        Pre-specified threshold (Day 85)
    99 (97 to 100)
    No statistical analyses for this end point

    Primary: 5.Percentage of subjects who developed antibody to Haemophilus influenzae type b above pre-specified threshold.

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    End point title
    		 5.Percentage of subjects who developed antibody to Haemophilus influenzae type b above pre-specified threshold. [5]
    End point description
    Seroprotective activity of Quinvaxem against Haemophilus influenzae type b was defined as anti-Polyribosyl phosphate antibody concentration ≥0.15 mcg/ml. The percentage of subjects with seroprotective antibody concentration was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity-PPS population, ie. all subjects in the Full Analysis Set who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Primary
    End point timeframe
    One month after the third vaccination (day 85).
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: statistical analyses not applicable for this endpoint.
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PRP >=0.15 mcg/mL (Day 1)
    68 (61 to 75)
        Anti-PRP >=0.15 mcg/mL (Day 85)
    100 (93 to 100)
    No statistical analyses for this end point

    Secondary: 6.Geometric Mean Concentration of antibody against diphtheria, tetanus, pertussis, Hepatitis B, Haemophilus influenza type b, one month after third vaccination with Quinvaxem.

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    End point title
    		 6.Geometric Mean Concentration of antibody against diphtheria, tetanus, pertussis, Hepatitis B, Haemophilus influenza type b, one month after third vaccination with Quinvaxem.
    End point description
    The human Serum Bactericidal Activity (hSBA) antibody concentration, one month after receiving the third vaccination of Quinvaxem vaccination, is reported as geometric mean concentration (GMC). Analysis was done on Immunogenicity-PPS population.
    End point type
    Secondary
    End point timeframe
    One month after the third vaccination (day 85).
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-diphtheria GMCs (Day 1)
    0.061 (0.057 to 0.066)
        Anti-diphtheria GMCs (Day 85)
    1.28 (1.08 to 1.52)
        Anti-tetanus GMCs (Day 1)
    2.68 (2.35 to 3.06)
        Anti-tetanus GMCs (Day 85)
    2.51 (2.18 to 2.89)
        Anti-pertussis GMCs (Day 1)
    4.07 (3.53 to 4.68)
        Anti-pertussis GMCs (Day 85)
    54 (51 to 57)
        Anti-Hepatitis B GMCs (Day 1) (N=160)
    6.47 (5.56 to 7.53)
        Anti-Hepatitis B GMCs (Day 85)
    373 (296 to 470)
        Anti-PRP GMCs (Day 1)
    0.27 (0.23 to 0.33)
        Anti-PRP GMCs (Day 85)
    15 (12 to 18)
    No statistical analyses for this end point

    Secondary: 7.Percentage of subjects with antibody concentration anti-Polyribosylphosphate (PRP) ≥1.0 mcg/mL

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    End point title
    		 7.Percentage of subjects with antibody concentration anti-Polyribosylphosphate (PRP) ≥1.0 mcg/mL
    End point description
    Long term seroprotective activity of Quinvaxem against Haemophilus influenzae type b was defined as anti-PRP antibody concentration ≥1.0 mcg/mL. The percentage of subjects with antibody concentration >=1.0 mcg/mL was evaluated one month after the third vaccination with Quinvaxem. Analysis was done on Immunogenicity-PPS population, ie. all subjects in the FAS who received all three vaccinations, provided evaluable serum samples at defined end points and have no major protocol violation.
    End point type
    Secondary
    End point timeframe
    One month after the third vaccination (day 85).
    End point values
    		 Quinvaxem
    Number of subjects analysed
    161
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PRP ≥1.0 mcg/mL (day 1)
    14 (9 to 21)
        Anti-PRP ≥1.0 mcg/mL (day 85)
    95 (90 to 98)
    No statistical analyses for this end point

    Secondary: 8.Number of subjects reporting solicited local and systemic adverse events after each vaccination.

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    End point title
    		 8.Number of subjects reporting solicited local and systemic adverse events after each vaccination.
    End point description
    Safety was determined by solicited local and systemic adverse events (AEs) reported 7 days after each vaccination and defined by percentage of subjects with reactogenicity. Analysis was done on Safety population. ie all subjects in the enrolled population who received at least one dose of vaccine and provided post vaccination safety data.
    End point type
    Secondary
    End point timeframe
    7 days after each vaccination day (day 7, day 35 and day 63).
    End point values
    		 Quinvaxem
    Number of subjects analysed
    172
    Units: Number of subjects
        Injection site Erythema (1st vaccination, N=172)
    34
        Injection site Induration (1st vaccination, N=172)
    22
        Injection site Tenderness (1st vaccination, N=172)
    50
        Fever ≥ 38 °C (1st vaccination, N=172)
    36
        Injection site Erythema (2nd vaccination, N=169)
    23
        Injection site Induration (2nd vaccination, N=169)
    17
        Injection site Tenderness (2nd vaccination, N=169)
    30
        Fever ≥ 38 °C (2nd vaccination, N=169)
    30
        Injection site Erythema (3rd vaccination, N=165)
    18
        Injection site Induration (3rd vaccination, N=165)
    7
        Injection site Tenderness (3rd vaccination, N=165)
    17
        Fever ≥ 38 °C (3rd vaccination, N=165)
    62
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout duration of the study.
    Adverse event reporting additional description
    All AEs (including Serious Adverse Events (SAEs) and AEs leading to withdrawal of subject) and concomitant medications were collected throughout the duration of the study (day 1 through day 85 or time of early termination).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Quinvaxem
    Reporting group description
    		 Infants, ≥42 to ≤64 days of age, receiving three doses of vaccine at approximately 6, 10, and 14 weeks of age (study days 1, 29 and 57).

    Serious adverse events
    		 Quinvaxem
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 172 (0.58%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Quinvaxem
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 172 (65.70%)
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    31 / 172 (18.02%)
         occurrences all number
    47
    Injection site erythema
         subjects affected / exposed
    48 / 172 (27.91%)
         occurrences all number
    79
    Pyrexia
         subjects affected / exposed
    66 / 172 (38.37%)
         occurrences all number
    100
    Injection site pain
         subjects affected / exposed
    64 / 172 (37.21%)
         occurrences all number
    97
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    9 / 172 (5.23%)
         occurrences all number
    10

    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/23783081
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