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    Clinical Trial Results:
    A phase III open-label randomised study to evaluate the immunogenicity and safety of the concomitant administration of a new Hexavalent DTaP-IPV-HB-Hib combined vaccine (Hexavalent vaccine) given at 2, 3, and 4 months of age with a meningococcal serogroup C conjugate (MenC) vaccine given at 2 and 4 months of age. Short title: Concomitant administration of a new hexavalent vaccine (Hexavalent vaccine) with a meningococcal serogroup C conjugate vaccine in healthy infants during primary series immunisation followed by booster vaccination

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-005547-24
    Trial protocol
    		 FI  
    Global end of trial date
    11 Feb 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Apr 2016
    First version publication date
    18 Mar 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    The analysis stage is now final and the Form can be completed with the last study period.

    Trial information

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    Trial identification
    Sponsor protocol code
    HXM01C
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01839175
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur MSD S.N.C.
    Sponsor organisation address
    162 avenue Jean Jaurès - CS 50712, Lyon Cedex 07, France, 69367
    Public contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com
    Scientific contact
    Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PRIMARY SERIES (Period 2): - To demonstrate that the concomitant administration of the Hexavalent vaccine given at 2, 3 and 4 months of age with a meningococcal serogroup C conjugate (MenC) vaccine given at 2 and 4 months of age is non inferior to the administration of the Hexavalent vaccine without a MenC vaccine concomitantly in term of seroprotection rate for hepatitis B 1 month after the 3rd dose of the Hexavalent vaccine. - To demonstrate that the concomitant administration of a MenC vaccine given at 2 and 4 months of age with the Hexavalent vaccine given at 2, 3 and 4 months of age induces an acceptable response for MenC in term of seroprotection rate (SPR) 1 month after the 2nd dose of MenC. BOOSTER (Period 3): To describe the immunogenicity of a booster dose of the Hexavalent vaccine and of a meningococcal group ACWY conjugate vaccine either co-administered at 12 months of age or given separately.
    Protection of trial subjects
    Subjects in the study received 3 injections during primary series (period 2) and 1 injection during the booster part (period 3) of a single dose of the study vaccine DTaP-IPV-HB-Hib supplied in a pre-filled 0.5 mL syringe that was administered by qualified study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After each vaccination, subjects were also kept under observation for 30 minutes to ensure their safety. Appropriate equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    		 Not Applicable
    Evidence for comparator
    		 The control group complies with the recommended vaccination schedules for all vaccines (i.e. Study vaccine and routine vaccines) as per their respective Summaries of Product Characteristics (SmPCs).
    Actual start date of recruitment
    29 Apr 2013
    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
    Finland: 350
    Worldwide total number of subjects
    350
    EEA total number of subjects
    350
    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)
    350
    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
    		 Study subjects were enrolled from 29 April 2013 to 09 August 2013 in 11 clinical centers in Finland.

    Pre-assignment
    Screening details
    		 # Period 1 (Randomisation): 354 subjects screened. # Period 2 (Primary Series): 350 subjects randomised (1:1); 350 subjects vaccinated (at least 1 dose) and 346 subjects received the 3 doses of the primary series; 345 subjects completed the period. # Period 3 (Booster): 346 subjects randomised (1:1:1); 312 vaccinated; 311 completed the period.

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study as the number of vaccines administered in each group was different at several visits. Blinding would have required a placebo injection which was not deemed necessary since the primary end points were based on immunological criteria. Serology tests for the Hexavalent vaccine antigens were performed by laboratory staff blinded to subject group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hexavalent vaccine co-administered with MenC vaccine
    Arm description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, (ii) at 3 months of age before any other vaccination (=post-dose 1 of MenC vaccine), and (iii) at 5 months of age (=post-dose 3 of Hexavalent vaccine=post-dose 2 of MenC vaccine).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular (IM) route, 1 dose at 2, 3, and 4 months of age.

    Investigational medicinal product name
    NeisVac-C®
    Investigational medicinal product code
    MenC vaccine
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at 2, and 4 months of age.

    Arm title
    		 Hexavalent vaccine without MenC vaccine
    Arm description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, and (ii) at 5 months of age (=post-dose 3 of Hexavalent vaccine).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at 2, 3, and 4 months of age.

    Number of subjects in period 1
    		Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Started
    175
    175
    Completed
    175
    175
    Period 2
    Period 2 title
    Primary Series
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study as the number of vaccines administered in each group was different at several visits. Blinding would have required a placebo injection which was not deemed necessary since the primary end points were based on immunological criteria. Serology tests for the Hexavalent vaccine antigens were performed by laboratory staff blinded to subject group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hexavalent vaccine co-administered with MenC vaccine
    Arm description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, (ii) at 3 months of age before any other vaccination (=post-dose 1 of MenC vaccine), and (iii) at 5 months of age (=post-dose 3 of Hexavalent vaccine=post-dose 2 of MenC vaccine).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at 2, 3, and 4 months of age.

    Investigational medicinal product name
    NeisVac-C®
    Investigational medicinal product code
    MenC vaccine
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at 2, and 4 months of age.

    Arm title
    		 Hexavalent vaccine without MenC vaccine
    Arm description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, and (ii) at 5 months of age (=post-dose 3 of Hexavalent vaccine).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at 2, 3, and 4 months of age.

    Number of subjects in period 2
    		Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Started
    175
    175
    Completed
    173
    172
    Not completed
    2
    4
         Adverse event, non-fatal
    1
    2
         Transferred to other arm/group
    1
    -
         Lost to follow-up
    -
    2
    Joined
    0
    1
         Transferred in from other group/arm
    -
    1
    Period 3
    Period 3 title
    Booster
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study as the number of vaccines administered in each group was different at the 12 months vaccination visit (and subsequently at the 13 months vaccination visit). Blinding would have required a placebo injection which was not deemed necessary since the primary end points were based on immunological criteria. Serology tests for the Hexavalent vaccine antigens and for MenACWY vaccine antigens were performed by laboratory staff blinded to subject group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hexavalent vaccine co-administered with MenACWY vaccine
    Arm description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine co-administered with 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before Hexavalent vaccine booster dose (=pre-booster), and (ii) 1 month after Hexavalent vaccine booster dose (=post-booster), before any other vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (contralateral thigh from MenACWY injection-site), 1 dose at approximately 12 months of age.

    Investigational medicinal product name
    Nimenrix®
    Investigational medicinal product code
    MenACWY vaccine
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route (contralateral thigh from Hexavalent vaccine injection-site), 1 dose at approximately 12 months of age.

    Arm title
    		 Hexavalent vaccine only
    Arm description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of MenC vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before Hexavalent vaccine booster dose (=pre-booster), and (ii) 1 month after Hexavalent vaccine booster dose (=post-booster), before any other vaccination.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at approximately 12 months of age.

    Arm title
    		 MenACWY vaccine only
    Arm description
    		 # Subjects from the Primary Series period received 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also 1 booster dose of Hexavalent vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before MenACWY vaccine dose, and (ii) 1 month after MenACWY vaccine dose, before any other vaccination.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nimenrix®
    Investigational medicinal product code
    MenACWY vaccine
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at approximately 12 months of age.

    Investigational medicinal product name
    Hexyon® (Hexavalent vaccine)
    Investigational medicinal product code
    DTaP-IPV-HB-Hib
    Other name
    Hexacima® / Hexaxim®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM route, 1 dose at approximately 13 months of age.

    Number of subjects in period 3 [1]
    		Hexavalent vaccine co-administered with MenACWY vaccine Hexavalent vaccine only MenACWY vaccine only
    Started
    104
    105
    103
    Completed
    104
    104
    103
    Not completed
    0
    1
    0
         Lost to follow-up
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 34 subjects of the Primary Series period (period 2) were not randomised in the Booster period (period 3): 32 "screen failure", and 2 "non-compliance with the protocol".

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hexavalent vaccine co-administered with MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, (ii) at 3 months of age before any other vaccination (=post-dose 1 of MenC vaccine), and (iii) at 5 months of age (=post-dose 3 of Hexavalent vaccine=post-dose 2 of MenC vaccine).

    Reporting group title
    Hexavalent vaccine without MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, and (ii) at 5 months of age (=post-dose 3 of Hexavalent vaccine).

    Reporting group values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine Total
    Number of subjects
    		 175 175 350
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 175 175 350
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 62.8 ± 7 63.2 ± 7 -
    Gender categorical
    Units: Subjects
        Female
    		 83 82 165
        Male
    		 92 93 185

    End points

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    End points reporting groups
    Reporting group title
    Hexavalent vaccine co-administered with MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, (ii) at 3 months of age before any other vaccination (=post-dose 1 of MenC vaccine), and (iii) at 5 months of age (=post-dose 3 of Hexavalent vaccine=post-dose 2 of MenC vaccine).

    Reporting group title
    Hexavalent vaccine without MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, and (ii) at 5 months of age (=post-dose 3 of Hexavalent vaccine).
    Reporting group title
    Hexavalent vaccine co-administered with MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, (ii) at 3 months of age before any other vaccination (=post-dose 1 of MenC vaccine), and (iii) at 5 months of age (=post-dose 3 of Hexavalent vaccine=post-dose 2 of MenC vaccine).

    Reporting group title
    Hexavalent vaccine without MenC vaccine
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age. # Blood samples were collected (i) at 2 months of age before any vaccination, and (ii) at 5 months of age (=post-dose 3 of Hexavalent vaccine).
    Reporting group title
    Hexavalent vaccine co-administered with MenACWY vaccine
    Reporting group description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine co-administered with 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before Hexavalent vaccine booster dose (=pre-booster), and (ii) 1 month after Hexavalent vaccine booster dose (=post-booster), before any other vaccination.

    Reporting group title
    Hexavalent vaccine only
    Reporting group description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of MenC vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before Hexavalent vaccine booster dose (=pre-booster), and (ii) 1 month after Hexavalent vaccine booster dose (=post-booster), before any other vaccination.

    Reporting group title
    MenACWY vaccine only
    Reporting group description
    		 # Subjects from the Primary Series period received 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also 1 booster dose of Hexavalent vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age. # Blood samples were collected (i) before MenACWY vaccine dose, and (ii) 1 month after MenACWY vaccine dose, before any other vaccination.

    Primary: Primary Series # Seroprotection against Hepatitis B 1 month after vaccination with either Hexavalent vaccine co-administered with MenC vaccine or Hexavalent vaccine without MenC vaccine

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    End point title
    		 Primary Series # Seroprotection against Hepatitis B 1 month after vaccination with either Hexavalent vaccine co-administered with MenC vaccine or Hexavalent vaccine without MenC vaccine
    End point description
    Percentage of subjects with an anti-Hepatitis B surface antigen (Hep B) concentration ≥10 mIU/mL (measured by hepatitis B enhanced Chemiluminescence assay, ECi). Analysis was done on the Per Protocol Set, i.e., all subjects without any protocol deviation that could interfere with the vaccines immunogenicity.
    End point type
    Primary
    End point timeframe
    1 month post-dose 3 of Hexavalent vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    160
    155
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Hep B ≥10 mIU/mL
    97.5 (93.7 to 99.3)
    96.1 (91.8 to 98.6)
    Statistical analysis title
    		 Non-inferiority of the immune response
    Statistical analysis description
    To demonstrate the non-inferiority of the immune response of the concomitant administration of the Hexavalent vaccine co-administered with MenC vaccine as compared to the Hexavalent vaccine without Men C vaccine 1 month after the 3rd dose.
    Comparison groups
    Hexavalent vaccine co-administered with MenC vaccine v Hexavalent vaccine without MenC vaccine
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 Wilson score Method without cc
    Parameter type
    		 Difference in percentages of subjects
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.92
         upper limit
    		 5.95
    Notes
    [1] - The immune response of Hexavalent vaccine co-administered with MenC vaccine was considered as non-inferior to Hexavalent vaccine without MenC vaccine if the lower bound of the 2-sided 95.0% Confidence Intervals (CI) of the difference in the percentages of subjects with anti-Hep B ≥10 mIU/mL measured 1 month after the 3rd dose was greater than -10%. CI was based on the Wilson score method without continuity correction (cc).

    Primary: Primary Series # Seroprotection for MenC 1 month after vaccination with 2 doses of MenC vaccine

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    End point title
    		 Primary Series # Seroprotection for MenC 1 month after vaccination with 2 doses of MenC vaccine [2]
    End point description
    Percentages of subjects with an anti-MenC titer ≥8 (1/dilution (dil)) (measured by Serum Bactericidal Antibody assay with rabbit complement, rSBA) 1 month after 2 doses of MenC vaccine. The immune response to MenC vaccine was considered as acceptable if the lower bound of the 2-sided 95.0% CI of the percentage of subjects with anti-MenC ≥8 (1/dil) 1 month after the 2nd dose was greater than 90%. Analysis was done on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    1 month post-dose 2 of MenC vaccine.
    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: There was no comparison between groups in this end point. As specified above, the immune response to MenC vaccine was considered as acceptable if the lower bound of the 2-sided 95.0% CI of the percentage of subjects with anti-MenC ≥8 (1/dil) 1 month after the 2nd dose was greater than 90%. Acceptability criteria was met for MenC.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine
    Number of subjects analysed
    162
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-MenC ≥8 (1/dil)
    100 (97.7 to 100)
    No statistical analyses for this end point

    Primary: Booster # Response rates to all Hexavalent vaccine antigens 1 month after Hexavalent vaccine booster dose, co-administered or not with MenACWY

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    End point title
    		 Booster # Response rates to all Hexavalent vaccine antigens 1 month after Hexavalent vaccine booster dose, co-administered or not with MenACWY [3]
    End point description
    Percentages of subjects with anti-D concentration ≥0.10 IU/mL & ≥1.0 IU/mL for Diphtheria (measured by MIT), anti-T concentration ≥0.10 IU/mL & ≥1.0 IU/mL for Tetanus (measured by ELISA), anti-IPV titer ≥8 (1/dil) for Poliovirus types 1, 2, & 3 (measured by MIT), anti-Hep B concentration ≥10 mIU/mL & ≥100 mIU/mL (measured by Hep B ECi), anti-PRP concentration ≥0.15 ug/mL & ≥1.0 ug/mL for Hib (measured by Farr type radioimmunoassay, RIA), anti-PT vaccine response (VR), anti-FHA VR, & 4-fold increase from pre-vaccination to post-booster (PT & FHA) for Pertussis (measured by ELISA). Pertussis VR was defined as: - If pre-vaccination (pre-dose 1) antibody concentration <4xLLOQ, post-booster antibody concentration ≥4xLLOQ, - If pre-vaccination (pre-dose 1) antibody concentration ≥4xLLOQ, post-booster antibody concentration >pre-vaccination antibody concentration. Analysis was done on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    1 month post-booster dose of Hexavalent vaccine, co-administered or not with MenACWY.
    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: Objectives of the Booster period (period 3) were only descriptive. Thus no formal statistical hypothesis was tested in this period.
    End point values
    		 Hexavalent vaccine co-administered with MenACWY vaccine Hexavalent vaccine only
    Number of subjects analysed
    87
    91
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-D ≥0.10 IU/mL (N=87, 91)
    100 (95.8 to 100)
    100 (96 to 100)
        Anti-D ≥1.0 IU/mL (N=87, 91)
    89.7 (81.3 to 95.2)
    96.7 (90.7 to 99.3)
        Anti-T ≥0.10 IU/mL (N=87, 91)
    100 (95.8 to 100)
    100 (96 to 100)
        Anti-T ≥1.0 IU/mL (N=87, 91)
    96.6 (90.3 to 99.3)
    96.7 (90.7 to 99.3)
        Anti-IPV1 ≥8 (1/dil) (N=87, 91)
    98.9 (93.8 to 100)
    98.9 (94 to 100)
        Anti-IPV2 ≥8 (1/dil) (N=87, 91)
    100 (95.8 to 100)
    100 (96 to 100)
        Anti-IPV3 ≥8 (1/dil) (N=87, 90)
    100 (95.8 to 100)
    100 (96 to 100)
        Anti-Hep B ≥10 mIU/mL (N=87, 91)
    98.9 (93.8 to 100)
    98.9 (94 to 100)
        Anti-Hep B ≥100 mIU/mL (N=85, 87)
    97.7 (91.9 to 99.7)
    95.6 (89.1 to 98.8)
        Anti-PRP ≥ 0.15 ug/mL (N=87, 91)
    100 (95.8 to 100)
    100 (96 to 100)
        Anti-PRP ≥ 1.0 ug/mL (N=87, 91)
    97.7 (91.9 to 99.7)
    100 (96 to 100)
        Anti-PT VR (N=85, 86)
    98.8 (93.6 to 100)
    98.8 (93.7 to 100)
        Anti-PT 4-fold (N=85, 86)
    83.5 (73.9 to 90.7)
    88.4 (79.7 to 94.3)
        Anti-FHA VR (N=85, 89)
    100 (95.8 to 100)
    100 (95.9 to 100)
        Anti-FHA 4-fold (N=85, 89)
    96.5 (90 to 99.3)
    92.1 (84.5 to 96.8)
    No statistical analyses for this end point

    Primary: Booster # Geometric Mean Titers (GMTs) or Concentrations (GMCs) of antibodies to all Hexavalent vaccine antigens 1 month after Hexavalent vaccine booster dose, co-administered or not with MenACWY

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    End point title
    		 Booster # Geometric Mean Titers (GMTs) or Concentrations (GMCs) of antibodies to all Hexavalent vaccine antigens 1 month after Hexavalent vaccine booster dose, co-administered or not with MenACWY [4]
    End point description
    Antibody titers or concentrations were measured for Diphtheria (D) by MIT (IU/mL), for Tetanus (T) by ELISA (IU/mL), for Poliovirus (IPV) types 1, 2, and 3 by MIT (1/dil), for Hepatitis B (Hep B) by ECi (mIU/mL), for Haemophilus influenzae type b (PRP) by Farr type RIA (ug/mL), and for Pertussis antigens (PT & FHA) by ELISA (EU/mL). Analysis was done on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    1 month post-booster dose of Hexavalent vaccine, co-administered or not with MenACWY.
    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: Objectives of the Booster period (period 3) were only descriptive. Thus no formal statistical hypothesis was tested in this period.
    End point values
    		 Hexavalent vaccine co-administered with MenACWY vaccine Hexavalent vaccine only
    Number of subjects analysed
    87
    91
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-D GMC (N=87, 91)
    3.07 (2.49 to 3.79)
    3.24 (2.69 to 3.91)
        Anti-T GMC (N=87, 91)
    6.89 (5.78 to 8.21)
    6.25 (5.3 to 7.37)
        Anti-IPV1 GMT (N=87, 91)
    2174.05 (1606.18 to 2942.7)
    2040.21 (1522.96 to 2733.14)
        Anti-IPV2 GMT (N=87, 91)
    1678.14 (1203.6 to 2339.77)
    1738.58 (1242.59 to 2432.56)
        Anti-IPV3 GMT (N=87, 90)
    3086.91 (2278.1 to 4182.89)
    4127.67 (3175.4 to 5365.53)
        Anti-Hep B GMC (N=87, 91)
    2230.68 (1597.48 to 3114.87)
    2233.15 (1597.3 to 3122.13)
        Anti-PRP GMC (N=87, 91)
    22.7 (17.2 to 29.96)
    27.82 (21.89 to 35.35)
        Anti-PT GMC (N=87, 91)
    111.78 (97.9 to 127.63)
    114.72 (102.68 to 128.16)
        Anti-FHA GMC (N=87, 91)
    174.98 (153.98 to 198.86)
    184.57 (162.43 to 209.72)
    No statistical analyses for this end point

    Primary: Booster # Response rates to all MenACWY vaccine antigens 1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine booster dose

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    End point title
    		 Booster # Response rates to all MenACWY vaccine antigens 1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine booster dose [5]
    End point description
    Percentages of subjects with anti-MenA, anti-MenW-135, and anti-MenY titers ≥8 (1/dil), and anti-MenC titers ≥8 (1/dil) & ≥128 (1/dil) measured by rSBA 1 month after MenACWY, co-administered or not with Hexavalent vaccine booster dose. Anti-MenC response rates were determined in all subjects, and subjects previously vaccinated or not with MenC vaccine during Primary (Iry) Series ("All subjects", "MenC IrySeries", and "No MenC IrySeries" respectively in the table below). Analysis was done on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine booster dose.
    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: Objectives of the Booster period (period 3) were only descriptive. Thus no formal statistical hypothesis was tested in this period.
    End point values
    		 Hexavalent vaccine co-administered with MenACWY vaccine MenACWY vaccine only
    Number of subjects analysed
    87
    94
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-MenA ≥8 (1/dil) (N=87,94)
    100 (95.8 to 100)
    100 (96.2 to 100)
        Anti-MenC ≥8 (1/dil)-All subjects (N=87,94)
    98.9 (93.8 to 100)
    95.7 (89.5 to 98.8)
        Anti-MenC ≥8 (1/dil)-MenC IrySeries (N=43,47)
    100 (91.8 to 100)
    97.9 (88.7 to 99.9)
        Anti-MenC ≥8 (1/dil)- No MenC IrySeries (N=44,47)
    97.7 (88 to 99.9)
    93.6 (82.5 to 98.7)
        Anti-MenC ≥128 (1/dil)-All subjects (N=87,94)
    97.7 (91.9 to 99.7)
    90.4 (82.6 to 95.5)
        Anti-MenC ≥128 (1/dil)-MenC IrySeries (N=43,47)
    100 (91.8 to 100)
    97.9 (88.7 to 99.9)
        Anti-MenC ≥128 (1/dil)-No MenC IrySeries (N=44,47)
    95.5 (84.5 to 99.4)
    83 (69.2 to 92.4)
        Anti-MenW-135 ≥8 (1/dil) (N=87,94)
    100 (95.8 to 100)
    98.9 (94.2 to 100)
        Anti-MenY ≥8 (1/dil) (N=87,94)
    100 (95.8 to 100)
    100 (96.2 to 100)
    No statistical analyses for this end point

    Primary: Booster # Geometric Mean Titers (GMTs) of antibodies to all MenACWY vaccine antigens 1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine

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    End point title
    		 Booster # Geometric Mean Titers (GMTs) of antibodies to all MenACWY vaccine antigens 1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine [6]
    End point description
    Antibody titers were measured for MenA, MenC, MenW-135, and MenY (1/dil) by rSBA 1 month after MenACWY, co-administered or not with Hexavalent vaccine booster dose. Anti-MenC GMTs were determined in all subjects, and subjects previously vaccinated or not with MenC vaccine during Primary (Iry) Series ("All subjects", "MenC IrySeries", and "No MenC IrySeries" respectively in the table below). Analysis was done on the Per Protocol Set.
    End point type
    Primary
    End point timeframe
    1 month after MenACWY vaccine, co-administered or not with Hexavalent vaccine booster dose.
    Notes
    [6] - 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: Objectives of the Booster period (period 3) were only descriptive. Thus no formal statistical hypothesis was tested in this period.
    End point values
    		 Hexavalent vaccine co-administered with MenACWY vaccine MenACWY vaccine only
    Number of subjects analysed
    87
    94
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-MenA GMT (N=87, 94)
    4096 (3335.98 to 5029.17)
    5302.07 (4249.49 to 6615.38)
        Anti-MenC GMT-All subjects (N=87, 94)
    693.03 (524.15 to 916.33)
    620.2 (425.53 to 903.94)
        Anti-MenC GMT-MenC IrySeries (N=43, 47)
    1262.73 (901.11 to 1769.46)
    1617.53 (1083.22 to 2415.39)
        Anti-MenC GMT-No MenC IrySeries (N=44, 47)
    385.59 (264.11 to 562.93)
    237.8 (141.85 to 398.66)
        Anti-MenW-135 GMT (N=87, 94)
    2148.28 (1650.66 to 2795.91)
    2555.07 (1930.58 to 3381.58)
        Anti-MenY GMT (N=87, 94)
    1952.4 (1538.58 to 2477.53)
    2003.19 (1592.49 to 2519.81)
    No statistical analyses for this end point

    Secondary: Primary Series # Response rates for all Hexavalent vaccine antigens 1 month after 3 doses of Hexavalent vaccine co-administered with MenC vaccine or 3 doses of Hexavalent vaccine without MenC vaccine

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    End point title
    		 Primary Series # Response rates for all Hexavalent vaccine antigens 1 month after 3 doses of Hexavalent vaccine co-administered with MenC vaccine or 3 doses of Hexavalent vaccine without MenC vaccine
    End point description
    Percentages of subjects with an anti-Hep B concentration ≥10 mIU/mL (measured by Hep B ECi), anti-PRP concentration ≥0.15ug/mL for Hib (measured by Farr type RIA), anti-D concentration ≥0.01 IU/mL and ≥0.1 IU/mL for Diphtheria (measured by MIT), anti-T concentration ≥0.01 IU/mL and ≥0.1 IU/mL for Tetanus (measured by ELISA), anti-IPV titer ≥8 (1/dil) for Poliovirus types 1, 2, and 3 (measured by MIT), anti-PT vaccine response (VR, EU/mL), anti-FHA VR (EU/mL), & 4-fold increase (PT & FHA) for Pertussis (measured by ELISA). Pertussis VR was defined as: - If pre-vaccination (pre-dose 1) antibody concentration <4xLLOQ, post-vaccination antibody concentration ≥4xLLOQ, - If pre-vaccination (pre-dose 1) antibody concentration ≥4xLLOQ, post-vaccination antibody concentration ≥pre-immunisation levels. Analysis was done on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    1 month post-dose 3 of Hexavalent vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    162
    160
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Hep B ≥10 mIU/mL (N=160, 155)
    97.5 (93.7 to 99.3)
    96.1 (91.8 to 98.6)
        Anti-PRP ≥0.15 ug/mL (N=160, 158)
    98.1 (94.6 to 99.6)
    94.3 (89.5 to 97.4)
        Anti-D ≥0.01 IU/mL (N=160, 158)
    100 (97.7 to 100)
    99.4 (96.5 to 100)
        Anti-D ≥0.1 IU/mL (N=160, 158)
    35 (27.6 to 42.9)
    41.1 (33.4 to 49.2)
        Anti-T ≥0.01 IU/mL (N=159, 156)
    100 (97.7 to 100)
    100 (97.7 to 100)
        Anti-T ≥0.1 IU/mL (N=159, 156)
    100 (97.7 to 100)
    99.4 (96.5 to 100)
        Anti-IPV1 ≥8 (1/dil) (N=159, 152)
    100 (97.7 to 100)
    98.7 (95.3 to 99.8)
        Anti-IPV2 ≥8 (1/dil) (N=159, 152)
    100 (97.7 to 100)
    100 (97.6 to 100)
        Anti-IPV3 ≥8 (1/dil) (N=159, 152)
    100 (97.7 to 100)
    99.3 (96.4 to 100)
        Anti-PT VR (N=154, 154)
    98.7 (95.4 to 99.8)
    100 (97.6 to 100)
        Anti-PT 4-fold (N=154, 154)
    88.3 (82.2 to 92.9)
    88.3 (82.2 to 92.9)
        Anti-FHA VR (N=154, 153)
    99.4 (96.4 to 100)
    100 (97.6 to 100)
        Anti-FHA 4-fold (N=154, 153)
    89.6 (83.7 to 93.9)
    91.5 (85.9 to 95.4)
    No statistical analyses for this end point

    Secondary: Primary Series # Response rates for MenC 1 month after vaccination with 1 dose or 2 doses of MenC vaccine

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    End point title
    		 Primary Series # Response rates for MenC 1 month after vaccination with 1 dose or 2 doses of MenC vaccine
    End point description
    Percentages of subjects with anti-MenC titers ≥8 (1/dil) or ≥128 (1/dil) (measured by rSBA) 1 month after 1 dose or 1 month after 2 doses of MenC vaccine. Analysis was done on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    1 month post-dose 1 or post-dose 2 of MenC vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine
    Number of subjects analysed
    162
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-MenC ≥8 (1/dil) post-dose 1 (N=157)
    99.4 (96.5 to 100)
        Anti-MenC ≥128 (1/dil) post-dose 1 (N=157)
    98.1 (94.5 to 99.6)
        Anti-MenC ≥8 (1/dil) post-dose 2 (N=162)
    100 (97.7 to 100)
        Anti-MenC ≥128 (1/dil) post-dose 2 (N=162)
    96.3 (92.1 to 98.6)
    No statistical analyses for this end point

    Secondary: Primary Series # Geometric Mean Titers or Concentrations of Antibodies 1 month after 3 doses of Hexavalent vaccine co-administered with MenC vaccine or 3 doses of Hexavalent vaccine without MenC vaccine

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    End point title
    		 Primary Series # Geometric Mean Titers or Concentrations of Antibodies 1 month after 3 doses of Hexavalent vaccine co-administered with MenC vaccine or 3 doses of Hexavalent vaccine without MenC vaccine
    End point description
    Antibody titers or concentrations were measured for Hepatitis B (Hep B) by Hep B ECi (mIU/mL), for Haemophilus influenzae type b (PRP) by Farr type RIA (ug/mL), for Diphtheria (D) by MIT (IU/mL), for Tetanus (T) by ELISA (IU/mL), for Poliovirus (IPV) types 1, 2, and 3 by MIT (1/dil), and for Pertussis antigens (PT & FHA) by ELISA (EU/mL)). Analysis was done on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    1 month post-dose 3 of Hexavalent vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    162
    160
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-Hep B (N=160, 155)
    242.75 (195.05 to 302.11)
    267.58 (212.65 to 336.7)
        Anti-PRP (N=160, 158)
    3.49 (2.88 to 4.24)
    1.89 (1.49 to 2.38)
        Anti-D (N=160, 158)
    0.08 (0.07 to 0.1)
    0.09 (0.08 to 0.1)
        Anti-T (N=159, 156)
    1.17 (1.07 to 1.29)
    0.78 (0.7 to 0.87)
        Anti-IPV1 (N=159, 152)
    92.49 (75.06 to 113.97)
    126.84 (101.46 to 158.56)
        Anti-IPV2 (N=159, 152)
    90.9 (73.23 to 112.83)
    104.72 (82.66 to 132.67)
        Anti-IPV3 (N=159, 152)
    173.3 (138.2 to 217.31)
    250.78 (197.56 to 318.34)
        Anti-PT (N=160, 159)
    129.74 (118.93 to 141.52)
    139.91 (126.98 to 154.15)
        Anti-FHA (N=158, 156)
    123.54 (112.47 to 135.69)
    147.77 (134.82 to 161.97)
    No statistical analyses for this end point

    Secondary: Primary Series # Geometric Mean Titers of Antibodies 1 month after 1 dose or 2 doses of MenC vaccine co-administered with Hexavalent vaccine

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    End point title
    		 Primary Series # Geometric Mean Titers of Antibodies 1 month after 1 dose or 2 doses of MenC vaccine co-administered with Hexavalent vaccine
    End point description
    Antibody titers were measured by rSBA (1/dil) 1 month after 1 dose or 2 doses of MenC vaccine. Analysis was done on the Per Protocol Set.
    End point type
    Secondary
    End point timeframe
    1 month post-dose 1 or post-dose 2 of MenC vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine
    Number of subjects analysed
    162
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-MenC post-dose 1 (N=157)
    885.17 (737.06 to 1063.04)
        Anti-MenC post-dose 2 (N=162)
    579.64 (505.36 to 664.84)
    No statistical analyses for this end point

    Secondary: Primary Series # Percentage of subjects reporting solicited injection-site or systemic reactions after Hexavalent vaccine co-administered with MenC vaccine or Hexavalent vaccine without MenC

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    End point title
    		 Primary Series # Percentage of subjects reporting solicited injection-site or systemic reactions after Hexavalent vaccine co-administered with MenC vaccine or Hexavalent vaccine without MenC
    End point description
    Solicited injection-site reactions (ISRs: Erythema, Pain, and Swelling) and solicited systemic reactions (Crying, Decreased appetite, Irritability, Pyrexia, Somnolence, and Vomiting) within 7 days after any Hexavalent vaccine injection with or without MenC vaccine. Solicited reactions were always considered as related to vaccines. The percentage of subjects presenting at least once the considered events after any vaccination is reported hereafter. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 dose of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    Day 0 up to 7 days following any dose.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    174
    176
    Units: Percentage of subjects
    number (confidence interval 95%)
        Solicited reaction any dose
    100 (97.9 to 100)
    100 (97.9 to 100)
        Solicited ISR
    89.1 (83.5 to 93.3)
    73.9 (66.7 to 80.2)
        Solicited ISR after Hexavalent vaccine
    84.5 (78.2 to 89.5)
    73.9 (66.7 to 80.2)
        Erythema after Hexavalent vaccine
    54.6 (46.9 to 62.1)
    55.1 (47.4 to 62.6)
        Pain after Hexavalent vaccine
    69 (61.5 to 75.7)
    61.9 (54.3 to 69.1)
        Swelling after Hexavalent vaccine
    34.5 (27.5 to 42.1)
    34.7 (27.7 to 42.2)
        Solicited ISR after MenC vaccine
    71.3 (63.9 to 77.9)
    0 (0 to 0)
        Erythema after MenC vaccine
    44.8 (37.3 to 52.5)
    0 (0 to 0)
        Pain after MenC vaccine
    60.9 (53.2 to 68.2)
    0 (0 to 0)
        Swelling after MenC vaccine
    25.9 (19.5 to 33)
    0 (0 to 0)
        Solicited systemic reaction
    100 (97.9 to 100)
    100 (97.9 to 100)
        Crying
    85.1 (78.9 to 90)
    71 (63.7 to 77.6)
        Decreased appetite
    56.3 (48.6 to 63.8)
    54.5 (46.9 to 62.1)
        Irritability
    95.4 (91.1 to 98)
    94.3 (89.8 to 97.2)
        Pyrexia
    72.4 (65.1 to 78.9)
    72.2 (64.9 to 78.6)
        Somnolence
    82.8 (76.3 to 88.1)
    85.8 (79.7 to 90.6)
        Vomiting
    36.2 (29.1 to 43.8)
    26.7 (20.3 to 33.9)
    No statistical analyses for this end point

    Secondary: Booster - Antibody persistence # Response rates to all Hexavalent vaccine antigens at 12 months of age, before Hexavalent vaccine booster dose

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    End point title
    		 Booster - Antibody persistence # Response rates to all Hexavalent vaccine antigens at 12 months of age, before Hexavalent vaccine booster dose
    End point description
    Percentages of subjects with anti-D concentration ≥0.01 IU/mL & ≥0.10 IU/mL for Diphtheria (measured by MIT), anti-T concentration ≥0.01 IU/mL & ≥0.10 IU/mL for Tetanus by ELISA, anti-IPV titer ≥8 (1/dil) for Poliovirus types 1, 2, & 3 by MIT, anti-Hep B concentration ≥10 mIU/mL & ≥100 mIU/mL by Hep B ECi, anti-PRP concentration ≥0.15 ug/mL & ≥1.0 ug/mL for Hib by Farr type RIA, anti-PT & anti-FHA concentration ≥LLOQ and ≥2xLLOQ for Pertussis by ELISA (LLOQ=2 EU/mL). Analysis was done on the Persistence Analysis Set, i.e., all randomised subjects in the Booster Period with available serology data on Day 0 of the Booster period, and according to Iry series groups.
    End point type
    Secondary
    End point timeframe
    On entry within Booster period, prior to vaccination with Hexavalent vaccine booster dose and/or MenACWY vaccine.
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    152
    151
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-D ≥0.01 IU/mL (N=151, 150)
    98 (94.3 to 99.6)
    99.3 (96.3 to 100)
        Anti-D ≥0.10 IU/mL (N=151, 150)
    41.1 (33.1 to 49.3)
    47.3 (39.1 to 55.6)
        Anti-T ≥0.01 IU/mL (N=151, 150)
    100 (97.6 to 100)
    100 (97.6 to 100)
        Anti-T ≥0.10 IU/mL (N=151, 150)
    100 (97.6 to 100)
    92 (86.4 to 95.8)
        Anti-IPV1 ≥8 (1/dil) (N=151, 150)
    80.8 (73.6 to 86.7)
    84.7 (77.9 to 90)
        Anti-IPV2 ≥8 (1/dil) (N=151, 150)
    64.9 (56.7 to 72.5)
    76 (68.4 to 82.6)
        Anti-IPV3 ≥8 (1/dil) (N=150, 148)
    82 (74.9 to 87.8)
    88.5 (82.2 to 93.2)
        Anti-Hep B ≥10 mIU/mL (N=152, 151)
    90.1 (84.2 to 94.4)
    91.4 (85.7 to 95.3)
        Anti-Hep B ≥100 mIU/mL (N=152, 151)
    47.4 (39.2 to 55.6)
    51 (42.7 to 59.2)
        Anti-PRP ≥0.15 ug/mL (N=151, 150)
    86.8 (80.3 to 91.7)
    77.3 (69.8 to 83.8)
        Anti-PRP ≥1.0 ug/mL (N=151, 150)
    46.4 (38.2 to 54.6)
    47.3 (39.1 to 55.6)
        Anti-PT ≥LLOQ (N=151, 148)
    100 (97.6 to 100)
    99.3 (96.3 to 100)
        Anti-PT ≥2xLLOQ (N=151, 148)
    99.3 (96.4 to 100)
    99.3 (96.3 to 100)
        Anti-FHA ≥LLOQ (N=151, 149)
    100 (97.6 to 100)
    100 (97.6 to 100)
        Anti-FHA ≥2xLLOQ (N=151, 149)
    100 (97.6 to 100)
    100 (97.6 to 100)
    No statistical analyses for this end point

    Secondary: Booster - Antibody persistence # Geometric Mean Titers (GMTs) or Concentrations (GMCs) of antibodies to all Hexavalent vaccine antigens at 12 months of age, before Hexavalent vaccine booster dose

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    End point title
    		 Booster - Antibody persistence # Geometric Mean Titers (GMTs) or Concentrations (GMCs) of antibodies to all Hexavalent vaccine antigens at 12 months of age, before Hexavalent vaccine booster dose
    End point description
    Antibody titers or concentrations were measured for Diphtheria (D) by MIT (IU/mL), for Tetanus (T) by ELISA (IU/mL), for Poliovirus (IPV) types 1, 2, and 3 by MIT (1/dil), for Hepatitis B (Hep B) by ECi (mIU/mL), for Haemophilus influenzae type b (PRP) by Farr type RIA (ug/mL), and for Pertussis antigens (PT & FHA) by ELISA (EU/mL). Analysis was done on the Persistence Analysis Set.
    End point type
    Secondary
    End point timeframe
    On Day 0 of the Booster period, before Hexavalent vaccine booster dose (pre-booster).
    End point values
    		 Hexavalent vaccine co-administered with MenC vaccine Hexavalent vaccine without MenC vaccine
    Number of subjects analysed
    152
    151
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-D GMC (N=151, 150)
    0.08 (0.06 to 0.09)
    0.1 (0.08 to 0.12)
        Anti-T GMC (N=151, 150)
    0.61 (0.55 to 0.68)
    0.34 (0.29 to 0.39)
        Anti-IPV1 GMT (N=151, 150)
    26.7 (20.8 to 34.27)
    39.4 (30.4 to 51.07)
        Anti-IPV2 GMT (N=151, 150)
    17.67 (13.31 to 23.44)
    26.48 (19.83 to 35.35)
        Anti-IPV3 GMT (N=150, 148)
    42.44 (32 to 56.27)
    73.16 (55.37 to 96.67)
        Anti-Hep B GMC (N=152, 151)
    76.58 (59.77 to 98.12)
    95.78 (74.89 to 122.5)
        Anti-PRP GMC (N=151, 150)
    0.81 (0.64 to 1.04)
    0.62 (0.47 to 0.82)
        Anti-PT GMC (N=151, 148)
    14.36 (12.77 to 16.16)
    16.43 (14.59 to 18.5)
        Anti-FHA GMC (N=151, 149)
    30.24 (26.82 to 34.09)
    36.46 (32.66 to 40.7)
    No statistical analyses for this end point

    Secondary: Booster # Percentage of subjects reporting solicited injection-site or systemic reactions after vaccination after Hexavalent or MenACWY vaccines, administered concomitantly or separately

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    End point title
    		 Booster # Percentage of subjects reporting solicited injection-site or systemic reactions after vaccination after Hexavalent or MenACWY vaccines, administered concomitantly or separately
    End point description
    Solicited Injection Site Reactions (ISRs: Erythema, Pain, Swelling, and extensive swelling of vaccinated limb (extensive swelling of vaccinated limb for Hexavalent vaccine only)) and solicited systemic reactions (Crying, Decreased appetite, Irritability, Pyrexia, Somnolence, and Vomiting) within 7 days after Hexavalent or MenACWY vaccines, administered concomitantly or separately. Solicited reactions were always considered as related to vaccines. The percentage of subjects presenting at least once the considered events after any vaccination is reported hereafter. Analysis was done on the Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    Day 0 up to 7 days following Hexavalent or MenACWY vaccines, administered concomitantly or separately.
    End point values
    		 Hexavalent vaccine co-administered with MenACWY vaccine Hexavalent vaccine only MenACWY vaccine only
    Number of subjects analysed
    103
    105
    103
    Units: Percentage of subjects
    number (confidence interval 95%)
        Solicited reaction any dose
    93.2 (86.5 to 97.2)
    91.4 (84.4 to 96)
    77.7 (68.4 to 85.3)
        Solicited ISR
    68.9 (59.1 to 77.7)
    60 (50 to 69.4)
    32 (23.2 to 42)
        Solicited ISR after Hexavalent vaccine
    66 (56 to 75.1)
    60 (50 to 69.4)
    0 (0 to 0)
        Erythema after Hexavalent vaccine
    35.9 (26.7 to 46)
    26.7 (18.5 to 36.2)
    0 (0 to 0)
        Pain after Hexavalent vaccine
    57.3 (47.2 to 67)
    50.5 (40.5 to 60.4)
    0 (0 to 0)
        Swelling after Hexavalent vaccine
    25.2 (17.2 to 34.8)
    21 (13.6 to 30)
    0 (0 to 0)
        Solicited ISR after MenACWY vaccine
    47.6 (37.6 to 57.6)
    0 (0 to 0)
    32 (23.2 to 42)
        Erythema after MenACWY vaccine
    16.5 (9.9 to 25.1)
    0 (0 to 0)
    15.5 (9.1 to 24)
        Pain after MenACWY vaccine
    46.6 (36.7 to 56.7)
    0 (0 to 0)
    17.5 (10.7 to 26.2)
        Swelling after MenACWY vaccine
    8.7 (4.1 to 15.9)
    0 (0 to 0)
    5.8 (2.2 to 12.2)
        Solicited systemic reaction
    88.3 (80.5 to 93.8)
    85.7 (77.5 to 91.8)
    72.8 (63.2 to 81.1)
        Crying
    50.5 (40.5 to 60.5)
    48.6 (38.7 to 58.5)
    30.1 (21.5 to 39.9)
        Decreased appetite
    48.5 (38.6 to 58.6)
    34.3 (25.3 to 44.2)
    30.1 (21.5 to 39.9)
        Irritability
    76.7 (67.3 to 84.5)
    71.4 (61.8 to 79.8)
    48.5 (38.6 to 58.6)
        Pyrexia
    30.1 (21.5 to 39.9)
    35.2 (26.2 to 45.2)
    10.7 (5.5 to 18.3)
        Somnolence
    52.4 (42.4 to 62.4)
    42.9 (33.2 to 52.9)
    32 (23.2 to 42)
        Vomiting
    19.4 (12.3 to 28.4)
    9.5 (4.7 to 16.8)
    11.7 (6.2 to 19.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From D0 to D30 after each vaccination: unsolicited adverse events (AEs). From the 1st vaccination to the last visit of each period: serious AEs (SAEs) & deaths. From the end of Primary Series to Booster: related SAEs, deaths & AEs of special interest.
    Adverse event reporting additional description
    Analysis of AEs was done on the Safety Set, i.e., all subjects who received at least 1 dose of the study vaccines and who had safety follow-up data. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥5% in at least 1 group are presented hereafter. 1 SAE (Pyrexia during Primary Series) was assessed as vaccine-related.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Primary Series # Hexavalent vaccine co-administered with MenC
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age co-administered with 2 doses of MenC vaccine with 1 dose each at 2, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age.

    Reporting group title
    Primary Series # Hexavalent vaccine without MenC
    Reporting group description
    		 # Subjects received 3 doses of Hexavalent vaccine with 1 dose each at 2, 3, and 4 months of age. # Subjects received also routine vaccination: RotaTeq at 2, 3, and 4 months of age and Prevenar 13 at 2, and 4 months of age.

    Reporting group title
    Booster # MenACWY vaccine only
    Reporting group description
    		 # Subjects from the Primary Series period received 1 dose of MenACWY vaccine at approximately 12 months of age.

    Reporting group title
    Booster # Hexavalent vaccine co-administered with MenACWY
    Reporting group description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine co-administered with 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of Prevenar 13 ± 1 optional dose of M-MRvaxPRO at approximately 13 months of age.

    Reporting group title
    Booster # Hexavalent vaccine only
    Reporting group description
    		 # Subjects from the Primary Series period received 1 booster dose of Hexavalent vaccine at approximately 12 months of age. # Subjects received also routine vaccination: 1 dose of MenC vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age.

    Reporting group title
    Booster # MenACWY followed by Hexavalent vaccine 1 month later
    Reporting group description
    		 # Subjects from the Primary Series period received 1 dose of MenACWY vaccine at approximately 12 months of age. # Subjects received also 1 booster dose of Hexavalent vaccine + 1 dose of Prevenar 13 ± 1 optional dose of M-M-RvaxPRO at approximately 13 months of age.

    Serious adverse events
    		 Primary Series # Hexavalent vaccine co-administered with MenC Primary Series # Hexavalent vaccine without MenC Booster # MenACWY vaccine only Booster # Hexavalent vaccine co-administered with MenACWY Booster # Hexavalent vaccine only Booster # MenACWY followed by Hexavalent vaccine 1 month later
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 174 (2.87%)
    2 / 176 (1.14%)
    1 / 103 (0.97%)
    1 / 103 (0.97%)
    1 / 105 (0.95%)
    0 / 103 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin neoplasm bleeding
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 176 (0.57%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
    Additional description: Severe transient (1 day) SAE occurring concomitantly with Pneumonia respiratory syncytial viral infection 24 days after MenACWY dose in "Booster # MenACWY vaccine only" group; assessed as AE of SpeciaI Interest and not vaccine-related.
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 176 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyporesponsive to stimuli
    Additional description: Transient (1 day) SAE occurring 170 days after the 3rd dose of the Primary Series schedule and prior to the booster dose in 1 subject of the "Booster # MenACWY vaccine only" group. The AE was assessed as not vaccine-related.
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 176 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 176 (0.57%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    1 / 105 (0.95%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 176 (0.00%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
    Additional description: Severe SAE occurring 115 days after the 3rd dose of the Primary Series schedule and prior to the booster dose in "Primary Series # Hexavalent vaccine co-administered with MenC" group, lasting 42 days; assessed as not vaccine-related.
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 176 (0.00%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Primary Series # Hexavalent vaccine co-administered with MenC Primary Series # Hexavalent vaccine without MenC Booster # MenACWY vaccine only Booster # Hexavalent vaccine co-administered with MenACWY Booster # Hexavalent vaccine only Booster # MenACWY followed by Hexavalent vaccine 1 month later
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 174 (60.34%)
    109 / 176 (61.93%)
    60 / 103 (58.25%)
    55 / 103 (53.40%)
    51 / 105 (48.57%)
    45 / 103 (43.69%)
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    9 / 174 (5.17%)
    7 / 176 (3.98%)
    0 / 103 (0.00%)
    6 / 103 (5.83%)
    2 / 105 (1.90%)
    1 / 103 (0.97%)
         occurrences all number
    11
    7
    0
    7
    2
    1
    Injection site induration
         subjects affected / exposed
    14 / 174 (8.05%)
    9 / 176 (5.11%)
    1 / 103 (0.97%)
    3 / 103 (2.91%)
    2 / 105 (1.90%)
    1 / 103 (0.97%)
         occurrences all number
    25
    10
    1
    3
    2
    1
    Pyrexia
         subjects affected / exposed
    5 / 174 (2.87%)
    10 / 176 (5.68%)
    5 / 103 (4.85%)
    5 / 103 (4.85%)
    6 / 105 (5.71%)
    24 / 103 (23.30%)
         occurrences all number
    6
    11
    5
    5
    6
    26
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 174 (8.05%)
    12 / 176 (6.82%)
    6 / 103 (5.83%)
    2 / 103 (1.94%)
    3 / 105 (2.86%)
    1 / 103 (0.97%)
         occurrences all number
    17
    15
    6
    2
    3
    1
    Flatulence
         subjects affected / exposed
    7 / 174 (4.02%)
    9 / 176 (5.11%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    7
    12
    0
    0
    0
    0
    Teething
         subjects affected / exposed
    9 / 174 (5.17%)
    5 / 176 (2.84%)
    10 / 103 (9.71%)
    5 / 103 (4.85%)
    5 / 105 (4.76%)
    1 / 103 (0.97%)
         occurrences all number
    12
    5
    10
    5
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 174 (5.17%)
    9 / 176 (5.11%)
    1 / 103 (0.97%)
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    12
    9
    1
    0
    0
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    24 / 174 (13.79%)
    26 / 176 (14.77%)
    7 / 103 (6.80%)
    5 / 103 (4.85%)
    5 / 105 (4.76%)
    3 / 103 (2.91%)
         occurrences all number
    34
    32
    7
    5
    5
    3
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 174 (14.37%)
    27 / 176 (15.34%)
    15 / 103 (14.56%)
    16 / 103 (15.53%)
    14 / 105 (13.33%)
    3 / 103 (2.91%)
         occurrences all number
    29
    27
    15
    18
    14
    3
    Otitis media
         subjects affected / exposed
    4 / 174 (2.30%)
    5 / 176 (2.84%)
    12 / 103 (11.65%)
    8 / 103 (7.77%)
    8 / 105 (7.62%)
    7 / 103 (6.80%)
         occurrences all number
    4
    5
    13
    8
    8
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2013
    Amendment 1 to Protocol (leading to Version 2.0) was produced to provide details regarding the booster vaccination at 12 to 13 months of age with Hexavalent vaccine, 13-valent pneumococcal polysaccharide conjugate vaccine and meningococcal C containing vaccine.

    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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