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    Clinical Trial Results:
    Open, Randomised, Comparative, Multicentre Study of the Immunogenicity and Safety of Concomitant versus Separate administration of a combined measles, mumps, rubella and varicella live vaccine (ProQuad®) and a Booster dose of Infanrix® hexa in Healthy Children 12 to 23 months of age

    Summary
    EudraCT number
    		 2006-004129-27
    Trial protocol
    		 DE   IT  
    Global end of trial date
    27 Mar 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    X06-MMRV-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00432042
    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
    27 Mar 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that ProQuad® can be administered concomitantly with a booster dose of Infanrix® hexa to healthy children of 12 to 23 months of age without impairing neither the antibody response rates to measles, mumps, rubella, varicella, hepatitis B, and Haemophilus influenzae type b, or to the 3 pertussis antibody titres measured at 42 days following vaccination.
    Protection of trial subjects
    Healthy subjects with prior known sensitivity/allergy to any component of the vaccine including neomycin, sorbitol or gelatine were excluded. Vaccines were administered by qualified study personnel. After each vaccination, subjects were kept under observation for at least 20 minutes to ensure their safety. Appropriate medical treatment and supervision were always readily available in case of a rare anaphylactic reaction following the administration of the vaccine.
    Background therapy
    		 # For Italy, primary vaccination with the combined diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and Haemophilus influenzae type b vaccine Infanrix hexa as a 2-dose schedule, with receipt of the 2nd dose ≥6 months prior to inclusion. # For Germany, primary vaccination with the combined diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and Haemophilus influenzae type b vaccine Infanrix hexa as a 3-dose schedule, with receipt of the 3rd dose ≥6 months prior to inclusion.
    Evidence for comparator
    		 The immunisation schedule of hexavalent vaccines consists of a primary series followed by a booster dose given at the same age as ProQuad. The rationale of the study was to generate immunogenicity and safety data for ProQuad when administered concomitantly either with the 3rd dose of Infanrix hexa (Italian schedule) or with the 4th dose of Infanrix hexa (German schedule) given in the 2nd year of life. Therefore, concomitant administration of ProQuad and Infanrix hexa was compared to administration of each of these vaccines alone.
    Actual start date of recruitment
    12 Jan 2007
    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
    Germany: 728
    Country: Number of subjects enrolled
    Italy: 227
    Worldwide total number of subjects
    955
    EEA total number of subjects
    955
    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)
    954
    Children (2-11 years)
    1
    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 between 12 January 2007 and 13 February 2008 in 51 active centres: 6 vaccination centres in Italy, and 45 private paediatricians in Germany.

    Pre-assignment
    Screening details
    		 963 subjects were screened. 955 subjects were randomised (14 subjects randomised in 1 centre in Germany were excluded from analyses due to a major Good Clinical Practice (GCP) non compliance (non reliability of vaccination history)). 952 subjects received at least 1 vaccine dose. 945 subjects completed the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable as this study was open-label. For immunogenicity data, serology tests were performed by laboratory staffs who were blinded to which vaccine each subject received.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: ProQuad + Infanrix hexa
    Arm description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route concomitantly with Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ProQuad®
    Investigational medicinal product code
    MMRV
    Other name
    ProQuad
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous route (deltoid region), 1 dose at 12-23 months of age. ProQuad had to be administered in the contralateral arm than the one for Infanrix hexa.

    Investigational medicinal product name
    Infanrix® hexa
    Investigational medicinal product code
    DTaP-HBs-IPV//Hib
    Other name
    Infanrix hexa
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (deltoid region), 1 dose at 12-23 months of age. Infanrix hexa had to be administered in the contralateral arm than the one for ProQuad.

    Arm title
    		 Group 2: ProQuad
    Arm description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ProQuad®
    Investigational medicinal product code
    MMRV
    Other name
    ProQuad
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous route (deltoid region), 1 dose at 12-23 months of age.

    Arm title
    		 Group 3: Infanrix hexa
    Arm description
    		 # Subjects received Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Infanrix® hexa
    Investigational medicinal product code
    DTaP-HBs-IPV//Hib
    Other name
    Infanrix hexa
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (deltoid region), 1 dose at 12-23 months of age.

    Number of subjects in period 1
    		Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa
    Started
    479
    235
    241
    Completed
    472
    234
    239
    Not completed
    7
    1
    2
         Personal reason
    -
    -
    2
         Lost to follow-up
    5
    1
    -
         Protocol deviation
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: ProQuad + Infanrix hexa
    Reporting group description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route concomitantly with Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Reporting group title
    Group 2: ProQuad
    Reporting group description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Reporting group title
    Group 3: Infanrix hexa
    Reporting group description
    		 # Subjects received Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Reporting group values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa Total
    Number of subjects
    		 479 235 241 955
    Age categorical
    Age at vaccination.
    Units: Subjects
        ≥12 and <24 months
    		 474 234 238 946
        <12 or ≥24 months
    		 5 1 3 9
    Age continuous
    Age at vaccination (3 missing values: N=477, 235, 240 respectively)
    Units: months
        arithmetic mean (standard deviation)
    		 13.6 ± 1.9 13.4 ± 1.5 13.5 ± 1.7 -
    Gender categorical
    Units: Subjects
        Female
    		 222 112 114 448
        Male
    		 257 123 127 507

    End points

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    End points reporting groups
    Reporting group title
    Group 1: ProQuad + Infanrix hexa
    Reporting group description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route concomitantly with Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Reporting group title
    Group 2: ProQuad
    Reporting group description
    		 # Subjects received ProQuad (measles, mumps, rubella and varicella (live attenuated)) vaccine dose 1 by subcutaneous route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Reporting group title
    Group 3: Infanrix hexa
    Reporting group description
    		 # Subjects received Infanrix hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) booster dose by intramuscular route at 12-23 months of age. # Subjects were blood sampled at (i) Day -7 (D-7) to D0 before vaccination = pre-vaccination, and (ii) 6 weeks (D42 to D56) after vaccination = post-vaccination.

    Primary: Antibody (Ab) response rates to Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2)

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    End point title
    		 Antibody (Ab) response rates to Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2) [1]
    End point description
    Percentage of subjects with an Ab titre ≥255 mIU/mL for Measles, ≥10 ELISA Ab units/mL for Mumps, ≥10 IU/mL for Rubella, and ≥5 gpELISA units/mL for Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. All Ab titres were measured by Enzyme-Linked Immunosorbent Assay (ELISA), except Ab to Varicella determined by glycoprotein ELISA (gpELISA). Analysis was done on the Antigen-Specific Per Protocol Set (PPS), i.e. all randomised subjects initially seronegative for those antigens (Measles Ab titre <255 mIU/mL, Mumps Ab titre <10 ELISA Ab units/mL, Rubella Ab titre <10 IU/mL, and Varicella Ab titre <1.25 gpELISA units/mL) excluding subjects with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “ProQuad” groups, respectively.
    End point type
    Primary
    End point timeframe
    6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the antibody response rates to Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. So this endpoint did not concern subjects of the "Infanrix hexa" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad
    Number of subjects analysed
    431
    215
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Measles ≥255 mIU/mL (N=421, 215)
    97.4 (95.4 to 98.7)
    96.3 (92.8 to 98.4)
        Anti-Mumps ≥10 ELISA Ab units/mL (N=427, 212)
    96.7 (94.6 to 98.2)
    98.6 (95.9 to 99.7)
        Anti-Rubella ≥10 IU/mL (N=431, 215)
    97.9 (96.1 to 99)
    99.1 (96.7 to 99.9)
        Anti-Varicella ≥5 gpELISA units/mL (N=394, 205)
    97.7 (95.7 to 99)
    95.1 (91.2 to 97.6)
    Statistical analysis title
    		 Non-inferiority for Measles
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 2 (ProQuad) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 2 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the Antigen-specific PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 2: ProQuad
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 4.82
    Notes
    [2] - For Measles: # Antigen-specific PPS, N=421, 215 (Groups 1 & 2) # Response rate based on Ab titre ≥255 mIU/mL # Non-inferiority margin, -10%.
    Statistical analysis title
    		 Non-inferiority for Mumps
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 2 (ProQuad) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 2 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the Antigen-specific PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 2: ProQuad
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    -1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.21
         upper limit
    		 1.1
    Notes
    [3] - For Mumps: # Antigen-specific PPS, N=427, 212 (Groups 1 & 2) # Response rate based on Ab titre ≥10 ELISA Ab units/mL # Non-inferiority margin, -10%.
    Statistical analysis title
    		 Non-inferiority for Rubella
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 2 (ProQuad) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 2 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the Antigen-specific PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 2: ProQuad
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.19
         upper limit
    		 1.35
    Notes
    [4] - For Rubella: # Antigen-specific PPS, N=431, 215 (Groups 1 & 2) # Response rate based on Ab titre ≥10 IU/mL # Non-inferiority margin, -10%.
    Statistical analysis title
    		 Non-inferiority for Varicella
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 2 (ProQuad) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 2 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the Antigen-specific PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 2: ProQuad
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 6.58
    Notes
    [5] - For Varicella: # Antigen-specific PPS, N=394, 205 (Groups 1 & 2) # Response rate based on Ab titre ≥5 gpELISA units/mL # Non-inferiority margin, -10%.

    Primary: Antibody (Ab) response rates to Hepatitis B and Haemophilus influenzae type b (PRP) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Antibody (Ab) response rates to Hepatitis B and Haemophilus influenzae type b (PRP) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [6]
    End point description
    Percentage of subjects with an Ab titre ≥10 IU/mL for Hepatitis B, and ≥1 µg/mL for Haemophilus influenzae type b (polyribosylribitol phosphate, PRP) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. Ab titres were measured by enhanced chemiluminescence (ECi) assay for Hepatitis B and Farr-type radioimmunoassay for PRP. Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “Infanrix hexa” groups, respectively.
    End point type
    Primary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the antibody response rates to Hepatitis B and Haemophilus influenzae type b (PRP) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    411
    215
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Hepatitis B ≥10 IU/mL (N=411, 215)
    99.5 (98.3 to 99.9)
    98.1 (95.3 to 99.5)
        Anti-PRP ≥1 µg/mL (N=387, 211)
    98.2 (96.3 to 99.3)
    95.3 (91.5 to 97.7)
    Statistical analysis title
    		 Non-inferiority for Hepatitis B
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 3 (Infanrix hexa) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 3 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 3: Infanrix hexa
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 4.24
    Notes
    [7] - For Hepatitis B: # PPS, N=411, 215 (Groups 1 & 3) # Response rate based on Ab titre ≥10 IU/mL # Non-inferiority margin, -5%.
    Statistical analysis title
    		 Non-inferiority for PRP
    Statistical analysis description
    The estimates of the differences between Group 1 (ProQuad + Infanrix hexa) & Group 3 (Infanrix hexa) response rates were calculated with their 2-sided 95% confidence interval (CI). If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 response rates were non-inferior to Group 3 response rates. Statistical analysis was based on the Miettinen & Nurminen method with stratification by region. Analysis was done on the PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 3: Infanrix hexa
    Number of subjects included in analysis
    626
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference in percentage of subjects
    Point estimate
    2.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 6.89
    Notes
    [8] - For PRP: # PPS, N=387, 211 (Groups 1 & 3) # Response rate based on Ab titre ≥1 µg/mL # Non-inferiority margin, -5%.

    Primary: Geometric Mean Titres (GMT) for the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Geometric Mean Titres (GMT) for the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [9]
    End point description
    Antibody titres expressed in EU/mL were measured for the 3 pertussis antigens (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA) & Pertactin (PRN)) by Enzyme-Linked Immunosorbent Assay (ELISA) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “Infanrix hexa” groups, respectively.
    End point type
    Primary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the Geometric Mean Titres (GMT) for the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    386
    211
    Units: Titres
    geometric mean (confidence interval 95%)
        Anti-PT GMT (N=379, 209)
    132.6 (123.8 to 142)
    139.1 (126.7 to 152.8)
        Anti-FHA GMT (N=386, 211)
    210.9 (195.7 to 227.2)
    189.9 (170.2 to 211.8)
        Anti-PRN GMT (N=385, 211)
    310 (282.2 to 340.7)
    259.7 (226.3 to 298.1)
    Statistical analysis title
    		 Non-inferiority for PT
    Statistical analysis description
    The estimates of the post-vaccination GMT ratios Group 1 (ProQuad + Infanrix hexa) / Group 3 (Infanrix hexa) were calculated with their 2-sided 95% confidence interval (CI) and adjusted for pre-vaccination titres, Infanrix hexa primary vaccination & region. If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 GMT were non-inferior to Group 3 GMT. Analysis was done on the PPS.
    Comparison groups
    Group 3: Infanrix hexa v Group 1: ProQuad + Infanrix hexa
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.08
    Notes
    [10] - For PT: # PPS, N=379, 209 (Groups 1 & 3) # Non-inferiority margin, 0.5. Statistical analysis was based on an ANCOVA model with the log-transformed post-vaccination titres as response, the log-transformed baseline titres as covariate, the Infanrix hexa primary vaccination, the Region (nested effect) and the Group as fixed effects.
    Statistical analysis title
    		 Non-inferiority for FHA
    Statistical analysis description
    The estimates of the post-vaccination GMT ratios Group 1 (ProQuad + Infanrix hexa) / Group 3 (Infanrix hexa) were calculated with their 2-sided 95% confidence interval (CI) and adjusted for pre-vaccination titres, Infanrix hexa primary vaccination & region. If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 GMT were non-inferior to Group 3 GMT. Analysis was done on the PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 3: Infanrix hexa
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.23
    Notes
    [11] - For FHA: # PPS, N=386, 211 (Groups 1 & 3) # Non-inferiority margin, 0.5. Statistical analysis was based on an ANCOVA model with the log-transformed post-vaccination titres as response, the log-transformed baseline titres as covariate, the Infanrix hexa primary vaccination, the Region (nested effect) and the Group as fixed effects.
    Statistical analysis title
    		 Non-inferiority for PRN
    Statistical analysis description
    The estimates of the post-vaccination GMT ratios Group 1 (ProQuad + Infanrix hexa) / Group 3 (Infanrix hexa) were calculated with their 2-sided 95% confidence interval (CI) and adjusted for pre-vaccination titres, Infanrix hexa primary vaccination & region. If the lower bounds of the 95% CI were greater than the non-inferiority margin, it was concluded that Group 1 GMT were non-inferior to Group 3 GMT. Analysis was done on the PPS.
    Comparison groups
    Group 1: ProQuad + Infanrix hexa v Group 3: Infanrix hexa
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.36
    Notes
    [12] - For PRN: # PPS, N=385, 211 (Groups 1 & 3) # Non-inferiority margin, 0.5. Statistical analysis was based on an ANCOVA model with the log-transformed post-vaccination titres as response, the log-transformed baseline titres as covariate, the Infanrix hexa primary vaccination, the Region (nested effect) and the Group as fixed effects.

    Secondary: Geometric Mean Titres (GMT) for Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2)

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    End point title
    		 Geometric Mean Titres (GMT) for Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2) [13]
    End point description
    Antibody (Ab) titres were measured for Measles, Mumps & Rubella by ELISA, and for Varicella by gpELISA 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. Ab titres are expressed in ELISA mIU/mL for Measles, ELISA Ab units/mL for Mumps, IU/mL for Rubella, & gpELISA units /mL for Varicella. Analysis was done on the Antigen-Specific Per Protocol Set (PPS), i.e. all randomised subjects initially seronegative for those antigens (Measles Ab titre <255 mIU/mL, Mumps Ab titre <10 ELISA Ab units/mL, Rubella Ab titre <10 IU/mL, and Varicella Ab titre <1.25 gpELISA units/mL) excluding subjects with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “ProQuad” groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the Geometric Mean Titres (GMT) for Measles, Mumps, Rubella, and Varicella 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. So this endpoint did not concern subjects of the "Infanrix hexa" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad
    Number of subjects analysed
    431
    215
    Units: Titres
    geometric mean (confidence interval 95%)
        Anti-Measles GMT (N=421, 215)
    4581 (4148 to 5061)
    4056 (3520 to 4672)
        Anti-Mumps GMT (N=427, 212)
    116 (107 to 127)
    126 (113 to 139)
        Anti-Rubella GMT (N=431, 215)
    90 (83 to 97)
    90 (81 to 99)
        Anti-Varicella GMT (N=394, 205)
    16.64 (15.61 to 17.75)
    15.31 (13.91 to 16.86)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-Varicella antibody (Ab) titre ≥1.25 gpELISA units/mL 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2)

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    End point title
    		 Percentage of subjects with anti-Varicella antibody (Ab) titre ≥1.25 gpELISA units/mL 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2) [14]
    End point description
    Percentage of subjects with anti-Varicella Ab titre ≥1.25 gpELISA units/mL measured by glycoprotein ELISA (gpELISA) 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. Analysis was done on the Varicella-Specific Per Protocol Set (PPS), i.e. all randomised subjects initially seronegative for Varicella (Ab titre <1.25 gpELISA units/mL) excluding subjects with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “ProQuad” groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the of subjects with anti-Varicella antibody (Ab) titre ≥1.25 gpELISA units/mL 6 weeks after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. So this endpoint did not concern subjects of the "Infanrix hexa" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad
    Number of subjects analysed
    394
    205
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Varicella ≥1.25 gpELISA units/mL (N=394, 205)
    98.5 (96.7 to 99.4)
    98.5 (95.8 to 99.7)
    No statistical analyses for this end point

    Secondary: Antibody (Ab) response rates to Diphtheria, Tetanus, and Poliomyelitis types 1, 2 & 3, 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Antibody (Ab) response rates to Diphtheria, Tetanus, and Poliomyelitis types 1, 2 & 3, 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [15]
    End point description
    Percentage of subjects with an Ab titre ≥0.1 IU/mL for Diphtheria & Tetanus, and ≥8 (1/dil) for Poliomyelitis types 1, 2 & 3, 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. Ab titres were measured by a toxin neutralization test for Diphtheria, by ELISA for Tetanus, and by seroneutralisation (SN) for Poliomyelitis types 1, 2 & 3. Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “Infanrix hexa” groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the antibody response rates to Diphtheria, Tetanus, and Poliomyelitis types 1, 2 & 3, 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    375
    208
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Diphtheria ≥0.1 IU/mL (N=375, 206)
    99.7 (98.5 to 100)
    100 (98.2 to 100)
        Anti-Tetanus ≥0.1 IU/mL (N=375, 208)
    100 (99 to 100)
    100 (98.2 to 100)
        Anti-Poliomyelitis type 1 ≥8 (1/dil) (N=360, 203)
    100 (99 to 100)
    99.5 (97.3 to 100)
        Anti-Poliomyelitis type 2 ≥8 (1/dil) (N=361, 200)
    100 (99 to 100)
    100 (98.2 to 100)
        Anti-Poliomyelitis type 3 ≥8 (1/dil) (N=358, 201)
    100 (99 to 100)
    99.5 (97.3 to 100)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titres (GMT) for Diphtheria, Tetanus, Poliomyelitis types 1, 2 & 3, Hepatitis B and Haemophilus influenzae type b 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Geometric Mean Titres (GMT) for Diphtheria, Tetanus, Poliomyelitis types 1, 2 & 3, Hepatitis B and Haemophilus influenzae type b 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [16]
    End point description
    Antibody (Ab) titres were measured for Diphtheria by a toxin neutralization test, for Tetanus by ELISA, for Poliomyelitis types 1, 2 & 3 by SN, for Hepatitis B by ECi assay, and for Haemophilus influenzae type b (PRP) by Farr-type radioimmunoassay 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. Ab titres are expressed in IU/mL for Diphtheria & Tetanus, 1/dil for Poliomyelitis types 1, 2 & 3, mIU/mL for Hepatitis B, and µg/mL for PRP. Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the “ProQuad + Infanrix hexa” and “Infanrix hexa” groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the Geometric Mean Titres (GMT) for Diphtheria, Tetanus, Poliomyelitis types 1, 2 & 3, Hepatitis B and Haemophilus influenzae type b 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    411
    215
    Units: Titres
    geometric mean (confidence interval 95%)
        Anti-Diphtheria GMT (N=375, 206)
    3.11 (2.8 to 3.45)
    2.83 (2.46 to 3.26)
        Anti-Tetanus GMT (N=375, 208)
    4.8 (4.4 to 5.24)
    4.04 (3.6 to 4.53)
        Anti-Poliomyelitis type 1 GMT (N=360, 203)
    8161 (7085 to 9399)
    5494 (4492 to 6720)
        Anti-Poliomyelitis type 2 GMT (N=361, 200)
    9841 (8590 to 11274)
    6439 (5195 to 7981)
        Anti-Poliomyelitis type 3 GMT (N=358, 201)
    11070 (9603 to 12762)
    7956 (6436 to 9834)
        Anti-Hepatitis B GMT (N=411, 215)
    2662 (2240 to 3163)
    1809 (1424 to 2298)
        Anti-PRP GMT (N=387, 211)
    34.3 (29.8 to 39.6)
    20.9 (17.2 to 25.5)
    No statistical analyses for this end point

    Secondary: Antibody (Ab) response rates to the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Antibody (Ab) response rates to the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [17]
    End point description
    Percentage of subjects with pertussis Ab titres for the 3 pertussis antigens (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA) & Pertactin (PRN)) ≥Lower Limit of Quantification (LLOQ) in subjects with baseline Ab titres <LLOQ, or with Ab titres equal or greater than the baseline titres in subjects with baseline Ab titres ≥LLOQ 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. Ab titres were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "ProQuad + Infanrix hexa" and "Infanrix hexa" groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the antibody response rates to the 3 pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    354
    205
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PT (N=345, 199)
    99.7 (98.4 to 100)
    99.5 (97.2 to 100)
        Anti-FHA (N=354, 205)
    99.2 (97.5 to 99.8)
    98 (95.1 to 99.5)
        Anti-PRN (N=354, 205)
    99.4 (98 to 99.9)
    99.5 (97.3 to 100)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titres Ratios (GMTR) for the 3 Pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Geometric Mean Titres Ratios (GMTR) for the 3 Pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [18]
    End point description
    Study participants were blood sampled between Day -7 (D-7) and D0 before vaccination (pre-vaccination) and 6 weeks (D42 to D56) after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (post-vaccination). Antibody (Ab) titres were measured by ELISA for the 3 Pertussis antigens (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA) & Pertactin (PRN)). Individual post- / pre-vaccination anti-Pertussis Ab titres ratios were calculated for the 3 Pertussis antigens (PT, FHA & PRN). Analysis was done on the Per Protocol Set (PPS), i.e. all randomised subjects excluding those with protocol violations which may interfere with the immunogenicity evaluation. Note: (N=***, ***) represents the number of assessed subjects in the "ProQuad + Infanrix hexa" and "Infanrix hexa" groups, respectively.
    End point type
    Secondary
    End point timeframe
    6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the Geometric Mean Titres Ratios (GMTR) of individual post-/pre-vaccination anti-Pertussis antibody (Ab) titres for the 3 Pertussis antigens (PT, FHA & PRN) 6 weeks after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. So this endpoint did not concern subjects of the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    354
    205
    Units: Not applicable
    geometric mean (confidence interval 95%)
        Anti-PT GMTR (N=345, 199)
    6.9 (6.4 to 7.5)
    6.9 (6.2 to 7.7)
        Anti-FHA GMTR (N=354, 205)
    7.5 (6.9 to 8.2)
    7.1 (6.3 to 8)
        Anti-PRN GMTR (N=354, 205)
    16 (14.6 to 17.7)
    14 (12.2 to 16.1)
    No statistical analyses for this end point

    Secondary: Global summary of safety from D0 to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone

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    End point title
    		 Global summary of safety from D0 to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone
    End point description
    Adverse events (AEs) occurring after vaccination with ProQuad and Infanrix hexa, administered concomitantly or alone, were recorded as follows: 1/ From D0 to D4: solicited injection-site adverse reactions (ISRs: erythema, pain, and swelling). 2/ From D0 to D28: # unsolicited ISRs (including erythema, pain, and swelling from D5 to D28), # AEs of interest (a/ injection-site rashes of interest, b/ non-injection site rashes of interest (Measles-like rash, Rubella-like rash, Varicella-like rash and Herpes zoster-like rash), c/ Mumps-like illness), # rectal or equivalent temperature, and # unsolicited systemic AEs. AEs at injection sites were always considered as related to ProQuad or Infanrix hexa vaccines (ISRs). The investigator had to assess whether systemic AEs were vaccine-related systemic AEs or not. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data. Note: "0" means not applicable.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D28 after administration of ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa
    Number of subjects analysed
    474
    234
    239
    Units: Percentage of subjects
    number (not applicable)
        At least 1 AE (ISR or systemic AE) (D0-D28)
    90.5
    72.6
    84.1
        At least 1 ProQuad-related AE (D0-D28)
    54.4
    46.6
    0
        At least 1 Infanrix hexa-related AE (D0-D28)
    71.9
    0
    69.5
        At least 1 ISR (D0-D28)
    73.4
    26.5
    65.3
        At least 1 ISR to ProQuad (D0-D28)
    36.3
    26.5
    0
        At least 1 solicited ISR to ProQuad (D0-D4)
    31.6
    19.7
    0
        At least 1 ISR to Infanrix hexa (D0-D28)
    65.8
    0
    65.3
        At least 1 solicited ISR to Infanrix hexa (D0-D4)
    65.4
    0
    65.3
        At least 1 systemic AE (D0-D28)
    70
    65
    62.3
        At least 1 ProQuad-related systemic AE (D0-D28)
    32.1
    29.5
    0
        At least 1 Infanrix hexa-related syst. AE (D0-D28)
    21.1
    0
    16.7
        At least 1 rectal temperature ≥38°C (D0-D28)
    69.3
    61.1
    57.3
        At least 1 rectal temperature ≥39.4°C (D0-D28)
    22.6
    20.5
    15.9
    No statistical analyses for this end point

    Secondary: Solicited injection-site reactions (ISRs) to ProQuad from D0 to D4 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2)

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    End point title
    		 Solicited injection-site reactions (ISRs) to ProQuad from D0 to D4 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2) [19]
    End point description
    Solicited injection-site adverse reactions (ISRs) to ProQuad were recorded from D0 to D4 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose. AEs at ProQuad injection site were always considered as related to ProQuad (ISRs). Percentage of subjects presenting at least once the considered ISRs are presented here. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D4 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the solicited ISRs to ProQuad vaccine. So this endpoint did not include the "Infanrix hexa" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad
    Number of subjects analysed
    474
    234
    Units: Percentage of subjects
    number (not applicable)
        Injection-site erythema
    16.7
    10.7
        Injection-site pain
    20.9
    14.1
        Injection-site swelling
    9.7
    2.6
    No statistical analyses for this end point

    Secondary: Solicited injection-site reactions (ISRs) to Infanrix hexa from D0 to D4 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Solicited injection-site reactions (ISRs) to Infanrix hexa from D0 to D4 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [20]
    End point description
    Solicited injection-site adverse reactions (ISRs) to Infanrix hexa were recorded from D0 to D4 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1. AEs at Infanrix hexa injection site were always considered as related to Infanrix hexa (ISRs). Percentage of subjects presenting at least once the considered ISRs are presented here. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D4 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the solicited ISRs to Infanrix hexa. So this endpoint did not include the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    474
    239
    Units: Percentage of subjects
    number (not applicable)
        Injection-site erythema
    49.8
    52.7
        Injection-site pain
    39
    35.1
        Injection-site swelling
    38
    38.9
    No statistical analyses for this end point

    Secondary: Unsolicited injection-site reactions (ISRs) to ProQuad from D0 to D28 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2)

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    End point title
    		 Unsolicited injection-site reactions (ISRs) to ProQuad from D0 to D28 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose (Group 1 vs Group 2) [21]
    End point description
    Unsolicited injection-site adverse reactions (ISRs) to ProQuad occurring from D0 to D28, including erythema, pain, and swelling from D5 to D28 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose, were reported. AEs at ProQuad injection site were always considered as related to ProQuad (ISRs). Percentage of subjects presenting at least once the considered ISRs are presented here. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D28 after ProQuad dose 1, administered concomitantly or not with Infanrix hexa booster dose.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the unsolicited ISRs to ProQuad vaccine. So this endpoint did not include the "Infanrix hexa" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad
    Number of subjects analysed
    474
    234
    Units: Percentage of subjects
    number (not applicable)
        Injection-site bruising
    0.4
    0
        Injection-site dryness
    0
    0.4
        Injection-site erythema
    3.8
    2.6
        Injection-site haematoma
    0.4
    1.3
        Injection-site induration
    0.4
    0.4
        Injection-site nodule
    0.2
    0
        Injection-site papule
    0
    0.4
        Injection-site pustule
    0.4
    0
        Injection-site rash
    2.7
    4.3
        Injection-site swelling
    0.8
    0.4
        Injection-site warmth
    0.2
    0
    No statistical analyses for this end point

    Secondary: Unsolicited injection-site reactions (ISRs) to Infanrix hexa from D0 to D28 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3)

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    End point title
    		 Unsolicited injection-site reactions (ISRs) to Infanrix hexa from D0 to D28 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1 (Group 1 vs Group 3) [22]
    End point description
    Unsolicited injection-site adverse reactions (ISRs) to Infanrix hexa occurring from D0 to D28, including erythema, pain, and swelling from D5 to D28 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1, were reported. AEs at Infanrix hexa injection site were always considered as related to Infanrix hexa (ISRs). Percentage of subjects presenting at least once the considered ISRs are presented here. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D28 after Infanrix hexa booster dose, administered concomitantly or not with ProQuad dose 1.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The objective of this endpoint was to evaluate the unsolicited ISRs to Infanrix hexa. So this endpoint did not include the "ProQuad" arm.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 3: Infanrix hexa
    Number of subjects analysed
    474
    239
    Units: Percentage of subjects
    number (not applicable)
        Injection-site erythema
    0.6
    0
        Injection-site haemorrhage
    0.2
    0
        Injection-site haematoma
    1.1
    0.4
        Injection-site hypersensitivity
    0
    0.4
        Injection-site induration
    2.1
    1.7
        Injection-site pain
    0.2
    0
        Injection-site pruritus
    0.2
    0
        Injection-site rash
    0.2
    0.8
        Injection-site reaction
    0.2
    0
        Injection-site swelling
    0.4
    0
        Injection-site warmth
    1.3
    0.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects reporting adverse events of interest from D0 to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone

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    End point title
    		 Percentage of subjects reporting adverse events of interest from D0 to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone
    End point description
    Injection-site rashes of interest, non-injection site rashes of interest (Measles-like rash, Rubella-like rash, Varicella-like rash and Herpes zoster-like rash), and Mumps-like illness were reported from D0 to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone. Percentage of subjects presenting at least once the considered events are presented here. Analysis was done on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data.
    End point type
    Secondary
    End point timeframe
    From Day 0 (D0) to D28 after vaccination with ProQuad dose 1 and Infanrix hexa booster dose, administered concomitantly or alone.
    End point values
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa
    Number of subjects analysed
    474
    234
    239
    Units: Percentage of subjects
    number (not applicable)
        At least 1 injection-site rash of interest
    3
    4.3
    0.8
        At least 1 non-injection-site rash of interest
    13.5
    10.3
    3.8
        Measles / Measles-like rash
    7
    6.8
    2.1
        Rubella / Rubella-like rash
    3.8
    2.6
    0.4
        Varicella / Varicella-like rash
    3.2
    0.9
    1.3
        Herpes zoster / Herpes zoster-like rash
    0.2
    0.4
    0
        Mumps / mumps-like illness
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Unsolicited non-serious systemic adverse events (AEs) were collected from D0 to D28 following vaccination. Serious AEs and deaths were collected throughout the study.
    Adverse event reporting additional description
    Analysis of AEs was performed on the Safety Analysis Set, i.e. all subjects who received at least 1 of the study vaccine(s) and who had safety follow-up data. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥1% in at least 1 reporting group are presented hereafter. None of the serious AEs were vaccine-related.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Group 1: ProQuad + Infanrix hexa
    Reporting group description
    		 # Subjects received ProQuad dose 1 by subcutaneous route concomitantly with Infanrix hexa (DTaP-HBV-IPV-Hib) booster dose by intramuscular route at 12-23 months of age. # Respectively, 332 (70.0%) subjects reported at least 1 non-serious unsolicited systemic AE, 152 (32.1%) subjects reported at least 1 ProQuad-related non-serious unsolicited systemic AE, and 100 (21.1%) subjects reported at least 1 Infanrix hexa-related non-serious unsolicited systemic AE within 28 days after ProQuad dose 1 administered concomitantly with Infanrix hexa booster dose.

    Reporting group title
    Group 2: ProQuad
    Reporting group description
    		 # Subjects received ProQuad dose 1 by subcutaneous route at 12-23 months of age. # Respectively, 152 (65.0%) subjects reported at least 1 non-serious unsolicited systemic AE, and 69 (29.5%) subjects reported at least 1 ProQuad-related non-serious unsolicited systemic AE within 28 days after ProQuad dose 1.

    Reporting group title
    Group 3: Infanrix hexa
    Reporting group description
    		 # Subjects received Infanrix hexa (DTaP-HBV-IPV-Hib) booster dose by intramuscular route at 12-23 months of age. # Respectively, 149 (62.3%) subjects reported at least 1 non-serious unsolicited systemic AE, and 40 (16.7%) subjects reported at least 1 Infanrix hexa-related non-serious unsolicited systemic AE within 28 days after Infanrix hexa booster dose.

    Serious adverse events
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 474 (1.48%)
    6 / 234 (2.56%)
    4 / 239 (1.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 234 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    2 / 474 (0.42%)
    0 / 234 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 474 (0.00%)
    3 / 234 (1.28%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 234 (0.43%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 234 (0.43%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 234 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 234 (0.43%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 474 (0.00%)
    0 / 234 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 234 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 474 (0.00%)
    1 / 234 (0.43%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 234 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 474 (0.21%)
    0 / 234 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Group 1: ProQuad + Infanrix hexa Group 2: ProQuad Group 3: Infanrix hexa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    332 / 474 (70.04%)
    152 / 234 (64.96%)
    149 / 239 (62.34%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 474 (0.21%)
    1 / 234 (0.43%)
    3 / 239 (1.26%)
         occurrences all number
    1
    1
    3
    Head injury
         subjects affected / exposed
    3 / 474 (0.63%)
    0 / 234 (0.00%)
    5 / 239 (2.09%)
         occurrences all number
    3
    0
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    184 / 474 (38.82%)
    80 / 234 (34.19%)
    68 / 239 (28.45%)
         occurrences all number
    263
    104
    91
    Irritability
         subjects affected / exposed
    7 / 474 (1.48%)
    3 / 234 (1.28%)
    3 / 239 (1.26%)
         occurrences all number
    13
    3
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    9 / 474 (1.90%)
    6 / 234 (2.56%)
    4 / 239 (1.67%)
         occurrences all number
    9
    7
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 474 (4.64%)
    14 / 234 (5.98%)
    14 / 239 (5.86%)
         occurrences all number
    23
    14
    14
    Teething
         subjects affected / exposed
    14 / 474 (2.95%)
    9 / 234 (3.85%)
    6 / 239 (2.51%)
         occurrences all number
    21
    12
    6
    Constipation
         subjects affected / exposed
    1 / 474 (0.21%)
    3 / 234 (1.28%)
    1 / 239 (0.42%)
         occurrences all number
    1
    3
    1
    Enteritis
         subjects affected / exposed
    10 / 474 (2.11%)
    2 / 234 (0.85%)
    5 / 239 (2.09%)
         occurrences all number
    10
    3
    5
    Vomiting
         subjects affected / exposed
    14 / 474 (2.95%)
    2 / 234 (0.85%)
    14 / 239 (5.86%)
         occurrences all number
    15
    2
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 474 (6.54%)
    13 / 234 (5.56%)
    11 / 239 (4.60%)
         occurrences all number
    32
    15
    11
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    20 / 474 (4.22%)
    6 / 234 (2.56%)
    10 / 239 (4.18%)
         occurrences all number
    20
    6
    10
    Rash morbilliform
         subjects affected / exposed
    33 / 474 (6.96%)
    16 / 234 (6.84%)
    5 / 239 (2.09%)
         occurrences all number
    36
    16
    6
    Rash rubelliform
         subjects affected / exposed
    17 / 474 (3.59%)
    6 / 234 (2.56%)
    1 / 239 (0.42%)
         occurrences all number
    17
    6
    1
    Rash vesicular
         subjects affected / exposed
    14 / 474 (2.95%)
    3 / 234 (1.28%)
    3 / 239 (1.26%)
         occurrences all number
    15
    3
    3
    Dermatitis
         subjects affected / exposed
    7 / 474 (1.48%)
    1 / 234 (0.43%)
    4 / 239 (1.67%)
         occurrences all number
    7
    1
    4
    Eczema
         subjects affected / exposed
    9 / 474 (1.90%)
    2 / 234 (0.85%)
    1 / 239 (0.42%)
         occurrences all number
    9
    2
    1
    Erythema
         subjects affected / exposed
    5 / 474 (1.05%)
    0 / 234 (0.00%)
    1 / 239 (0.42%)
         occurrences all number
    6
    0
    1
    Rash
         subjects affected / exposed
    7 / 474 (1.48%)
    4 / 234 (1.71%)
    2 / 239 (0.84%)
         occurrences all number
    7
    4
    2
    Psychiatric disorders
    Crying
         subjects affected / exposed
    3 / 474 (0.63%)
    3 / 234 (1.28%)
    0 / 239 (0.00%)
         occurrences all number
    3
    3
    0
    Restlessness
         subjects affected / exposed
    10 / 474 (2.11%)
    3 / 234 (1.28%)
    2 / 239 (0.84%)
         occurrences all number
    11
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    27 / 474 (5.70%)
    15 / 234 (6.41%)
    12 / 239 (5.02%)
         occurrences all number
    28
    15
    12
    Gastroenteritis
         subjects affected / exposed
    17 / 474 (3.59%)
    4 / 234 (1.71%)
    4 / 239 (1.67%)
         occurrences all number
    18
    4
    4
    Influenza
         subjects affected / exposed
    6 / 474 (1.27%)
    7 / 234 (2.99%)
    6 / 239 (2.51%)
         occurrences all number
    6
    8
    8
    Nasopharyngitis
         subjects affected / exposed
    48 / 474 (10.13%)
    14 / 234 (5.98%)
    18 / 239 (7.53%)
         occurrences all number
    50
    16
    18
    Rhinitis
         subjects affected / exposed
    27 / 474 (5.70%)
    20 / 234 (8.55%)
    9 / 239 (3.77%)
         occurrences all number
    28
    23
    10
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 474 (2.95%)
    9 / 234 (3.85%)
    7 / 239 (2.93%)
         occurrences all number
    16
    10
    7
    Ear infection
         subjects affected / exposed
    2 / 474 (0.42%)
    3 / 234 (1.28%)
    1 / 239 (0.42%)
         occurrences all number
    2
    3
    1
    Exanthema subitum
         subjects affected / exposed
    5 / 474 (1.05%)
    2 / 234 (0.85%)
    2 / 239 (0.84%)
         occurrences all number
    6
    2
    2
    Otitis media
         subjects affected / exposed
    10 / 474 (2.11%)
    4 / 234 (1.71%)
    2 / 239 (0.84%)
         occurrences all number
    10
    4
    2
    Pharyngitis
         subjects affected / exposed
    3 / 474 (0.63%)
    4 / 234 (1.71%)
    4 / 239 (1.67%)
         occurrences all number
    3
    4
    4
    Respiratory tract infection
         subjects affected / exposed
    5 / 474 (1.05%)
    3 / 234 (1.28%)
    1 / 239 (0.42%)
         occurrences all number
    5
    3
    1
    Tonsillitis
         subjects affected / exposed
    6 / 474 (1.27%)
    0 / 234 (0.00%)
    5 / 239 (2.09%)
         occurrences all number
    6
    0
    5
    Viral infection
         subjects affected / exposed
    4 / 474 (0.84%)
    3 / 234 (1.28%)
    5 / 239 (2.09%)
         occurrences all number
    5
    3
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    3 / 474 (0.63%)
    3 / 234 (1.28%)
    2 / 239 (0.84%)
         occurrences all number
    3
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2007
    Update of study calendar due to the extension of the subject recruitment period, and the changes in the distribution of subjects between Germany and Italy (competitive recruitment) implemented to ensure the best recruitment rate and the achievement of the global targeted included population. (This change was not expected to impact the primary objective of the study since both Infanrix hexa primary vaccination schedules provide similar protection to the subjects. In addition, the statistical models include stratification by country.)
    26 Nov 2007
    Further updated study calendar required in order to ensure the planned sample size, and the labelling of the new lot of ProQuad which was sourced from commercial product.
    11 Mar 2008
    Changes implemented concerning polio testing (Vero cells replacing Hep-2 cells).

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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