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    Clinical Trial Results:
    A Phase III Randomized, Double-Blind, Active-Comparator Controlled Clinical Trial to Study the Safety, Tolerability, and Immunogenicity of V419 in Healthy Infants When Given at 2, 4, and 11 to 12 Months

    Summary
    EudraCT number
    2010-021491-28
    Trial protocol
    FI   SE   IT  
    Global end of trial date
    09 Oct 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    V419-008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01480258
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000394-PIP01-08
    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
    09 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the immunogenicity of PR5I when given at 2, 4, and 11 to 12 months of age.
    Protection of trial subjects
    This study was conducted in healthy infants. Subjects with known or suspected hypersensitivity to any of the vaccine components or history of a life-threatening reaction to a vaccine containing the same substances as the study vaccines or concomitant vaccines were excluded. Vaccines were administered by qualified study personnel. After each vaccination, subjects were kept under observation for 30 minutes to ensure their safety. Adequate treatment provisions, including epinephrine, were available for immediate use in case of anaphylactic or anaphylactoid reactions occurring during or immediately following vaccination.
    Background therapy
    -
    Evidence for comparator
    This study was conducted in healthy infants to assess the safety, tolerability, and immunogenicity of 3 doses of the hexavalent PR5I vaccine when given at 2, 4 and 11 to 12 months of age. INFANRIX™ hexa was chosen as the active comparator because it was the only hexavalent pediatric vaccine licensed in Europe at the time this study was conducted.
    Actual start date of recruitment
    23 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 132
    Country: Number of subjects enrolled
    Finland: 919
    Country: Number of subjects enrolled
    Italy: 264
    Worldwide total number of subjects
    1315
    EEA total number of subjects
    1315
    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)
    1315
    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 23 November 2011 (first subject entered) in 23 active centres in 3 European countries (Finland, Italy, and Sweden).

    Pre-assignment
    Screening details
    1325 subjects were screened. 1315 subjects were randomised. 1312 subjects were vaccinated. 1300 subjects received the 2 doses of the infant series (period 1). 1281 subjects received the toddler dose (period 2).

    Period 1
    Period 1 title
    Infant Series
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    The parent(s)/legal representative of the subject, the Investigator, laboratory testing personnel, and sponsor/sponsor representative personnel (except for an unblinded sponsor representative) were blinded to the vaccination group assigned. Because INFANRIX™ hexa is to be reconstituted and PR5I is ready to use, an unblinded individual at each study site who was otherwise not involved in the conduct of the study was required to prepare study vaccines to maintain the study blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PR5I
    Arm description
    # Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.
    Arm type
    Experimental

    Investigational medicinal product name
    PR5I vaccine
    Investigational medicinal product code
    DTaP-HB-IPV-Hib
    Other name
    V419
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 2 and 4 months of age.

    Investigational medicinal product name
    Prevenar 13™
    Investigational medicinal product code
    PCV-13
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 2 and 4 months of age.

    Investigational medicinal product name
    Rotarix™
    Investigational medicinal product code
    Rotarix
    Other name
    Pharmaceutical forms
    Oral liquid, Oral solution, Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    1.5 mL, oral route, one dose at 2 and 4 months of age.

    Investigational medicinal product name
    RotaTeq™
    Investigational medicinal product code
    RotaTeq
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    2 mL, oral route, one dose at 2, 4 and 5 months of age. Note: The 3rd dose of RotaTeq was to be given to subjects at least 4 weeks after the 2nd dose and no later than 26 weeks of age.

    Arm title
    INFANRIX hexa
    Arm description
    # Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.
    Arm type
    Active comparator

    Investigational medicinal product name
    INFANRIX™ hexa
    Investigational medicinal product code
    DTaP-HBV-IPV-Hib
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 2 and 4 months of age.

    Investigational medicinal product name
    Prevenar 13™
    Investigational medicinal product code
    PCV-13
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 2 and 4 months of age.

    Investigational medicinal product name
    Rotarix™
    Investigational medicinal product code
    Rotarix
    Other name
    Pharmaceutical forms
    Oral liquid, Oral solution, Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    1.5 mL, oral route, one dose at 2 and 4 months of age.

    Investigational medicinal product name
    RotaTeq™
    Investigational medicinal product code
    RotaTeq
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    2 mL, oral route, one dose at 2, 4 and 5 months of age. Note: The 3rd dose of RotaTeq was to be given to subjects at least 4 weeks after the 2nd dose and no later than 26 weeks of age.

    Number of subjects in period 1
    PR5I INFANRIX hexa
    Started
    656
    659
    Completed
    649
    651
    Not completed
    7
    8
         Protocol deviation
             2
             -
         Physician decision
             -
             1
         Not vaccinated
             3
             -
         Adverse event, non-fatal
             1
             1
         Consent withdrawn by subject
             1
             6
    Period 2
    Period 2 title
    Toddler Dose
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The parent(s)/legal representative of the subject, the Investigator, laboratory testing personnel, and sponsor/sponsor representative personnel (except for an unblinded sponsor representative) were blinded to the vaccination group assigned. Because INFANRIX™ hexa is to be reconstituted and PR5I is ready to use, an unblinded individual at each study site who was otherwise not involved in the conduct of the study was required to prepare study vaccines to maintain the study blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PR5I
    Arm description
    # Subjects (arm 1 - period 1) received at 11 to 12 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose.
    Arm type
    Experimental

    Investigational medicinal product name
    PR5I vaccine
    Investigational medicinal product code
    DTaP-HB-IPV-Hib
    Other name
    V419
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 11 to 12 months of age.

    Investigational medicinal product name
    Prevenar 13™
    Investigational medicinal product code
    PCV-13
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 11 to 12 months of age.

    Arm title
    INFANRIX hexa
    Arm description
    # Subjects (arm 2 - period 1) received at 12 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose.
    Arm type
    Active comparator

    Investigational medicinal product name
    INFANRIX™ hexa
    Investigational medicinal product code
    DTaP-HBV-IPV-Hib
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 11 to 12 months of age.

    Investigational medicinal product name
    Prevenar 13™
    Investigational medicinal product code
    PCV-13
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 11 to 12 months of age.

    Number of subjects in period 2 [1]
    PR5I INFANRIX hexa
    Started
    639
    642
    Completed
    639
    642
    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: # In the PR5I arm, 10 subjects discontinued the study between the Infant Series and Toddler Dose: 1 "physician decision" and 9 "consent withdrawn by subject". # In the INFANRIX hexa arm, 9 subjects discontinued the study between the Infant Series and Toddler Dose: 2 "lost to follow-up", 1 "protocol deviation", and 6 "consent withdrawn by subject".

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PR5I
    Reporting group description
    # Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.

    Reporting group title
    INFANRIX hexa
    Reporting group description
    # Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.

    Reporting group values
    PR5I INFANRIX hexa Total
    Number of subjects
    656 659 1315
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    656 659 1315
    Age continuous
    # Subjects vaccinated: age (in days) at date of vaccination dose 1. # Subjects randomised but not vaccinated: age (in days) calculated as date of visit 1 - date of birth.
    Units: days
        arithmetic mean (standard deviation)
    68 ± 10.3 68.1 ± 10.5 -
    Gender categorical
    Units: Subjects
        Female
    323 313 636
        Male
    333 346 679

    End points

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    End points reporting groups
    Reporting group title
    PR5I
    Reporting group description
    # Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.

    Reporting group title
    INFANRIX hexa
    Reporting group description
    # Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.
    Reporting group title
    PR5I
    Reporting group description
    # Subjects (arm 1 - period 1) received at 11 to 12 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose.

    Reporting group title
    INFANRIX hexa
    Reporting group description
    # Subjects (arm 2 - period 1) received at 12 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose.

    Subject analysis set title
    PR5I - Rotarix
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    # Subjects (arm 1 - period 1 - sub-group Rotarix) received 1 dose of PR5I (DTaP-HB-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) + 1 dose of Rotarix (in Italy & Sweden) by oral route at 2 and 4 months of age. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.

    Subject analysis set title
    INFANRIX hexa - Rotarix
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    # Subjects (arm 2 - period 1 - sub-group Rotarix) received 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) + 1 dose of Rotarix (in Italy & Sweden) by oral route at 2 and 4 months of age. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.

    Primary: Acceptability of antibody (Ab) response or seroresponse rates to all antigens contained in PR5I vaccine one month after the Toddler dose of PR5I (11 to 12 months of age)

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    End point title
    Acceptability of antibody (Ab) response or seroresponse rates to all antigens contained in PR5I vaccine one month after the Toddler dose of PR5I (11 to 12 months of age) [1]
    End point description
    % of subjects with an Ab titre ≥1.0 μg/mL for Haemophilus influenzae type b (Hib) (polyribosylribitol phosphate, PRP); ≥10 mIU/mL for Hepatitis B (HBsAg); ≥0.1 IU/mL for diphtheria & tetanus; ≥8 (1/dil) for IPV1, 2 & 3, and % of pertussis seroresponder subjects (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA), Fimbriae types 2 & 3 (FIM) & Pertactin (PRN)) 1 month Post-Toddler dose of PR5I. Seroresponse was defined: (1) If pre-Dose 1 Ab concentration (cc) was <LLOQ (lower limit of quantitation), postvaccination Ab cc was ≥LLOQ, (2) If pre-Dose 1 Ab cc was ≥LLOQ, postvaccination Ab cc was ≥prevaccination levels. Ab titres were measured by Radioimmunoassay (RIA) for PRP, enhanced Chemiluminescence assay (ECi) for HBsAg, Micrometabolic inhibition test (MIT) for diphtheria & poliovirus, and Enzyme-Linked Immunosorbent Assay (ELISA) for PT, FHA, FIM, PRN & tetanus. Analysis was done on the Per Protocol Revised Windows (PP-RW) population.
    End point type
    Primary
    End point timeframe
    1 month after the Toddler dose of PR5I (Post-Toddler Dose).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint includes only one arm. The immune response to PR5I vaccine was considered as acceptable if the lower bounds of the 2-sided 95% CI for the response rates were greater than the predetermined lower limits: 75% for PRP, PT, FHA, FIM & PRN, 80% for diphtheria, and 90% for HBsAg, tetanus and IPV1, 2 & 3. Acceptability criteria were met for all PR5I antigens. Note: (N=***) represents the number of assessed subjects.
    End point values
    PR5I
    Number of subjects analysed
    638
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PRP ≥1.0 µg/mL (N=454)
    89.87 (86.72 to 92.49)
        Anti-HBsAg ≥10 mIU/mL (N=377)
    98.14 (96.21 to 99.25)
        Anti-Diphtheria ≥0.1 IU/mL (N= 590)
    98.64 (97.35 to 99.41)
        Anti-Tetanus ≥0.1 IU/mL (N=589)
    99.83 (99.06 to 100)
        Anti-PT seroresponse (N=566)
    99.12 (97.95 to 99.71)
        Anti-FHA seroresponse (N=582)
    97.42 (95.78 to 98.55)
        Anti-FIM seroresponse (N=581)
    98.28 (96.86 to 99.17)
        Anti-PRN seroresponse (N=582)
    96.91 (95.16 to 98.16)
        Anti-IPV1 ≥8 (1/dil) (N=591)
    99.32 (98.28 to 99.82)
        Anti-IPV2 ≥8 (1/dil) (N=591)
    99.83 (99.06 to 100)
        Anti-IPV3 ≥8 (1/dil) (N=590)
    99.49 (98.52 to 99.9)
    No statistical analyses for this end point

    Secondary: Non-inferiority of antibody (Ab) response rate to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa

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    End point title
    Non-inferiority of antibody (Ab) response rate to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa
    End point description
    Percentage of subjects with an Ab titre ≥1.0 μg/mL for Hib (polyribosylribitol phosphate, PRP) measured by RIA 1 month Post-Dose 2 of PR5I or INFANRIX hexa. Analysis was done on the Per Protocol Revised Windows (PP-RW) population, i.e. PP population using a blood draw sample window of Days 28 to 51 Post-Dose 2 or Post-Toddler dose. Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
    End point type
    Secondary
    End point timeframe
    1 month after the 2nd dose of PR5I or INFANRIX hexa (Post-Dose 2).
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    649
    651
    Units: Percentage of subjects
    number (not applicable)
        Anti-PRP ≥1.0 µg/mL (N=609, 592)
    72.86
    26.66
    Statistical analysis title
    Non-inferiority for PRP
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=609, 592 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1300
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    46.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    41.05
         upper limit
    51.06
    Notes
    [2] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.

    Secondary: Superiority of antibody (Ab) response rates to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa

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    End point title
    Superiority of antibody (Ab) response rates to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa
    End point description
    Percentage of subjects with an Ab titre ≥1.0 μg/mL for Hib (polyribosylribitol phosphate, PRP) measured by RIA 1 month Post-Dose 2 of PR5I or INFANRIX hexa. Analysis was done on the PP-RW population. Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
    End point type
    Secondary
    End point timeframe
    1 month after the 2nd dose of PR5I or INFANRIX hexa (Post-Dose 2).
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    649
    651
    Units: Percentage of subjects
    number (not applicable)
        Anti-PRP ≥1.0 µg/mL (N=609, 592)
    72.86
    26.66
    Statistical analysis title
    Superiority for PRP
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than 0, it was concluded that PR5I group response rate was superior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=609, 592 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1300
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    46.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    41.05
         upper limit
    51.06
    Notes
    [3] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.

    Secondary: Non-inferiority of antibody (Ab) response rates to PR5I antigens one month after the Toddler dose of PR5I (11 to 12 months of age) as compared with INFANRIX hexa

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    End point title
    Non-inferiority of antibody (Ab) response rates to PR5I antigens one month after the Toddler dose of PR5I (11 to 12 months of age) as compared with INFANRIX hexa
    End point description
    % of subjects with an Ab titre ≥1.0 μg/mL for Hib (PRP); ≥10 mIU/mL for Hepatitis B (HBsAg); ≥0.1 IU/mL for diphtheria & tetanus; ≥8 (1/dil) for IPV1, 2 & 3, and % of pertussis seroresponder subjects (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA) & Pertactin (PRN)) 1 month Post-Toddler dose of PR5I. Seroresponse was defined: (1) If pre-Dose 1 Ab concentration (cc) was <LLOQ (lower limit of quantitation), postvaccination Ab cc was ≥LLOQ, (2) If pre-Dose 1 Ab cc was ≥LLOQ, postvaccination Ab cc was ≥prevaccination levels. Ab titres were measured by RIA for PRP, ECi for HBsAg, MIT for diphtheria & poliovirus, and ELISA for PT, FHA, PRN & tetanus. Analysis was done on the PP-RW population. Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
    End point type
    Secondary
    End point timeframe
    1 month after the Toddler dose of PR5I or INFANRIX hexa (Post-Toddler Dose).
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    638
    642
    Units: Percentage of subjects
    number (not applicable)
        Anti-PRP ≥1.0 µg/mL (N=454, 478)
    89.8
    91.06
        Anti-HBsAg ≥10 mIU/mL (N=377, 391)
    98.14
    98.73
        Anti-Diphtheria ≥0.1 IU/mL (N= 590, 578)
    98.62
    99.83
        Anti-Tetanus ≥0.1 IU/mL (N=589, 577)
    99.83
    100
        Anti-PT seroresponse (N=566, 561)
    99.11
    99.64
        Anti-FHA seroresponse (N=582, 571)
    97.4
    99.13
        Anti-PRN seroresponse (N=582, 572)
    96.86
    98.28
        Anti-IPV1 ≥8 (1/dil) (N=591, 580)
    99.32
    99.83
        Anti-IPV2 ≥8 (1/dil) (N=591, 579)
    99.83
    100
        Anti-IPV3 ≥8 (1/dil) (N=590, 579)
    99.49
    99.65
    Statistical analysis title
    Non-inferiority for PRP
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=454, 478 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.13
         upper limit
    2.52
    Notes
    [4] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for HBsAg
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in HBsAg response rate (based on Ab titre ≥10 mIU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=377, 391 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.66
         upper limit
    1.35
    Notes
    [5] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for Diphtheria
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in Diphtheria response rate (based on Ab titre ≥0.1 IU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=590, 578 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.54
         upper limit
    -0.22
    Notes
    [6] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for Tetanus
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in Tetanus response rate (based on Ab titre ≥0.1 IU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=589, 577 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.95
         upper limit
    0.5
    Notes
    [7] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for PT
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for PT was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=566, 561 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [8]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.75
         upper limit
    0.49
    Notes
    [8] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for FHA
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for FHA was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=582, 571 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -1.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    -0.26
    Notes
    [9] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for PRN
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for PRN was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=582, 572 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [10]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.42
         upper limit
    0.39
    Notes
    [10] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for IPV1
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in IPV1 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=591, 580 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [11]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.59
         upper limit
    0.34
    Notes
    [11] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for IPV2
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in IPV2 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=591, 579 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [12]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    0.49
    Notes
    [12] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.
    Statistical analysis title
    Non-inferiority for IPV3
    Statistical analysis description
    The estimate of the difference between PR5I & INFANRIX hexa groups in IPV3 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate. Analysis was done on the PP-RW population: N=590, 579 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1280
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [13]
    P-value
    < 0.001
    Method
    Miettinen & Nurminen with stratification
    Parameter type
    Difference in percentages of subjects
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.82
    Notes
    [13] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country.

    Secondary: Non-inferiority of Rotavirus response (geometric mean titer, GMT) one month after the 2nd dose of Rotarix (4 months of age) administered concomitantly with PR5I versus INFANRIX hexa

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    End point title
    Non-inferiority of Rotavirus response (geometric mean titer, GMT) one month after the 2nd dose of Rotarix (4 months of age) administered concomitantly with PR5I versus INFANRIX hexa
    End point description
    Antibody titres expressed in units/mL were measured for Rotavirus IgA by Enzyme Immunoassay (EIA), 1 month after the 2nd dose of Rotarix, administered concomitantly with PR5I or INFANRIX hexa (Post-Dose 2). Analysis was done on the PP-RW population, subgroups "PR5I - Rotarix" and "INFANRIX hexa - Rotarix". Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
    End point type
    Secondary
    End point timeframe
    1 month after the 2nd dose of Rotarix, administered concomitantly with PR5I or INFANRIX hexa (Post-Dose 2).
    End point values
    PR5I - Rotarix INFANRIX hexa - Rotarix
    Number of subjects analysed
    160
    171
    Units: Titre
    geometric mean (confidence interval 95%)
        Rotavirus IgA GMT (N=160, 171)
    96.41 (71.69 to 129.65)
    122.24 (92.48 to 161.58)
    Statistical analysis title
    Non-inferiority for Rotavirus IgA
    Statistical analysis description
    The estimate for anti-rotavirus IgA GMT ratio (PR5I group/INFANRIX hexa group) was calculated with its 1-sided P-value and 2-sided 95% CI. If the lower bound of the 95% CI for GMT ratio was greater than 0.50 (non-inferiority margin), it was concluded that the Rotarix antigen response in the PR5I group was not inferior to the Rotarix antigen response in the INFANRIX hexa group. Analysis was done on the PP-RW population, Subgroups Rotarix: N=160, 171 (PR5I group, INFANRIX hexa group).
    Comparison groups
    PR5I - Rotarix v INFANRIX hexa - Rotarix
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [14]
    P-value
    = 0.011
    Method
    ANCOVA
    Parameter type
    Geometric Mean Titer (GMT) ratio
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.2
    Notes
    [14] - Statistical analysis was based on an ANCOVA model.

    Secondary: Global safety from D1 to D15 after any vaccination

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    End point title
    Global safety from D1 to D15 after any vaccination
    End point description
    Injection-site and systemic adverse events (AEs) were reported daily on the Vaccination Report Card (VRC) by the parent(s) or legal representative from Day 1 (D1) to D15 after each vaccination. Solicited injection-site and systemic AEs were reported daily from D1 to D5 after each vaccination. AEs at injection sites were always considered as vaccine-related (V-related) (Injection-Site Reactions (ISRs)). The investigator had to assess whether systemic AEs were related or not to the vaccine. All AEs (related and unrelated) are displayed here. Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D15 after any vaccination.
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    653
    659
    Units: Percentage of subjects
    number (not applicable)
        At least 1 ISR or systemic AE (D1-D15)
    99.5
    99.2
        At least 1 ISR or V-related systemic AE (D1-D15)
    99.5
    98.8
        At least 1 ISR (D1-D15)
    90.8
    88.2
        At least 1 solicited ISR (D1-D5)
    90.4
    87.9
        At least 1 systemic AE (D1-D15)
    99.1
    98.9
        At least 1 V-related systemic AE (D1-D15)
    99.1
    98.3
        At least 1 solicited systemic AE (D1-D5)
    99.1
    98.3
        At least 1 V-related solicited systemic AE (D1-D5)
    99.1
    98.2
    Statistical analysis title
    ISRs or systemic AEs
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    1.4
    Statistical analysis title
    ISRs or vaccine-related systemic AEs
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    2
    Statistical analysis title
    At least 1 ISR
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    6
    Statistical analysis title
    At least 1 solicited ISR
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    5.9
    Statistical analysis title
    At least 1 systemic AE
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    1.4
    Statistical analysis title
    At least 1 vaccine-related systemic AE
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    2.2
    Statistical analysis title
    At least 1 solicited systemic AE
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    2.2
    Statistical analysis title
    At least 1 vaccine-related solicited systemic AE
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    2.3

    Secondary: Proportion of subjects reporting solicited ISRs from D1 to D5 after any vaccination

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    End point title
    Proportion of subjects reporting solicited ISRs from D1 to D5 after any vaccination
    End point description
    Adverse events at injection sites were always considered as related to vaccine (Injection-Site Reactions (ISRs)). Solicited ISRs were defined as injection-site erythema, injection-site pain, and injection-site swelling occurring from Day 1 (D1) to D5 after vaccination. Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D5 after any vaccination.
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    653
    659
    Units: Percentage of subjects
    number (not applicable)
        Injection-site erythema
    68.6
    60.4
        Injection-site pain
    73.4
    70
        Injection-site swelling
    56.8
    49.3
    Statistical analysis title
    Injection-site erythema
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    8.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3
         upper limit
    13.3
    Notes
    [15] - Injection-site erythema: the 95% CI of the difference between the PR5I and INFANRIX™ hexa groups excluded 0 and was therefore statistically significant. The difference was not considered to be clinically significant as none of these events were considered serious or led to study discontinuation, and the majority were mild or moderate in intensity.
    Statistical analysis title
    Injection-site pain
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    8.3
    Statistical analysis title
    Injection-site swelling
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    12.9
    Notes
    [16] - Injection-site swelling: the 95% CI of the difference between the PR5I and INFANRIX™ hexa groups excluded 0 and was therefore statistically significant. The difference was not considered to be clinically significant as none of these events were considered serious or led to study discontinuation, and the majority were mild or moderate in intensity.

    Secondary: Proportion of subjects reporting unsolicited ISRs from D1 to D15 after any vaccination

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    End point title
    Proportion of subjects reporting unsolicited ISRs from D1 to D15 after any vaccination
    End point description
    Adverse events at injection sites were always considered as related to vaccine (Injection-Site Reactions (ISRs)). Unsolicited ISRs occurring from Day 1 (D1) to D15 after any vaccination were reported daily on the VRC by the parent(s) or legal representative. Unsolicited ISRs with incidence ≥1% are reported below. Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D15 after any vaccination.
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    653
    659
    Units: Percentage of subjects
    number (not applicable)
        Injection-site bruising
    0.9
    2
        Injection-site haemorrhage
    1.8
    1.8
        Injection-site induration
    15.8
    13.2
        Injection-site nodule
    1.1
    0.8
        Injection-site warmth
    2.3
    1.2
    Statistical analysis title
    Injection-site bruising
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    0.3
    Statistical analysis title
    Injection-site haemorrhage
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    1.6
    Statistical analysis title
    Injection-site induration
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    6.4
    Statistical analysis title
    Injection-site nodule
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    1.5
    Statistical analysis title
    Injection-site warmth
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out. Analysis was done on the All Subjects as Treated (ASaT) population.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    2.7

    Secondary: Proportion of subjects reporting solicited systemic adverse events (AEs) from D1 to D5 after any vaccination

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    End point title
    Proportion of subjects reporting solicited systemic adverse events (AEs) from D1 to D5 after any vaccination
    End point description
    Solicited systemic AEs were defined as crying, decreased appetite, irritability, pyrexia (rectal temperature ≥38.0°C), somnolence, and vomiting occurring from Day 1 (D1) to D5 after vaccination. The investigator had to assess whether these systemic AEs were related or not to the vaccines. All (related and unrelated) are displayed here. Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
    End point type
    Secondary
    End point timeframe
    From Day 1 (D1) to D5 after any vaccination.
    End point values
    PR5I INFANRIX hexa
    Number of subjects analysed
    653
    659
    Units: Percentage of subjects
    number (not applicable)
        Crying
    89.3
    87.1
        Decreased appetite
    65.8
    62.2
        Irritability
    91.6
    89.4
        Pyrexia
    73.8
    67.4
        Somnolence
    86.1
    80.3
        Vomiting
    32.8
    31
    Statistical analysis title
    Crying
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    5.7
    Statistical analysis title
    Decreased appetite
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    8.8
    Statistical analysis title
    Irritability
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    5.4
    Statistical analysis title
    Pyrexia
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    11.3
    Notes
    [17] - Pyrexia: the 95% CI of the difference between PR5I and INFANRIX™ hexa groups excluded 0 and was statistically significant. The difference was not considered to be clinically significant as the majority were of mild to moderate intensity and did not result in any study discontinuations.
    Statistical analysis title
    Somnolence
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.7
         upper limit
    9.8
    Notes
    [18] - The 95% CI of the difference between PR5I and INFANRIX™ hexa groups excluded 0 and was statistically significant. The difference was not considered to be clinically significant as the majority were of mild to moderate intensity and did not result in any study discontinuations.
    Statistical analysis title
    Vomiting
    Statistical analysis description
    The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
    Comparison groups
    PR5I v INFANRIX hexa
    Number of subjects included in analysis
    1312
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    6.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Unsolicited non-serious and serious adverse events (AEs) were collected from D1 to D15 after each hexavalent vaccination. Vaccine-related serious AEs and deaths were collected for the duration of the study.
    Adverse event reporting additional description
    Analysis of AEs was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up. Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥2.5% are presented hereafter.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    PR5I
    Reporting group description
    # Subjects received 1 dose of PR5I (DTaP-HB-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) at 2 and 4 months of age. # Subjects also received either 1 dose of Rotarix at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq at 2, 4, and 5 months of age (in Finland), both by oral route. # Respectively, 342 (52.4%) subjects reported at least 1 unsolicited non-serious systemic AE, and 172 (26.3%) subjects reported at least 1 vaccine-related unsolicited non-serious systemic AE within 15 days after any vaccination.

    Reporting group title
    INFANRIX hexa
    Reporting group description
    # Subjects received 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) at 2 and 4 months of age. # Subjects also received either 1 dose of Rotarix at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq at 2, 4, and 5 months of age (in Finland), both by oral route. # Respectively, 319 (48.4%) subjects reported at least 1 unsolicited non-serious systemic AE, and 149 (22.6%) subjects reported at least 1 vaccine-related unsolicited non-serious systemic AE within 15 days after any vaccination.

    Serious adverse events
    PR5I INFANRIX hexa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 653 (0.77%)
    7 / 659 (1.06%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Heart disease congenital
         subjects affected / exposed
    1 / 653 (0.15%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitello-intestinal duct remnant
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 653 (0.15%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection-site abscess
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 653 (0.15%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 653 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 653 (0.15%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 653 (0.15%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2.5%
    Non-serious adverse events
    PR5I INFANRIX hexa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 653 (52.37%)
    319 / 659 (48.41%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 653 (4.59%)
    24 / 659 (3.64%)
         occurrences all number
    30
    24
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    19 / 653 (2.91%)
    16 / 659 (2.43%)
         occurrences all number
    19
    16
    Irritability
         subjects affected / exposed
    14 / 653 (2.14%)
    20 / 659 (3.03%)
         occurrences all number
    14
    20
    Pyrexia
         subjects affected / exposed
    32 / 653 (4.90%)
    28 / 659 (4.25%)
         occurrences all number
    32
    28
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 653 (3.06%)
    10 / 659 (1.52%)
         occurrences all number
    20
    10
    Constipation
         subjects affected / exposed
    22 / 653 (3.37%)
    16 / 659 (2.43%)
         occurrences all number
    22
    16
    Diarrhoea
         subjects affected / exposed
    76 / 653 (11.64%)
    70 / 659 (10.62%)
         occurrences all number
    76
    70
    Flatulence
         subjects affected / exposed
    29 / 653 (4.44%)
    25 / 659 (3.79%)
         occurrences all number
    29
    25
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    35 / 653 (5.36%)
    36 / 659 (5.46%)
         occurrences all number
    35
    36
    Otitis media
         subjects affected / exposed
    24 / 653 (3.68%)
    15 / 659 (2.28%)
         occurrences all number
    24
    15
    Rhinitis
         subjects affected / exposed
    34 / 653 (5.21%)
    41 / 659 (6.22%)
         occurrences all number
    34
    41
    Upper respiratory tract infection
         subjects affected / exposed
    42 / 653 (6.43%)
    44 / 659 (6.68%)
         occurrences all number
    42
    44

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2011
    Protocol Amendment submitted to the regulatory authority in Finland only. # This amendment was in response to the change in Rotarix™ availability in some EU countries. This amendment allowed for subsets of subjects to receive 1 of 2 available rotavirus vaccines, either Rotarix™ or RotaTeq™. The specific primary changes were as follows: 1. Designation that a subset of subjects were to receive Rotarix™ concomitantly with PR5I or INFANRIX™ hexa, while another subset of subjects were to receive RotaTeq™ concomitantly with PR5I or INFANRIX™ hexa. Vaccine designation was to be site specific. 2. Revision of the power statement for the secondary hypothesis for Rotarix™ immunogenicity since Rotarix™ was to be administered to a subset of subjects, and not the entire study population as the original protocol indicated. 3. Indication that RotaTeq™ was to be administered at 2, 4, and 5 months of age. This dosing schedule was consistent with the product label. # In addition, the text in all relevant sections was updated to reflect a change in timing of when non-study vaccines could be received during the study; non-study licensed pediatric vaccines were not to be administered within 30 days before or after any dose of study vaccine, except for inactivated influenza vaccine, which was not to be administered within 14 days before or after any dose of study vaccine.
    13 May 2011
    Protocol Amendment submitted to the regulatory authority in Finland, Italy and Sweden. This amendment stated that RotaTeq™, a vaccine administered concomitantly with PR5I that was not evaluated for immunogenicity, was to be supplied centrally by the Sponsor Representative (it was originally planned to be sourced locally by study sites, but local sourcing was not operationally feasible). This was also to have the additional benefit of greater control over vaccine accountability and cold-chain.
    20 Jan 2012
    Country-specific protocol amendment for Finland. This amendment allowed the 1st dose of RotaTeq™ to be given in Finland prior to Visit 1 outside the study, as RotaTeq™ is recommended to be given as early as 6 weeks of age in the Finnish pediatric vaccination schedule. This amendment was to allow for flexibility for study entry within the full prespecified age range (46 to 89 days), even if a subject had received RotaTeq™ through the Finnish national vaccine program.
    25 Apr 2013
    Country-specific protocol amendment for Finland. # Section 2.7.1, Immunogenicity of PR5I: - Addition of a new primary statistical analysis method for all GMT analyses (i.e., MI ANCOVA) to account for missing baseline titers due to limited serum volumes obtained from 2-month old infant subjects at study entry. - Addition of a second PP population (referred to as PP-RW) in addition to the existing PP population (referred to as PP-OW) to account for subjects who received study vaccinations and/or blood draws outside of narrow protocol-defined visit windows. The success of the hypothesis test will be based on the results from the PP-RW population. PP-RW is defined as the PP population using a blood draw sample window of Days 28 to 51 following Dose 2 or the Toddler dose. PP-OW is defined as the PP population using a blood draw sample window of Days 28 to 44 following Dose 2 or the Toddler dose. The change to the SAP was introduced into all 4 Phase III studies (V419-005, V419-006, V419-007, and V419-008). # Section 3.5, SAP: - Addition of 2 sensitivity analyses: (1) analysis of GMT endpoints with no baseline adjustment and (2) analysis of GMT endpoints based on data from subjects with both baseline and postvaccination titers to support the ANCOVA MI primary analysis for GMT endpoints.
    26 Apr 2013
    Protocol Amendment applicable only to Italy and Sweden. Same as Protocol Amendment 4 (issued on 25 April 2013) which was only applicable to Finland.

    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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