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    Clinical Trial Results:
    A phase IV, randomised, open-label, controlled study to assess the immunogenicity and safety of the diphtheria, tetanus, pertussis and inactivated poliovirus (DPT-IPV) vaccine Squarekids when co-administered with GSK Biologicals' oral live attenuated human rotavirus (HRV) liquid vaccine Rotarix in healthy Japanese infants aged 6 - 12 weeks at the time of the first dose of HRV vaccination.

    Summary
    EudraCT number
    		 2014-005282-78
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 May 2018
    First version publication date
    31 May 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    114720
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02907216
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, 1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)2089 904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, (44)2089 904466, GSKClinicalSupportHD@gsk.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
    22 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the immunogenicity to the antigens contained in DPT-IPV vaccine is not impaired by the co-administration with GSK Biologicals' liquid HRV vaccine.
    Protection of trial subjects
    All vaccinated subjects were observed closely for at least 30 minutes following the administration of the vaccines, with appropriate medical treatment readily available in case of anaphylaxis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 2016
    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
    Japan: 292
    Worldwide total number of subjects
    292
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    292
    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
    		 -

    Pre-assignment
    Screening details
    		 146 subjects i.e., the first 73 subjects enrolled into each of the 2 study groups were allocated to the HRV immunogenicity sub-cohort to evaluate immunogenicity of the liquid HRV vaccine.

    Pre-assignment period milestones
    Number of subjects started
    		 292
    Number of subjects completed
    		 292

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Co-administration Group
    Arm description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Two doses administered orally

    Investigational medicinal product name
    Squarekids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Three doses administered subcutaneously in the upper arm or thigh

    Arm title
    		 Staggered Group
    Arm description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4.5, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3.5 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Squarekids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Three doses administered subcutaneously in the upper arm or thigh

    Investigational medicinal product name
    Rotarix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Two doses administered orally

    Number of subjects in period 1
    		Co-administration Group Staggered Group
    Started
    147
    145
    Completed
    146
    144
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    -
         No benefit to be obtained by continuing
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Co-administration Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Reporting group title
    Staggered Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4.5, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3.5 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Reporting group values
    		 Co-administration Group Staggered Group Total
    Number of subjects
    		 147 145
    Age categorical
    Units: Subjects
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 9.5 ( 1.1 ) 9.4 ( 1.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 72 65 137
        Male
    		 75 80 155
    Race/Ethnicity, Customized
    Units: Subjects
        Asian - Japanese Heritage
    		 147 145 292
    Age Continuous - Weeks of age at Dose 2 of HRV
    Units: Weeks
        arithmetic mean (standard deviation)
    		 14 ( 1.1 ) 15.5 ( 1.3 ) -
    Age Continuous - Weeks of age at Dose 1 of DPT-IPV
    Units: Weeks
        arithmetic mean (standard deviation)
    		 14 ( 1.1 ) 13.9 ( 1 ) -
    Age Continuous - Weeks of age at Dose 2 of DPT-IPV
    Units: Weeks
        arithmetic mean (standard deviation)
    		 18.5 ( 1.2 ) 20 ( 1.4 ) -
    Age Continuous - Weeks of age at Dose 3 of DPT-IPV
    Units: Weeks
        arithmetic mean (standard deviation)
    		 23.7 ( 1.8 ) 25 ( 1.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Co-administration Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Reporting group title
    Staggered Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the Squarekids vaccine (diphtheria, tetanus, pertussis and inactivated poliovirus [DPT-IPV] vaccine) according to a 3, 4.5, 6 month schedule and the liquid Rotarix vaccine (oral live attenuated human rotavirus [HRV] vaccine) according to a 2, 3.5 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Primary: Percentage of subjects with anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibody concentrations greater than or equal to (≥) the cut-off value

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    End point title
    		 Percentage of subjects with anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibody concentrations greater than or equal to (≥) the cut-off value
    End point description
    Percentage of subjects with anti-D and anti-T antibody concentrations ≥ 0.1 international units per milliliter (IU/mL).
    End point type
    Primary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    141
    138
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-D antibody ≥ 0.1 IU/mL (N=141; 137)
    100 (97.4 to 100)
    100 (97.3 to 100)
        Anti-T antibody ≥ 0.1 IU/mL (N=141; 138)
    98.6 (95 to 99.8)
    99.3 (96 to 100)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-D antibody concentration ≥ 0.1 IU/mL.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference-Seroprotective concentration
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 2.74
    Notes
    [1] - Criteria for non-inferiority: The Lower Limit (LL) of the standardised asymptotic 95% Confidence Interval (CI) on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective concentrations ≥ 0.1 IU/mL for anti-D antibodies should be ≥ -10%.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-T antibody concentration ≥ 0.1 IU/mL.
    Comparison groups
    Co-administration Group v Staggered Group
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference-Seroprotective concentration
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.39
         upper limit
    		 2.71
    Notes
    [2] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective concentrations ≥ 0.1 IU/mL for anti-T antibodies should be ≥ -10%.

    Primary: Percentage of subjects with anti-pertussis toxoid (anti-PT) and anti-filamentous haemagglutinin (anti-FHA) antibody concentrations ≥ the cut-off value

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    End point title
    		 Percentage of subjects with anti-pertussis toxoid (anti-PT) and anti-filamentous haemagglutinin (anti-FHA) antibody concentrations ≥ the cut-off value
    End point description
    Percentage of subjects with anti-PT and anti-FHA antibody concentrations ≥ 10 IU/mL.
    End point type
    Primary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    141
    138
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-PT antibody ≥ 10 IU/mL
    95.7 (91 to 98.4)
    92.8 (87.1 to 96.5)
        Anti-FHA antibody ≥ 10 IU/mL
    100 (97.4 to 100)
    100 (97.4 to 100)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-FHA antibody concentration ≥ 10 IU/mL.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference-Seroprotective concentration
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 2.72
    Notes
    [3] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective concentrations ≥ 10 IU/mL for anti-FHA antibodies should be ≥ -10%.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-PT antibody concentration ≥ 10 IU/mL.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference-Seroprotective concentration
    Point estimate
    2.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 9.12
    Notes
    [4] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective concentrations ≥ 10 IU/mL for anti-PT antibodies should be ≥ -10%.

    Primary: Percentage of subjects with anti-poliovirus serotypes 1, 2 and 3 (anti-polio 1, 2 and 3) antibody titers ≥ the cut-off value

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    End point title
    		 Percentage of subjects with anti-poliovirus serotypes 1, 2 and 3 (anti-polio 1, 2 and 3) antibody titers ≥ the cut-off value
    End point description
    Percentage of subjects with anti-polio 1, 2 and 3 antibody titers ≥ 8 estimated doses 50% (ED50).
    End point type
    Primary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    140
    137
    Units: Percentage of subjects
    number (confidence interval 95%)
        Anti-Polio 1 antibody ≥ 8 ED50 (N=140; 137)
    100 (97.4 to 100)
    100 (97.3 to 100)
        Anti-Polio 2 antibody ≥ 8 ED50 (N=128; 127)
    100 (97.2 to 100)
    100 (97.1 to 100)
        Anti-Polio 3 antibody ≥ 8 ED50 (N=132; 123)
    100 (97.2 to 100)
    99.2 (95.6 to 100)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-polio 1 seroprotective titres ≥ 8 ED50.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in seroprotective titer
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.68
         upper limit
    		 2.74
    Notes
    [5] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective titers ≥ 8 ED50 for anti-polio 1 antibodies should be ≥ -10%.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-polio 2 seroprotective titres ≥ 8 ED50.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in seroprotective titer
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.92
         upper limit
    		 2.95
    Notes
    [6] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective titers ≥ 8 ED50 for anti-polio 2 antibodies should be ≥ -10%.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Difference between Co-administration Group minus Staggered Group in terms of percentage of subjects with anti-polio 3 seroprotective titres ≥ 8 ED50.
    Comparison groups
    Staggered Group v Co-administration Group
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in seroprotective titer
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 4.47
    Notes
    [7] - Criteria for non-inferiority: The LL of the standardised asymptotic 95% CI on the difference (Co-administration Group minus Staggered Group) in the percentage of subjects with seroprotective titers ≥ 8 ED50 for anti-polio 3 antibodies should be ≥ -10%.

    Secondary: Percentage of seropositive subjects for serum anti-rotavirus (anti-RV) immunoglobulin A (IgA) antibodies

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    End point title
    		 Percentage of seropositive subjects for serum anti-rotavirus (anti-RV) immunoglobulin A (IgA) antibodies
    End point description
    A seropositive subject for serum anti-RV IgA antibodies was defined as a subject with anti-RV IgA antibody concentration ≥ the seropositivity cut-off value of 20 units per milliliter (U/mL).
    End point type
    Secondary
    End point timeframe
    One month post second dose of liquid HRV vaccine (At Month 2 for the Co-administration Group and at Month 2.5 for the Staggered Group)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    69
    67
    Units: Percentage of subjects
    number (confidence interval 95%)
        Percentage of subjects
    92.8 (83.9 to 97.6)
    92.5 (83.4 to 97.5)
    No statistical analyses for this end point

    Secondary: Serum anti-RV IgA antibody concentration to evaluate immunogenicity

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    End point title
    		 Serum anti-RV IgA antibody concentration to evaluate immunogenicity
    End point description
    Concentration of serum anti-RV IgA antibody was assessed by Enzyme Linked Immunosorbent Assay (ELISA) and expressed as geometric mean concentration (GMC) in U/mL. The assay cut-off was 20 U/mL.
    End point type
    Secondary
    End point timeframe
    One month post second dose of liquid HRV vaccine (At Month 2 for the Co-administration Group and at Month 2.5 for the Staggered Group)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    69
    67
    Units: U/mL
    geometric mean (confidence interval 95%)
        U/mL
    350.1 (223.3 to 548.8)
    362.5 (251 to 523.5)
    No statistical analyses for this end point

    Secondary: Anti-D and anti-T antibody concentrations to evaluate immunogenicity

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    End point title
    		 Anti-D and anti-T antibody concentrations to evaluate immunogenicity
    End point description
    Concentrations of anti-D and anti-T antibodies were assessed by ELISA, presented as GMCs and expressed in IU/mL. The assay cut-off for anti-D and anti-T antibody concentrations was 0.1 IU/mL.
    End point type
    Secondary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    141
    138
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D antibody (N=141; 137)
    5.4 (4.9 to 6)
    6 (5.5 to 6.6)
        Anti-T antibody (N=141; 138)
    1.6 (1.3 to 2)
    2 (1.7 to 2.4)
    No statistical analyses for this end point

    Secondary: Anti-polio 1, 2 and 3 antibodies titers to evaluate immunogenicity

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    End point title
    		 Anti-polio 1, 2 and 3 antibodies titers to evaluate immunogenicity
    End point description
    Titers of anti-polio 1, 2 and 3 were assessed by Neutralisation Assay (NEU) and presented as Geometric Mean Titers (GMTs). The assay cut-off was 8 ED50.
    End point type
    Secondary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    140
    137
    Units: Titer
    geometric mean (confidence interval 95%)
        Anti-Polio 1 antibody (N=140; 137)
    404.7 (341.4 to 479.8)
    427.9 (359.3 to 509.6)
        Anti-Polio 2 antibody (N=128; 127)
    371 (307 to 448.5)
    470.6 (388.3 to 570.3)
        Anti-Polio 3 antibody (N=132; 123)
    436.3 (365.6 to 520.7)
    409.8 (330.8 to 507.5)
    No statistical analyses for this end point

    Secondary: Anti-PT and anti-FHA antibody concentrations to evaluate immunogenicity

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    End point title
    		 Anti-PT and anti-FHA antibody concentrations to evaluate immunogenicity
    End point description
    Concentrations of anti-PT and anti-FHA antibodies were assessed by ELISA, presented as GMCs and expressed in IU/mL. The assay cut-offs for anti-PT and anti-FHA antibody concentrations were 2.693 IU/mL and 2.046 IU/mL respectively.
    End point type
    Secondary
    End point timeframe
    One month post third dose of DTP-IPV vaccine (At Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    141
    138
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-PT antibody
    31.5 (28.4 to 34.9)
    31.5 (27.9 to 35.6)
        Anti-FHA antibody
    83.7 (74.8 to 93.6)
    97.2 (86.7 to 109)
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general adverse events (AEs) after each dose of liquid HRV vaccine

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    End point title
    		 Number of subjects with any solicited general adverse events (AEs) after each dose of liquid HRV vaccine
    End point description
    Assessed solicited general AEs were fever (defined as axillary temperature ≥ 37.5 degrees Celsius [°C]), irritability/fussiness, diarrhoea (defined as passage of three or more looser than normal stools within a day), vomiting (defined as one or more episodes of forceful emptying of partially digested stomach contents ≥ 1 hour after feeding within a day), loss of appetite and cough/runny nose. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 8-day (Days 0-7) follow-up period after each dose of liquid HRV vaccine
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    145
    Units: Participants
        Any Fever, Dose 1
    31
    32
        Any Irritability / Fussiness, Dose 1
    66
    62
        Any Diarrhoea, Dose 1
    30
    32
        Any Vomiting, Dose 1
    19
    19
        Any Loss of Appetite, Dose 1
    18
    10
        Any Cough, Dose 1
    41
    40
        Any Fever, Dose 2
    31
    15
        Any Irritability / Fussiness, Dose 2
    61
    41
        Any Diarrhoea, Dose 2
    22
    26
        Any Vomiting, Dose 2
    14
    18
        Any Loss of Appetite, Dose 2
    17
    9
        Any Cough, Dose 2
    53
    45
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited local AEs after first dose of DTP-IPV vaccine

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    End point title
    		 Number of subjects with any solicited local AEs after first dose of DTP-IPV vaccine
    End point description
    Assessed solicited local AEs were pain, redness and swelling at injection site. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 8-day (Days 0-7) follow-up period after first dose of DTP-IPV vaccine
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    144
    Units: Participants
        Any Pain
    32
    24
        Any Redness (mm)
    85
    84
        Any Swelling (mm)
    50
    44
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general AEs after first dose of DTP-IPV vaccine

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    End point title
    		 Number of subjects with any solicited general AEs after first dose of DTP-IPV vaccine
    End point description
    Assessed solicited general AEs were drowsiness, fever (defined as axillary temperature ≥ 37.5 °C), irritability/fussiness and loss of appetite. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 8-day (Days 0-7) follow-up period after first dose of DTP-IPV vaccine
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    144
    Units: Participants
        Any Drowiness
    37
    39
        Any Fever
    31
    32
        Any Irritability / Fussiness
    61
    59
        Any Loss of Appetite
    17
    18
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited AEs after each dose of liquid HRV vaccine

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    End point title
    		 Number of subjects with any unsolicited AEs after each dose of liquid HRV vaccine
    End point description
    Unsolicited AEs were defined as any AE reported in addition to those solicited during the clinical study and any solicited AE with onset outside the specified period of follow-up for solicited AEs. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 0-30) follow-up period after each dose of liquid HRV vaccine
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    145
    Units: Participants
        Participants
    88
    81
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited AE after first dose of DTP-IPV vaccine

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    End point title
    		 Number of subjects with any unsolicited AE after first dose of DTP-IPV vaccine
    End point description
    Unsolicited AEs were defined as any AE reported in addition to those solicited during the clinical study and any solicited AE with onset outside the specified period of follow-up for solicited AEs. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 0-30) follow-up period after first dose of DTP-IPV vaccine
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    144
    Units: Participants
        Participants
    65
    59
    No statistical analyses for this end point

    Secondary: Number of subjects with any serious adverse events (SAEs)

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    End point title
    		 Number of subjects with any serious adverse events (SAEs)
    End point description
    Assessed SAEs included any untoward medical occurrence that resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (from Day 0 to Month 5)
    End point values
    		 Co-administration Group Staggered Group
    Number of subjects analysed
    147
    145
    Units: Participants
        Participants
    4
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local & general AE: 8-day post-vaccination after DTP-IPV 1st dose; solicited general AE: 8-day post-vaccination after HRV each dose. Unsolicited AE: 31-day post-vaccination after DTP-IPV 1st dose & HRV each dose. SAE: entire study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Co-administration Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the DPT-IPV vaccine according to a 3, 4, 6 month schedule and the liquid HRV vaccine according to a 2, 3 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Reporting group title
    Staggered Group
    Reporting group description
    		 Subjects aged 6 to 12 weeks who received the DPT-IPV vaccine according to a 3, 4.5, 6 month schedule and the liquid HRV vaccine according to a 2, 3.5 month schedule. The HRV vaccine was administered orally while the DTP-IPV vaccine was administered subcutaneously in the upper arm or upper thigh.

    Serious adverse events
    		 Co-administration Group Staggered Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 147 (2.72%)
    5 / 145 (3.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Fibrinous bronchitis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         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 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Co-administration Group Staggered Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 147 (95.92%)
    143 / 145 (98.62%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    85 / 147 (57.82%)
    84 / 145 (57.93%)
         occurrences all number
    85
    84
    Injection site induration
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Injection site pain
         subjects affected / exposed
    32 / 147 (21.77%)
    24 / 145 (16.55%)
         occurrences all number
    32
    24
    Injection site swelling
         subjects affected / exposed
    50 / 147 (34.01%)
    44 / 145 (30.34%)
         occurrences all number
    50
    44
    Irritability postvaccinal
         subjects affected / exposed
    93 / 147 (63.27%)
    99 / 145 (68.28%)
         occurrences all number
    127
    162
    Peripheral swelling
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 145 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    54 / 147 (36.73%)
    56 / 145 (38.62%)
         occurrences all number
    62
    80
    Swelling
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Vaccination site induration
         subjects affected / exposed
    2 / 147 (1.36%)
    4 / 145 (2.76%)
         occurrences all number
    2
    4
    Vaccination site swelling
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    69 / 147 (46.94%)
    72 / 145 (49.66%)
         occurrences all number
    95
    85
    Nasal congestion
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    7 / 147 (4.76%)
    6 / 145 (4.14%)
         occurrences all number
    7
    6
    Upper respiratory tract inflammation
         subjects affected / exposed
    18 / 147 (12.24%)
    20 / 145 (13.79%)
         occurrences all number
    21
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Superficial injury of eye
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    37 / 147 (25.17%)
    39 / 145 (26.90%)
         occurrences all number
    37
    39
    Ear and labyrinth disorders
    Excessive cerumen production
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Otorrhoea
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eczema eyelids
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Eye discharge
         subjects affected / exposed
    3 / 147 (2.04%)
    1 / 145 (0.69%)
         occurrences all number
    3
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 147 (1.36%)
    3 / 145 (2.07%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    41 / 147 (27.89%)
    50 / 145 (34.48%)
         occurrences all number
    52
    61
    Haematochezia
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Mucous stools
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    24 / 147 (16.33%)
    30 / 145 (20.69%)
         occurrences all number
    33
    38
    Skin and subcutaneous tissue disorders
    Asteatosis
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 145 (1.38%)
         occurrences all number
    0
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 145 (0.69%)
         occurrences all number
    2
    1
    Dry skin
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 145 (0.00%)
         occurrences all number
    2
    0
    Eczema
         subjects affected / exposed
    9 / 147 (6.12%)
    10 / 145 (6.90%)
         occurrences all number
    9
    10
    Eczema asteatotic
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 145 (0.00%)
         occurrences all number
    2
    0
    Eczema infantile
         subjects affected / exposed
    13 / 147 (8.84%)
    11 / 145 (7.59%)
         occurrences all number
    14
    11
    Erythema
         subjects affected / exposed
    3 / 147 (2.04%)
    1 / 145 (0.69%)
         occurrences all number
    4
    1
    Erythema multiforme
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Leukoderma
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 145 (0.00%)
         occurrences all number
    2
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 145 (1.38%)
         occurrences all number
    1
    2
    Skin induration
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 145 (1.38%)
         occurrences all number
    1
    2
    Bronchitis
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 145 (0.69%)
         occurrences all number
    2
    1
    Candida infection
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 145 (1.38%)
         occurrences all number
    0
    2
    Conjunctivitis
         subjects affected / exposed
    3 / 147 (2.04%)
    4 / 145 (2.76%)
         occurrences all number
    3
    4
    Exanthema subitum
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 145 (0.69%)
         occurrences all number
    2
    1
    Influenza
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 145 (1.38%)
         occurrences all number
    0
    2
    Metapneumovirus infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    22 / 147 (14.97%)
    33 / 145 (22.76%)
         occurrences all number
    26
    37
    Otitis media
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 145 (0.69%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 145 (0.69%)
         occurrences all number
    2
    2
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    6 / 147 (4.08%)
    5 / 145 (3.45%)
         occurrences all number
    6
    5
    Rhinitis
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 145 (0.69%)
         occurrences all number
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 145 (0.69%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 147 (2.72%)
    2 / 145 (1.38%)
         occurrences all number
    6
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    27 / 147 (18.37%)
    31 / 145 (21.38%)
         occurrences all number
    35
    37
    Lactose intolerance
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 145 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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