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    Clinical Trial Results:
    A Phase 2b, Open Label, Randomized, Parallel-Group, Multi-Center Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered with or without Routine Infant Vaccinations to Healthy Infants According to Different Immunization Schedules

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2008-001592-30
    Trial protocol
    		 GB   DE   ES   IT   BE   CZ  
    Global end of trial date
    02 Jul 2010

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    V72P12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00721396
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics S.r.l.
    Sponsor organisation address
    Via Fiorentina, 1, Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000139-PIP01-07
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary :1.To demonstrate a sufficient immune response of rMenB+OMV NZ, when given concomitantly with routine infant vaccines to healthy infants at 2, 4 and 6 and 2, 3 and 4 months of age, as measured by percentage of subjects with serum bactericidal activity (SBA) titer ≥1:5, at 1 month after the third vaccination Secondary :To demonstrate that immunogenicity of routine infant vaccines, when given concomitantly with rMenB+OMV NZ to healthy infants at 2, 3 and 4 months of age, was non-inferior to that of routine infant vaccines given without rMenB+OMV NZ. 2. To demonstrate that the immunogenicity of rMenB+OMV NZ when given concomitantly with routine infant vaccines was non-inferior to that of rMenB+OMV NZ given without routine infant vaccines at 2, 4 and 6 months of age. 3. To assess prevalence of meningococcal B antibodies over the study period by evaluation of SBA, at baseline and at 1 month after third vaccination, in subjects- received routine infant vaccine without rMenB+OMV NZ
    Protection of trial subjects
    Novartis Vaccines or the investigator provided the ethics committee (EC) with all appropriate material,including the Informed Consent Form (ICF), according to local regulations. The EC also was asked for a written statement regarding the composition of the committee and to comply with GCP (Good Clinical Practices) and with the applicable regulatory requirement(s). The trial was not initiated until appropriate EC approval of the protocol and the ICF was obtained. In addition, all documents were submitted to other authorities in compliance with local jurisdictions. Prior to enrollment, the sponsor and the investigator exchanged written confirmation that their ethical and legal responsibilities had been observed. The EC and, if applicable, other authorities were informed of protocol amendments in accordance with local legal requirements. Appropriate reports on the progress of the study were made to the EC and the sponsor by the investigator in accordance with applicable governmental regulations and in agreement with policy established by the sponsor.
    Background therapy
    		 The Novartis meningococcal B recombinant vaccine (rMenB + OMV), was supplied as 0.5mL dose in pre-filled syringes and administered by intramuscular (IM) injection into the anterolateral region of the right thigh. The active ingredients were 50μg of each of the following N. meningitidis purified antigens: 961c, 936-741, ΔG287-953. In addition, 25 μg OMV from N. meningitidis strain NZ98/254. Routine vaccines (Infanrix® Hexa and Prevenar®) were administered along with the study vaccine where appropriate.
    Evidence for comparator
    		 There was no reference vaccine in this study
    Actual start date of recruitment
    15 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 317
    Country: Number of subjects enrolled
    Belgium: 248
    Country: Number of subjects enrolled
    Czech Republic: 283
    Country: Number of subjects enrolled
    Italy: 371
    Country: Number of subjects enrolled
    Spain: 105
    Country: Number of subjects enrolled
    United Kingdom: 561
    Worldwide total number of subjects
    1885
    EEA total number of subjects
    1885
    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)
    1885
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 4 centers in UK, 5 centers in Italy, 16 centers in Spain, 6 centers in Belgium, 25 centers in Germany and 4 centers in Czech Republic

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 B+R246
    Arm description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Novartis Meningococcal B Recombinant Vaccine
    Investigational medicinal product code
    V72
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL/1 dose

    Arm title
    		 B246_R357
    Arm description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age; routine infant vaccinations were administered at 3, 5 and 7 months of age
    Arm type
    		 Experimental

    Investigational medicinal product name
    Novartis Meningococcal B Recombinant Vaccine
    Investigational medicinal product code
    V72
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL/1 dose

    Arm title
    		 B+R234
    Arm description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 3, 4 months of age, administered concomitantly with routine infant vaccinations
    Arm type
    		 Experimental

    Investigational medicinal product name
    Novartis Meningococcal B Recombinant Vaccine
    Investigational medicinal product code
    V72
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL/1 dose

    Arm title
    		 R234
    Arm description
    		 Subjects in this group received routine infant vaccines administered at 2, 3 and 4 months of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Infanrix Hexa and Prevenar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL/1 dose

    Number of subjects in period 1
    		B+R246 B246_R357 B+R234 R234
    Started
    627
    628
    318
    312
    Completed
    597
    592
    308
    302
    Not completed
    30
    36
    10
    10
         Adverse event, serious fatal
    4
    7
    2
    -
         Consent withdrawn by subject
    12
    15
    3
    7
         Inappropriate enrollment
    -
    2
    -
    -
         Lost to follow-up
    7
    9
    3
    3
         Administrative reason
    3
    -
    1
    -
         Protocol deviation
    4
    3
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    B+R246
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    B246_R357
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age; routine infant vaccinations were administered at 3, 5 and 7 months of age

    Reporting group title
    B+R234
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 3, 4 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    R234
    Reporting group description
    		 Subjects in this group received routine infant vaccines administered at 2, 3 and 4 months of age.

    Reporting group values
    		 B+R246 B246_R357 B+R234 R234 Total
    Number of subjects
    		 627 628 318 312 1885
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 68.7 ( 8.9 ) 68.8 ( 9.4 ) 68.8 ( 9.1 ) 68.1 ( 9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 292 312 164 159 927
        Male
    		 335 316 154 153 958

    End points

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    End points reporting groups
    Reporting group title
    B+R246
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    B246_R357
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age; routine infant vaccinations were administered at 3, 5 and 7 months of age

    Reporting group title
    B+R234
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 3, 4 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    R234
    Reporting group description
    		 Subjects in this group received routine infant vaccines administered at 2, 3 and 4 months of age.

    Primary: 1. Percentage of Subjects With Serum Bactericidal Activity ≥ 1:5

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    End point title
    		 1. Percentage of Subjects With Serum Bactericidal Activity ≥ 1:5 [1]
    End point description
    The percentage of subjects with serum bactericidal activity(hSBA)titer ≥1:5 after receiving three doses of rMenB+OMV NZ vaccine were evaluated to demonstrate sufficient immune response following rMenB+OMV NZ vaccination, when given concomitantly with routine infant vaccines to healthy infants The serum bactericidal antibodies directed against serogroup B meningococci, are measured by human complement Serum Bactericidal Assay (hSBA). The immune response was considered sufficient for groups B+R246 and B+R234 if the lower limit of the 2-sided 95% confidence interval was ≥ 70% for all three strains. The analysis was conducted on the MIIT population.
    End point type
    Primary
    End point timeframe
    One month after third Men B vaccination
    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: No statistical analysis is associated to this endpoint. Analyses were run descriptively.
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    582
    583
    298
    292
    Units: Percentages of Participants
    number (confidence interval 95%)
        Baseline (5/99 strain; N=580,577,294,289)
    5 (4 to 8)
    7 (5 to 9)
    5 (3 to 8)
    6 (3 to 9)
        Postvacc. (5/99 strain; N=551,554,285,245)
    99 (98 to 100)
    99 (98 to 100)
    100 (99 to 100)
    5 (3 to 8)
        Baseline (NZ98/254 strain; N=582,583,298,292)
    3 (2 to 5)
    1 (0 to 2)
    2 (1 to 4)
    1 (0.083 to 2)
        Postvacc. (NZ98/254 strain; N=555,559,284,269)
    79 (75 to 82)
    87 (84 to 89)
    81 (76 to 85)
    4 (2 to 8)
        Postvacc. (44/76-SL strain;N=550,561,283,265)
    9 (6 to 11)
    7 (5 to 9)
    6 (4 to 10)
    6 (4 to 10)
        Baseline (44/76-SL strain; N= 587,589,300,291)
    99 (98 to 100)
    99 (98 to 100)
    99 (97 to 100)
    4 (2 to 7)
    No statistical analyses for this end point

    Primary: 2. Safety and Tolerability of 3 Doses of rMenB

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    End point title
    		 2. Safety and Tolerability of 3 Doses of rMenB [2]
    End point description
    Safety and Tolerability of 3 Doses of rMenB was assessed in terms of the number of subjects who reported solicited local and systemic adverse events when administered concomitantly with routine infant vaccines at 2,4,6 months of age (B+R246) to when rMenB+OMV NZ and routine vaccines were administered separately (group B246_R357). Analysis was done on safety population.
    End point type
    Primary
    End point timeframe
    10 months (groups 1 and 2); 8 months (groups 3 and 4)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is associated to this endpoint. Analyses were run descriptively.
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    624
    627
    318
    311
    Units: Participants
        Tenderness
    529
    491
    265
    0
        Erythema
    506
    516
    257
    0
        Induration
    447
    465
    230
    0
        Swelling
    290
    324
    149
    0
        Change Eat. Habits (N=624,626,318,311)
    470
    473
    249
    159
        Sleepiness (N=624,626,318,311)
    523
    525
    282
    224
        Vomiting (N=624,626,318,310)
    193
    234
    97
    83
        Diarrhea (N=624,626,318,311)
    284
    327
    138
    113
        Irritability (N=624,626,318,311)
    543
    527
    289
    220
        Unusual Crying
    526
    515
    268
    186
        Rash (N=624,626,318,311)
    84
    130
    42
    39
        Fever (≥ 38.0C; N=624,627,318,311)
    501
    447
    243
    160
    No statistical analyses for this end point

    Secondary: 3. Non-inferiority of Immune Response to rMenB+OMV NZ Vaccination

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    End point title
    		 3. Non-inferiority of Immune Response to rMenB+OMV NZ Vaccination [3]
    End point description
    The non-inferiority of immune response to rMenB+OMV NZ vaccination when administered concomitantly with routine infant vaccines at 2,4,6 months of age (B+R246) to when rMenB+OMV NZ and routine vaccines were administered separately (group B246_R357) was assessed in terms of percentage of subjects With hSBA ≥ 1:5. Analysis was done on Per Protocol (PP) population.
    End point type
    Secondary
    End point timeframe
    One month after 3rd Men B vaccination
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis is associated to this endpoint. Analyses were run descriptively.
    End point values
    		 B+R246 B246_R357
    Number of subjects analysed
    556
    548
    Units: Percentage of Participants
    number (confidence interval 95%)
        Baseline(44/76-SL strain)
    8 (6 to 11)
    7 (5 to 9)
        1 month post 3rd vacc.(44/76-SL; N=525,534)
    100 (99 to 100)
    100 (99 to 100)
        Baseline(5/99 strain; N=551,537)
    6 (4 to 8)
    7 (5 to 9)
        1 month post 3rd vacc.(5/99strain; N=527,529)
    100 (99 to 100)
    99 (98 to 100)
        Baseline(NZ98/254 strain; N=554,543)
    3 (2 to 5)
    1 (0 to 2)
        1 month post 3rdvacc.(NZ98/254; N=530,534)
    79 (76 to 83)
    87 (84 to 90)
    Statistical analysis title
    		 Non-inferiority of immune responses against H44/76
    Statistical analysis description
    Non-inferiority of immune responses against H44/76-SL strain when rMenB+OMV NZ vaccine was administered concomitantly with routine infant vaccines as compared to when rMenB+OMV NZ vaccine and routine vaccines were given separately
    Comparison groups
    B246_R357 v B+R246
    Number of subjects included in analysis
    1104
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference % (B+R246 minusB246_R357
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Notes
    [4] - Immune response of Group B+R246 was considered non-inferior to response of Group B246_R357, if at one month after the third rMenB+OMV NZ injection the 2-sided 95% lower confidence limit of the difference in the percentage of subjects with hSBA titer ≥5 was greater than -10% for each of the 3 strains.
    Statistical analysis title
    		 Non-inferiority of immune responses against 5/99
    Statistical analysis description
    Non-inferiority of immune responses against 5/99 strain when rMenB+OMV NZ vaccine was administered concomitantly with routine infant vaccines as compared to when rMenB+OMV NZ vaccine and routine vaccines were given separately.
    Comparison groups
    B+R246 v B246_R357
    Number of subjects included in analysis
    1104
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference % (B+R246 minusB246_R357
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Notes
    [5] - Immune response of Group B+R246 was considered non-inferior to response of Group B246_R357, if at one month after the third rMenB+OMV NZ injection the 2-sided 95% lower confidence limit of the difference in the percentage of subjects with hSBA titer ≥5 was greater than -10% for each of the 3 strains.
    Statistical analysis title
    		 Non-inferiority of immune responses -NZ98/254
    Statistical analysis description
    Non-inferiority of immune responses against NZ98/254 strain when rMenB+OMV NZ vaccine was administered concomitantly with routine infant vaccines as compared to when rMenB+OMV NZ vaccine and routine vaccines were given separately
    Comparison groups
    B+R246 v B246_R357
    Number of subjects included in analysis
    1104
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference % (B+R246 minusB246_R357
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 -4
    Variability estimate
    Standard deviation
    Notes
    [6] - Immune response of Group B+R246 was considered non-inferior to response of Group B246_R357, if at one month after the third rMenB+OMV NZ injection the 2-sided 95% lower confidence limit of the difference in the percentage of subjects with hSBA titer ≥5 was greater than -10% for each of the 3 strains.

    Secondary: 4. Non-inferiority of Immune Response to Diptheria and Tetanus Antigens

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    End point title
    		 4. Non-inferiority of Immune Response to Diptheria and Tetanus Antigens [7]
    End point description
    Non-inferiority of immune response to routine vaccine antigens when routine vaccines were administered concomitantly with rMenB+OMV NZ vaccine [group B+R234] to when only routine vaccines were given [Group R234] were assessed in terms of percentage of subjects with antibody concentrations ≥1.0 IU/mL against Diphtheria and Tetanus antigens as measured by enzyme-linked immunosorbent assay. Analysis was done on PP population.
    End point type
    Secondary
    End point timeframe
    1 month after 3rd vaccination
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis is associated to this endpoint. Analyses were run descriptively.
    End point values
    		 B+R234 R234
    Number of subjects analysed
    269
    259
    Units: Percentage of Participants
    number (confidence interval 95%)
        Baseline (Diptheria)
    25 (20 to 30)
    21 (16 to 26)
        1 month after 3rd vacc. (Diptheria; N=261,232)
    100 (99 to 100)
    100 (98 to 100)
        Baseline (Tetanus)
    81 (76 to 86)
    86 (81 to 90)
        1 month after 3rd vacc. (Tetanus; N=261,232)
    100 (99 to 100)
    100 (98 to 100)
    Statistical analysis title
    		 Non-inferiority -immune response against Diptheria
    Statistical analysis description
    Non-inferiority of immune responses against Diptheria antigen when routine vaccine was administered concomitantly with rMenB+OMV NZ vaccine to when only routine vaccines were administered
    Comparison groups
    B+R234 v R234
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference % (B+R234 minus R234)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 2
    Variability estimate
    Standard deviation
    Notes
    [8] - Immune response of Group B+R234 was considered non-inferior to response of Group R234, if at one month after the third injection the 2-sided 95% lower confidence limit for the difference in the percentage of subjects with antibody response greater than the pre-specified cut off of for diphtheria (≥0.1 IU/mL) was >-10%.
    Statistical analysis title
    		 Non-inferiority- immune response against Tetanus
    Statistical analysis description
    Non-inferiority of immune responses against Tetanus antigen when routine vaccine was administered concomitantly with rMenB+OMV NZ vaccine to when only routine vaccines were administered
    Comparison groups
    B+R234 v R234
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference % (B+R234 minus R234)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 2
    Variability estimate
    Standard deviation
    Notes
    [9] - Immune response of Group B+R234 was considered non-inferior to response of Group R234, if at one month after the third injection the 2-sided 95% lower confidence limit for the difference in the percentage of subjects with antibody response greater than the pre-specified cut off of for diphtheria (≥0.1 IU/mL) was >-10%.

    Secondary: 5. Geometric Mean Titers Against Neisseria Meningitidis Serogroup B

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    End point title
    		 5. Geometric Mean Titers Against Neisseria Meningitidis Serogroup B
    End point description
    The hSBA antibody titers when rMenB+OMV NZ vaccine is administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately are reported in terms of vaccine group- specific geometric mean titers. Analysis was done on PP population.
    End point type
    Secondary
    End point timeframe
    One month after third Men B vaccination
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    556
    548
    285
    277
    Units: Titres
    geometric mean (confidence interval 95%)
        Baseline (44/76-SL strain; N=556,548,285,277)
    1.49 (1.4 to 1.59)
    1.36 (1.28 to 1.46)
    1.34 (1.23 to 1.46)
    1.28 (1.19 to 1.37)
        post vacc. (44/76-SL; N=525,534,273,253)
    86 (80 to 92)
    113 (105 to 121)
    82 (75 to 91)
    1.16 (1.09 to 1.24)
        Baseline (5/99 strain; N=551,537,280,275)
    1.3 (1.21 to 1.39)
    1.28 (1.2 to 1.37)
    1.19 (1.09 to 1.3)
    1.24 (1.15 to 1.33)
        post vacc. (5/99 strain; N=527,529,275,236)
    537 (494 to 584)
    699 (643 to 759)
    325 (292 to 362)
    1.25 (1.08 to 1.45)
        Baseline (NZ98/254 strain; N=554,543,283,278)
    1.13 (1.08 to 1.18)
    1.08 (1.04 to 1.13)
    1.06 (1 to 1.12)
    1.07 (1.03 to 1.1)
        post vacc. (NZ98/254strain; N=530,534,274,257)
    12 (11 to 14)
    18 (16 to 20)
    11 (9.14 to 12)
    1.11 (1.04 to 1.19)
    No statistical analyses for this end point

    Secondary: 6. Geometric Mean Ratio of hSBA Titers

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    End point title
    		 6. Geometric Mean Ratio of hSBA Titers
    End point description
    The geometric mean ratio (GMR) of GMTs at 1 month after 3rd rMenB+OMV NZ vaccination to prevaccination GMTs, when rMenB+OMV NZ was administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately. Analysis was done on PP population.
    End point type
    Secondary
    End point timeframe
    One month after third Men B vaccination versus baseline
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    504
    507
    274
    238
    Units: Ratio
    number (confidence interval 95%)
        44/76-SL strain (N=501,507,262,236)
    58 (52 to 64)
    83 (74 to 92)
    61 (53 to 70)
    0.91 (0.83 to 1)
        5/99 strain (N=497,494,257,217)
    430 (379 to 487)
    553 (489 to 625)
    271 (231 to 318)
    1.03 (0.86 to 1.22)
        NZ98/254 strain (N=504,503,258,238)
    11 (9.28 to 12)
    16 (14 to 19)
    10 (8.52 to 12)
    1.05 (0.97 to 1.14)
    No statistical analyses for this end point

    Secondary: 7. Percentage of Subjects With hSBA ≥ 1:8

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    End point title
    		 7. Percentage of Subjects With hSBA ≥ 1:8
    End point description
    The percentage of subjects with hSBA titers ≥ 1:8, following rMenB+OMV NZ vaccination when given concomitantly with routine infant vaccines to when rMenB+OMV NZ and routine vaccines were given separately. Analysis was done on PP population.
    End point type
    Secondary
    End point timeframe
    Percentage of Subjects With hSBA ≥ 1:8
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    556
    548
    285
    278
    Units: Percentage of Participants
    number (confidence interval 95%)
        Baseline (44/76-SLstrain; N=556,548,285,277)
    4 (3 to 6)
    3 (2 to 5)
    4 (2 to 7)
    2 (1 to 5)
        Post vacc. (44/76-SL; N=525,534,273,253)
    99 (98 to 100)
    100 (99 to 100)
    99 (97 to 100)
    2 (0 to 4)
        Baseline (5/99strain; N=551,537,280,275)
    4 (2 to 6)
    3 (2 to 5)
    2 (1 to 5)
    4 (2 to 7)
        Post vacc. (5/99strain; N=527,529,275,236)
    100 (99 to 100)
    99 (98 to 100)
    100 (99 to 100)
    3 (1 to 7)
        Baseline(NZ98/254strain; N=554,543,283,278)
    1 (1 to 3)
    1 (0 to 2)
    1 (0.086 to 3)
    0.1 (0.0091 to 2)
        Post vacc.(NZ98/254 strain; N=530,534,274,257)
    67 (63 to 71)
    79 (75 to 82)
    69 (63 to 74)
    2 (1 to 5)
    No statistical analyses for this end point

    Secondary: 8. Percentage of Subjects With 4-fold Rise in hSBA Titers

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    End point title
    		 8. Percentage of Subjects With 4-fold Rise in hSBA Titers
    End point description
    The percentage of subjects with 4-fold rise in hSBA titers at 1 month after 3rd rMenB+OMV NZ vaccination from baseline, when rMenB+OMV NZ was administered concomitantly with routine infant vaccines to when rMenB+OMV NZ vaccine and routine vaccines were given separately. Analysis was done on PP population.
    End point type
    Secondary
    End point timeframe
    One month after third Men B vaccination
    End point values
    		 B+R246 B246_R357 B+R234 R234
    Number of subjects analysed
    501
    507
    262
    238
    Units: Percentage of Participants
    number (confidence interval 95%)
        44/76-SL strain (N=501,507,262,236)
    97 (96 to 99)
    99 (97 to 99)
    98 (96 to 99)
    1 (0 to 4)
        5/99 strain (N=497,494,257,217)
    99 (98 to 100)
    99 (98 to 100)
    100 (99 to 100)
    3 (1 to 7)
        NZ98/254 strain (N=504,503,258,238)
    66 (62 to 70)
    78 (74 to 81)
    69 (63 to 75)
    3 (1 to 5)
    No statistical analyses for this end point

    Secondary: 9. Non-inferiority of Immune Response to Acellular Pertussis Antigens

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    End point title
    		 9. Non-inferiority of Immune Response to Acellular Pertussis Antigens [10]
    End point description
    Non-inferiority of immune response to routine vaccine antigens when routine vaccines were administered concomitantly with rMenB+OMV NZ vaccine [group B+R234] to when only routine vaccines were given [Group R234] were assessed in terms of percentage of subjects achieving seroconversion for pertussis antigens -FHA, Pertactin and PT at 1 month after 3rd vaccination versus baseline Seroconversion was defined as a 4-fold increase for each pertussis antigen or in those initially seropositive, persistence of the pre-vaccination antibody concentration at least at the same antibody concentration as before vaccination, taking into account the decay of maternal antibodies
    End point type
    Secondary
    End point timeframe
    1 month after 3rd vaccination
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis is associated to this endpoint. Analyses were run descriptively.
    End point values
    		 B+R234 R234
    Number of subjects analysed
    239
    210
    Units: Percentage of Participants
    number (confidence interval 95%)
        FHA
    94 (90 to 97)
    95 (91 to 97)
        Pertactin
    92 (88 to 95)
    95 (91 to 97)
        PT
    97 (94 to 99)
    98 (95 to 99)
    Statistical analysis title
    		 Non-inferiority -immune response against Pertussis
    Statistical analysis description
    Non-inferiority of immune responses against Pertussis antigen FHA when routine vaccine was administered concomitantly with rMenB+OMV NZ vaccine to when only routine vaccines were administered
    Comparison groups
    B+R234 v R234
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference %(B+R234 minus R234)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 4
    Variability estimate
    Standard deviation
    Notes
    [11] - Group B+R234 was to be considered non-inferior to Group R234 if the 2-sided 95% lower confidence limit of this difference at 30 days after the last injection was greater than -10% for each of the antigens of the routine vaccinations
    Statistical analysis title
    		 Non-inferiority- immune response against Pertussis
    Statistical analysis description
    Non-inferiority of immune responses against Pertussis antigen Pertactin when routine vaccine was administered concomitantly with rMenB+OMV NZ vaccine to when only routine vaccines were administered
    Comparison groups
    B+R234 v R234
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference %(B+R234 minus R234)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 2
    Variability estimate
    Standard deviation
    Notes
    [12] - Group B+R234 was to be considered non-inferior to Group R234 if the 2-sided 95% lower confidence limit of this difference at 30 days after the last injection was greater than -10% for each of the antigens of the routine vaccinations
    Statistical analysis title
    		 Non-inferiority- immune response against Pertussis
    Statistical analysis description
    Non-inferiority of immune responses against Pertussis antigen PT when routine vaccine was administered concomitantly with rMenB+OMV NZ vaccine to when only routine vaccines were administered
    Comparison groups
    B+R234 v R234
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    		 Miettinen and Nurminen method
    Parameter type
    		 Difference %(B+R234 minus R234)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 2
    Variability estimate
    Standard deviation
    Notes
    [13] - Group B+R234 was to be considered non-inferior to Group R234 if the 2-sided 95% lower confidence limit of this difference at 30 days after the last injection was greater than -10% for each of the antigens of the routine vaccinations

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    B+R246
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 4, and 6 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    B246_R357
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at at 2, 4, and 6 months of age; routine infant vaccinations were administered at 3, 5 and 7 months of age

    Reporting group title
    B+R234
    Reporting group description
    		 Subjects in this group received rMenB+OMV NZ vaccine at 2, 3, 4 months of age, administered concomitantly with routine infant vaccinations

    Reporting group title
    R234
    Reporting group description
    		 Subjects in this group received routine infant vaccines administered at 2, 3 and 4 months of age.

    Serious adverse events
    		 B+R246 B246_R357 B+R234 R234
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 625 (10.08%)
    57 / 627 (9.09%)
    19 / 318 (5.97%)
    19 / 312 (6.09%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioma
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Prophylaxis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 625 (0.80%)
    4 / 627 (0.64%)
    1 / 318 (0.31%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoeic attack
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Breath holding
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase abnormal
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Exposure Via Ingestion
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    3 / 625 (0.48%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exposure to toxic agent
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 625 (0.00%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 625 (0.00%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital musculoskeletal anomaly
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniosynostosis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cryptorchism
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Talipes
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urachal abnormality
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crying
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 625 (0.00%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 625 (0.16%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonic hyporesponsive episode
         subjects affected / exposed
    2 / 625 (0.32%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadentitis
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal dystrophy
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Strangulated hernia
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux Disease
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    3 / 318 (0.94%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Vesicoureteric reflux
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 625 (0.00%)
    0 / 627 (0.00%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 625 (0.32%)
    3 / 627 (0.48%)
    2 / 318 (0.63%)
    3 / 312 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 625 (0.64%)
    6 / 627 (0.96%)
    2 / 318 (0.63%)
    2 / 312 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 625 (0.16%)
    4 / 627 (0.64%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    7 / 625 (1.12%)
    7 / 627 (1.12%)
    2 / 318 (0.63%)
    4 / 312 (1.28%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and mouth Disease
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 625 (0.32%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 625 (0.32%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    3 / 625 (0.48%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 625 (0.00%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 625 (0.00%)
    2 / 627 (0.32%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 625 (0.16%)
    1 / 627 (0.16%)
    1 / 318 (0.31%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 625 (0.48%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 625 (0.16%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    4 / 625 (0.64%)
    1 / 627 (0.16%)
    0 / 318 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 625 (0.32%)
    0 / 627 (0.00%)
    0 / 318 (0.00%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 B+R246 B246_R357 B+R234 R234
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    620 / 625 (99.20%)
    623 / 627 (99.36%)
    316 / 318 (99.37%)
    305 / 312 (97.76%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    523 / 625 (83.68%)
    525 / 627 (83.73%)
    282 / 318 (88.68%)
    224 / 312 (71.79%)
         occurrences all number
    1229
    1846
    681
    492
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    489 / 625 (78.24%)
    519 / 627 (82.78%)
    254 / 318 (79.87%)
    204 / 312 (65.38%)
         occurrences all number
    2553
    2741
    1357
    681
    Pyrexia
         subjects affected / exposed
    514 / 625 (82.24%)
    462 / 627 (73.68%)
    246 / 318 (77.36%)
    176 / 312 (56.41%)
         occurrences all number
    1294
    1471
    590
    344
    Injection site erythema
         subjects affected / exposed
    535 / 625 (85.60%)
    553 / 627 (88.20%)
    271 / 318 (85.22%)
    229 / 312 (73.40%)
         occurrences all number
    3395
    3462
    1787
    924
    Injection site swelling
         subjects affected / exposed
    328 / 625 (52.48%)
    383 / 627 (61.08%)
    170 / 318 (53.46%)
    115 / 312 (36.86%)
         occurrences all number
    1276
    1307
    697
    305
    Crying
         subjects affected / exposed
    526 / 625 (84.16%)
    516 / 627 (82.30%)
    268 / 318 (84.28%)
    187 / 312 (59.94%)
         occurrences all number
    1303
    1781
    674
    400
    Injection Site Pain
         subjects affected / exposed
    544 / 625 (87.04%)
    536 / 627 (85.49%)
    279 / 318 (87.74%)
    182 / 312 (58.33%)
         occurrences all number
    3087
    2552
    1624
    612
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    302 / 625 (48.32%)
    338 / 627 (53.91%)
    145 / 318 (45.60%)
    123 / 312 (39.42%)
         occurrences all number
    519
    798
    263
    243
    Teething
         subjects affected / exposed
    30 / 625 (4.80%)
    51 / 627 (8.13%)
    7 / 318 (2.20%)
    13 / 312 (4.17%)
         occurrences all number
    33
    62
    7
    13
    Vomiting
         subjects affected / exposed
    208 / 625 (33.28%)
    245 / 627 (39.07%)
    100 / 318 (31.45%)
    85 / 312 (27.24%)
         occurrences all number
    356
    461
    169
    145
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    51 / 625 (8.16%)
    96 / 627 (15.31%)
    35 / 318 (11.01%)
    41 / 312 (13.14%)
         occurrences all number
    62
    121
    43
    49
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    100 / 625 (16.00%)
    142 / 627 (22.65%)
    50 / 318 (15.72%)
    47 / 312 (15.06%)
         occurrences all number
    136
    228
    64
    66
    Eczema
         subjects affected / exposed
    29 / 625 (4.64%)
    35 / 627 (5.58%)
    12 / 318 (3.77%)
    17 / 312 (5.45%)
         occurrences all number
    34
    41
    15
    20
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    543 / 625 (86.88%)
    527 / 627 (84.05%)
    289 / 318 (90.88%)
    220 / 312 (70.51%)
         occurrences all number
    1486
    2326
    775
    544
    Eating disorder
         subjects affected / exposed
    470 / 625 (75.20%)
    473 / 627 (75.44%)
    249 / 318 (78.30%)
    159 / 312 (50.96%)
         occurrences all number
    1035
    1444
    548
    316
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    78 / 625 (12.48%)
    98 / 627 (15.63%)
    29 / 318 (9.12%)
    35 / 312 (11.22%)
         occurrences all number
    113
    126
    33
    51
    Rhinitis
         subjects affected / exposed
    67 / 625 (10.72%)
    91 / 627 (14.51%)
    28 / 318 (8.81%)
    36 / 312 (11.54%)
         occurrences all number
    77
    121
    36
    48
    Bronchitis
         subjects affected / exposed
    72 / 625 (11.52%)
    82 / 627 (13.08%)
    31 / 318 (9.75%)
    23 / 312 (7.37%)
         occurrences all number
    107
    113
    40
    30
    Upper respiratory tract infection
         subjects affected / exposed
    76 / 625 (12.16%)
    72 / 627 (11.48%)
    24 / 318 (7.55%)
    16 / 312 (5.13%)
         occurrences all number
    100
    108
    32
    24
    Conjunctivitis
         subjects affected / exposed
    53 / 625 (8.48%)
    72 / 627 (11.48%)
    26 / 318 (8.18%)
    22 / 312 (7.05%)
         occurrences all number
    63
    84
    34
    28
    Viral infection
         subjects affected / exposed
    42 / 625 (6.72%)
    53 / 627 (8.45%)
    17 / 318 (5.35%)
    26 / 312 (8.33%)
         occurrences all number
    49
    64
    19
    29
    Ear infection
         subjects affected / exposed
    48 / 625 (7.68%)
    52 / 627 (8.29%)
    15 / 318 (4.72%)
    14 / 312 (4.49%)
         occurrences all number
    62
    69
    19
    16
    Gastroenteritis
         subjects affected / exposed
    40 / 625 (6.40%)
    45 / 627 (7.18%)
    11 / 318 (3.46%)
    12 / 312 (3.85%)
         occurrences all number
    43
    51
    12
    13

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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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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