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    Clinical Trial Results:
    A randomised, controlled, multidose, multicentre, adaptive phase II/III study in infants with proliferating infantile hemangiomas requiring systemic therapy to compare four regimens of propranolol (1 or 3 mg/kg/day for 3 or 6 months) to placebo (double blind).

    Summary
    EudraCT number
    		 2009-013262-84
    Trial protocol
    		 FR   DE   ES   IT   HU   LT   CZ   RO  
    Global end of trial date
    05 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2016
    First version publication date
    17 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V00400SB201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01056341
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Dermatologie
    Sponsor organisation address
    45, Place Abel Gance, Boulogne, France, 92100
    Public contact
    Medical and/or Clinical Study Manager, Pierre Fabre Dermatologie, contact_essais_cliniques@pierre-fabre.com
    Scientific contact
    Medical and/or Clinical Study Manager, Pierre Fabre Dermatologie, contact_essais_cliniques@pierre-fabre.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000511-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify the appropriate dose and duration of propranolol treatment (as coded V0400SB) out of four regimens of oral propranolol (1 or 3 mg/kg/day twice a day for 3 or 6 months), and to demonstrate its superiority over placebo based on the complete/nearly complete resolution of the target IH at Week 24.
    Protection of trial subjects
    Clinical (including respiratory rate and vital sign measurements) and paraclinical (lab tests (haematology, biochemistry, glycaemia (pin-prick), and ECG) examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 17 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 114
    Country: Number of subjects enrolled
    Germany: 60
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Lithuania: 18
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Peru: 35
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    New Zealand: 5
    Worldwide total number of subjects
    456
    EEA total number of subjects
    305
    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)
    456
    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

    		 Close Top of page
    Recruitment
    Recruitment details
    		 510 patients were included in the study (Informed Consent Form signed). Among these 510 patients, 50 were screen failure, 460 were randomized and 456 were randomized and treated.

    Pre-assignment
    Screening details
    		 Infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months).

    Period 1
    Period 1 title
    24-week study treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment with placebo for 6 months twice daily.

    Arm title
    		 Propranolol 1mg/kg/day - 3 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Propranolol hydrochloride oral solution 1mg/kg/day for 3 months, then placebo for 3 months.

    Arm title
    		 Propranolol 1mg/kg/day - 6 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Propranolol hydrochloride oral solution 1mg/kg/day for 6 months.

    Arm title
    		 Propranolol 3 mg/kg/day - 3 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Propranolol hydrochloride oral solution 3 mg/kg/day for 3 months, then placebo for 3 months.

    Arm title
    		 Propranolol 3 mg/kg/day - 6 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Propranolol hydrochloride oral solution 3mg/kg/day for 6 months.

    Number of subjects in period 1
    		Placebo Propranolol 1mg/kg/day - 3 months Propranolol 1mg/kg/day - 6 months Propranolol 3 mg/kg/day - 3 months Propranolol 3 mg/kg/day - 6 months
    Started
    55
    98
    102
    100
    101
    Interim analysis
    25
    41 [1]
    40 [2]
    39 [3]
    43 [4]
    Completed
    19
    63
    88
    65
    88
    Not completed
    36
    35
    14
    35
    13
         Consent withdrawn by subject
    3
    1
    4
    3
    2
         Physician decision
    -
    -
    -
    1
    -
         Treatment intolerance
    -
    2
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    4
    1
         Moving of parents
    -
    1
    -
    2
    -
         Lost to follow-up
    1
    1
    2
    -
    1
         Lack of efficacy
    32
    30
    7
    25
    9
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A planned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. At this milestone, all patients were not included in the arm (41/98). During this analysis, the recruitment was not interrupted.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A planned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. At this milestone, all patients were not included in the arm (40/102). During this analysis, the recruitment was not interrupted.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A planned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. At this milestone, all patients were not included in the arm (30/100). During this analysis, the recruitment was not interrupted.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A planned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. At this milestone, all patients were not included in the arm (43/101). During this analysis, the recruitment was not interrupted.
    Period 2
    Period 2 title
    72-week follow-up period (no study drug)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Propranolol 1mg/kg/day - 3 months
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Propranolol 1mg/kg/day - 6 months
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Propranolol 3 mg/kg/day - 3 months
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Propranolol 3 mg/kg/day - 6 months
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [5]
    		Placebo Propranolol 1mg/kg/day - 3 months Propranolol 1mg/kg/day - 6 months Propranolol 3 mg/kg/day - 3 months Propranolol 3 mg/kg/day - 6 months
    Started
    19
    60
    85
    65
    87
    Completed
    28
    75
    82
    78
    80
    Not completed
    5
    10
    9
    9
    15
         Physician decision
    -
    -
    1
    -
    1
         Patient's Parent(s) or guardian(s) decision
    3
    5
    4
    7
    7
         Visit schedule not respected
    -
    -
    2
    -
    -
         Lost to follow-up
    2
    4
    2
    2
    6
         off-label medication started
    -
    -
    -
    -
    1
         Patient moved to another city
    -
    1
    -
    -
    -
    Joined
    14
    25
    6
    22
    8
         prematurely discontinued the treatment period
    14
    25
    6
    22
    8
    Notes
    [5] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 7 patients discontinued study after the end of treatment period, and patients prematurely discontinued the treatment period could also entered the follow period. -Placebo group : 33 patients entered the follow-up period(FU), 19 completed(C) + 14 prematurely discontinued(PDO) for the treatment period - 1mg/kg/day-3months group: 85 FU= 60(C)+25(PDO) - 1mg/kg/day-6months group: 91 FU=85(C)+6(PDO) - 3mg/kg/day-3months group, 87 FU=65(C)+22(PDO) - 3mg/kg/day-6months group, 95 FU= 87(C)+8(PDO)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 6 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 6 months
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Propranolol 1mg/kg/day - 3 months Propranolol 1mg/kg/day - 6 months Propranolol 3 mg/kg/day - 3 months Propranolol 3 mg/kg/day - 6 months Total
    Number of subjects
    		 55 98 102 100 101 456
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 103.91 ( 31.06 ) 103.58 ( 33.07 ) 102.65 ( 30.12 ) 107.53 ( 30.14 ) 101.63 ( 31 ) -
    Gender categorical
    Units: Subjects
        Female
    		 38 68 70 79 70 325
        Male
    		 17 30 32 21 31 131
    Subject analysis sets

    Subject analysis set title
    24-week treatment safety analysis data set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients randomized and treated.

    Subject analysis set title
    72-week follow-up safety analysis data set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Among the 456 patients randomized and treated, 391 entered the 72-week follow-up period.

    Subject analysis sets values
    		 24-week treatment safety analysis data set 72-week follow-up safety analysis data set
    Number of subjects
    456
    391
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    103.85 ( 31.02 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    325
        Male
    131

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 6 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 6 months
    Reporting group description
    		 -
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 1mg/kg/day - 6 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 3 months
    Reporting group description
    		 -

    Reporting group title
    Propranolol 3 mg/kg/day - 6 months
    Reporting group description
    		 -

    Subject analysis set title
    24-week treatment safety analysis data set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients randomized and treated.

    Subject analysis set title
    72-week follow-up safety analysis data set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Among the 456 patients randomized and treated, 391 entered the 72-week follow-up period.

    Primary: Interim analysis - Complete/nearly complete resolution of target IH at Week 24

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    End point title
    		 Interim analysis - Complete/nearly complete resolution of target IH at Week 24
    End point description
    Percentage of patients with complete/nearly complete resolution (CR/NCR) of target IH at week 24 (based on Intra-patient Blinded Centralized Independent Qualitative Assessments of Photographs at week 24 compared to baseline) in the interim efficacy analysis set (n=188 patients having completed their week 24 or been withdrawn prematurely from treatment period).
    End point type
    Primary
    End point timeframe
    Week 24 (endpoint)
    End point values
    		 Placebo Propranolol 1mg/kg/day - 3 months Propranolol 1mg/kg/day - 6 months Propranolol 3 mg/kg/day - 3 months Propranolol 3 mg/kg/day - 6 months
    Number of subjects analysed
    25
    41
    40
    39
    43
    Units: percentage of patients
        number (not applicable)
    8
    9.8
    37.5
    7.7
    62.8
    Statistical analysis title
    		 Interim analysis Target IH CR/NCR at Week24
    Comparison groups
    Placebo v Propranolol 1mg/kg/day - 3 months v Propranolol 1mg/kg/day - 6 months v Propranolol 3 mg/kg/day - 3 months v Propranolol 3 mg/kg/day - 6 months
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Z-tests
    Confidence interval

    Primary: Primary analysis - Success on target IH evolution at Week 24

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    End point title
    		 Primary analysis - Success on target IH evolution at Week 24 [1]
    End point description
    Percentage of patients with success at week 24 = Percentage of patients with CR/NCR of target IH at week 24 (based on the intra-patient blinded centralized independent qualitative assessments of photographs of the target IH at week 24 compared to baseline) with no additional criteria of failure (early treatment withdrawal, use of prohibited treatment, no centralized or investigator's assessment of target IH evolution at week 24) in the ITT set (n=276). The final comparison is performed between the ITT placebo and propranolol 3 mg/kg/day - 6 months groups (n=156).
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The primary analysis of the primary endpoint compared only the selected regimen (3mg/kg/day-6months) to placebo. No statistical comparaison on the other arms to placebo were performed at Week 24.
    End point values
    		 Placebo Propranolol 3 mg/kg/day - 6 months
    Number of subjects analysed
    55
    101
    Units: percentage of patients
        number (not applicable)
    3.6
    60.4
    Statistical analysis title
    		 W24 primary analysis - Primary efficacy endpoint
    Statistical analysis description
    Posch et al method for an adaptive confirmatory design with a single selection at an interim analysis with a type I error level maintained at 0.005
    Comparison groups
    Placebo v Propranolol 3 mg/kg/day - 6 months
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Posh et al method,type I error at 0.005
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the whole study period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    W24-treatment period-safety set- Placebo
    Reporting group description
    		 -

    Reporting group title
    W24-treatment period-safety set-1mg/kg/D,3months
    Reporting group description
    		 -

    Reporting group title
    W24-treatment period-safety set-1mg/kg/D,6months
    Reporting group description
    		 -

    Reporting group title
    W24-treatment period-safety set-3mg/kg/D,3months
    Reporting group description
    		 -

    Reporting group title
    W24-treatment period-safety set-3mg/kg/D,6months
    Reporting group description
    		 -

    Reporting group title
    W72-follow-up period of placebo group-safety set
    Reporting group description
    		 -

    Reporting group title
    W72-follow-up period of 1mg/kg/D,3months group-safety set
    Reporting group description
    		 -

    Reporting group title
    W72-follow-up period of 1mg/kg/D,6months group-safety set
    Reporting group description
    		 -

    Reporting group title
    W72-follow-up period of 3mg/kg/D,3months group-safety set
    Reporting group description
    		 -

    Reporting group title
    W72-follow-up period of 3mg/kg/D,6months group-safety set
    Reporting group description
    		 -

    Serious adverse events
    		 W24-treatment period-safety set- Placebo W24-treatment period-safety set-1mg/kg/D,3months W24-treatment period-safety set-1mg/kg/D,6months W24-treatment period-safety set-3mg/kg/D,3months W24-treatment period-safety set-3mg/kg/D,6months W72-follow-up period of placebo group-safety set W72-follow-up period of 1mg/kg/D,3months group-safety set W72-follow-up period of 1mg/kg/D,6months group-safety set W72-follow-up period of 3mg/kg/D,3months group-safety set W72-follow-up period of 3mg/kg/D,6months group-safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 98 (5.10%)
    3 / 102 (2.94%)
    9 / 100 (9.00%)
    6 / 101 (5.94%)
    5 / 33 (15.15%)
    6 / 85 (7.06%)
    5 / 91 (5.49%)
    5 / 87 (5.75%)
    7 / 95 (7.37%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Traumatic brain injury
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 101 (0.99%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hip dysplasia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileostomy closure
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Finger amputation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip surgery
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal operation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug ineffective
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 101 (0.99%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Condition aggravated
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    2 / 100 (2.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    1 / 101 (0.99%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    1 / 101 (0.99%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    1 / 101 (0.99%)
    1 / 33 (3.03%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    2 / 87 (2.30%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    2 / 85 (2.35%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 W24-treatment period-safety set- Placebo W24-treatment period-safety set-1mg/kg/D,3months W24-treatment period-safety set-1mg/kg/D,6months W24-treatment period-safety set-3mg/kg/D,3months W24-treatment period-safety set-3mg/kg/D,6months W72-follow-up period of placebo group-safety set W72-follow-up period of 1mg/kg/D,3months group-safety set W72-follow-up period of 1mg/kg/D,6months group-safety set W72-follow-up period of 3mg/kg/D,3months group-safety set W72-follow-up period of 3mg/kg/D,6months group-safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 55 (72.73%)
    88 / 98 (89.80%)
    92 / 102 (90.20%)
    92 / 100 (92.00%)
    96 / 101 (95.05%)
    27 / 33 (81.82%)
    66 / 85 (77.65%)
    70 / 91 (76.92%)
    65 / 87 (74.71%)
    75 / 95 (78.95%)
    Injury, poisoning and procedural complications
    Vaccination complication
         subjects affected / exposed
    2 / 55 (3.64%)
    7 / 98 (7.14%)
    9 / 102 (8.82%)
    8 / 100 (8.00%)
    8 / 101 (7.92%)
    1 / 33 (3.03%)
    1 / 85 (1.18%)
    1 / 91 (1.10%)
    2 / 87 (2.30%)
    2 / 95 (2.11%)
         occurrences all number
    2
    7
    12
    8
    9
    2
    1
    1
    2
    2
    Vascular disorders
    Peripheral coldness
         subjects affected / exposed
    1 / 55 (1.82%)
    8 / 98 (8.16%)
    10 / 102 (9.80%)
    1 / 100 (1.00%)
    10 / 101 (9.90%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    1
    9
    12
    1
    10
    0
    0
    0
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 55 (1.82%)
    6 / 98 (6.12%)
    4 / 102 (3.92%)
    1 / 100 (1.00%)
    1 / 101 (0.99%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    1
    13
    5
    1
    1
    0
    0
    0
    0
    0
    Hypotonia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    2 / 33 (6.06%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 55 (10.91%)
    21 / 98 (21.43%)
    24 / 102 (23.53%)
    22 / 100 (22.00%)
    28 / 101 (27.72%)
    6 / 33 (18.18%)
    21 / 85 (24.71%)
    15 / 91 (16.48%)
    20 / 87 (22.99%)
    24 / 95 (25.26%)
         occurrences all number
    6
    32
    40
    34
    36
    16
    31
    24
    41
    36
    Irritability
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 98 (5.10%)
    6 / 102 (5.88%)
    1 / 100 (1.00%)
    2 / 101 (1.98%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    3
    7
    6
    1
    2
    0
    0
    1
    0
    0
    Condition aggravated
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 98 (3.06%)
    1 / 102 (0.98%)
    3 / 100 (3.00%)
    2 / 101 (1.98%)
    2 / 33 (6.06%)
    1 / 85 (1.18%)
    1 / 91 (1.10%)
    1 / 87 (1.15%)
    3 / 95 (3.16%)
         occurrences all number
    0
    4
    2
    3
    2
    3
    1
    1
    1
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 98 (4.08%)
    8 / 102 (7.84%)
    2 / 100 (2.00%)
    8 / 101 (7.92%)
    1 / 33 (3.03%)
    7 / 85 (8.24%)
    8 / 91 (8.79%)
    7 / 87 (8.05%)
    9 / 95 (9.47%)
         occurrences all number
    3
    6
    9
    2
    10
    1
    9
    12
    11
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 55 (7.27%)
    16 / 98 (16.33%)
    14 / 102 (13.73%)
    17 / 100 (17.00%)
    28 / 101 (27.72%)
    1 / 33 (3.03%)
    4 / 85 (4.71%)
    4 / 91 (4.40%)
    10 / 87 (11.49%)
    9 / 95 (9.47%)
         occurrences all number
    9
    26
    17
    20
    51
    1
    4
    4
    13
    9
    Teething
         subjects affected / exposed
    6 / 55 (10.91%)
    19 / 98 (19.39%)
    23 / 102 (22.55%)
    16 / 100 (16.00%)
    22 / 101 (21.78%)
    0 / 33 (0.00%)
    5 / 85 (5.88%)
    9 / 91 (9.89%)
    7 / 87 (8.05%)
    8 / 95 (8.42%)
         occurrences all number
    7
    25
    45
    25
    34
    0
    5
    15
    15
    13
    Vomiting
         subjects affected / exposed
    3 / 55 (5.45%)
    16 / 98 (16.33%)
    13 / 102 (12.75%)
    10 / 100 (10.00%)
    13 / 101 (12.87%)
    2 / 33 (6.06%)
    3 / 85 (3.53%)
    3 / 91 (3.30%)
    4 / 87 (4.60%)
    2 / 95 (2.11%)
         occurrences all number
    7
    24
    16
    11
    25
    2
    3
    3
    5
    3
    Toothache
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 98 (5.10%)
    2 / 102 (1.96%)
    8 / 100 (8.00%)
    10 / 101 (9.90%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    4 / 95 (4.21%)
         occurrences all number
    2
    6
    3
    14
    12
    0
    1
    0
    0
    6
    Constipation
         subjects affected / exposed
    1 / 55 (1.82%)
    9 / 98 (9.18%)
    6 / 102 (5.88%)
    9 / 100 (9.00%)
    4 / 101 (3.96%)
    1 / 33 (3.03%)
    1 / 85 (1.18%)
    4 / 91 (4.40%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    3
    15
    9
    11
    4
    1
    1
    4
    0
    1
    Gingival pain
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 98 (3.06%)
    0 / 102 (0.00%)
    5 / 100 (5.00%)
    2 / 101 (1.98%)
    1 / 33 (3.03%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences all number
    2
    3
    0
    9
    2
    1
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 55 (7.27%)
    14 / 98 (14.29%)
    18 / 102 (17.65%)
    16 / 100 (16.00%)
    14 / 101 (13.86%)
    4 / 33 (12.12%)
    8 / 85 (9.41%)
    5 / 91 (5.49%)
    7 / 87 (8.05%)
    7 / 95 (7.37%)
         occurrences all number
    8
    16
    23
    22
    22
    5
    14
    6
    9
    8
    Nasal congestion
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 98 (3.06%)
    6 / 102 (5.88%)
    4 / 100 (4.00%)
    4 / 101 (3.96%)
    0 / 33 (0.00%)
    1 / 85 (1.18%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    2
    3
    8
    6
    8
    0
    1
    1
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 98 (3.06%)
    3 / 102 (2.94%)
    8 / 100 (8.00%)
    3 / 101 (2.97%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    3 / 87 (3.45%)
    5 / 95 (5.26%)
         occurrences all number
    3
    4
    3
    13
    3
    0
    0
    0
    6
    6
    Asthma
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    2 / 101 (1.98%)
    0 / 33 (0.00%)
    2 / 85 (2.35%)
    3 / 91 (3.30%)
    5 / 87 (5.75%)
    5 / 95 (5.26%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    4
    3
    12
    7
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 98 (4.08%)
    5 / 102 (4.90%)
    4 / 100 (4.00%)
    9 / 101 (8.91%)
    1 / 33 (3.03%)
    4 / 85 (4.71%)
    2 / 91 (2.20%)
    3 / 87 (3.45%)
    3 / 95 (3.16%)
         occurrences all number
    2
    4
    7
    5
    13
    1
    4
    2
    3
    3
    Eczema
         subjects affected / exposed
    1 / 55 (1.82%)
    8 / 98 (8.16%)
    4 / 102 (3.92%)
    2 / 100 (2.00%)
    2 / 101 (1.98%)
    2 / 33 (6.06%)
    4 / 85 (4.71%)
    2 / 91 (2.20%)
    4 / 87 (4.60%)
    4 / 95 (4.21%)
         occurrences all number
    1
    10
    4
    2
    2
    2
    4
    3
    4
    4
    Dermatitis atopic
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 98 (2.04%)
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    3 / 101 (2.97%)
    2 / 33 (6.06%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    2 / 87 (2.30%)
    2 / 95 (2.11%)
         occurrences all number
    1
    3
    1
    1
    3
    2
    0
    0
    2
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 55 (1.82%)
    12 / 98 (12.24%)
    6 / 102 (5.88%)
    1 / 100 (1.00%)
    7 / 101 (6.93%)
    1 / 33 (3.03%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    1 / 95 (1.05%)
         occurrences all number
    1
    16
    11
    1
    8
    1
    1
    0
    1
    1
    Middle insomnia
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 98 (6.12%)
    4 / 102 (3.92%)
    7 / 100 (7.00%)
    6 / 101 (5.94%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    3
    7
    4
    7
    10
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 98 (3.06%)
    1 / 102 (0.98%)
    3 / 100 (3.00%)
    3 / 101 (2.97%)
    1 / 33 (3.03%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    3
    3
    1
    3
    3
    1
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    6 / 102 (5.88%)
    3 / 100 (3.00%)
    0 / 101 (0.00%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    0
    1
    6
    3
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 55 (18.18%)
    29 / 98 (29.59%)
    21 / 102 (20.59%)
    32 / 100 (32.00%)
    34 / 101 (33.66%)
    8 / 33 (24.24%)
    26 / 85 (30.59%)
    20 / 91 (21.98%)
    24 / 87 (27.59%)
    30 / 95 (31.58%)
         occurrences all number
    13
    51
    31
    51
    47
    13
    45
    27
    39
    50
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 55 (7.27%)
    6 / 98 (6.12%)
    13 / 102 (12.75%)
    20 / 100 (20.00%)
    16 / 101 (15.84%)
    5 / 33 (15.15%)
    7 / 85 (8.24%)
    15 / 91 (16.48%)
    13 / 87 (14.94%)
    11 / 95 (11.58%)
         occurrences all number
    5
    7
    16
    28
    19
    8
    12
    27
    21
    16
    Bronchitis
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 98 (5.10%)
    8 / 102 (7.84%)
    10 / 100 (10.00%)
    16 / 101 (15.84%)
    3 / 33 (9.09%)
    12 / 85 (14.12%)
    14 / 91 (15.38%)
    18 / 87 (20.69%)
    20 / 95 (21.05%)
         occurrences all number
    1
    8
    8
    15
    22
    5
    24
    18
    28
    34
    Gastroenteritis
         subjects affected / exposed
    2 / 55 (3.64%)
    2 / 98 (2.04%)
    5 / 102 (4.90%)
    4 / 100 (4.00%)
    11 / 101 (10.89%)
    4 / 33 (12.12%)
    7 / 85 (8.24%)
    9 / 91 (9.89%)
    14 / 87 (16.09%)
    14 / 95 (14.74%)
         occurrences all number
    2
    3
    5
    4
    11
    4
    8
    9
    15
    16
    Bronchiolitis
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 98 (5.10%)
    7 / 102 (6.86%)
    5 / 100 (5.00%)
    9 / 101 (8.91%)
    2 / 33 (6.06%)
    6 / 85 (7.06%)
    4 / 91 (4.40%)
    9 / 87 (10.34%)
    11 / 95 (11.58%)
         occurrences all number
    3
    8
    8
    6
    12
    3
    6
    4
    14
    14
    Rhinitis
         subjects affected / exposed
    5 / 55 (9.09%)
    13 / 98 (13.27%)
    13 / 102 (12.75%)
    5 / 100 (5.00%)
    5 / 101 (4.95%)
    3 / 33 (9.09%)
    9 / 85 (10.59%)
    7 / 91 (7.69%)
    1 / 87 (1.15%)
    6 / 95 (6.32%)
         occurrences all number
    5
    16
    13
    5
    6
    4
    14
    13
    1
    10
    Ear infection
         subjects affected / exposed
    0 / 55 (0.00%)
    7 / 98 (7.14%)
    6 / 102 (5.88%)
    7 / 100 (7.00%)
    4 / 101 (3.96%)
    6 / 33 (18.18%)
    13 / 85 (15.29%)
    13 / 91 (14.29%)
    14 / 87 (16.09%)
    17 / 95 (17.89%)
         occurrences all number
    0
    9
    6
    13
    6
    11
    30
    23
    28
    37
    Tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    3 / 33 (9.09%)
    7 / 85 (8.24%)
    6 / 91 (6.59%)
    7 / 87 (8.05%)
    10 / 95 (10.53%)
         occurrences all number
    0
    2
    0
    0
    0
    3
    12
    8
    10
    13
    Pharyngitis
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 98 (4.08%)
    3 / 102 (2.94%)
    2 / 100 (2.00%)
    3 / 101 (2.97%)
    0 / 33 (0.00%)
    5 / 85 (5.88%)
    4 / 91 (4.40%)
    6 / 87 (6.90%)
    8 / 95 (8.42%)
         occurrences all number
    0
    5
    3
    2
    3
    0
    8
    4
    7
    13
    Otitis media
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    3 / 100 (3.00%)
    2 / 101 (1.98%)
    6 / 33 (18.18%)
    5 / 85 (5.88%)
    4 / 91 (4.40%)
    4 / 87 (4.60%)
    5 / 95 (5.26%)
         occurrences all number
    0
    1
    1
    3
    2
    7
    6
    6
    8
    6
    Influenza
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 98 (1.02%)
    3 / 102 (2.94%)
    3 / 100 (3.00%)
    4 / 101 (3.96%)
    1 / 33 (3.03%)
    2 / 85 (2.35%)
    0 / 91 (0.00%)
    2 / 87 (2.30%)
    5 / 95 (5.26%)
         occurrences all number
    1
    1
    3
    5
    4
    1
    2
    0
    2
    6
    Varicella
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    2 / 33 (6.06%)
    5 / 85 (5.88%)
    4 / 91 (4.40%)
    6 / 87 (6.90%)
    4 / 95 (4.21%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    5
    5
    6
    4
    Roseola
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    2 / 100 (2.00%)
    0 / 101 (0.00%)
    1 / 33 (3.03%)
    3 / 85 (3.53%)
    5 / 91 (5.49%)
    1 / 87 (1.15%)
    4 / 95 (4.21%)
         occurrences all number
    1
    1
    0
    2
    0
    1
    3
    5
    1
    4
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    2 / 33 (6.06%)
    1 / 85 (1.18%)
    2 / 91 (2.20%)
    3 / 87 (3.45%)
    3 / 95 (3.16%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    2
    3
    5
    Acute tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    2 / 101 (1.98%)
    2 / 33 (6.06%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    2 / 95 (2.11%)
         occurrences all number
    0
    0
    0
    0
    2
    3
    1
    0
    1
    2
    Croup infectious
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 101 (0.99%)
    2 / 33 (6.06%)
    1 / 85 (1.18%)
    1 / 91 (1.10%)
    1 / 87 (1.15%)
    1 / 95 (1.05%)
         occurrences all number
    0
    2
    1
    0
    1
    2
    1
    1
    1
    1
    Eye Infection
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    0 / 101 (0.00%)
    3 / 33 (9.09%)
    0 / 85 (0.00%)
    0 / 91 (0.00%)
    1 / 87 (1.15%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    3
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 101 (0.99%)
    2 / 33 (6.06%)
    1 / 85 (1.18%)
    0 / 91 (0.00%)
    0 / 87 (0.00%)
    0 / 95 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    2
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 98 (5.10%)
    3 / 102 (2.94%)
    5 / 100 (5.00%)
    1 / 101 (0.99%)
    0 / 33 (0.00%)
    0 / 85 (0.00%)
    1 / 91 (1.10%)
    0 / 87 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    1
    6
    3
    5
    1
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2010
    Changes discussed with and agreed by the FDA and the EMEA: - Reduction of the number of patients/placebo arm - Extension from facial to non-facial IH - Suppression of the 50:50 balance USA/EU - Clarifications concerning monitoring process and statistical analysis.
    21 Sep 2010
    Local to Czech Repulic to comply with the Czech rules : Addition of an exclusion criteria - Exclusion of patients in whom a systemic corticosteroid treatment was the most advisable therapy in the opinion of the Investigator.
    29 Nov 2010
    - Clarification of the list of treatment (authorized and not authorized) - Clarification of monitoring process linked to patient safety - Modification according some national regulations.
    19 Mar 2012
    Clarification of pharmaceutical, monitoring, statistical process/analysis.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25693013
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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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