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    Clinical Trial Results:
    RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-1 (rhIGF-1) TREATMENT OF PREPUBERTAL CHILDREN WITH GROWTH FAILURE ASSOCIATED WITH PRIMARY IGF-1 DEFICIENCY: A PHASE 3, RANDOMIZED, OPEN LABEL, OBSERVATION-CONTROLLED, MULTICENTER, PARALLEL-DOSE COMPARISON TRIAL.

    Summary
    EudraCT number
    2019-001020-36
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    02 Jul 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Sep 2019
    First version publication date
    22 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00125164
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ipsen Pharma
    Sponsor organisation address
    65 Quai Georges Gorse, Boulogne Billancourt, France, 92100
    Public contact
    Medical Director, Ipsen Pharma, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen Pharma, clinical.trials@ipsen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jul 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the safety and efficacy of recombinant human insulin-like growth factor-1 (rhIGF-1) in promoting the growth of children with growth failure associated with Primary IGF-1 deficiency (IGFD).
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice, the ethical principles that have their origins in the Declaration of Helsinki, and applicable national and local regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Mar 2004
    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
    United States: 137
    Worldwide total number of subjects
    137
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    133
    Adolescents (12-17 years)
    4
    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
    This was a Phase 3, randomised, open-label, observation-controlled, multi-centre, parallel-dose comparison trial of rhIGF-1 in prepubertal male and female subjects with growth failure associated with Primary IGFD. The trial was conducted at 30 clinical sites in the United States from 02 July 2008 to 14 March 2014.

    Pre-assignment
    Screening details
    Subjects were initially randomised to 40 micrograms (μg) rhIGF-1 per kilogram (kg) twice a day (BID), 80 μg rhIGF-1 per kg BID, or untreated control. Following a protocol amendment, a 120 μg/kg BID arm was added, randomisation to the 40 μg/kg BID arm was discontinued and on-going subjects in this arm were reassigned to receive 120 μg/kg BID.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Untreated Control
    Arm description
    Subjects were randomised to the untreated control group and did not receive any investigational medical product for the duration of the 1 year study period.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    40 μg/kg rhIGF-1 BID
    Arm description
    Subjects were initially randomised to receive 40 μg/kg rhIGF-1 BID. Following a protocol amendment, the 11 subjects in this arm who had not already completed the study at this dose were reassigned to receive 120 μg/kg rhIGF-1 BID for the remainder of the 1 year study period. All 16 subjects initially randomised to this arm were excluded from the efficacy analyses.
    Arm type
    Experimental

    Investigational medicinal product name
    rhIGF-1
    Investigational medicinal product code
    Other name
    mecasermin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injections of 40 μg/kg rhIGF-1, BID, for up to 1 year or until dose group was discontinued following protocol amendment. Doses were up-titrated from 20 μg/kg rhIGF-1 to the final dose of 40 μg/kg rhIGF-1 over the first 2 weeks of the study. Injections were given immediately before breakfast and dinner. After the protocol amendment, subjects on-going in this group r commenced therapy at 80 μg/kg rhIFG-1 BID for 2 weeks followed by 120 μg/kg rhIFG-1 BID for the remainder of the trial. Dose adjustments were made every 3 months based upon the subject’s weight.

    Arm title
    80 μg/kg rhIGF-1 BID
    Arm description
    Subjects were randomised to receive 80 μg/kg rhIGF-1 BID for the duration of the 1 year study period.
    Arm type
    Experimental

    Investigational medicinal product name
    rhIGF-1
    Investigational medicinal product code
    Other name
    mecasermin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injections of 80 μg/kg rhIGF-1 BID, for up to 1 year. Doses were up-titrated from 20 μg/kg rhIGF-1 to the final dose of 80 μg/kg rhIGF-1 over the first 4 weeks of the study. Injections were given immediately before breakfast and dinner. Dose adjustments were made every 3 months based upon the subject’s weight.

    Arm title
    120 μg/kg rhIGF-1 BID
    Arm description
    Subjects were randomised to receive 120 μg/kg rhIGF-1 BID for the duration of the 1 year study period.
    Arm type
    Experimental

    Investigational medicinal product name
    rhIGF-1
    Investigational medicinal product code
    Other name
    mecasermin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injections of 120 μg/kg rhIGF-1 BID, for up to 1 year. Doses were up-titrated from 40 μg/kg rhIGF-1 to the final dose of 120 μg/kg rhIGF-1 over the first 4 weeks of the study. Injections were given immediately before breakfast and dinner. Dose adjustments were made every 3 months based upon the subject’s weight.

    Number of subjects in period 1 [1]
    Untreated Control 40 μg/kg rhIGF-1 BID 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Started
    25
    16
    44
    51
    Completed
    23
    16
    40
    45
    Not completed
    2
    0
    4
    6
         Adverse event, non-fatal
    -
    -
    2
    4
         Consent withdrawn by subject
    2
    -
    1
    1
         Lost to follow-up
    -
    -
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Consent for one randomised subject was withdrawn prior to any study measurements. This subject was excluded from the baseline population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Untreated Control
    Reporting group description
    Subjects were randomised to the untreated control group and did not receive any investigational medical product for the duration of the 1 year study period.

    Reporting group title
    40 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were initially randomised to receive 40 μg/kg rhIGF-1 BID. Following a protocol amendment, the 11 subjects in this arm who had not already completed the study at this dose were reassigned to receive 120 μg/kg rhIGF-1 BID for the remainder of the 1 year study period. All 16 subjects initially randomised to this arm were excluded from the efficacy analyses.

    Reporting group title
    80 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 80 μg/kg rhIGF-1 BID for the duration of the 1 year study period.

    Reporting group title
    120 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 120 μg/kg rhIGF-1 BID for the duration of the 1 year study period.

    Reporting group values
    Untreated Control 40 μg/kg rhIGF-1 BID 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID Total
    Number of subjects
    25 16 44 51 136
    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: years
        arithmetic mean (standard deviation)
    7.0 ± 2.4 7.6 ± 2.4 7.7 ± 2.4 7.6 ± 2.7 -
    Gender categorical
    Units: Subjects
        Female
    10 4 14 8 36
        Male
    15 12 30 43 100
    Race/Ethnicity
    Units: Subjects
        Asian
    1 0 1 2 4
        Black
    0 0 0 2 2
        Native Hawaiian or Pacific Islander
    0 0 0 1 1
        White
    22 16 38 41 117
        Hispanic
    2 0 4 4 10
        Other
    0 0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Untreated Control
    Reporting group description
    Subjects were randomised to the untreated control group and did not receive any investigational medical product for the duration of the 1 year study period.

    Reporting group title
    40 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were initially randomised to receive 40 μg/kg rhIGF-1 BID. Following a protocol amendment, the 11 subjects in this arm who had not already completed the study at this dose were reassigned to receive 120 μg/kg rhIGF-1 BID for the remainder of the 1 year study period. All 16 subjects initially randomised to this arm were excluded from the efficacy analyses.

    Reporting group title
    80 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 80 μg/kg rhIGF-1 BID for the duration of the 1 year study period.

    Reporting group title
    120 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 120 μg/kg rhIGF-1 BID for the duration of the 1 year study period.

    Subject analysis set title
    Untreated Control
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects randomised to the untreated control group.

    Subject analysis set title
    80 μg/kg rhIGF-1 BID
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects randomised to the 80 μg/kg rhIGF-1 BID group.

    Subject analysis set title
    120 μg/kg rhIGF-1 BID
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects randomised to the 120 μg/kg rhIGF-1 BID group.

    Primary: Height Velocity at 1 Year

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    End point title
    Height Velocity at 1 Year
    End point description
    Height was measured standing, without shoes, as the average of 3 measurements by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer at Day 1 (baseline) and each study visit up to 1 year (12 months). First-year height velocity (growth in centimetres [cm]) is presented for all subjects with a baseline height measurement and at least 1 on-treatment height measurement. Missing first-year (Month 12) height measurements were imputed using the last observation carried forward method.
    End point type
    Primary
    End point timeframe
    Baseline and at 1 year.
    End point values
    Untreated Control 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Number of subjects analysed
    22
    42
    49
    Units: cm/year
        arithmetic mean (standard deviation)
    5.2 ± 1.0
    6.9 ± 1.0
    7.7 ± 1.5
    Statistical analysis title
    80 μg/kg rhIGF-1 BID versus Untreated Control
    Statistical analysis description
    Comparison of 80 μg/kg rhIGF-1 BID group with the untreated control group using analysis of covariance (ANCOVA), where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    Untreated Control v 80 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    1.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.19
         upper limit
    2.39
    Notes
    [1] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.
    Statistical analysis title
    120 μg/kg rhIGF-1 BID versus Untreated Control
    Statistical analysis description
    Comparison of 120 μg/kg rhIGF-1 BID group with the untreated control group using ANCOVA, where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    Untreated Control v 120 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    2.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.99
         upper limit
    3.16
    Notes
    [2] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.
    Statistical analysis title
    80 μg/kg rhIGF-1 BID versus 120 μg/kg rhIGF-1 BID
    Statistical analysis description
    Comparison of the 80 μg/kg rhIGF-1 BID group with the 120 μg/kg rhIGF-1 BID group using ANCOVA, where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    80 μg/kg rhIGF-1 BID v 120 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0032 [3]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.31
    Notes
    [3] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.

    Secondary: Mean Change From Baseline in Height Standard Deviation (SD) Score at 1 Year

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    End point title
    Mean Change From Baseline in Height Standard Deviation (SD) Score at 1 Year
    End point description
    Height was measured standing without shoes as the average of 3 measurements by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer at Day 1 (baseline) and each study visit up to 1 year (12 months). Height SD score was calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control as the subject value minus the mean divided by the standard deviation. The mean and the standard deviation could vary depending on the age and sex of the subject. Mean change from baseline in height SD score at 1 year is presented for all subjects with a baseline height measurement and at least 1 on-treatment height measurement. Missing first-year (Month 12) height measurements were imputed using the last observation carried forward method.
    End point type
    Secondary
    End point timeframe
    Baseline and at 1 year.
    End point values
    Untreated Control 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Number of subjects analysed
    22
    42
    49
    Units: SD score/year
        arithmetic mean (standard deviation)
    0.02 ± 0.24
    0.38 ± 0.17
    0.48 ± 0.32
    Statistical analysis title
    80 μg/kg rhIGF-1 BID versus Untreated Control
    Statistical analysis description
    Comparison of 80 μg/kg BID group with the untreated control group using ANCOVA, where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    Untreated Control v 80 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.24
         upper limit
    0.5
    Notes
    [4] - The 2-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.
    Statistical analysis title
    120 μg/kg rhIGF-1 BID versus Untreated Control
    Statistical analysis description
    Comparison of 120 μg/kg rhIGF-1 BID group with the untreated control group using ANCOVA, where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    Untreated Control v 120 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.6
    Notes
    [5] - The 2-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.
    Statistical analysis title
    80 μg/kg rhIGF-1 BID versus 120 μg/kg rhIGF-1 BID
    Statistical analysis description
    Comparison of 80 μg/kgrhIGF-1 BID group with the 120 μg/kg rhIGF-1 BID group using ANCOVA, where the covariates are the baseline height SD score stratum used in the randomisation, the pretreatment height velocity, the baseline bone age, the baseline chronological age, and sex.
    Comparison groups
    120 μg/kg rhIGF-1 BID v 80 μg/kg rhIGF-1 BID
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0495 [6]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.22
    Notes
    [6] - The 2-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.

    Secondary: Mean Change from Baseline in Bone Age at 1 Year

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    End point title
    Mean Change from Baseline in Bone Age at 1 Year
    End point description
    Plain X-rays of the left hand and wrist exposed were taken at baseline and at 1 year for bone age appraisal. The films were sent to a central facility for standardised evaluation. The mean change in bone age from baseline at 1 year (Month 12) is presented for all subjects with both baseline and 1 year bone age measurements.
    End point type
    Secondary
    End point timeframe
    Baseline and at 1 year.
    End point values
    Untreated Control 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Number of subjects analysed
    23
    40
    44
    Units: Years
        arithmetic mean (standard deviation)
    0.8 ± 0.3
    1.1 ± 0.4
    1.2 ± 0.5
    No statistical analyses for this end point

    Secondary: Mean Percent Change From Baseline in Serum Growth Factor Concentrations at 1 Year

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    End point title
    Mean Percent Change From Baseline in Serum Growth Factor Concentrations at 1 Year
    End point description
    Growth factor panels were drawn at various visits during the study. Blood samples were collected while subjects were in a fasting state for measuring the level of serum IGF-1 and IGF binding protein (IGFBP)-3 and in a non-fasting state for IGF-2 and IGFBP-2. Mean percent change from baseline for each of the growth factor panels 1 year are presented. n = number of subjects with baseline measurement and 1 year measurements for each of the growth factor panels.
    End point type
    Secondary
    End point timeframe
    Baseline and at 1 year.
    End point values
    Untreated Control 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Number of subjects analysed
    25 [7]
    44 [8]
    51 [9]
    Units: Percent change
    arithmetic mean (standard deviation)
        IGF-1
    64 ± 120
    227 ± 220
    266 ± 215
        IGF-2
    14 ± 28
    -38 ± 37
    -37 ± 32
        IGFBP-2
    -16 ± 26
    58 ± 84
    61 ± 79
        IGFBP-3
    13 ± 33
    -19 ± 22
    -19 ± 28
    Notes
    [7] - IGF-1, n=18; IGF-2, n=17; IGFBP-2, n=15; IGFBP-3, n=18
    [8] - IGF-1, n=34; IGF-2, n=35; IGFBP-2, n=32; IGFBP-3, n=34
    [9] - IGF-1, n=42; IGF-2, n=40; IGFBP-2, n=34; IGFBP-3, n=42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected until 30 days after last subject visit or until resolution (up to approximately 13 months overall).
    Adverse event reporting additional description
    All subjects initially randomised to receive 40 μg/kg rhIGF-1 BID were analysed together, regardless of actual dose received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Untreated Control
    Reporting group description
    Subjects were randomised to the untreated control group and did not receive any investigational medical product for the duration of the 1 year study period.

    Reporting group title
    40 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were initially randomised to receive 40 μg/kg rhIGF-1 BID. Following a protocol amendment, subjects in this arm who had not already completed the study at this dose were reassigned to receive 120 μg/kg rhIGF-1 BID for the remainder of the 1 year study period.

    Reporting group title
    80 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 80 μg/kg rhIGF-1 BID and received this dose for the duration of the 1 year study period.

    Reporting group title
    120 μg/kg rhIGF-1 BID
    Reporting group description
    Subjects were randomised to receive 120 μg/kg rhIGF-1 BID for the duration of the 1 year study period.

    Serious adverse events
    Untreated Control 40 μg/kg rhIGF-1 BID 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 16 (6.25%)
    2 / 44 (4.55%)
    5 / 51 (9.80%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Cor triatriatum
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         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
    Nervous system disorders
    Benign intracranial hypertension
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (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 escherichia coli
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (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
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (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
    Endocrine disorders
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (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 viral
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Untreated Control 40 μg/kg rhIGF-1 BID 80 μg/kg rhIGF-1 BID 120 μg/kg rhIGF-1 BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 25 (92.00%)
    16 / 16 (100.00%)
    40 / 44 (90.91%)
    50 / 51 (98.04%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Surgical and medical procedures
    Orthodontic Procedure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Dysplastic Naevus Syndrome
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Melanocytic Naevus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Drug Eruption
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Multiple Allergies
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Seasonal Allergy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    2 / 44 (4.55%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    2
    1
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 16 (18.75%)
    6 / 44 (13.64%)
    4 / 51 (7.84%)
         occurrences all number
    0
    3
    10
    7
    Injection site pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    7 / 44 (15.91%)
    4 / 51 (7.84%)
         occurrences all number
    0
    2
    7
    6
    Chest Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    4
    Fatigue
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Feeling Abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Feeling Hot
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Flank Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Influenza Like Illness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    1
    0
    0
    4
    Injection Site Erythema
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    4 / 44 (9.09%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Injection Site Haematoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Injection Site Haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection Site Hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    2 / 44 (4.55%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    2
    3
    Injection Site Irritation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Injection Site Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    4
    1
    Injection Site Reaction
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    6 / 51 (11.76%)
         occurrences all number
    0
    0
    2
    19
    Injection Site Swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection Site Urticaria
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Irritability
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Malaise
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    1 / 44 (2.27%)
    3 / 51 (5.88%)
         occurrences all number
    0
    2
    1
    4
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 16 (12.50%)
    11 / 44 (25.00%)
    13 / 51 (25.49%)
         occurrences all number
    6
    5
    15
    18
    Psychiatric disorders
    Anger
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Attention Deficit/Hyperactivity Disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    0
    2
    Disturbance in attention
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    1
    3
    Mental Status Changes
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    1
    2
    Precocious Puberty
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Accidental Poisoning
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthropod Bite
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    0
    2
    Clavicle Fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Concussion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    3
    Excoriation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Foreign Body Trauma
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head Injury
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    1
    2
    Heat Exhaustion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint Injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint Sprain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    1
    0
    0
    2
    Laceration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post Procedural Discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Skin Laceration
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Thermal Burn
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    2
    Tooth Fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Upper Limb Fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    1
    Wrist Fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Blood Glucose Decreased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood Glucose Increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Blood Thyroid Stimulating Hormone Increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Body Temperature Increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Eosinophil Count Increased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Heart Rate Irregular
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 16 (25.00%)
    10 / 44 (22.73%)
    7 / 51 (13.73%)
         occurrences all number
    7
    6
    16
    7
    Nasal Congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 16 (25.00%)
    5 / 44 (11.36%)
    5 / 51 (9.80%)
         occurrences all number
    0
    5
    6
    7
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 16 (18.75%)
    4 / 44 (9.09%)
    4 / 51 (7.84%)
         occurrences all number
    0
    3
    4
    4
    Adenoidal Hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    0
    1
    Allergic Respiratory Symptom
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Asthma
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 16 (12.50%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Bronchial Hyperreactivity
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    1
    1
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Productive Cough
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    0
    2
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis Allergic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    2 / 51 (3.92%)
         occurrences all number
    1
    0
    2
    2
    Rhinitis Seasonal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    4
    3
    Sinus Congestion
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Snoring
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    1 / 44 (2.27%)
    3 / 51 (5.88%)
         occurrences all number
    0
    2
    1
    3
    Tonsillar Hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    1
    2
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    2 / 44 (4.55%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    5
    1
    Wheezing
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 16 (18.75%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    3
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 25 (16.00%)
    8 / 16 (50.00%)
    13 / 44 (29.55%)
    21 / 51 (41.18%)
         occurrences all number
    9
    16
    30
    35
    Dizziness
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    1
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Tension Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Tremor
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Hypermetropia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Pseudopapilloedema
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Superficial Injury Of Eye
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    6 / 51 (11.76%)
         occurrences all number
    0
    3
    1
    8
    Ear pain
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 16 (6.25%)
    3 / 44 (6.82%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    3
    2
    Ear Congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoacusis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Middle Ear Effusion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 16 (25.00%)
    6 / 44 (13.64%)
    2 / 51 (3.92%)
         occurrences all number
    0
    5
    7
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 16 (18.75%)
    4 / 44 (9.09%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    7
    4
    Abdominal Discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    2 / 44 (4.55%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    1 / 44 (2.27%)
    9 / 51 (17.65%)
         occurrences all number
    0
    2
    1
    12
    Breath Odour
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chapped Lips
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Colitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    2
    0
    4
    Dyspepsia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    2
    Gastritis
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 16 (25.00%)
    4 / 44 (9.09%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    4
    3
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingival Hypertrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    0
    1
    Inguinal Hernia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Mouth Ulceration
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural Nausea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Stomach Discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    1
    0
    3
    Toothache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 16 (31.25%)
    9 / 44 (20.45%)
    14 / 51 (27.45%)
         occurrences all number
    1
    6
    17
    21
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis Allergic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    3
    1
    Dermatitis Contact
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    3 / 44 (6.82%)
    2 / 51 (3.92%)
         occurrences all number
    1
    0
    3
    2
    Eczema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    0
    1
    Hair Texture Abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Lip Blister
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Lip Swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pityriasis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pityriasis Rosea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    2
    Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    2
    2
    Rash Generalised
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    1
    Rash Macular
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash Papular
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    2
    Rash Pruritic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Skin Exfoliation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin Hypopigmentation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    3 / 44 (6.82%)
    0 / 51 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Varicella
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 16 (6.25%)
    3 / 44 (6.82%)
    6 / 51 (11.76%)
         occurrences all number
    1
    1
    5
    7
    Arthralgia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    1
    2
    2
    Back Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    5
    Tendon Disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 16 (12.50%)
    3 / 44 (6.82%)
    9 / 51 (17.65%)
         occurrences all number
    1
    4
    3
    10
    Anorexia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    3
    1
    Decreased Appetite
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    3
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Increased Appetite
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    1
    2
    Lactose Intolerance
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 25 (24.00%)
    3 / 16 (18.75%)
    10 / 44 (22.73%)
    12 / 51 (23.53%)
         occurrences all number
    7
    5
    17
    13
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 16 (12.50%)
    5 / 44 (11.36%)
    7 / 51 (13.73%)
         occurrences all number
    3
    3
    5
    12
    Gastroenteritis viral
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 16 (18.75%)
    8 / 44 (18.18%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    10
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 16 (6.25%)
    4 / 44 (9.09%)
    7 / 51 (13.73%)
         occurrences all number
    2
    1
    6
    9
    Influenza
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 16 (6.25%)
    4 / 44 (9.09%)
    7 / 51 (13.73%)
         occurrences all number
    1
    1
    7
    10
    Otitis media
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 16 (18.75%)
    2 / 44 (4.55%)
    4 / 51 (7.84%)
         occurrences all number
    3
    3
    3
    6
    Sinusitis
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    4 / 51 (7.84%)
         occurrences all number
    4
    0
    1
    8
    Bronchitis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 16 (12.50%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Cellulitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Croup Infectious
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear Infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Hordeolum
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Impetigo
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Molluscum Contagiosum
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    2 / 44 (4.55%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Oral Herpes
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Otitis Externa
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    3
    0
    0
    1
    Otitis Media Acute
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 16 (6.25%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    3 / 44 (6.82%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Rotavirus Infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin Papilloma
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    1 / 44 (2.27%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Staphylococcal Skin Infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tinea Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    0
    1
    Tooth Abscess
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    0
    2
    Viral Infection
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 16 (6.25%)
    2 / 44 (4.55%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    2
    1
    Viral Upper Respiratory Tract
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 16 (0.00%)
    0 / 44 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2004
    Change in randomisation ratio, number of arms, and dose levels. Subjects were randomised in a 2:3:3 ratio to the untreated control arm or to one of two rhIGF-1 treatment arms at two dose levels: subcutaneous injections BID at 40 or 80 μg/kg body weight. The randomisation ratio was changed to enhance the power of the test. Anthropometry (hand, foot, and jaw lengths) was added to the safety endpoints to detect acromegalic growth. Dose adjustments were revised to allow up-titration of doses to the new specified doses.Certain exclusion criterion were updated and timing of blood draws revised.
    15 Jul 2004
    Other sponsor-approved stimulants were allowed in addition to arginine-clonidine GH stimulation tests. Visits 3 and 4 could be combined if all eligibility criteria were met prior to Visit 3. The rhIGF-1 dosing instructions were changed to instruct the subject to eat a meal within 30 minutes of the injection, either before or after.
    01 Dec 2004
    Age range was expanded from 4-10 to 3-10 years for girls, and from 4-11 to 3-11 years for boys.
    10 Nov 2005
    Dose levels were increased from 40 or 80 μg/kg body weight BID to 80 or 120 μg/kg body weight BID. In addition, subjects who were already assigned to a BID of 40μg/kg body weight, prior to Amendment 4, were reassigned to a BID dose of 120 μg/kg body weight. Dose adjustments were also revised. Funduscopic examination was added to safety endpoints.

    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.
    Following a protocol amendment on 10 November 2005 subjects assigned to 40 μg/kg rhIGF-1 BID arm were excluded from all efficacy analyses.
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