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    Clinical Trial Results:
    Evolution of Growth Rate in Children Suffering From a Disease Associated With Growth Retardation and Treated by Genotonorm. A Pilot Study

    Summary
    EudraCT number
    2004-002991-40
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    05 Oct 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A6281269
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00163215
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias: 93-8122-001; CTN 93-8122-001
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer Call Center, Pfizer Inc, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer Call Center, Pfizer Inc, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    06 Mar 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show an increase in annual growth rate (AGR) 3 years after Visit 2. Annual growth rate in standard deviation (SD) after 3 years will be compared to growth rate before the start of growth hormone (GH) treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jan 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    25
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Total number of subjects screened were 64, out of which 46 were enrolled in the study. The study was conducted in France which started on 17 January 2005 and completed on 05 October 2011.

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

    Arms
    Arm title
    Genotonorm
    Arm description
    Genotonorm (recombinant somatropin) up to maximum of 50 microgram/kilogram/day (mcg/kg/day) subcutaneously as decided by the investigator, divided in 7 daily doses for up to 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Genotonorm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Genotonorm was administered up to maximum of 50 mcg/kg/day, divided in 7 daily doses for up to 3 years.

    Number of subjects in period 1
    Genotonorm
    Started
    46
    Completed
    31
    Not completed
    15
         Withdrawal by Subject
    5
         Lack of efficacy
    3
         Unspecified
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    Subjects were administered with Genotonorm (recombinant somatropin) up to maximum of 50 mcg/kg/day subcutaneously as decided by the investigator, divided in 7 daily doses for up to 3 years.

    Reporting group values
    Overall Study Total
    Number of subjects
    46 46
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.3 ± 3.6 -
    Gender categorical
    Units: Subjects
        Female
    12 12
        Male
    34 34

    End points

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    End points reporting groups
    Reporting group title
    Genotonorm
    Reporting group description
    Genotonorm (recombinant somatropin) up to maximum of 50 microgram/kilogram/day (mcg/kg/day) subcutaneously as decided by the investigator, divided in 7 daily doses for up to 3 years.

    Primary: Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36 in Intent-to-Treat (ITT) Population

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    End point title
    Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36 in Intent-to-Treat (ITT) Population [1]
    End point description
    Change in annual growth rate (AGR) standard deviation score (SDS) for chronological age (CA) derived by subtracting AGR SDS CA at baseline from each time point (Yx) value. AGR at Yx= (height Yx–height Y[x-1])/([date of Yx–date of Y{x-1}]/365.25). AGR as SDS calculated using Sempe reference means and standard deviations (SD) for growth rate. AGR SDS CA (for both baseline and Yx)= (AGR-reference mean for growth rate CA)/reference SD for growth rate CA. CA calculated as integer (Date of height measurement-Date of birth)/365.25*12. SDS indicates how similar subject was to reference population. Intent to Treat (ITT) set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Primary
    End point timeframe
    Baseline, Month 36
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Genotonorm
    Number of subjects analysed
    42 [2]
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n = 42)
    -1.29 ± 1.79
        Change at Month 36 (n = 26)
    2.36 ± 1.98
    Notes
    [2] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Primary: Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36 in Per-Protocol (PP) Population

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    End point title
    Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36 in Per-Protocol (PP) Population [3]
    End point description
    Change in AGR, SDS for CA derived by subtracting AGR, SDS and CA at baseline from each time point (Yx) value. AGR at Yx= (height Yx–height Y[x-1])/([date of Yx–date of Y{x-1}]/365.25). AGR as SDS calculated using Sempe reference means and SD for growth rate. AGR SDS CA (for both baseline and Yx)= (AGR-reference mean for growth rate CA)/reference SD for growth rate CA. CA calculated as integer (Date of height measurement-Date of birth)/365.25*12. SDS indicates how similar subject was to reference population. PP analysis set included all subjects in the ITT set without a major protocol violation. Here “n” signifies subjects evaluated at that time point.
    End point type
    Primary
    End point timeframe
    Baseline, Month 36
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Genotonorm
    Number of subjects analysed
    14 [4]
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n = 14)
    -1.98 ± 1.06
        Change at Month 36 (n = 12)
    2.7 ± 2.02
    Notes
    [4] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Annual Growth Rate at Month 12, Month 24 and Month 36 in ITT Population

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    End point title
    Change From Baseline in Annual Growth Rate at Month 12, Month 24 and Month 36 in ITT Population
    End point description
    Change in AGR at Yx was derived by subtracting AGR at baseline from Yx value. AGR was calculated each year and rescaled to 1 year if the interval between Yx and Y[x-1] was not 365 days, as long as a subject remained in the study. AGR at Yx was calculated using the previous height measurements (Y[x-1]) and height recorded at Yx (AGR Yx = [height Yx–height Y{x-1}] / ([date of Yx – date of Y{x-1}] /365.25). ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    42 [5]
    Units: centimeter per year (cm/year)
    arithmetic mean (standard deviation)
        Baseline (n = 42)
    4.5 ± 1.8
        Change at Month 12 (n = 36)
    3.3 ± 2.9
        Change at Month 24 (n = 35)
    2.5 ± 2.7
        Change at Month 36 (n = 26)
    2 ± 2
    Notes
    [5] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Annual Growth Rate at Month 12, Month 24, Month 36 in PP Population

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    End point title
    Change From Baseline in Annual Growth Rate at Month 12, Month 24, Month 36 in PP Population
    End point description
    Change in AGR at Yx was derived by subtracting AGR at baseline from Yx value. AGR was calculated each year and rescaled to 1 year if the interval between Yx and Y[x-1] was not 365 days, as long as a subject remained in the study. AGR at Yx was calculated using the previous height measurements (Y[x-1]) and height recorded at Yx (AGR Yx = [height Yx–height Y{x-1}] / ([date of Yx – date of Y{x-1}] /365.25). PP analysis set included all subjects in the ITT set without a major protocol violation. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    14 [6]
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (n = 14)
    4 ± 1
        Change at Month 12 (n = 14)
    4 ± 1
        Change at Month 24 (n = 14)
    2.5 ± 1.3
        Change at Month 36 (n = 12)
    1.8 ± 1.1
    Notes
    [6] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Height

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    End point title
    Height
    End point description
    Height was measured using a wall mounted device (example, Harpenden stadiometer). The standing height of the subjects was measured two times and the mean of these measurements was recorded. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    44
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n = 44)
    123.9 ± 17.3
        Month 12 (n = 39)
    130.3 ± 17.5
        Month 24 (n = 39)
    137.8 ± 16.9
        Month 36 (n = 27)
    143.5 ± 15.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height at Month 12, Month 24 and Month 36

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    End point title
    Change From Baseline in Height at Month 12, Month 24 and Month 36
    End point description
    Height was measured using a wall mounted device (example, Harpenden stadiometer). The standing height of the subjects was measured two times and the mean of these measurements was recorded. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    39 [7]
    Units: cm
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 39)
    7.7 ± 2.1
        Change at Month 24 (n = 39)
    14.9 ± 3.4
        Change at Month 36 (n = 27)
    22.3 ± 3.7
    Notes
    [7] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Mean Height Standard Deviation Score (SDS) for Chronological Age (CA)

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    End point title
    Mean Height Standard Deviation Score (SDS) for Chronological Age (CA)
    End point description
    Height was measured using a wall mounted device (example, Harpenden stadiometer). The standing height of the subject was measured two times and the mean of these measurements was recorded. Height SDS CA Yx = (height Yx – reference mean for CA Yx) / reference SD for CA Yx. Height in SDS was calculated using Sempe reference means and SD for height. CA calculated as integer (Date of height measurement–Date of birth)/365.25*12. SDS indicates how similar the subject was to the reference population. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here“n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    44
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n = 44)
    -2.84 ± 0.91
        Month 12 (n = 39)
    -2.42 ± 0.98
        Month 24 (n = 39)
    -2.09 ± 1.08
        Month 36 (n = 27)
    -1.72 ± 0.96
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12, Month 24 and Month 36

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    End point title
    Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12, Month 24 and Month 36
    End point description
    Change in height SDS CA was derived by subtracting height SDS CA at baseline from Yx value. Height SDS CA (for both baseline and Yx) = (height – reference mean for CA)/reference SD for CA. Height in SDS was calculated using Sempe reference means and SD for height. CA calculated as integer (Date of height measurement – Date of birth)/365.25*12. SDS indicates how similar the subject was to the reference population. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    39 [8]
    Units: SDS
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 39)
    0.41 ± 0.42
        Change at Month 24 (n = 39)
    0.81 ± 0.6
        Change at Month 36 (n = 27)
    1.03 ± 0.62
    Notes
    [8] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Mean Height Standard Deviation Score (SDS) for Bone Age (BA)

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    End point title
    Mean Height Standard Deviation Score (SDS) for Bone Age (BA)
    End point description
    Height SDS BA Yx = (height Yx – reference mean for BA Yx) / reference SD for BA Yx. Height in SDS was calculated using Sempe reference means and SD for height. BA was estimated locally using an X-ray from the left wrist and hand. SDS indicates how similar the subject was to the reference population. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    35 [9]
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n = 35)
    -0.71 ± 1.52
        Month 12 (n = 32)
    -0.55 ± 1.68
        Month 24 (n = 32)
    -0.49 ± 1.77
        Month 36 (n = 20)
    -0.3 ± 1.46
    Notes
    [9] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height Standard Deviation Score (SDS) for Bone Age (BA) at Month 12, Month 24 and Month 36

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    End point title
    Change From Baseline in Height Standard Deviation Score (SDS) for Bone Age (BA) at Month 12, Month 24 and Month 36
    End point description
    Change in height SDS BA was derived by subtracting height SDS BA at baseline from Yx value. Height SDS BA (for both baseline and Yx) = (height–reference mean for BA)/reference SD for BA. Height in SDS was calculated using Sempe reference means and SD for height. BA was estimated locally using an X-ray from the left wrist and hand. SDS indicates how similar the subjects was to the reference population. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    28 [10]
    Units: SDS
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 28)
    -0.05 ± 1.04
        Change at Month 24 (n = 27)
    0.06 ± 1.36
        Change at Month 36 (n = 17)
    0.05 ± 1.32
    Notes
    [10] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12 and Month 24 in ITT Population

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    End point title
    Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12 and Month 24 in ITT Population
    End point description
    Change in AGR SDS for CA derived by subtracting AGR SDS CA at baseline from Yx value. AGR at Yx= (height Yx–height Y[x-1])/([date of Yx–date of Y{x-1}]/365.25). AGR as SDS calculated using Sempe reference means and standard deviations (SD) for growth rate. AGR SDS CA (for both baseline and Yx)= (AGR-reference mean for growth rate CA)/reference SD for growth rate CA. CA calculated as integer (Date of height measurement-Date of birth)/365.25*12. SDS indicates how similar subject was to reference population. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    Genotonorm
    Number of subjects analysed
    36 [11]
    Units: SDS
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 36)
    3.23 ± 2.66
        Change at Month 24 (n = 35)
    2.62 ± 2.05
    Notes
    [11] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12 and Month 24 in PP Population

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    End point title
    Change From Baseline in Annual Growth Rate Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12 and Month 24 in PP Population
    End point description
    Change in AGR, SDS for CA derived by subtracting AGR SDS CA at baseline from each time point (Yx) value. AGR at Yx= (height Yx–height Y[x-1])/([date of Yx–date of Y{x-1}]/365.25). AGR as SDS calculated using Sempe reference means and standard deviations (SD) for growth rate. AGR SDS CA (for both baseline and Yx)= (AGR-reference mean for growth rate CA)/reference SD for growth rate CA. CA calculated as integer (Date of height measurement-Date of birth)/365.25*12. SDS indicates how similar subject was to reference population. PP analysis set included all subjects in the ITT set without a major protocol violation.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    Genotonorm
    Number of subjects analysed
    14 [12]
    Units: SDS
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 14)
    4.4 ± 2.12
        Change at Month 24 (n = 14)
    2.97 ± 1.68
    Notes
    [12] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Mean Growth Rate Standard Deviation Score (SDS) for Bone Age (BA)

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    End point title
    Mean Growth Rate Standard Deviation Score (SDS) for Bone Age (BA)
    End point description
    AGR at Yx was derived by subtracting AGR at baseline from Yx value. AGR was calculated each year and rescaled to 1 year if the interval between Yx and Y[x-1] was not 365 days, as long as a subject remained in the study. AGR at Yx = [height Yx–height Y{x-1}] / ([date of Yx – date of Y{x-1}] /365.25). GR in SDS was calculated using Sempe reference means and SD for growth. BA was estimated locally using an X-ray from the left wrist and hand. SDS indicates how similar the subject was to the reference population. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    28 [13]
    Units: SDS
    arithmetic mean (standard deviation)
        Month 12 (n = 28)
    1.06 ± 1.57
        Month 24 (n = 25)
    0.46 ± 1.15
        Month 36 (n = 19)
    -0.01 ± 1.19
    Notes
    [13] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Body Mass Index (BMI)

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    End point title
    Body Mass Index (BMI)
    End point description
    BMI was used to measure body fat based on height and weight. It was calculated as body weight (kilogram) divided by the height (meter) squared. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies those subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    44
    Units: kilogram per square meter (kg/m^2)
    arithmetic mean (standard deviation)
        Baseline (n = 44)
    16.57 ± 2.37
        Month 12 (n = 39)
    16.96 ± 2.64
        Month 24 (n = 39)
    17.59 ± 2.69
        Month 36 (n = 27)
    17.67 ± 2.08
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI) at Month 12, Month 24 and Month 36

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    End point title
    Change From Baseline in Body Mass Index (BMI) at Month 12, Month 24 and Month 36
    End point description
    BMI was used to measure body fat based on height and weight. It was calculated as body weight (kilogram) divided by the height (meter) squared. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    39 [14]
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Change at Month 12 (n = 39)
    0.52 ± 1.01
        Change at Month 24 (n = 39)
    1.3 ± 1.35
        Change at Month 36 (n = 27)
    1.89 ± 1.61
    Notes
    [14] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Age (BA) at Month 12, Month 24 and Month 36

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    End point title
    Change From Baseline in Bone Age (BA) at Month 12, Month 24 and Month 36
    End point description
    BA was estimated locally using an X-ray from the left wrist and hand. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    40 [15]
    Units: years
    arithmetic mean (standard deviation)
        Baseline (n = 40)
    8.7 ± 3.28
        Change at Month 12 (n = 28)
    1.69 ± 0.9
        Change at Month 24 (n = 28)
    2.6 ± 0.97
        Change at Month 36 (n = 21)
    4.04 ± 1.09
    Notes
    [15] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Ratio of Bone Age (BA) to Chronological Age (CA)

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    End point title
    Ratio of Bone Age (BA) to Chronological Age (CA)
    End point description
    BA was estimated locally using an X-ray from the left wrist and hand. CA at the date of corresponding X-ray (Date of X-ray – Date of birth)/365.25. Ratio of BA/CA at each annual study visit was calculated. ITT set included all subjects who received at least 1 dose of study medication and had at least 1 evaluation of height after start of study medication. Here “n” signifies subjects evaluated at that time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 36
    End point values
    Genotonorm
    Number of subjects analysed
    40 [16]
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 40)
    0.79 ± 0.15
        Month 12 (n = 30)
    0.83 ± 0.15
        Month 24 (n = 32)
    0.85 ± 0.12
        Month 36 (n = 23)
    0.89 ± 0.14
    Notes
    [16] - N= (Number of subjects analyzed) signifies those subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from Baseline up to the end of treatment (month 36). SAEs were reported any time during the study through and including 28 days after the last dose of the study drug.
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another, or 1 subject may have experienced both serious, nonserious event during study. EU BR specific AE tables were generatedseparately as per EU format using latest coding.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Genotonorm
    Reporting group description
    Genotonorm (recombinant somatropin) up to maximum of 50 microgram/kilogram/day (mcg/kg/day) subcutaneously as decided by the investigator, divided in 7 daily doses for up to 3 years.

    Serious adverse events
    Genotonorm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 46 (8.70%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Genotonorm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 46 (45.65%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Surgical and medical procedures
    Ear tube insertion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Encopresis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Investigations
    Ammonia increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    Loss of consciousness
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Renal failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Nail disorder
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Skin irritation
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Bone pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Knee deformity
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Rickets
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Scoliosis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Insulin resistance
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Infections and infestations
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    3
    Tracheitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2011
    Following review of growth hormone (GH) data conducted by the European Medicines Agency (EMA) and the Committee for Medicinal Products for Human use (CHMP), the agencies had requested that the highest approved dose in Europe of 50 mcg/kg/day of recombinant human GH not be exceeded.

    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.
    Certain GCP compliance issues noted at one site for this study. Impact on the study results from noted GCP compliance issues could not be fully assessed; however, it was considered that the results were compromised for the interpretation of efficacy
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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