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    Clinical Trial Results:
    Evolution of growth rate in children with growth retardation related to long-term glucocorticosteroid therapy and treated by Genotonorm

    Summary
    EudraCT number
    2004-002992-17
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    23 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A6281271
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00163189
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov.inquiries@pfizer.com
    Scientific contact
    ClinicalTrials.gov 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
    29 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show an increase in height after 3 years of growth hormone (GH) treatment. However subjects will be followed for up to 5 years of treatment. Height in standard deviation (SD) for chronological age (CA) after 3 years will be compared to Height in SD for CA before inclusion in the trial.
    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
    10 Jan 2005
    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
    France: 98
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    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)
    37
    Adolescents (12-17 years)
    60
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The reason ‘Study Terminated by Sponsor’ mentioned in the subject disposition indicates the termination of study at a site (due to Good Clinical Practice [CP] compliance issues) and does not reflect the overall status of study.

    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
    Subjects received genotonorm administered weekly, divided into 7 daily subcutaneous injections for up to 60 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Genotonorm
    Investigational medicinal product code
    Other name
    Recombinant somatropin
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 0.46 milligram per kilogram (mg/kg) of genotonorm (maximum dose not exceeding 50 microgram/kg/day (mcg/kg/day) for up to 60 months.

    Number of subjects in period 1
    Genotonorm
    Started
    98
    Completed
    35
    Not completed
    63
         Death
    3
         ' Adverse Event'
    6
         Did not meet continuation criterion
    16
         ' Protocol Violation'
    2
         Lack of efficacy
    7
         Study terminated by sponsor
    11
         Unspecified
    6
         Consent withdrawn by subject
    11
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genotonorm
    Reporting group description
    Subjects received genotonorm administered weekly, divided into 7 daily subcutaneous injections for up to 60 months.

    Reporting group values
    Genotonorm Total
    Number of subjects
    98 98
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.8 ± 3.2 -
    Gender categorical
    Units: Subjects
        Female
    24 24
        Male
    74 74

    End points

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    End points reporting groups
    Reporting group title
    Genotonorm
    Reporting group description
    Subjects received genotonorm administered weekly, divided into 7 daily subcutaneous injections for up to 60 months.

    Primary: Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36: Full Analysis Population

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    End point title
    Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 36: Full Analysis Population [1]
    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; Yx refers to the value at particular timepoint x. 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. Full analysis set (FAS) included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified 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: Statistical analysis has been provided in the attachment.
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: Standard Deviation Score (SDS)
    arithmetic mean (standard deviation)
         Baseline (n=58)
    -2.91 ± 1.19
        Change at Month 36 (n=30)
    0.8 ± 1.03
    Attachments
    Change in Height SDS for CA: FAS population
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Standard Deviation Score (SD) for Chronological Age (CA) at Month 36: Per Protocol (PP) Population

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    End point title
    Change From Baseline in Height Standard Deviation Score (SD) for Chronological Age (CA) at Month 36: Per Protocol (PP) Population [2]
    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; Yx refers to the value at particular timepoint x. 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. PP analysis set included all subjects (excluding a site with GCP issues) who received at least 1 dose of GH, had at least 1 subsequent rating of height, no major protocol violation till first 3 years post initiation of treatment and total GH treatment duration of 36 months or more. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Primary
    End point timeframe
    Baseline, Month 36
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis has been provided in the attachment.
    End point values
    Genotonorm
    Number of subjects analysed
    21
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=21)
    -2.86 ± 0.89
        Change at Month 36 (n=19)
    0.81 ± 1.18
    Attachments
    Change in height SDS for CA: PP population
    No statistical analyses for this end point

    Secondary: Mean Height

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    End point title
    Mean Height
    End point description
    The standing height measurements were performed 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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: centimeters (cm)
    arithmetic mean (standard deviation)
         Baseline (n=58)
    133.9 ± 15.7
        Month 12 (n=50)
    139.5 ± 16.8
        Month 24 (n=41)
    146 ± 16.4
        Month 36 (n=30)
    150.4 ± 16
         Month 48 (n=14)
    152.4 ± 16
        Month 60 (n=9)
    156 ± 11.3
    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
    The standing height measurements were performed 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 BA Yx = (height Yx – reference mean for BA Yx) / reference SD for BA Yx; Yx refers to the value at particular timepoint x. 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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=51)
    -0.29 ± 1.15
        Month 12 (n=40)
    -0.36 ± 1.52
        Month 24 (n=29)
    0.11 ± 1.36
        Month 36 (n=24)
    0.14 ± 1.48
        Month 48 (n=13)
    -0.26 ± 1.28
        Month 60 (n=7)
    -0.19 ± 1.15
    No statistical analyses for this end point

    Secondary: Annual Growth Rate (AGR)

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    End point title
    Annual Growth Rate (AGR)
    End point description
    AGR at Yx was derived by subtracting AGR at baseline from Yx value. AGR was calculated each year and re scaled 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). Yx refers to the value at particular timepoint x. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (n=52)
    3 ± 2
        Month 12 (n=49)
    6.7 ± 2.6
        Month 24 (n=41)
    6 ± 2.7
        Month 36 (n=30)
    5.9 ± 2.7
        Month 48 (n=14)
    4.8 ± 2.5
        Month 60 (n=9)
    4.9 ± 3
    No statistical analyses for this end point

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

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    End point title
    Growth Rate (GR) Standard Deviation Score (SDS) for Bone Age (BA)
    End point description
    GR SDS BA Yx = (GR Yx – reference mean for BA Yx) / reference SD for BA Yx; Yx refers to the value at particular timepoint x. GR in SDS was calculated using Sempe reference means and SD for GR. BA was estimated locally using an X-ray from the left wrist and hand. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: SDS
    arithmetic mean (standard deviation)
        Month 12 (n=36)
    -0.13 ± 2.15
        Month 24 (n=25)
    0.07 ± 2.51
        Month 36 (n=20)
    0.05 ± 1.94
        Month 48 (n=11)
    -1 ± 1.38
        Month 60 (n=7)
    -0.43 ± 1.22
    No statistical analyses for this end point

    Secondary: Growth Rate (GR) Standard Deviation Score (SDS) for Chronological Age (CA)

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    End point title
    Growth Rate (GR) Standard Deviation Score (SDS) for Chronological Age (CA)
    End point description
    GR SDS CA Yx = (GR Yx – reference mean for CA Yx) / reference SD for CA Yx; Yx refers to the value at particular timepoint x. GR in SDS was calculated using Sempe reference means and SD for GR. CA calculated as integer (Date of height measurement–Date of birth)/365.25*12. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=52)
    -2.04 ± 2.03
        Month 12 (n=49)
    1.77 ± 4.29
        Month 24 (n=41)
    5.26 ± 16.79
        Month 36 (n=29)
    3.64 ± 9.06
        Month 48 (n=13)
    0.93 ± 2.73
        Month 60 (n=9)
    1.4 ± 1.71
    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 calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Baseline (n=58)
    19.4 ± 3.6
        Month 12 (n=50)
    19.1 ± 3.1
        Month 24 (n=41)
    19.4 ± 3
        Month 36 (n=30)
    19.4 ± 2.4
        Month 48 (n=14)
    19.7 ± 3
        Month 60 (n=9)
    20.8 ± 3.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height at Month 12, 24, 36, 48 and 60

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    End point title
    Change From Baseline in Height at Month 12, 24, 36, 48 and 60
    End point description
    The standing height measurements were performed 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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=58)
    133.9 ± 15.7
        Change at Month 12 (n=50)
    6.8 ± 2.8
        Change at Month 24 (n=41)
    12.9 ± 4.7
        Change at Month 36 (n=30)
    18.8 ± 6.1
        Change at Month 48 (n=14)
    23.9 ± 8.5
        Change at Month 60 (n=9)
    30.3 ± 7.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12, 24, 48 and 60

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    End point title
    Change From Baseline in Height Standard Deviation Score (SDS) for Chronological Age (CA) at Month 12, 24, 48 and 60
    End point description
    The standing height measurements were performed 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; Yx refers to the value at particular timepoint x. 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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=58)
    -2.91 ± 1.19
        Change at Month 12 (n=50)
    0.28 ± 0.57
        Change at Month 24 (n=41)
    0.57 ± 0.95
        Change at Month 48 (n=14)
    0.82 ± 1.42
        Change at Month 60 (n=9)
    0.75 ± 1.13
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height Standard Deviation Score (SDS) for Bone Age (BA) at Month 12, 24, 36, 48 and 60

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    End point title
    Change From Baseline in Height Standard Deviation Score (SDS) for Bone Age (BA) at Month 12, 24, 36, 48 and 60
    End point description
    The standing height measurements were performed 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 BA Yx = (height Yx – reference mean for BA Yx) / reference SD for BA Yx; Yx refers to the value at particular timepoint x. 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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=51)
    -0.29 ± 1.15
        Change at Month 12 (n=36)
    -0.02 ± 0.99
        Change at Month 24 (n=26)
    0.28 ± 1.18
        Change at Month 36 (n=21)
    0.31 ± 1.17
        Change at Month 48 (n=13)
    -0.08 ± 1.3
        Change at Month 60 (n=7)
    0.01 ± 1.33
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Age (BA) at Month 12, 24, 36, 48 and 60

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    End point title
    Change From Baseline in Bone Age (BA) at Month 12, 24, 36, 48 and 60
    End point description
    BA was estimated locally using an X-ray from the left wrist and hand. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: months
    arithmetic mean (standard deviation)
        Baseline (n=58)
    117.9 ± 34.6
        Change at Month 12 (n=37)
    17.8 ± 11
        Change at Month 24 (n=32)
    28.2 ± 17.9
        Change at Month 36 (n=23)
    36.5 ± 17.8
        Change at Month 48 (n=13)
    52.8 ± 21.2
        Change at Month 60 (n=7)
    70 ± 27
    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. FAS included all subjects (excluding a site with GCP issues) who had received at least 1 injection of GH and had at least 1 post-Baseline measurement of height. Here "n" signifies those subjects who were evaluable for the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    58
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=58)
    0.78 ± 0.1
        Month 12 (n=37)
    0.82 ± 0.11
        Month 24 (n=32)
    0.8 ± 0.09
        Month 36 (n=23)
    0.79 ± 0.1
        Month 48 (n=13)
    0.81 ± 0.08
        Month 60 (n=7)
    0.85 ± 0.1
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs include both SAEs and non-SAEs. Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 28 days after last study treatment
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: subjects
        AEs
    84
        SAEs
    45
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Significant Changes in Physical Examinations

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    End point title
    Number of Subjects With Significant Changes in Physical Examinations
    End point description
    Number of subjects with clinically significant physical examinations changes since previous visit were reported. Physical examination including estimation of pubertal stage and blood pressure measurement. Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Month 12, 24, 36, 48, 60, End of Treatment (EOT)
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: subjects
        Baseline (n=93)
    1
        Month 12 (n=93)
    16
        Month 24 (n=72)
    16
        Month 36 (n=52)
    5
        Month 48 (n=23)
    4
        Month 60 (n=12)
    2
        EOT (n=44)
    11
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With at Least 1 Medical or Surgical History

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    End point title
    Number of Subjects With at Least 1 Medical or Surgical History
    End point description
    Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Screening
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: subjects
    67
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects Who Received Concomitant Medications

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    End point title
    Number of Subjects Who Received Concomitant Medications
    End point description
    Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Month 60
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: subjects
    98
    No statistical analyses for this end point

    Other pre-specified: Fasting Serum Insulin Like Growth Factor-1 (IGF-1) Levels

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    End point title
    Fasting Serum Insulin Like Growth Factor-1 (IGF-1) Levels
    End point description
    Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Screening, Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Screening (n=93)
    335 ± 157
        Month 6 (n=63)
    604 ± 291
        Month 12 (n=71)
    538 ± 268
        Month 18 (n=47)
    624 ± 251
        Month 24 (n=62)
    579 ± 262
        Month 30 (n=50)
    559 ± 250
        Month 36 (n=44)
    511 ± 186
        Month 42 (n=22)
    555 ± 224
        Month 48 (n=21)
    581 ± 244
        Month 54 (n=16)
    593 ± 184
        Month 60 (n=10)
    501 ± 180
    No statistical analyses for this end point

    Other pre-specified: Fasting and Postprandial Plasma Glucose Levels at Month 12, 24, 36, 48 and 60

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    End point title
    Fasting and Postprandial Plasma Glucose Levels at Month 12, 24, 36, 48 and 60
    End point description
    Fasting and 2 hours plasma glucose levels were assessed using standard oral glucose tolerance test (OGTT). Safety analysis set included all subjects (including a site with GCP issues) who had received at least 1 study dose of GH.
    End point type
    Other pre-specified
    End point timeframe
    Screening, Month 12, 24, 36, 48, 60
    End point values
    Genotonorm
    Number of subjects analysed
    98
    Units: milli mole per liter (mmol/L)
    arithmetic mean (standard deviation)
        Glucose Fasting: Screening (n=91)
    4.5 ± 0.7
        Glucose Fasting: Month 12 (n=69)
    4.6 ± 0.7
        Glucose Fasting: Month 24 (n=59)
    4.7 ± 0.6
        Glucose Fasting: Month 36 (n=45)
    4.6 ± 0.5
        Glucose Fasting: Month 48 (n=20)
    4.7 ± 0.4
        Glucose Fasting: Month 60 (n=14)
    4.5 ± 0.6
        Glucose Postprandial: Screening (n=94)
    5.6 ± 1.2
        Glucose Postprandial: Month 12 (n=66)
    6.1 ± 1.4
        Glucose Postprandial: Month 24 (n=59)
    6.1 ± 1.4
        Glucose Postprandial: Month 36 (n=41)
    6.4 ± 1.6
        Glucose Postprandial: Month 48 (n=19)
    6.1 ± 1.1
        Glucose Postprandial: Month 60 (n=13)
    6.3 ± 1.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline till 28 days after last study treatment
    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 one subject and as nonserious in another subject, or one subject may have experienced both a serious and non serious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Genotonorm
    Reporting group description
    Subjects received genotonorm administered weekly, divided into 7 daily subcutaneous injections for up to 60 months.

    Serious adverse events
    Genotonorm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 98 (45.92%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral coldness
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrostomy closure
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic operation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Treatment noncompliance
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Polycystic ovaries
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    accident
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Alcohol poisoning
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Subvalvular aortic stenosis
         subjects affected / exposed
    1 / 98 (1.02%)
         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 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Benign intracranial hypertension
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Protein-losing gastroenteropathy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cytolytic hepatitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    7 / 98 (7.14%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Proteinuria
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epiphysiolysis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint destruction
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Knee deformity
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Varicella
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Empedobacter brevis infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis cryptosporidial
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nail bed infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pertussis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 98 (1.02%)
         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
    81 / 98 (82.65%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    4
    Thrombosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    4
    Acrochordon
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Skin papilloma
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Vasculitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    7 / 98 (7.14%)
         occurrences all number
    7
    Fatigue
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Injection site pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Oedema
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Affective disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Graft dysfunction
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Joint sprain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Investigations
    Insulin-like growth factor increased
         subjects affected / exposed
    13 / 98 (13.27%)
         occurrences all number
    19
    Weight decreased
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    8
    Epistaxis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Lung disorder
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Pharyngeal erythema
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    3
    Rhinitis allergic
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Haemoptysis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Lymphadenopathy
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    3
    Anaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Lymphadenitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences all number
    15
    Dizziness
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Hemicephalalgia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hyperreflexia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypotonia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    4
    Conjunctivitis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    4
    Ocular hypertension
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Papilloedema
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Uveitis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    3
    Chalazion
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Eye disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Myopia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Night blindness
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Periorbital disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Retinal detachment
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Visual acuity reduced
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Vitritis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 98 (9.18%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Gastritis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Duodenitis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Gingivitis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Odynophagia
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Gingival hypertrophy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Ileus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Intestinal polyp
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Oral disorder
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cytolytic hepatitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    11 / 98 (11.22%)
         occurrences all number
    37
    Dysuria
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Proteinuria
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    6
    Enuresis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Renal impairment
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    7
    Skin lesion
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Skin striae
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Dermatomyositis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    3
    Acanthosis nigricans
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Dermal cyst
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Ecchymosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypertrichosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Ingrowing nail
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Pityriasis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Rash macular
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Scar
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Skin nodule
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Swelling face
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 98 (9.18%)
         occurrences all number
    9
    Back pain
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Juvenile arthritis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    4
    Muscle spasms
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Scoliosis
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    3
    Arthritis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    4
    Knee deformity
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Amyotrophy
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Bone pain
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Joint effusion
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Joint stiffness
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Mobility decreased
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Osteoporosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    3
    Tendonitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Glucose tolerance impaired
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences all number
    8
    Anorexia
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Diabetes mellitus
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Obesity
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences all number
    13
    Nasopharyngitis
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    6
    Tonsillitis
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    6
    Gastroenteritis
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Pharyngitis
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    5
    Rhinitis
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    4
    Varicella
         subjects affected / exposed
    4 / 98 (4.08%)
         occurrences all number
    4
    Ear infection
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 98 (3.06%)
         occurrences all number
    6
    Otitis media
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    3
    Respiratory tract infection
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Tinea pedis
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Viral infection
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Chikungunya virus infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Dermatophytosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Eye infection toxoplasmal
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Gangrene
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Oral fungal infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Penile infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Pyelonephritis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    2
    Tinea versicolour
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Tracheitis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Trichophytosis
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2005
    1) Extended BA at the inclusion to less than (<) 15 years for males and <13 years for females. 2) Subjects treated with glucocorticoids at a dose lower than 0.2 mg/kg/day were also included.
    13 Nov 2008
    1) Inclusion period was extended 18 December 2009 in the study. 2) Duration of Genotonorm treatment was extended up to 5 years.
    16 Feb 2011
    1) The maximal tolerated dose of the genotonorm was specified to be limited to 50 mcg/kg/day.
    14 Aug 2012
    1) Inclusion criteria was changed to include obtaining agreement of subjects of childbearing potential to use a highly effective method of contraception throughout the study and for 28 days after the last dose of assigned treatment.

    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.
    One site in this study was found to have GCP related issues and was discontinued. Consequently, the Sponsor determined that the data from this site would be excluded from all efficacy analyses. For analysis of safety data, all sites were included.
    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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