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    Clinical Trial Results:
    Prevention of Retarded Growth by Early Treatment with Recombinant Human Growth Factor Genotonorm (Registered) in Children with Systemic Forms of Chronic Juvenile Arthritis Receiving Long-term Corticosteroid Therapy. Extension of the Study Beyond Three Years

    Summary
    EudraCT number
    2014-004105-32
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    28 Oct 2011

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

    Trial information

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    Trial identification
    Sponsor protocol code
    307-MET-9002-052
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00174291
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias: A6281024
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer 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
    06 Nov 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2011
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    -To evaluate the effect of increasing the Human growth hormone (hGH) dose (0.6 versus 0.46 milligram per kilogram per week [mg/kg/week ] or 1.8 versus 1.4 international unit per kilogram per week [IU/kg/week]) on the statural response: 1) in subjects initially in the treated group of Study CTN 97-8129-016, by comparing the statural response observed with that obtained during the first therapeutic phase at a dose of 0.46 mg/kg/week, or 1.4 IU/kg/week. 2) in subjects initially in the control group of Study CTN 97-8129-016, by comparing the statural response observed with that of subjects in study CTN 94-8123-014. -To assess the value of early treatment during the course of arthritic disease by comparing the height acquired in the medium term by subjects in the two dose groups: treated from the start or 1 year to 15 months after the diagnosis of Chronic Juvenile Arthritis (CJA), or treated for 4 years after the diagnosis.
    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
    26 Mar 2002
    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: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    18
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects included in previous study CTN 97-8129-016 were eligible for this study.

    Pre-assignment
    Screening details
    This study was conducted in France from 26 March 2002 to 28 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
    Are arms mutually exclusive
    Yes

    Arm title
    Somatropin (Without Previous Somatropin Exposure)
    Arm description
    Subjects who received matching placebo for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 microgram/kilogram/day (mcg/kg/day), subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was less than or equal (<=) 1.5 centimeter (cm) per year during the preceding 12 months and bone age was greater than or equal to (>=) 17 years for boys and 15 years for girls.
    Arm type
    Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    Genotonorm
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received somatropin (Genotonorm) up to 0.6 mg/kg/week, equivalent to 1.8 IU/kg/week, divided in 7 daily doses subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, equivalent to 1.4 IU/kg/week, divided in 7 daily doses subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, equivalent to 0.35 mg/kg/week or 1.05 IU/kg/week, subcutaneously until the final height was reached or up to Year 8.5.

    Arm title
    Somatropin (With Previous Somatropin Exposure)
    Arm description
    Subjects who received low dose of somatropin (Genotonorm) for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was <=1.5 cm per year during the preceding 12 months and bone age was >=17 years for boys and 15 years for girls.
    Arm type
    Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    Genotonorm
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received somatropin (Genotonorm) up to 0.6 mg/kg/week, equivalent to 1.8 IU/kg/week, divided in 7 daily doses initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, equivalent to 1.4 IU/kg/week, divided in 7 daily doses until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, equivalent to 0.35 mg/kg/week or 1.05 IU/kg/week, until the final height was reached or up to Year 8.5.

    Number of subjects in period 1
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Started
    10
    11
    Completed
    4
    6
    Not completed
    6
    5
         Study terminated by sponsor
    -
    1
         Protocol Violation
    2
    -
         Consent withdrawn by subject
    3
    3
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Somatropin (Without Previous Somatropin Exposure)
    Reporting group description
    Subjects who received matching placebo for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 microgram/kilogram/day (mcg/kg/day), subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was less than or equal (<=) 1.5 centimeter (cm) per year during the preceding 12 months and bone age was greater than or equal to (>=) 17 years for boys and 15 years for girls.

    Reporting group title
    Somatropin (With Previous Somatropin Exposure)
    Reporting group description
    Subjects who received low dose of somatropin (Genotonorm) for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was <=1.5 cm per year during the preceding 12 months and bone age was >=17 years for boys and 15 years for girls.

    Reporting group values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure) Total
    Number of subjects
    10 11 21
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    8.5 ± 3.3 8.3 ± 2.6 -
    Gender, Male/Female
    Units: subjects
        Female
    4 6 10
        Male
    6 5 11

    End points

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    End points reporting groups
    Reporting group title
    Somatropin (Without Previous Somatropin Exposure)
    Reporting group description
    Subjects who received matching placebo for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 microgram/kilogram/day (mcg/kg/day), subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was less than or equal (<=) 1.5 centimeter (cm) per year during the preceding 12 months and bone age was greater than or equal to (>=) 17 years for boys and 15 years for girls.

    Reporting group title
    Somatropin (With Previous Somatropin Exposure)
    Reporting group description
    Subjects who received low dose of somatropin (Genotonorm) for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was <=1.5 cm per year during the preceding 12 months and bone age was >=17 years for boys and 15 years for girls.

    Primary: Change from Baseline in Annual Rate of Growth Standard Deviation Score (SDS) at Year 3

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    End point title
    Change from Baseline in Annual Rate of Growth Standard Deviation Score (SDS) at Year 3 [1]
    End point description
    Annual rate of growth SDS was obtained by measuring the annual growth rate, subtracting chronological age- and gender-appropriate mean annual growth rate and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. Full Analysis Set (FAS) included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement.
    End point type
    Primary
    End point timeframe
    Baseline, Year 3
    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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    9 [2]
    6 [3]
    Units: SDS
    median (full range (min-max))
        Baseline
    -2.96 (-6.4 to 1.5)
    -0.21 (-3 to 4.5)
        Change at Year 3
    3.52 (-5.1 to 11.2)
    1.34 (-3.6 to 6.2)
    Notes
    [2] - Subjects who were evaluable for this measure.
    [3] - Subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Primary: Change from Baseline in Annual Rate of Growth Standard Deviation Score (SDS) at Final Height

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    End point title
    Change from Baseline in Annual Rate of Growth Standard Deviation Score (SDS) at Final Height [4]
    End point description
    Annual rate of growth SDS was obtained by measuring the annual growth rate, subtracting chronological age- and gender-appropriate mean annual growth rate and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population.
    End point type
    Primary
    End point timeframe
    Baseline, final height (assessed up to Year 9.5)
    Notes
    [4] - 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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: SDS
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [5] - Data was not analyzed because of change in planned analysis after early termination of the study.
    [6] - Data was not analyzed because of change in planned analysis after early termination of the study.
    No statistical analyses for this end point

    Primary: Change from Baseline in Height Standard Deviation Score (SDS) at Year 3

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    End point title
    Change from Baseline in Height Standard Deviation Score (SDS) at Year 3 [7]
    End point description
    Height was measured using a wall mounted device (example, Harpenden stadiometer). Height SDS was obtained by measuring the height, subtracting chronological age- and gender-appropriate mean height and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement.
    End point type
    Primary
    End point timeframe
    Baseline, Year 3
    Notes
    [7] - 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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    9 [8]
    6 [9]
    Units: SDS
    median (full range (min-max))
        Baseline
    -2.34 (-4.8 to -1.4)
    -0.61 (-3.7 to 1.4)
        Change at Year 3
    1.21 (-0.7 to 2.4)
    0.73 (-2.4 to 2.6)
    Notes
    [8] - Subjects who were evaluable for this measure.
    [9] - Subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Primary: Change from Baseline in Height Standard Deviation Score (SDS) at Final Height

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    End point title
    Change from Baseline in Height Standard Deviation Score (SDS) at Final Height [10]
    End point description
    Height was measured using a wall mounted device (example, Harpenden stadiometer). Height SDS was obtained by measuring the height, subtracting chronological age- and gender-appropriate mean height and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement.
    End point type
    Primary
    End point timeframe
    Baseline, final height (assessed up to Year 9.5)
    Notes
    [10] - 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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    2 [11]
    3 [12]
    Units: SDS
    median (full range (min-max))
        Baseline
    -0.94 (-1.4 to -0.5)
    0.96 (-3.7 to 2.3)
        Change at Final Height
    0.08 (-0.7 to 0.9)
    -0.43 (-0.8 to 0.5)
    Notes
    [11] - Subjects who were evaluable for this measure.
    [12] - Subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Primary: Change from Baseline in Predicted Height Standard Deviation Score (SDS) at Year 3

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    End point title
    Change from Baseline in Predicted Height Standard Deviation Score (SDS) at Year 3 [13]
    End point description
    Predicted height was calculated according to Greulich and Pyle using Bayley Pinneau method. Predicted height SDS was obtained by calculating the predicted height, subtracting chronological age- and gender-appropriate mean predicted height and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement.
    End point type
    Primary
    End point timeframe
    Baseline, Year 3
    Notes
    [13] - 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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    3 [14]
    4 [15]
    Units: SDS
    median (full range (min-max))
        Baseline
    -2.43 (-2.6 to -1.6)
    -0.76 (-1.8 to 0.7)
        Change at Year 3
    1.63 (0.1 to 2.3)
    0.68 (-2.6 to 2)
    Notes
    [14] - Subjects who were evaluable for this measure.
    [15] - Subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Primary: Change from Baseline in Predicted Height Standard Deviation Score (SDS) at Final Height

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    End point title
    Change from Baseline in Predicted Height Standard Deviation Score (SDS) at Final Height [16]
    End point description
    Predicted height was calculated according to Greulich and Pyle using Bayley Pinneau method. Predicted height SDS was obtained by calculating the predicted height, subtracting chronological age- and gender-appropriate mean predicted height and dividing the result by standard deviation of that mean (as obtained from chronological age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement.
    End point type
    Primary
    End point timeframe
    Baseline, final height (assessed up to Year 9.5)
    Notes
    [16] - 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
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    2 [17]
    2 [18]
    Units: SDS
    median (full range (min-max))
        Baseline
    -1.74 (-2.4 to -1.1)
    -0.84 (-1.8 to 0.1)
        Change at Final Height
    0.71 (0.1 to 1.3)
    -0.67 (-2.4 to 1)
    Notes
    [17] - Subjects who were evaluable for this measure.
    [18] - Subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) Concentration at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9

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    End point title
    Change From Baseline in Insulin-like Growth Factor-1 (IGF-1) Concentration at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9
    End point description
    FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement. Here, 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. Here "99999" in the median and full range values signifies not estimable (NA), since none of the subjects were available in the group "Somatropin (With Previous Somatropin Exposure)" at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    10
    11
    Units: milligram per deciliter (mg/dL)
    median (full range (min-max))
        Baseline (n = 10, 11)
    0.0165 (0.0075 to 0.0517)
    0.0361 (0.0181 to 0.0868)
        Change at Year 0.5 (n = 10, 9)
    0.0255 (-0.0145 to 0.039)
    0.0017 (-0.0256 to 0.0681)
        Change at Year 1 (n = 10, 11)
    0.0329 (-0.0061 to 0.0531)
    0.0093 (-0.0358 to 0.0488)
        Change at Year 1.5 (n = 9, 11)
    0.0406 (-0.0035 to 0.0754)
    0.0066 (-0.0194 to 0.0599)
        Change at Year 2 (n = 9, 10)
    0.0223 (0.0055 to 0.0673)
    0.0221 (-0.0292 to 0.0534)
        Change at Year 2.5 (n = 8, 8)
    0.0366 (-0.0109 to 0.0558)
    0.0201 (-0.0237 to 0.047)
        Change at Year 3 (n = 9, 7)
    0.0445 (-0.006 to 0.0557)
    0.013 (-0.0049 to 0.0648)
        Change at Year 3.5 (n = 7, 7)
    0.0396 (0.0014 to 0.0707)
    0.01 (-0.0022 to 0.0436)
        Change at Year 4 (n = 7, 6)
    0.0453 (0.0175 to 0.0646)
    0.0212 (-0.0014 to 0.0485)
        Change at Year 4.5 (n = 6, 5)
    0.0431 (0.008 to 0.1233)
    0.0142 (0.0042 to 0.0303)
        Change at Year 5 (n = 7, 5)
    0.0369 (0.0258 to 0.0902)
    0.0236 (0.0164 to 0.053)
        Change at Year 5.5 (n = 5, 4)
    0.0448 (0.0258 to 0.0965)
    0.0186 (0.0119 to 0.0356)
        Change at Year 6 (n = 5, 4)
    0.0454 (0.0155 to 0.0718)
    0.0256 (0 to 0.0434)
        Change at Year 6.5 (n = 5, 2)
    0.0593 (0.0512 to 0.0766)
    0.0195 (0.0125 to 0.0264)
        Change at Year 7 (n = 5, 1)
    0.0424 (0.0393 to 0.0766)
    0.0254 (0.0254 to 0.0254)
        Change at Year 7.5 (n = 3, 0)
    0.0529 (0.0527 to 0.0599)
    99999 (99999 to 99999)
        Change at Year 8 (n = 2, 0)
    0.0576 (0.0468 to 0.0683)
    99999 (99999 to 99999)
        Change at Year 8.5 (n = 1, 0)
    0.028 (0.028 to 0.028)
    99999 (99999 to 99999)
        Change at Year 9 (n = 1, 2)
    0.0403 (0.0403 to 0.0403)
    0.0363 (0.0159 to 0.0567)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGFBP3) Concentration at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9

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    End point title
    Change From Baseline in Insulin-like Growth Factor Binding Protein 3 (IGFBP3) Concentration at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: mg/dL
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [19] - Data was not statistically summarized due to early termination of the study.
    [20] - Data was not statistically summarized due to early termination of the study.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Lean Mass and Fat Mass at Year 1, 2, 3, 4, 5, 6, 7, 8 and 9

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    End point title
    Change from Baseline in Lean Mass and Fat Mass at Year 1, 2, 3, 4, 5, 6, 7, 8 and 9
    End point description
    Lean mass and fat mass: measurements of body composition assessed using Dual Energy X-ray Absorptiometry (DEXA) scan.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1, 2, 3, 4, 5, 6, 7, 8, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: kg
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [21] - Data was not statistically summarized due to early termination of the study.
    [22] - Data was not statistically summarized due to early termination of the study.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bone Mineralization at Year 1, 2, 3, 4, 5, 6, 7, 8 and 9

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    End point title
    Change from Baseline in Bone Mineralization at Year 1, 2, 3, 4, 5, 6, 7, 8 and 9
    End point description
    Bone mineralization, an estimate of the amount of mineral (such as calcium) in the bone, was assessed using DEXA scan. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement. Here, 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. Here "99999" in the median and full range values signifies not estimable (NA), since none of the subjects were available in the group "Somatropin (With Previous Somatropin Exposure)" at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1, 2, 3, 4, 5, 6, 7, 8, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    10
    11
    Units: grams
    median (full range (min-max))
        Baseline (n = 10, 11)
    565.4 (136 to 1305)
    643 (454 to 998)
        Change at Year 1 (n = 10, 11)
    104.67 (9 to 340)
    118.4 (-792.7 to 459.6)
        Change at Year 2 (n = 9, 10)
    272.7 (63 to 590)
    231.3 (-47.5 to 774.4)
        Change at Year 3 (n = 8, 7)
    375.27 (106 to 1084.9)
    403.8 (25 to 862.5)
        Change at Year 4 (n = 3, 4)
    518.7 (450.8 to 1047.9)
    903.2 (277.1 to 1448.1)
        Change at Year 5 (n = 7, 4)
    829 (421.7 to 1245.8)
    938.3 (591.8 to 1787.6)
        Change at Year 6 (n = 5, 4)
    818.4 (112.5 to 1105.5)
    998.05 (371.4 to 1984.2)
        Change at Year 7 (n = 5, 1)
    1206.1 (739.6 to 1437.3)
    1408.5 (1408.5 to 1408.5)
        Change at Year 8 (n = 2, 0)
    1376 (1351.7 to 1400.4)
    99999 (99999 to 99999)
        Change at Year 9 (n = 1, 2)
    1376.3 (1376.3 to 1376.3)
    1210.15 (898.6 to 1521.7)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Weight Standard Deviation Score (SDS) at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9

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    End point title
    Change from Baseline in Weight Standard Deviation Score (SDS) at Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9
    End point description
    Body weight was measured using a balance scale. Weight SDS was obtained by measuring the weight, subtracting age- and gender- appropriate mean weight and dividing the result by standard deviation of that mean (as obtained from age- and gender-specific population reference data). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) subject’s value was relative to the mean of the reference population. FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement. Here, 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. Here "99999" in the median and full range values signifies not estimable (NA), since none of the subjects were available in the group "Somatropin (With Previous Somatropin Exposure)" at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    10
    11
    Units: SDS
    median (full range (min-max))
        Baseline (n = 10, 11)
    -2.06 (-4 to 2.6)
    0.04 (-5.4 to 5)
        Change at Year 0.5 (n = 10, 9)
    0.25 (-0.7 to 0.4)
    0.06 (-0.8 to 1.2)
        Change at Year 1 (n = 10, 11)
    0.31 (-0.1 to 1.5)
    0.25 (-1.1 to 0.9)
        Change at Year 1.5 (n = 9, 11)
    0.62 (-0.3 to 2.3)
    0.34 (-1.6 to 2.3)
        Change at Year 2 (n = 9, 10)
    1.23 (-0.2 to 2.7)
    0.46 (-1.1 to 2.2)
        Change at Year 2.5 (n = 8, 8)
    1.51 (-0.9 to 3.2)
    0.77 (-1.1 to 2.6)
        Change at Year 3 (n = 9, 7)
    1.48 (-1.9 to 3.7)
    0.61 (-1.2 to 2.7)
        Change at Year 3.5 (n = 7, 7)
    1.56 (-1.9 to 3.7)
    0.78 (-1.3 to 3)
        Change at Year 4 (n = 7, 6)
    1.96 (-2.3 to 3.8)
    0.58 (-1 to 2.4)
        Change at Year 4.5 (n = 6, 5)
    1.78 (-2.7 to 4.1)
    1.46 (-0.4 to 2.7)
        Change at Year 5 (n = 7, 5)
    2.08 (-3 to 3.9)
    2.06 (0.1 to 2.8)
        Change at Year 5.5 (n = 5, 3)
    3.25 (1 to 3.8)
    2.1 (1.7 to 2.6)
        Change at Year 6 (n = 5, 3)
    2.95 (1.2 to 4.4)
    1.89 (1.8 to 2.2)
        Change at Year 6.5 (n = 5, 2)
    3.3 (0.8 to 5)
    2.03 (1.9 to 2.2)
        Change at Year 7 (n = 5, 1)
    2.91 (0.2 to 5.2)
    1.7 (1.7 to 1.7)
        Change at Year 7.5 (n = 3, 0)
    1.49 (0.3 to 3.1)
    99999 (99999 to 99999)
        Change at Year 8 (n = 2, 0)
    1.06 (0.5 to 1.6)
    99999 (99999 to 99999)
        Change at Year 8.5 (n = 1, 0)
    0.7 (0.7 to 0.7)
    99999 (99999 to 99999)
        Change at Year 9 (n = 1, 1)
    1.4 (1.4 to 1.4)
    2 (2 to 2)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Corticosteroid Dose at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9

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    End point title
    Change from Baseline in Corticosteroid Dose at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 and 9
    End point description
    FAS included all subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height measurement. Here, 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. Here "99999" in the median and full range values signifies not estimable (NA), since none of the subjects were available in the group "Somatropin (With Previous Somatropin Exposure)" at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9
    End point values
    Somatropin (Without Previous Somatropin Exposure) Somatropin (With Previous Somatropin Exposure)
    Number of subjects analysed
    10
    11
    Units: mg
    median (full range (min-max))
        Baseline (n = 10, 11)
    4.75 (2 to 13.5)
    7.5 (1 to 40)
        Change at Year 0.5 (n = 10, 9)
    0 (-2.5 to 4.8)
    0 (-11 to 0)
        Change at Year 1 (n = 9, 11)
    -0.67 (-8.5 to 36)
    0 (-15 to 20.3)
        Change at Year 1.5 (n = 8, 11)
    0.5 (-5 to 8.8)
    0 (-17 to 7.5)
        Change at Year 2 (n = 8, 10)
    -0.5 (-6.3 to 11.9)
    0 (-19 to 10.6)
        Change at Year 2.5 (n = 7, 8)
    1.83 (-7.8 to 11.9)
    0.04 (-28 to 7.5)
        Change at Year 3 (n = 7, 7)
    1.75 (-9.5 to 19.4)
    0 (-34.2 to 1)
        Change at Year 3.5 (n = 6, 7)
    1.83 (-10.3 to 12.5)
    -0.75 (-36 to 2.9)
        Change at Year 4 (n = 7, 6)
    0.25 (-10 to 9.7)
    -1.88 (-4.5 to 0)
        Change at Year 4.5 (n = 6, 5)
    0.23 (-9 to 215.4)
    -3.4 (-10 to 0)
        Change at Year 5 (n = 7, 5)
    -2 (-9.5 to 15)
    -3.5 (-10 to -0.6)
        Change at Year 5.5 (n = 5, 4)
    0.25 (-9.5 to 18.3)
    -1.83 (-4.5 to 486.5)
        Change at Year 6 (n = 5, 4)
    -1 (-11 to 10.6)
    -1.83 (-5.5 to 9)
        Change at Year 6.5 (n = 5, 2)
    -1 (-11 to 3)
    -2.46 (-3.7 to -1.3)
        Change at Year 7 (n = 5, 1)
    -1 (-11 to 2)
    -2.5 (-2.5 to -2.5)
        Change at Year 7.5 (n = 3, 0)
    -7 (-12 to 0.5)
    99999 (99999 to 99999)
        Change at Year 8 (n = 2, 0)
    -3.25 (-7 to 5)
    99999 (99999 to 99999)
        Change at Year 8.5 (n = 1, 0)
    0.5 (0.5 to 0.5)
    99999 (99999 to 99999)
        Change at Year 9 (n = 1, 2)
    -7 (-7 to -7)
    -3 (-3.5 to -2.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 7 days after last dose of 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 generated separately 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
    Somatropin (With Previous Somatropin Exposure)
    Reporting group description
    Subjects who received low dose of somatropin (Genotonorm) for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, equivalent to 1.8 IU/kg/week, divided in 7 daily doses subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, equivalent to 1.4 IU/kg/week, divided in 7 daily doses subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, equivalent to 0.35 mg/kg/week or 1.05 IU/kg/week, subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was <=to 1.5 cm per year during the preceding 12 months and bone age was >=17 years for boys and 15 years for girls.

    Reporting group title
    Somatropin (Without Previous Somatropin Exposure)
    Reporting group description
    Subjects who received matching placebo for 3 years during previous study CTN 97-8129-016, received somatropin (Genotonorm) up to 0.6 mg/kg/week, equivalent to 1.8 IU/kg/week, divided in 7 daily doses subcutaneously initially for first 3 years and then somatropin (Genotonorm) 0.46 mg/kg/week, equivalent to 1.4 IU/kg/week, divided in 7 daily doses subcutaneously until the additional study drug dose evaluation visit and thereafter received somatropin (Genotonorm) 50 mcg/kg/day, equivalent to 0.35 mg/kg/week or 1.05 IU/kg/week, subcutaneously until the final height was reached or up to Year 8.5. Final height was confirmed to have been achieved if the growth velocity was <=1.5 cm per year during the preceding 12 months and bone age was >=17 years for boys and 15 years for girls.

    Serious adverse events
    Somatropin (With Previous Somatropin Exposure) Somatropin (Without Previous Somatropin Exposure)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 11 (54.55%)
    2 / 10 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Gastrostomy closure
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lipoatrophy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Juvenile idiopathic arthritis
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondritis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Leishmaniasis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing fever
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Somatropin (With Previous Somatropin Exposure) Somatropin (Without Previous Somatropin Exposure)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    9 / 10 (90.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Poor peripheral circulation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Knee operation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Social circumstances
    Walking disability
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Ill-defined disorder
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Inflammation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Injection site haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Nodule
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Procedural vomiting
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Blood corticotrophin decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Blood urine present
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Glucose tolerance test
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Insulin-like growth factor increased
         subjects affected / exposed
    8 / 11 (72.73%)
    6 / 10 (60.00%)
         occurrences all number
    17
    12
    Weight decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Congenital scoliosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Lung disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Blood disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hyporeflexia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypotonia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Visual field defect
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Colitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Hypercalciuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Enuresis
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Nephrolithiasis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Renal colic
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Acne
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Ecchymosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Lividity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin atrophy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Amyotrophy
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 10 (30.00%)
         occurrences all number
    3
    5
    Arthritis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Joint effusion
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Juvenile idiopathic arthritis
         subjects affected / exposed
    4 / 11 (36.36%)
    4 / 10 (40.00%)
         occurrences all number
    6
    5
    Osteonecrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    Synovial cyst
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Glucose tolerance impaired
         subjects affected / exposed
    5 / 11 (45.45%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    Hyperinsulinaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Insulin resistance
         subjects affected / exposed
    6 / 11 (54.55%)
    5 / 10 (50.00%)
         occurrences all number
    7
    7
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 10 (30.00%)
         occurrences all number
    2
    3
    Ear infection
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    2
    Herpes simplex
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infectious mononucleosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Nail candida
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    4
    Nasopharyngitis
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Otitis externa
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Varicella
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2004
    1- Visits at month 3, month 9, month 15, month 21, month 27 and month 33 were not applicable for children who were not receiving Genotonorm due to the discontinuation of corticosteroid therapy. 2- If corticosteroid therapy was discontinued in children at the beginning or during the study for at least 6 months and the height was greater than (>) -2 Standard Deviation (SD) for chronological age, then Genotonorm treatment was stopped and could only be resumed if corticosteroid therapy was resumed for at least 3 months and the investigative doctor considered it beneficial for the child. 3- If 2 consecutive measurements of the level of IGF-1 were above 2 SD, then the daily dosage of Genotonorm was decreased by 20 percent (%). 4- If the measurement of glucose in the urine was found to be above 10 gram/24 hours on 3 occasions, then the dosage of the growth hormone was decreased by 20% and further metabolic monitoring (fasting blood glucose and glucose in the urine) was done in the month following the dose change.
    04 Feb 2005
    1- Every year, following examinations were required to be performed in addition to examinations performed during a six-month visit: Serum calcium; serum phosphorus; 25 hydroxy (OH) vitamin D3 and 1.25 dihydroxy (OH)2 vitamin D3 and Parathyroid hormone (PTH) levels; Oral glucose tolerance test (OGTT); Collection of 24-hour urine for calcium and creatinine; Collection of 2 mL of serum (4 x 0.5 mL); Bone age: radiography of 2 wrists. 2- The maximum dose administered was reduced to 0.46 mg 1.4 IU/kg/week from 0.6 mg 1.8 IU/kg/week. 3- Genotonorm treatment was adapted according to IGF-1 rates which were maintained below or equal to +2.5 SD for chronological age and If IGF-1 rates were above +2.5 SD the dose of growth hormone was decreased by 20%. 4- In the case of diabetes defined by blood glucose at time T120 mins of OGTT ≥11.1 millimole per liter (mmol/L) or fasting blood glucose >=7.0 mmol/L, the Genotonorm dose was reduced by 40% and another OGTT check was done after 3 months of dose adjustment. That diabetes was reported as an adverse event and If It persisted, Genotonorm treatment was interrupted and the event was reported as a serious adverse event.
    29 Nov 2007
    Genotonorm treatment was adapted according to IGF-1 levels which were maintained below or equal to +2 SD for chronological age and sex and If IGF-1 level was above +2 SD, then the growth hormone dose was decreased by 20%.
    16 Feb 2011
    The maximal dose of somatropin was limited up to 50 mcg/kg/day (0.35 mg [1.05 IU/kg/week]) in relation to the ongoing review of safety of somatropin- containing products.

    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.
    Data for bone mineral density (BMD), bone mineral content (BMC) and IGFBP3 were not analyzed because of change in planned analysis after the study was prematurely terminated due to Good Clinical Practice (GCP) non-compliance issues.
    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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