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    Clinical Trial Results:
    A Two Years Multicentre Study of Genotropin Treatment of Short Prepubertal Children With Intra-Uterine Growth Retardation

    Summary
    EudraCT number
    		 2014-004160-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    07 May 2009

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

    Trial information

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    Trial identification
    Sponsor protocol code
    93-8122-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01073605
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias: A6281186
    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 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, 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
    18 Jan 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of continuous and intermittent administration of Genotropin 16 international unit (IU) on stature in prepubertal short children with intra-uterine growth retardation (IUGR).
    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
    01 Jul 1993
    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: 206
    Worldwide total number of subjects
    206
    EEA total number of subjects
    206
    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)
    205
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 208 subjects were enrolled from 32 sites in France. Study started on 01 July 1993 and completed on 07 May 2009. Out of 208 enrolled subjects, only 206 subjects were treated.

    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
    		 Genotonorm 0.7 (Continuous Treatment)
    Arm description
    		 Subjects received 0.7 IU/kilogram (kg)/week of Genotonorm growth hormone (GH) as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Genotonorm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 0.7 IU/kg/week at a dose of 0.03 milligram (mg)/kg/day of Genotonorm growth hormone (GH) as a continuous treatment.

    Arm title
    		 Genotonorm 1.4 (Continuous Treatment)
    Arm description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Genotonorm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 1.4 IU/kg/week at a dose of 0.06 mg/kg/day of growth hormone Genotonorm as a continuous treatment.

    Arm title
    		 Genotonorm 1.4 (Intermittent Treatment)
    Arm description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Genotonorm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 1.4 IU/kg/week at a dose of 0.06 mg/kg/day of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Number of subjects in period 1
    		Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Started
    68
    70
    68
    Received Treatment
    68
    70
    68
    Completed
    6
    4
    8
    Not completed
    62
    66
    60
         Consent withdrawn by subject
    31
    39
    22
         Unknown
    25
    21
    29
         Ongoing at Cutoff Date
    1
    1
    -
         Adverse event
    2
    1
    -
         Lost to follow-up
    3
    4
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genotonorm 0.7 (Continuous Treatment)
    Reporting group description
    		 Subjects received 0.7 IU/kilogram (kg)/week of Genotonorm growth hormone (GH) as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Continuous Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Intermittent Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment) Total
    Number of subjects
    		 68 70 68 206
    Age, Customized
    Units: subjects
        Less than (<) 4 years
    		 15 8 6 29
        4 - 8 years
    		 29 32 29 90
        8 - 12 years
    		 23 30 33 86
        Greater than or equal to (>=) 12 years
    		 1 0 0 1
    Gender, Male/Female
    Units: subjects
        Female
    		 25 31 39 95
        Male
    		 43 39 29 111

    End points

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    End points reporting groups
    Reporting group title
    Genotonorm 0.7 (Continuous Treatment)
    Reporting group description
    		 Subjects received 0.7 IU/kilogram (kg)/week of Genotonorm growth hormone (GH) as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Continuous Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Intermittent Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Primary: Change from Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm

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    End point title
    		 Change from Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm
    End point description
    Annual growth rate was expressed as height velocity (centimeter [cm]/year). This was derived by substracting annual growth rate at Baseline from 2-year value. (Annual growth rate was calculated each year and rescaled to 1 year if the interval between x and x-1 was not 365 days, as long as a subject remains in the study): ANGRYx = (Height Yx – Height Y[x-1]) / ([Date of Yx – Date of Y{x-1}] /365.25). All subjects who received at least 1 study dose of Genotonorm were included in the Full Analysis Set (FAS).
    End point type
    Primary
    End point timeframe
    Baseline, 2 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    47 [1]
    37 [2]
    40 [3]
    Units: cm/year
        arithmetic mean (standard deviation)
    3.07 ± 2.21
    3.97 ± 1.72
    2.84 ± 1.71
    Notes
    [1] - N signifies number of subjects with change in annual growth rate at 2 years.
    [2] - N signifies number of subjects with change in annual growth rate at 2 years.
    [3] - N signifies number of subjects with change in annual growth rate at 2 years.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02922 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs 1.4 (Intermittent)
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74299 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent)
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00467 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.

    Secondary: Annual Growth Rate Standard Deviation Score (SDS)

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    End point title
    		 Annual Growth Rate Standard Deviation Score (SDS)
    End point description
    Calculated using Sempe reference means and standard deviations for growth rate according to age and sex. Standardization was performed for chronological age. FAS. Here, n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    50 [7]
    42 [8]
    43 [9]
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=50, 42, 43)
    -2.72 ± 1.83
    -2.58 ± 1.39
    -2.75 ± 1.73
        1 year (n=57, 55, 59)
    2.14 ± 1.52
    3.97 ± 2.26
    1.71 ± 1.51
        2 years (n=53, 49, 56)
    0.77 ± 1.57
    2 ± 1.73
    0.67 ± 1.22
        3 years (n=39, 34, 41)
    0.36 ± 1.14
    1.35 ± 1.78
    0.31 ± 1.12
        4 years (n=21, 18, 27)
    0.13 ± 1.55
    0.61 ± 1.2
    0.34 ± 1.2
        5 years (n=12, 10, 20)
    0.18 ± 1.24
    0.09 ± 0.88
    -0.02 ± 1.46
        6 years (n=11, 7, 19)
    0.9 ± 1.92
    0.59 ± 1.61
    0.05 ± 1.2
    Notes
    [7] - N signifies number of subjects with evaluable data at Baseline.
    [8] - N signifies number of subjects with evaluable data at Baseline.
    [9] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Annual Growth Rate SDS

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    End point title
    		 Change From Baseline in Annual Growth Rate SDS
    End point description
    Calculated corresponding to the gender and chronological age by substracting annual growth rate SDS at baseline from annual growth rate SDS at each year. FAS. Here, n = number of subjects with evaluable data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 3 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    49 [10]
    42 [11]
    42 [12]
    Units: SDS
    arithmetic mean (standard deviation)
        1 year (n=49, 42, 42)
    4.81 ± 2.27
    6.56 ± 2.55
    4.37 ± 2.16
        2 years (n=47, 37, 40)
    3.51 ± 2.5
    4.53 ± 1.89
    3.37 ± 2.33
        3 years (n=34, 25, 32)
    3.31 ± 2.06
    3.8 ± 2.2
    3.17 ± 1.86
    Notes
    [10] - N signifies number of subjects with evaluable data at 1 year.
    [11] - N signifies number of subjects with evaluable data at 1 year.
    [12] - N signifies number of subjects with evaluable data at 1 year.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Statistical analysis description
    Statistical analysis for 1 year.
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00125 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs. 1.4 (Intermittent)
    Statistical analysis description
    Statistical analysis for 1 year.
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25995 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent) Groups
    Statistical analysis description
    Statistical analysis for 1 year.
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 1.4 (Continuous Treatment)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00008 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Statistical analysis description
    Statistical analysis for 2 years.
    Comparison groups
    Genotonorm 0.7 (Continuous Treatment) v Genotonorm 1.4 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03273 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs. 1.4 (Intermittent)
    Statistical analysis description
    Statistical analysis for 2 years.
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68581 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent) Groups
    Statistical analysis description
    Statistical analysis for 2 years.
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0053 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Statistical analysis description
    Statistical analysis for 3 years.
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57556 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs. 1.4 (Intermittent)
    Statistical analysis description
    Statistical analysis for 3 years.
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63956 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [20] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent) Groups
    Statistical analysis description
    Statistical analysis for 3 years.
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16421 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.

    Secondary: Height (cm)

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    End point title
    		 Height (cm)
    End point description
    Performed by use of a wallmounted device (eg, Harpenden Stadiometer). Each subject was measured 3 times and the mean of these measurements was recorded as the present height. Final Height: Childrens were defined as reaching their final height when annual Growth Rate was less than 2 cm in the previous year and bone age was equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. FAS. Here, n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years, final height
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [22]
    56 [23]
    60 [24]
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=58, 56, 60)
    105.22 ± 15.04
    107.06 ± 12.29
    106.44 ± 12.04
        1 year (n=57, 55, 59)
    113.38 ± 15.09
    116.31 ± 12.24
    113.71 ± 12.01
        2 years (n=53, 49, 56)
    119.67 ± 15.18
    124.11 ± 13.02
    120.64 ± 12.34
        3 years (n=39, 34, 41)
    123.92 ± 15.08
    131.75 ± 13.76
    125.39 ± 12.52
        4 years (n=21, 18, 27)
    124.67 ± 13.14
    132.3 ± 13.23
    127.59 ± 11.51
        5 years (n=12, 10, 21)
    126.73 ± 10.01
    131.01 ± 9.26
    129.98 ± 9.93
        6 years (n=11, 7, 20)
    133.29 ± 10.46
    138.84 ± 8.69
    135.45 ± 10.1
        Final height (n=17, 12, 22)
    146.86 ± 11.26
    151.98 ± 6.52
    149.13 ± 9.07
    Notes
    [22] - N signifies number of subjects with evaluable data at Baseline.
    [23] - N signifies number of subjects with evaluable data at Baseline.
    [24] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height (cm)

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    End point title
    		 Change From Baseline in Height (cm)
    End point description
    Calculated by substracting height at Baseline from height at each year. Final Height: Children were defined as reaching their final height when annual Growth Rate was less than 2 cm in the previous year and bone age was equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. FAS. Here, n = number of subjects with evaluable data at Baseline and each time point. Data beyond 6 years were not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years, final height
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [25]
    56 [26]
    60 [27]
    Units: cm
    arithmetic mean (standard deviation)
        1 year (n=57, 55, 59)
    8.21 ± 1.38
    9.21 ± 1.45
    7.33 ± 1.32
        2 years (n=53, 49, 56)
    14.77 ± 2.45
    17.01 ± 2.21
    13.92 ± 2.03
        3 years (n=39, 34, 41)
    20.62 ± 3
    24.49 ± 3.04
    20.14 ± 2.78
        4 years (n=21, 18, 27)
    26.36 ± 4.37
    30.77 ± 3.43
    25.83 ± 3.26
        5 years (n=12, 10, 21)
    32.23 ± 5.92
    35.7 ± 4.27
    32.16 ± 3.81
        6 years (n=11, 7, 20)
    38.2 ± 6.66
    44.03 ± 3.09
    38.01 ± 4.82
        Final height (n=17, 12, 22)
    45.39 ± 13.08
    45.3 ± 13.72
    40.93 ± 9.22
    Notes
    [25] - N signifies number of subjects with evaluable data at Baseline.
    [26] - N signifies number of subjects with evaluable data at Baseline.
    [27] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Height (SDS)

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    End point title
    		 Height (SDS)
    End point description
    Calculated using Sempe reference means and standard deviations for height. Final Height: Children were defined as reaching their final height when annual Growth Rate was less than 2 cm in the previous year and bone age was equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. FAS. Here, n = number of subjects with evaluable data at each time point. Data beyond 6 years were not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years, final height
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [28]
    56 [29]
    60 [30]
    Units: SDS
    arithmetic mean (standard deviation)
        Baseline (n=58, 56, 60)
    -3.16 ± 0.52
    -3.07 ± 0.46
    -3.21 ± 0.65
        1 year (n=57, 55, 59)
    -2.49 ± 0.54
    -2.17 ± 0.5
    -2.68 ± 0.69
        2 years (n=53, 49, 56)
    -2.21 ± 0.66
    -1.68 ± 0.52
    -2.38 ± 0.75
        3 years (n=39, 34, 41)
    -2.17 ± 0.7
    -1.38 ± 0.57
    -2.24 ± 0.9
        4 years (n=21, 18, 27)
    -2.16 ± 1.03
    -1.16 ± 0.73
    -2.09 ± 0.96
        5 years (n=12, 10, 21)
    -1.95 ± 1.26
    -1.15 ± 0.83
    -1.96 ± 1.1
        6 years (n=11, 7, 19)
    -1.8 ± 1.28
    -0.67 ± 0.66
    -1.93 ± 1.18
        Final height (n=14, 9, 18)
    -2.06 ± 0.76
    -1.97 ± 0.95
    -2.29 ± 1.35
    Notes
    [28] - N signifies number of subjects with evaluable data at Baseline.
    [29] - N signifies number of subjects with evaluable data at Baseline.
    [30] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height (SDS)

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    End point title
    		 Change From Baseline in Height (SDS)
    End point description
    Calculated by substracting height SDS at Baseline from height SDS at each year. Final Height: Children were defined as reaching their final height when annual Growth Rate was less than 2 cm in the previous year and bone age was equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. FAS. Here, n = number of subjects with evaluable data at Baseline and each time point. Data beyond 6 years were not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years, final height
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [31]
    56 [32]
    60 [33]
    Units: SDS
    arithmetic mean (standard deviation)
        1 year (n=57, 55, 59)
    0.67 ± 0.28
    0.88 ± 0.3
    0.53 ± 0.28
        2 years (n=53, 49, 56)
    0.94 ± 0.45
    1.4 ± 0.43
    0.84 ± 0.37
        3 years (n=39, 34, 41)
    1.06 ± 0.54
    1.7 ± 0.54
    0.99 ± 0.51
        4 years (n=21, 18, 27)
    1.2 ± 0.81
    1.98 ± 0.69
    1.21 ± 0.54
        5 years (n=12, 10, 21)
    1.37 ± 1.12
    2.03 ± 0.87
    1.46 ± 0.69
        6 years (n=11, 7, 19)
    1.54 ± 1.12
    2.6 ± 0.66
    1.54 ± 0.86
        Final height (n=14, 9, 18)
    1 ± 0.53
    0.97 ± 0.95
    0.86 ± 1.16
    Notes
    [31] - N signifies number of subjects with evaluable data at Baseline.
    [32] - N signifies number of subjects with evaluable data at Baseline.
    [33] - N signifies number of subjects with evaluable data at Baseline.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Comparison groups
    Genotonorm 0.7 (Continuous Treatment) v Genotonorm 1.4 (Continuous Treatment)
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [34]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [34] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs. 1.4 (Intermittent)
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58324 [35]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [35] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent) Groups
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 1.4 (Continuous Treatment)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [36]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [36] - P-values for the 3 treatment comparisons should be interpreted in line with the Bonferroni stepwise (Holm) testing procedure, to maintain the Type 1 error at p=0.05.

    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. FAS. Here, n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [37]
    56 [38]
    60 [39]
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Baseline (n=58, 56, 60)
    14.74 ± 1.48
    15.14 ± 1.76
    14.59 ± 1.51
        1 year (n=56, 55, 59)
    14.82 ± 1.52
    15.44 ± 1.94
    14.87 ± 1.76
        2 years (n=53, 49, 56)
    15.33 ± 1.78
    15.92 ± 2.15
    15.29 ± 2
        3 years (n=39, 34, 41)
    15.59 ± 2.02
    16.65 ± 2.92
    15.58 ± 2.11
        4 years (n=21, 18, 27)
    15.32 ± 1.56
    17.03 ± 3.7
    15.8 ± 2.37
        5 years (n=12, 10, 21)
    15.8 ± 1.57
    16.25 ± 1.7
    16.69 ± 3.92
        6 years (n=11, 7, 20)
    16.21 ± 1.46
    16.34 ± 1.8
    17.28 ± 4.21
    Notes
    [37] - N signifies number of subjects with evaluable data at Baseline.
    [38] - N signifies number of subjects with evaluable data at Baseline.
    [39] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Weight

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    End point title
    		 Weight
    End point description
    FAS. Here, n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    58 [40]
    56
    60
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=58, 56, 60)
    16.77 ± 5.43
    17.7 ± 5.12
    16.79 ± 4.35
        1 year (n=56, 55, 59)
    19.71 ± 6.28
    21.29 ± 6.04
    19.56 ± 5.17
        2 years (n=53, 49, 56)
    22.66 ± 7.62
    25.08 ± 7.43
    22.64 ± 6.05
        3 years (n=39, 34, 41)
    24.77 ± 8.8
    29.61 ± 9.62
    24.98 ± 7.05
        4 years (n=21, 18, 27)
    24.3 ± 7.01
    30.56 ± 10.42
    26.28 ± 7.94
        5 years (n=12, 10, 21)
    25.74 ± 6.22
    28.07 ± 5.22
    28.52 ± 8.96
        6 years (n=11, 7, 21)
    29.13 ± 6.42
    31.94 ± 7.28
    32.3 ± 10.32
    Notes
    [40] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Age

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    End point title
    		 Change From Baseline in Bone Age
    End point description
    Bone age was determined by the Greulich-Pyle method. Calculated by substracting bone age at baseline from bone age at each year. Safety population = all subjects who received at least 1 study dose of GH. Here, n = number of subjects with evaluable data at baseline and each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 3 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    61 [41]
    62 [42]
    61 [43]
    Units: Years
    arithmetic mean (standard deviation)
        1 year (n=53, 60, 56)
    1.17 ± 0.51
    1.27 ± 0.72
    1.25 ± 0.54
        2 years (n=52, 51, 49)
    2.4 ± 0.9
    2.5 ± 1.08
    2.58 ± 0.97
        3 years (n=41, 39, 35)
    3.53 ± 1.22
    4.06 ± 1.05
    3.67 ± 0.97
    Notes
    [41] - N signifies number of subjects with evaluable data at Baseline.
    [42] - N signifies number of subjects with evaluable data at Baseline.
    [43] - N signifies number of subjects with evaluable data at Baseline.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Age/Change from Baseline in Chronological Age Ratio

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    End point title
    		 Change From Baseline in Bone Age/Change from Baseline in Chronological Age Ratio
    End point description
    Bone age was determined by the Greulich-Pyle method. Chronological Age (years) was calculated as: (Date minus Date of Birth) divided by 365.25. Chronological Age used was the age at the date that the corresponding Bone Age X-ray was performed. Ratio was calculated by change from Baseline in bone age divided by change from Baseline in chronological age. Safety population. Here, n = number of subjects with evaluable data at each time point.
    End point type
    Secondary
    End point timeframe
    1 to 3 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    53 [44]
    60 [45]
    56 [46]
    Units: ratio
    arithmetic mean (standard deviation)
        1 year (n=53, 60, 56)
    0.96 ± 0.41
    1.07 ± 0.62
    1.06 ± 0.45
        2 years (n=51, 51, 49)
    1.06 ± 0.41
    1.14 ± 0.5
    1.18 ± 0.44
        3 years (n=35, 37, 35)
    1.09 ± 0.39
    1.26 ± 0.32
    1.14 ± 0.29
    Notes
    [44] - N signifies number of subjects with evaluable data at 1 year.
    [45] - N signifies number of subjects with evaluable data at 1 year.
    [46] - N signifies number of subjects with evaluable data at 1 year.
    No statistical analyses for this end point

    Secondary: Chronological Age at Onset of Puberty

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    End point title
    		 Chronological Age at Onset of Puberty
    End point description
    Chronological age (years) at first study visit with onset of puberty = (Date of study visit minus Date of Birth) divided by 365.25. Safety population.
    End point type
    Secondary
    End point timeframe
    Onset of puberty
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    30 [47]
    35 [48]
    45 [49]
    Units: Years
        arithmetic mean (standard deviation)
    11.88 ± 2.22
    11.12 ± 1.74
    11.58 ± 1.42
    Notes
    [47] - N signifies number of subjects who started puberty by the end of the study.
    [48] - N signifies number of subjects who started puberty by the end of the study.
    [49] - N signifies number of subjects who started puberty by the end of the study.
    Statistical analysis title
    		 Genotonorm 0.7 vs. 1.4 (Continuous Treatment)
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 0.7 (Continuous Treatment)
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0681 [50]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 1.39
    Notes
    [50] - There is no adjustment for multiplicity of treatment comparisons. The Analysis of Covariance took into account the patient covariates age and gender.
    Statistical analysis title
    		 Genotonorm 0.7 (Continuous) vs. 1.4 (Intermittent)
    Comparison groups
    Genotonorm 1.4 (Intermittent Treatment) v Genotonorm 1.4 (Continuous Treatment)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8971 [51]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 0.74
    Notes
    [51] - There is no adjustment for multiplicity of treatment comparisons. The Analysis of Covariance took into account the patient covariates age and gender.
    Statistical analysis title
    		 Genotonorm 1.4 (Continuous vs.Intermittent) Groups
    Comparison groups
    Genotonorm 1.4 (Continuous Treatment) v Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0583 [52]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 0.02
    Notes
    [52] - There is no adjustment for multiplicity of treatment comparisons. The Analysis of Covariance took into account the patient covariates age and gender.

    Secondary: Number of Subjects Reaching Puberty

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    End point title
    		 Number of Subjects Reaching Puberty
    End point description
    The defined criteria for reaching puberty were: boy=if right or left testes volume >=4 ml; girl=if breast development >=2. Tanner Adolescent Pubertal Staging Questionnaire documents the stage of development of secondary sexual characteristics rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Onset of puberty was defined as the visit where the data recorded first met the above criteria for starting puberty. Safety population. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years. Started = started puberty; Not Started = not started puberty yet as per Tanner scale.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 to 6 years
    End point values
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Number of subjects analysed
    68
    70
    68
    Units: subjects
    number (not applicable)
        Baseline (Female, Not Started)
    25
    31
    39
        Baseline (Male, Not Started)
    43
    39
    29
        1 year (Female, Not Started)
    24
    27
    37
        1 year (Female, Started)
    1
    3
    2
        1 year (Male, Not Started)
    36
    35
    27
        1 year (Male, Started)
    4
    3
    1
        2 years (Female, Not Started)
    20
    20
    31
        2 years (Female, Started)
    3
    7
    6
        2 years (Male, Not Started)
    31
    28
    20
        2 years (Male, Started)
    9
    7
    6
        3 years (Female, Not Started)
    16
    10
    16
        3 years (Female, Started)
    3
    9
    11
        3 years (Male, Not Started)
    19
    15
    9
        3 years (Male, Started)
    6
    7
    4
        4 years (Female, Not Started)
    10
    7
    10
        4 years (Female, Started)
    2
    5
    7
        4 years (Male, Not Started)
    10
    5
    7
        4 years (Male, Started)
    1
    2
    3
        5 years (Female, Not Started)
    5
    4
    5
        5 years (Female, Started)
    2
    3
    10
        5 years (Male, Not Started)
    6
    6
    4
        5 years (Male, Started)
    2
    1
    1
        6 years (Female, Not Started)
    3
    3
    3
        6 years (Female, Started)
    3
    2
    12
        6 years (Male, Not Started)
    5
    4
    1
        6 years (Male, Started)
    3
    1
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events were reported from time of first dose of study treatment up to 7 days after last dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Genotonorm 0.7 (Continuous Treatment)
    Reporting group description
    		 Subjects received 0.7 IU/kg/week (0.03 milligram [mg]/kg/day) of Genotonorm growth hormone (GH) as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Continuous Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week (0.06 mg/kg/day) of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Reporting group title
    Genotonorm 1.4 (Intermittent Treatment)
    Reporting group description
    		 Subjects received 1.4 IU/kg/week (0.06 mg/kg/day) of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached.

    Serious adverse events
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 68 (8.82%)
    19 / 70 (27.14%)
    9 / 68 (13.24%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastoidectomy
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchidopexy
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthopaedic procedure
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal reconstruction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 68 (0.00%)
    3 / 70 (4.29%)
    4 / 68 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tenotomy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue tie operation
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillectomy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour excision
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric repair
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 70 (2.86%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular disorder
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular torsion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    DiGeorge's syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal prolapse
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nuchal rigidity
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 70 (1.43%)
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Genotonorm 0.7 (Continuous Treatment) Genotonorm 1.4 (Continuous Treatment) Genotonorm 1.4 (Intermittent Treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 68 (58.82%)
    42 / 70 (60.00%)
    35 / 68 (51.47%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 68 (0.00%)
    4 / 70 (5.71%)
    0 / 68 (0.00%)
         occurrences all number
    0
    5
    0
    Headache
         subjects affected / exposed
    2 / 68 (2.94%)
    5 / 70 (7.14%)
    3 / 68 (4.41%)
         occurrences all number
    5
    8
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 70 (4.29%)
    3 / 68 (4.41%)
         occurrences all number
    4
    4
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 70 (4.29%)
    4 / 68 (5.88%)
         occurrences all number
    6
    3
    4
    Diarrhoea
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 70 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    6
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 70 (4.29%)
    3 / 68 (4.41%)
         occurrences all number
    8
    3
    3
    Cough
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 70 (4.29%)
    5 / 68 (7.35%)
         occurrences all number
    1
    3
    6
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 70 (1.43%)
    1 / 68 (1.47%)
         occurrences all number
    9
    1
    1
    Urticaria
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 70 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    6
    0
    1
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 70 (5.71%)
    0 / 68 (0.00%)
         occurrences all number
    3
    5
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    13 / 68 (19.12%)
    9 / 70 (12.86%)
    17 / 68 (25.00%)
         occurrences all number
    20
    18
    32
    Ear infection
         subjects affected / exposed
    15 / 68 (22.06%)
    15 / 70 (21.43%)
    9 / 68 (13.24%)
         occurrences all number
    25
    39
    21
    Fungal infection
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
         occurrences all number
    4
    1
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 68 (5.88%)
    8 / 70 (11.43%)
    11 / 68 (16.18%)
         occurrences all number
    4
    11
    21
    Influenza
         subjects affected / exposed
    6 / 68 (8.82%)
    9 / 70 (12.86%)
    7 / 68 (10.29%)
         occurrences all number
    7
    15
    8
    Nasopharyngitis
         subjects affected / exposed
    16 / 68 (23.53%)
    16 / 70 (22.86%)
    11 / 68 (16.18%)
         occurrences all number
    27
    28
    21
    Pharyngitis
         subjects affected / exposed
    2 / 68 (2.94%)
    6 / 70 (8.57%)
    7 / 68 (10.29%)
         occurrences all number
    4
    8
    8
    Rhinitis
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 70 (2.86%)
    6 / 68 (8.82%)
         occurrences all number
    5
    2
    8
    Tracheitis
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 70 (7.14%)
    2 / 68 (2.94%)
         occurrences all number
    3
    6
    2
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 68 (27.94%)
    19 / 70 (27.14%)
    12 / 68 (17.65%)
         occurrences all number
    31
    39
    20
    Varicella
         subjects affected / exposed
    8 / 68 (11.76%)
    6 / 70 (8.57%)
    1 / 68 (1.47%)
         occurrences all number
    8
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 1995
    Treatment with Genotonorm was stopped in prepubescent children with short stature due to IUGR who, after 2 years on the initial protocol or during their third year of treatment, had begun puberty at least 6 months before. The aim of this change was to study the spontaneous progress of their growth until reaching final height.
    15 Jun 1998
    Treatment of children with Genotonorm ® for one additional year was continued , in order to obtain long-term data on the safety and efficacy of the product, that subjects who started puberty would continue to be treated according to the same therapeutic regimen, for the possibility of using the Genotonorm ® Pen 16 or 36, depending on the weight of the subject and subjects who had discontinued their treatment were to be followed in the context of the protocol so as to obtain data on their final height.
    17 Sep 2001
    A modification of the treatment period was done, allowing the administration of Genotonorm to children until they attain their final height in order to obtain long-term data on the safety and efficacy of the product. Changes in dosage units of 5.3 mg instead of 16 IU and 12 mg instead of 36 IU.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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