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    Clinical Trial Results:
    Efficacy and Safety of Somatropin in Combination With Leuprorelin Compared to Somatropin Alone in Pubertal Children With Idiopathic Short Stature (Phoenix)

    Summary
    EudraCT number
    		 2005-001750-25
    Trial protocol
    		 NL  
    Global end of trial date
    07 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Aug 2016
    First version publication date
    26 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9861
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00266656
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number : 9861, Trial Alias: B9R-FP-GDGI
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-285-4559,
    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
    07 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The present randomized trial was initially intended to study the benefits of a combined treatment with growth hormone (GH) and a gonadotropin-releasing hormone (GnRH) agonist for pubertal children with idiopathic short stature. However, treatments were stopped in January 2012 at the request of the French drug agency. Therefore, a protocol amendment divided the study in two study periods. Study Period 1 involved combined treatment with somatropin and leuprorelin or treatment with somatropin alone. Participants from France who participated in this Period 1 of the study were asked to participate in a long term safety follow up defined as a Period 2 of the study. Participants from the Netherlands were offered participation in Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS, clinicaltrials.gov Identifier: NCT01088412) for long term safety follow up independent of this study.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 42 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    France: 77
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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)
    42
    Adolescents (12-17 years)
    46
    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
    		 No Text Entered

    Pre-assignment
    Screening details
    		 No Text Entered

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Somatropin and Leuprorelin: Experimental Arm 1
    Arm description
    		 0.05 milligram (mg) per kilogram (kg) per day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first). One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    LY137998, Humatrope
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.05 milligram (mg) per kilogram (kg) per day

    Investigational medicinal product name
    Leuprorelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    11.25 mg every 3 months

    Arm title
    		 Somatropin: Experimental Arm 2
    Arm description
    		 0.05mg/kg/day subcutaneous somatropin only. One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    LY137998, Humatrope
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.05 milligram (mg) per kilogram (kg) per day

    Number of subjects in period 1
    		Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Started
    45
    43
    Received At Least One Dose of Study Drug
    45
    43
    Reached Final Height
    1 [1]
    1 [2]
    Did Not Reach Final Height
    44
    42
    Completed
    20
    19
    Not completed
    25
    24
         See justification section
    25
    24
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to system limitations, the participants listed as completed/not completed are the participants who participated/did not participate in study period 2. The actual completed/not completed participants are 1/44 for arm 1.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to system limitations, the participants listed as completed/not completed are the participants who participated/did not participate in study period 2. The actual completed/not completed participants are 1/43 for arm 2.
    Period 2
    Period 2 title
    Study Period 2 Long Term Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Somatropin and Leuprorelin: Experimental Arm 1
    Arm description
    		 No treatment was administered during the follow up period. Participants received the following during the treatment period: 0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first). Participants from the Netherlands exited the study after Study Period 1. Participants from France were given the option to re-consent for Study Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    LY137998, Humatrope
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.05 milligram (mg) per kilogram (kg) per day

    Investigational medicinal product name
    Leuprorelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    11.25 mg every 3 months

    Arm title
    		 Somatropin: Experimental Arm 2
    Arm description
    		 No treatment was administered during the follow up period. Participants received the following during the treatment period: 0.05mg/kg/day subcutaneous somatropin only. Participants from the Netherlands exited the study after Study Period 1. Participants from France were given the option to re-consent for Study Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    LY137998, Humatrope
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.05 milligram (mg) per kilogram (kg) per day

    Number of subjects in period 2
    		Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Started
    20
    19
    Completed
    19
    17
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Somatropin and Leuprorelin: Experimental Arm 1
    Reporting group description
    		 0.05 milligram (mg) per kilogram (kg) per day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first). One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.

    Reporting group title
    Somatropin: Experimental Arm 2
    Reporting group description
    		 0.05mg/kg/day subcutaneous somatropin only. One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.

    Reporting group values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2 Total
    Number of subjects
    		 45 43 88
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 20 22 42
        Adolescents (12-17 years)
    		 25 21 46
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.1 ( 1.41 ) 12.1 ( 1.33 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 26 20 46
        Male
    		 19 23 42
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 4 2 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 38 40 78
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 1 3
    Region of Enrollment
    Units: Subjects
        Netherlands
    		 6 5 11
        France
    		 39 38 77
    Standing Height SDS
    Units: Standard Deviation Score
        arithmetic mean (standard deviation)
    		 -2.5 ( 0.45 ) -2.5 ( 0.46 ) -
    Standing Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 131.6 ( 6.72 ) 131.6 ( 5.78 ) -

    End points

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    End points reporting groups
    Reporting group title
    Somatropin and Leuprorelin: Experimental Arm 1
    Reporting group description
    		 0.05 milligram (mg) per kilogram (kg) per day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first). One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.

    Reporting group title
    Somatropin: Experimental Arm 2
    Reporting group description
    		 0.05mg/kg/day subcutaneous somatropin only. One participant reached final height and completed the study. All participants from France were eligible to participate in the safety follow up period (study period 2 below). Participants from the Netherlands exited the study after Study Period 1.
    Reporting group title
    Somatropin and Leuprorelin: Experimental Arm 1
    Reporting group description
    		 No treatment was administered during the follow up period. Participants received the following during the treatment period: 0.05mg/kg/day subcutaneous somatropin and 3-month formulation, subcutaneous or intramuscular injection of 11.25mg leuprorelin for three years (or for a minimum of 2 years until a chronological age of 13 years for girls and 15 years for boys, whichever occurs first). Participants from the Netherlands exited the study after Study Period 1. Participants from France were given the option to re-consent for Study Period 2.

    Reporting group title
    Somatropin: Experimental Arm 2
    Reporting group description
    		 No treatment was administered during the follow up period. Participants received the following during the treatment period: 0.05mg/kg/day subcutaneous somatropin only. Participants from the Netherlands exited the study after Study Period 1. Participants from France were given the option to re-consent for Study Period 2.

    Subject analysis set title
    Arm: Somatropin and Leuprorelin: Experimental Arm 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants that started the study in addition to participants from previous control group who were ineligible to participate in the study were given somatropin and are included for AE assessment.

    Subject analysis set title
    Arm: Somatropin: Experimental Arm 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants that started the study in addition to participants from previous control group who were ineligible to participate in the study were given somatropin and are included for AE assessment.

    Primary: Number of Participants With One Or More Drug-related Adverse Events

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    End point title
    		 Number of Participants With One Or More Drug-related Adverse Events [1]
    End point description
    A drug-related AE was an AE that occurred postdose or was present predose and became more severe postdose and was considered to be related to study treatment. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. Population description: All participants who received at least one dose of study drug in Period 1 and all participants who entered Period 2 (safety population).
    End point type
    Primary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    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: No statistical analyses was planned after the discontinuation of treatments. Only descriptive statistics performed as participants were only followed up for safety.
    End point values
    		 Arm: Somatropin and Leuprorelin: Experimental Arm 1 Arm: Somatropin: Experimental Arm 2
    Number of subjects analysed
    46
    45
    Units: participants
    number (not applicable)
        Study Period 1 (n=46, 45)
    42
    38
        Study Period 2 (n=20, 19)
    11
    9
    No statistical analyses for this end point

    Primary: Adult Height Standard Deviation Score (SDS)

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    End point title
    		 Adult Height Standard Deviation Score (SDS) [2]
    End point description
    The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population description: All participants who received at least one dose of study drug with at least one follow up visit.
    End point type
    Primary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis for the primary efficacy objective on adult height SDS was not performed due to the early termination of study treatment. However, the height of patients was still monitored up to adult height in both treatment groups.
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    19
    16
    Units: standard deviation score
        arithmetic mean (standard deviation)
    -1.8 ( 0.53 )
    -1.9 ( 0.77 )
    No statistical analyses for this end point

    Secondary: Height Velocity

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    End point title
    		 Height Velocity
    End point description
    Height velocity is the difference between 2 height measurements, divided by years elapsed between measurements. Population description: All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    45
    43
    Units: centimeter per year
    arithmetic mean (standard deviation)
        Randomization (n=45, 43)
    7.8 ( 6.92 )
    7.4 ( 6.03 )
        Month 3 (n=45, 43)
    9.9 ( 3.94 )
    10.6 ( 3.53 )
        Month 6 (n=45, 42)
    8.1 ( 2.31 )
    9.7 ( 2.8 )
        Month 12 (n=44, 42)
    7 ( 1.64 )
    8.8 ( 2.33 )
        Month 18 (n=42, 42)
    6.6 ( 1.68 )
    8.4 ( 2.64 )
        Month 24 (n=37, 41)
    4.9 ( 1.33 )
    7.8 ( 3.36 )
        Month 30 (n=25, 25)
    6.2 ( 2.09 )
    5.8 ( 2.93 )
        Month 36 (n=18, 19)
    6.6 ( 3.25 )
    3.5 ( 2.71 )
        Month 42 (n=13, 14)
    5.7 ( 1.94 )
    3.7 ( 2.17 )
        Month 48 (n=7, 8)
    5.4 ( 2.27 )
    2.9 ( 2.73 )
        Month 54 (n=1, 1)
    6.3 ( 0 )
    7.1 ( 0 )
        Safety follow up 6 months (n=16, 9)
    4.6 ( 2.08 )
    4.5 ( 2.45 )
        Safety follow up 12 months(n=15, 8)
    2.9 ( 2.37 )
    2.3 ( 1.43 )
        Safety follow up 18 months (n=12, 4)
    3.3 ( 1.69 )
    1.2 ( 1.2 )
        Safety follow up 24 months (n=9, 1)
    2 ( 1.32 )
    2.5 ( 0 )
        Safety follow up 36 months (n=5, 0)
    1.3 ( 0.53 )
    0 ( 0 )
        Safety follow up 42 months (n=2, 0)
    2.1 ( 2.45 )
    0 ( 0 )
        Safety follow up 12 months (final height)(n=18,14)
    0.5 ( 0.86 )
    0.8 ( 1.59 )
        Safety follow up 24 months (final height) (n=7,10)
    0.3 ( 0.77 )
    0.3 ( 0.97 )
        Safety follow up 36 months (final height) (n=3,7)
    0.9 ( 0.78 )
    0.3 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Height SDS

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    End point title
    		 Height SDS
    End point description
    SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual’s height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population description: All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    45
    43
    Units: standard deviation score
    arithmetic mean (standard deviation)
        Randomization (n=45, 43)
    -2.5 ( 0.45 )
    -2.5 ( 0.46 )
        Month 3 (n=45, 43)
    -2.4 ( 0.42 )
    -2.4 ( 0.47 )
        Month 6 (n=45, 42)
    -2.3 ( 0.48 )
    -2.2 ( 0.52 )
        Month 12 (n=44, 42)
    -2.2 ( 0.5 )
    -2 ( 0.57 )
        Month 18 (n=42, 42)
    -2.2 ( 0.53 )
    -1.9 ( 0.63 )
        Month 24 (n=37, 41)
    -2.3 ( 0.58 )
    -1.8 ( 0.67 )
        Month 30 (n=25, 25)
    -2.2 ( 0.63 )
    -2 ( 0.58 )
        Month 36 (n=18, 19)
    -2 ( 0.65 )
    -2 ( 0.68 )
        Month 42 (n=13, 14)
    -1.8 ( 0.68 )
    -1.9 ( 0.66 )
        Month 48 (n=7, 8)
    -1.6 ( 0.52 )
    -1.9 ( 0.65 )
        Month 54 (n=1, 1)
    -1 ( 0 )
    -1.7 ( 0 )
        Safety follow up 6 months (n=16, 9)
    -2.1 ( 0.65 )
    -1.7 ( 0.77 )
        Safety follow up 12 months(n=15, 8)
    -1.9 ( 0.55 )
    -1.7 ( 0.77 )
        Safety follow up 18 months (n=12, 4)
    -1.9 ( 0.63 )
    -1.9 ( 0.78 )
        Safety follow up 24 months (n=9, 1)
    -1.9 ( 0.46 )
    -1.2 ( 0 )
        Safety follow up 36 months (n=5, 0)
    -1.9 ( 0.67 )
    0 ( 0 )
        Safety follow up 42 months (n=2, 0)
    -2.4 ( 0.18 )
    0 ( 0 )
        Safety follow up 12 months (final height)(n=18,14)
    -1.9 ( 0.46 )
    -1.8 ( 0.71 )
        Safety follow up 24 months (final height) (n=7,10)
    -1.6 ( 0.56 )
    -2 ( 0.79 )
        Safety follow up 36 months (final height) (n=3,7)
    -1.2 ( 0.9 )
    -2.2 ( 0.94 )
    No statistical analyses for this end point

    Secondary: Difference Between Adult Height SDS And Target Height SDS

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    End point title
    		 Difference Between Adult Height SDS And Target Height SDS
    End point description
    This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of target height [calculated as (mother’s height (SDS) + father’s height (SDS))/2] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population description: All participants who received who reached final height.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    16
    15
    Units: standard deviation score
        arithmetic mean (standard deviation)
    -0.6 ( 0.89 )
    -1.2 ( 0.8 )
    No statistical analyses for this end point

    Secondary: Difference Between Adult Height SDS And Baseline Predicted Height SDS

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    End point title
    		 Difference Between Adult Height SDS And Baseline Predicted Height SDS
    End point description
    This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline predicted height [calculated using the Bayley-Pinneau method based on height and bone age] for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population description: All participants who received who reached final height.
    End point type
    Secondary
    End point timeframe
    Baseline through End up Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    18
    16
    Units: standard deviation score
        arithmetic mean (standard deviation)
    1.1 ( 0.96 )
    1.2 ( 0.7 )
    No statistical analyses for this end point

    Secondary: Difference Between Adult Height SDS And Baseline Height SDS

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    End point title
    		 Difference Between Adult Height SDS And Baseline Height SDS
    End point description
    This is the difference between the gender, age and country matched standard deviation score of adult height and standard deviation score of baseline height for particular participant. The height of the participants were measured barefoot using a standard wall-mounted Harpenden stadiometer. SDS report the number of standard deviations from the mean for age and sex for an individual measurement (normal range: -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population description: All participants who received who reached final height.
    End point type
    Secondary
    End point timeframe
    Baseline through End up Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    19
    16
    Units: standard deviation score
        arithmetic mean (standard deviation)
    0.6 ( 0.59 )
    0.6 ( 0.67 )
    No statistical analyses for this end point

    Secondary: Percentage Of Children With Normal Adult Height SDS

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    End point title
    		 Percentage Of Children With Normal Adult Height SDS
    End point description
    Percentage of children with normal adult height SDS (greater than -2 SDS and less than +2 SDS). Population description: All participants who received at least one dose of study drug with at least one follow up visit.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    45
    43
    Units: percentage of participants
        number (not applicable)
    26.7
    25.6
    No statistical analyses for this end point

    Secondary: Bone Age

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    End point title
    		 Bone Age
    End point description
    Bone age measured using the X-Ray of left hand and wrist. Population description: All participants who received at least one dose of study drug with at least one follow up visit. The safety follow up participants did not reach final height at end of Period 1 unless final height is noted for participants that reached final height at the end of Period 1.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (up to 9 years)
    End point values
    		 Somatropin and Leuprorelin: Experimental Arm 1 Somatropin: Experimental Arm 2
    Number of subjects analysed
    45
    43
    Units: years
    arithmetic mean (standard deviation)
        Randomization (n=45, 43)
    10.8 ( 1.58 )
    11 ( 1.45 )
        Month 12 (n=40, 41)
    11.7 ( 1.59 )
    12.1 ( 1.12 )
        Month 24 (n=34, 37)
    12.4 ( 1.32 )
    13.4 ( 1.09 )
        Month 36 (n=18, 18)
    13.3 ( 1.49 )
    14.5 ( 1.64 )
        Month 48 (n=7, 8)
    14.8 ( 1.33 )
    15.4 ( 1.27 )
        Safety follow up 6 months (n=16, 7)
    14.1 ( 1.11 )
    14.9 ( 0.81 )
        Safety follow up 18 months (n=12, 3)
    15.2 ( 1.25 )
    17 ( 1 )
        Safety follow up 36 months (n=5, 0)
    15.7 ( 1.04 )
    0 ( 0 )
        Safety follow up 12 months (final height)(n=18,14)
    19.6 ( 14.53 )
    16.3 ( 1.27 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    All participants that started the study in addition to 3 participants from previous control group who were ineligible to participate in the study were given somatropin and are included in somatropin arm for AE assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Somatropin: Experimental Arm 2
    Reporting group description
    		 -

    Reporting group title
    Somatropin and Leuprorelin: Experimental Arm 1
    Reporting group description
    		 -

    Serious adverse events
    		 Somatropin: Experimental Arm 2 Somatropin and Leuprorelin: Experimental Arm 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 45 (15.56%)
    12 / 46 (26.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    histiocytosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    joint dislocation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radius fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    road traffic accident
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper limb fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wrist fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    congenital genital malformation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thyroglossal cyst
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    migraine
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    complication of device removal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    agitation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intentional self-injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mental disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    suicidal ideation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (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
    nephrolithiasis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal colic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    appendiceal abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    appendicitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    viral infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Somatropin: Experimental Arm 2 Somatropin and Leuprorelin: Experimental Arm 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 45 (80.00%)
    41 / 46 (89.13%)
    Injury, poisoning and procedural complications
    ligament sprain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    16 / 45 (35.56%)
    21 / 46 (45.65%)
         occurrences all number
    37
    51
    General disorders and administration site conditions
    injection site pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    8 / 46 (17.39%)
         occurrences all number
    0
    22
    pyrexia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 46 (8.70%)
         occurrences all number
    6
    4
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 46 (2.17%)
         occurrences all number
    4
    5
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    7 / 45 (15.56%)
    4 / 46 (8.70%)
         occurrences all number
    18
    4
    abdominal pain upper
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 45 (8.89%)
    3 / 46 (6.52%)
         occurrences all number
    10
    11
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 46 (6.52%)
         occurrences all number
    3
    14
    nausea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences all number
    3
    7
    toothache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    7
    vomiting
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 46 (6.52%)
         occurrences all number
    5
    5
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 45 (13.33%)
    3 / 46 (6.52%)
         occurrences all number
    15
    4
    epistaxis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences all number
    2
    4
    oropharyngeal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 45 (8.89%)
    5 / 46 (10.87%)
         occurrences all number
    6
    6
    Skin and subcutaneous tissue disorders
    acne
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 45 (11.11%)
    2 / 46 (4.35%)
         occurrences all number
    7
    2
    Endocrine disorders
    hypothyroidism
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 45 (8.89%)
    7 / 46 (15.22%)
         occurrences all number
    6
    11
    pain in extremity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 46 (8.70%)
         occurrences all number
    1
    4
    scoliosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 46 (8.70%)
         occurrences all number
    1
    4
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 46 (6.52%)
         occurrences all number
    2
    4
    cystitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    ear infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 46 (8.70%)
         occurrences all number
    8
    4
    gastroenteritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 45 (13.33%)
    11 / 46 (23.91%)
         occurrences all number
    9
    15
    influenza
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    9 / 45 (20.00%)
    15 / 46 (32.61%)
         occurrences all number
    16
    17
    nasopharyngitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    8 / 45 (17.78%)
    19 / 46 (41.30%)
         occurrences all number
    10
    36
    rhinitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    5 / 46 (10.87%)
         occurrences all number
    11
    5
    tonsillitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 45 (11.11%)
    6 / 46 (13.04%)
         occurrences all number
    12
    9
    tracheitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Metabolism and nutrition disorders
    vitamin d deficiency
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2008
    Study Period 1 treatment with Humatrope was suspended for all active participants. Participants from the Netherlands exited the study after Study Period 1 and participants from France were given the option to re-consent for Study Period 2.

    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.
    No statistical analyses was performed after the early treatment termination. All data represented is descriptive statistics only and no confirmatory conclusions can be drawn from this study.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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