Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Somatropin Therapy for Short Children Born of Premature Gestation: A Controlled, Prospective Randomized, Multicenter Study with an Untreated Control Group

    Summary
    EudraCT number
    		 2004-004781-33
    Trial protocol
    		 DE  
    Global end of trial date
    24 Mar 2010

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A6281273
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00174460
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1800 7181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1800 7181021, 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
    30 Sep 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether Growth Hormone (GH) therapy improves growth velocity and height Standard Deviation Score (SDS) after one year in very low birth weight (VLBW) preterm infants born appropriate-for-gestational age (AGA) with short stature.
    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
    29 Aug 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    33
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study started on 29-Aug-2005 and ended on 30-Sep-2010.There were 33 subjects enrolled in this study in Germany.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Somatropin
    Arm description
    		 The children were randomized into a treated group receiving subcutaneous somatropin according to exact body weight specific calculation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The children received 0.068 mg/kg/day (0.48mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation. Dose adjustments were made at 6 month intervals. (mg=milligrams, kg=kilograms).

    Arm title
    		 Control Arm
    Arm description
    		 The children were randomized into control group and after 1 year underwent Growth Hormone (GH) therapy, with subcutaneous somatropin according to exact body weight specific calculation.
    Arm type
    		 Control

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Control group after 1 year underwent GH therapy with 0.068 mg/kg/day (0.48mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation.

    Number of subjects in period 1
    		Somatropin Control Arm
    Started
    18
    15
    Completed
    18
    14
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Somatropin
    Reporting group description
    		 The children were randomized into a treated group receiving subcutaneous somatropin according to exact body weight specific calculation.

    Reporting group title
    Control Arm
    Reporting group description
    		 The children were randomized into control group and after 1 year underwent Growth Hormone (GH) therapy, with subcutaneous somatropin according to exact body weight specific calculation.

    Reporting group values
    		 Somatropin Control Arm Total
    Number of subjects
    		 18 15 33
    Age categorical
    1 subject in each treatment group was below the age of 4 at screening. However, both of them were 4 years old when treatment began; they did not violate the corresponding inclusion criterion.
    Units: Subjects
        Less than (<) 4 years
    		 1 1 2
        Greater than or equal to ≥ 4 years and < 8 years
    		 14 11 25
        ≥ 8 years and < 12 years
    		 3 3 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.4 ± 1.6 5.7 ± 1.9 -
    Gender categorical
    Units: Subjects
        Female
    		 9 7 16
        Male
    		 9 8 17

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Somatropin
    Reporting group description
    		 The children were randomized into a treated group receiving subcutaneous somatropin according to exact body weight specific calculation.

    Reporting group title
    Control Arm
    Reporting group description
    		 The children were randomized into control group and after 1 year underwent Growth Hormone (GH) therapy, with subcutaneous somatropin according to exact body weight specific calculation.

    Primary: Change in Height Standard Deviation Score (SDS) After 1 Year

    		 Close Top of page
    End point title
    		 Change in Height Standard Deviation Score (SDS) After 1 Year
    End point description
    Change in Height SDS after 1 year where SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). Full Analysis Set (FAS); all randomized subjects who had at least 1 post-baseline efficacy measurement; Control group received Somatropin from Month 12 onwards.
    End point type
    Primary
    End point timeframe
    Baseline to 1 year (Month 12)
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters
        least squares mean (standard error)
    1.099 ± 0.0714
    0.108 ± 0.0783
    Statistical analysis title
    		 Treatment difference for change in height SDS
    Statistical analysis description
    Results from analysis of covariance method (ANCOVA) adjusted for baseline height SDS and target height SDS; Last observation carried forward (LOCF).
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.991
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.773
         upper limit
    		 1.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1067

    Primary: Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year

    		 Close Top of page
    End point title
    		 Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year
    End point description
    Change in Growth Velocity (GV) SDS after 1 year where SDS= GV minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Primary
    End point timeframe
    Baseline to 1 year (Month 12)
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters per year
        least squares mean (standard error)
    7.117 ± 0.4384
    1.502 ± 0.4814
    Statistical analysis title
    		 Treatment difference in growth velocity SDS
    Statistical analysis description
    Results from ANCOVA adjusted for baseline growth velocity SDS and target height SDS; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.615
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.266
         upper limit
    		 6.963
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6591

    Secondary: Change From Baseline in Growth Velocity After 1 Year and After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Growth Velocity After 1 Year and After 2 Years
    End point description
    Growth velocity measured as centimeters per year. FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeter per year
    least squares mean (standard error)
        Month 12
    5.11 ± 0.2623
    0.695 ± 0.2881
        Month 24
    3.049 ± 0.3546
    3.934 ± 0.3893
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline growth velocity, target height SDS, sex, and age; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.415
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.605
         upper limit
    		 5.225
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.395
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline growth velocity, target height SDS, sex, and age; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.108
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.884
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.977
         upper limit
    		 0.208
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5327

    Secondary: Change From Baseline in Growth Velocity SDS After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Growth Velocity SDS After 2 Years
    End point description
    Change in Growth Velocity SDS after 2 years (24 months) where SDS = growth velocity minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeter per year
        least squares mean (standard error)
    4.751 ± 0.4716
    5.825 ± 0.5177
    Statistical analysis title
    		 Change From Baseline in Growth Velocity SDS
    Statistical analysis description
    Results from ANCOVA adjusted for baseline growth velocity SDS and target height SDS; LOCF.
    Comparison groups
    Control Arm v Somatropin
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.141
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.074
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.524
         upper limit
    		 0.376
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7089

    Secondary: Change From Baseline in Height After 1 Year and After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Height After 1 Year and After 2 Years
    End point description
    FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters
    least squares mean (standard error)
        Month 12
    10.467 ± 0.2439
    5.927 ± 0.2677
        Month 24
    18.908 ± 0.6507
    14.844 ± 0.7149
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline height, target height SDS, sex, and age; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.789
         upper limit
    		 5.291
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3661
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline height, target height SDS, sex, and age; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.049
         upper limit
    		 6.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9822

    Secondary: Change From Baseline in Height SDS After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Height SDS After 2 Years
    End point description
    Change in Height SDS after 2 years (24 months) where SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters
        least squares mean (standard error)
    1.71 ± 0.1075
    0.991 ± 0.1179
    Statistical analysis title
    		 Change From Baseline in Height SDS
    Statistical analysis description
    Results from ANCOVA adjusted for baseline height SDS and target height SDS; LOCF.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.719
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.047
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1606

    Secondary: Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps

    		 Close Top of page
    End point title
    		 Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps
    End point description
    Body composition measured as skinfold thickness at tricep in millimeters (mm); measured halfway down the left upper arm with arm hanging in relaxed position at subject's side. FAS; Control group received Somatropin from Month 12 onwards. Here n signifies the number of subjects evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: millimeters
    least squares mean (standard error)
        Month 12 (n=15, 14)
    -2.2 ± 0.341
    0.5 ± 0.353
        Month 24 (n=16, 14)
    -1.3 ± 0.511
    -0.83 ± 0.548
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, age, and sex; LOCF. For the treatment comparison, results were presented for 29 Subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.73
         upper limit
    		 -1.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.497
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, age, and sex; LOCF. For the treatment comparison, results were presented for 30 Subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.537
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.758

    Secondary: Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular

    		 Close Top of page
    End point title
    		 Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular
    End point description
    Body composition measured as subscapular skinfold thickness in mm; measured laterally just below the angle of the left scapula. FAS; Control group received Somatropin from Month 12 onwards. Here n signifies the number of subjects evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: millimeters
    least squares mean (standard error)
        Month 12 (n= 15, 14)
    0.51 ± 0.783
    0.45 ± 0.849
        Month 24 (n=16, 14)
    0.9 ± 0.688
    0.79 ± 0.774
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, sex, and age; LOCF. For the treatment comparison, results were presented for 29 subjects.
    Comparison groups
    Control Arm v Somatropin
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.364
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.405
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, sex, and age; LOCF. For the treatment comparison, results are presented for 30 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.506
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.345

    Secondary: Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac

    		 Close Top of page
    End point title
    		 Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac
    End point description
    Body composition measured as suprailiac skinfold thickness in mm; measured just above the iliac crest in the middle-axillary line. FAS; Control group received Somatropin from Month 12 onwards. Here n signifies the number of subjects evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: millimeter(s)
    least squares mean (standard error)
        Month 12 (n=14, 12)
    0.51 ± 0.783
    0.45 ± 0.849
        Month 24 (n=15, 12)
    0.9 ± 0.688
    0.79 ± 0.774
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, sex, and age; LOCF. For the treatment comparison, results were presented for 26 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.959
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 2.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.188
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline skinfold thickness, target height SDS, sex, and age; LOCF. For the treatment comparison, results were presented for 27 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.919
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 2.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.065

    Secondary: Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years
    End point description
    Volumetric Cortical BMD measured as milligrams per cubic millimeter (mg/mm^3). BMD (proximal radius) SDS (number of standard deviations a subject's BMD differs from the average BMD of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln [test result/M]/ S); Ln=natural logarithm; M=age- or height- and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; Here n signifies number of subjects from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        month 12 (n=2, 6)
    -1.055 ± 0.6802
    -0.162 ± 0.36
        Month 24(n=2, 6)
    0.284 ± 0.5023
    -0.433 ± 0.2658
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline volumetric cortical bone mineral density SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.336
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.892
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.158
         upper limit
    		 1.374
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8161
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline volumetric cortical bone mineral density SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.717
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.956
         upper limit
    		 2.391
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6027

    Secondary: Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA)
    End point description
    Bone structure Cortical CSA measured as millimeters squared (mm^2). CSA (proximal radius) SDS (number of standard deviations a subject's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; n=number of subjects from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        Month 12 (n=2, 5)
    -0.465 ± 0.7799
    0.017 ± 0.4559
        Month 24 (n=2, 6)
    -0.595 ± 0.7462
    0.609 ± 0.3907
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline cortical cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results are presented for 7 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.653
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.482
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.558
         upper limit
    		 2.595
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9666
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline cortical cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results are presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.251
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.701
         upper limit
    		 1.292
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8991

    Secondary: Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA)
    End point description
    Bone structure Total CSA measured as millimeters squared (mm^2). Total CSA (proximal radius) SDS (number of standard deviations a subject's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln [test result/M)] / S); Ln=natural logarithm; M = age- or height- and sex-specific mean value; S = age-(or height-) and sex-specific coefficient of variation then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; Here n signifies number of subjects from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        Month 12 (n=2, 5)
    0.375 ± 0.9345
    0.239 ± 0.5537
        Month 24 (n=2, 6)
    0.243 ± 0.3694
    -0.049 ± 0.1955
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline total cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 7 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.914
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.524
         upper limit
    		 3.795
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1499
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline total cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.547
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.939
         upper limit
    		 1.522
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4432

    Secondary: Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA)
    End point description
    Bone structure Muscle CSA measured as millimeters squared (mm^2). CSA (proximal radius) SDS (number of standard deviations a subject's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln [ test result/M] / S); Ln=natural logarithm; M = age- or height- and sex-specific mean value; S= age-(or height-) and sex-specific coefficient of variation then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; Here n signifies number of subjects from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        Month 12 (n=2, 6)
    2.084 ± 0.3628
    -0.227 ± 0.1688
        Month 24 (n=2, 6)
    2.402 ± 0.5221
    0.776 ± 0.2428
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline muscle cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.049
         upper limit
    		 3.572
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4542
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline muscle cross-sectional area SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.626
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.189
         upper limit
    		 3.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6536

    Secondary: Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Thickness (CT)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Thickness (CT)
    End point description
    Cortical Thickness measured as millimeters (mm). CT (proximal radius) SDS (number of standard deviations a subject's CT differs from the average CT of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln (test result/ M)]/S); Ln = natural logarithm; M = age- or height-) and sex-specific mean value; S = age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards. Cortical thickness was not analyzed as planned.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: z-score
        least squares mean (standard deviation)
    ±
    ±
    Notes
    [1] - Cortical thickness was not analyzed as planned.
    [2] - Cortical thickness was not analyzed as planned.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Marrow Area (MA)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Marrow Area (MA)
    End point description
    Marrow Area measured as millimeters squared (mm^2). MA (proximal radius) SDS (number of standard deviations a subject's MA differs from the average MA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S = age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards. Marrow Area was not analyzed as planned.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: z-score
        least squares mean (standard error)
    ±
    ±
    Notes
    [3] - Marrow Area was not analyzed as planned.
    [4] - Marrow Area was not analyzed as planned.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI)

    		 Close Top of page
    End point title
    		 Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI)
    End point description
    Bone stability expressed as polar SSI in cubic millimeters (mm^3). SSI (proximal radius) SDS (number of standard deviations a subject's SSI differs from the average SSI of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln [test result/M)] / S); Ln=natural logarithm; M=age- or height- and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation then change from baseline is calculated. Positive values are above the average for subject's age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; Here n signifies number of subjects from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        Month 12 (n=2, 6)
    0.648 ± 0.4224
    0.088 ± 0.2243
        Month 24 (n=2, 6)
    0.477 ± 0.3925
    0.363 ± 0.2084
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline strength-strain index SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.331
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.846
         upper limit
    		 1.965
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5061
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline strength-strain index SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 8 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.192
         upper limit
    		 1.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4703

    Secondary: Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years

    		 Close Top of page
    End point title
    		 Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years
    End point description
    Muscle strength determined by measuring grip force (kilograms) using hand grip dynamometer for subjects ≥6 years of age. Baseline and post-baseline SDS values transformed to age and sex specific z-score. Change in hand grip calculated as SDS where SDS = hand grip minus mean (age- and sex-matched reference) divided by SD (age- and sex-matched reference). Positive values are above the average for subjects age and sex; negative values are below the average. FAS; Control group received Somatropin from Month 12 onwards; Here n signifies the number of subjects ≥6 years of age with evaluable data at observation for Somatropin and Control Arm, respectively. SDS reference values used were for the right hand but the hand grip strength measured for this study was for the dominant hand (may not have been the right hand).
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: z-score
    least squares mean (standard error)
        Month 12 (n=7, 5)
    0.37 ± 0.268
    0.28 ± 0.318
        Month 24 (n=7, 6)
    1.14 ± 0.218
    0.92 ± 0.236
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from ANCOVA adjusted for baseline hand grip strength SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 12 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.844
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 1.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from ANCOVA adjusted for baseline hand grip strength SDS and target height SDS; LOCF. For the treatment comparison, results were presented for 13 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.519
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.329

    Secondary: Number of Subjects With Change in Insulin Sensitivity: Somatropin

    		 Close Top of page
    End point title
    		 Number of Subjects With Change in Insulin Sensitivity: Somatropin [5]
    End point description
    Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Somatropin treatment group = Month 24). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to >140 mg/dL; capillary (blood) with range minimum 120 mg/dL to >120 mg/dL; or method not known with range minimum 120 mg/dL to >120 mg/dL. FAS population was analyzed for the endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Comparison between groups was not planned. Data was not collected at Month 24 for Control Arm.
    End point values
    		 Somatropin
    Number of subjects analysed
    18
    Units: subjects
        Baseline: tolerant
    18
        Baseline: intolerant
    0
        Month 24: tolerant
    16
        Month 24: intolerant
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change in Insulin Sensitivity: Control Arm

    		 Close Top of page
    End point title
    		 Number of Subjects With Change in Insulin Sensitivity: Control Arm [6]
    End point description
    Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Control Arm=Month 36). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to >140 mg/dL; capillary (blood) with range minimum 120 mg/dL to >120 mg/dL; or method not known with range minimum 120 mg/dL to >120 mg/dL. FAS; Control group received Somatropin from Month 12 onwards.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: comparison between groups was not planned. Data was not collected at Month 36 for Somatropin group.
    End point values
    		 Control Arm
    Number of subjects analysed
    15
    Units: subjects
        Baseline: tolerant
    14
        Baseline: intolerant
    1
        Month 36: tolerant
    11
        Month 36: intolerant
    2
    No statistical analyses for this end point

    Secondary: Growth Curve Comparison Based on Height SDS

    		 Close Top of page
    End point title
    		 Growth Curve Comparison Based on Height SDS
    End point description
    Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). FAS; Control group received Somatropin from Month 12 onwards. Data for Month 36 (applicable only to the Control Arm) is reported in a separate outcome measure. Here n signifies the number of subjects evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters
    least squares mean (standard error)
        Month 12 (n=18, 15)
    -2.26 ± 0.0735
    -3.259 ± 0.0802
        Month 24 (n=18, 14)
    -1.638 ± 0.1016
    -2.327 ± 0.1122
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from repeated measures mixed models analysis adjusted for baseline height SDS, visit, visit*treatment and target height SDS.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.998
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.778
         upper limit
    		 1.219
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1095
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from repeated measures mixed models analysis adjusted for baseline height SDS, visit, visit*treatment and target height SDS. For the treatment comparison, results were presented for 32 Subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.688
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.382
         upper limit
    		 0.994
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1519

    Secondary: Growth Curve Comparison Based on Height SDS: Control Arm

    		 Close Top of page
    End point title
    		 Growth Curve Comparison Based on Height SDS: Control Arm [7]
    End point description
    Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). Control Arm final visit = Month 36. FAS; Control group received Somatropin from Month 12 onwards. Month 36 visit not applicable to Somatropin treatment group.
    End point type
    Secondary
    End point timeframe
    Month 36
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Comparison between groups was not planned at Month 36. No data was available for Somatropin group at Month 36.
    End point values
    		 Control Arm
    Number of subjects analysed
    14 [8]
    Units: centimeters
        least squares mean (standard error)
    -1.794 ± 0.1318
    Notes
    [8] - N=number of subjects with evaluable data at observation.
    No statistical analyses for this end point

    Secondary: Growth Curve Comparison Based on Height

    		 Close Top of page
    End point title
    		 Growth Curve Comparison Based on Height
    End point description
    Growth curve comparison with height in centimeters as the dependent variable. FAS; Control group received Somatropin from Month 12 onwards. Data for Month 36 (applicable only to the Control Arm) is reported in a separate outcome measure. Here n signifies the number of subjects evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    End point values
    		 Somatropin Control Arm
    Number of subjects analysed
    18
    15
    Units: centimeters
    least squares mean (standard error)
        Month 12
    114.228 ± 0.333
    109.644 ± 0.3733
        Month 24
    123.351 ± 0.483
    119.788 ± 0.5255
    Statistical analysis title
    		 Treatment difference Month 12
    Statistical analysis description
    Results from repeated measure mixed models analysis adjusted for baseline height, sex, age, visit, visit*treatment and target height SDS.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.806
         upper limit
    		 5.363
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3859
    Statistical analysis title
    		 Treatment difference Month 24
    Statistical analysis description
    Results from repeated measure mixed models analysis adjusted for baseline height, sex, age, visit, visit*treatment and target height SDS. For the treatment comparison, results were presented for 32 subjects.
    Comparison groups
    Somatropin v Control Arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.563
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.134
         upper limit
    		 4.992
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.708

    Secondary: Growth curve comparison with height in centimeters as the dependent variable.

    		 Close Top of page
    End point title
    		 Growth curve comparison with height in centimeters as the dependent variable. [9]
    End point description
    Growth curve comparison with height in centimeters as the dependent variable. FAS; Control group received Somatropin from Month 12 onwards. Month 36 visit not applicable to Somatropin treatment group.
    End point type
    Secondary
    End point timeframe
    Month 36
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Comparison between groups was not planned at Month 36. No data was available for Somatropin group at Month 36.
    End point values
    		 Control Arm
    Number of subjects analysed
    14 [10]
    Units: centimeters
        least squares mean (standard error)
    128.049 ± 0.7821
    Notes
    [10] - N = number of subjects with evaluable data at observation.
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days after last dose of study treatment.
    Adverse event reporting additional description
    Safety population=who received at least 1 dose of treatment. Same event may appear as AE, SAE.Distinct events are presented. Event may be categorized as serious in 1 subject, nonserious in another/subject may have experienced both serious, nonserious event during study. EU BR AE tables were generated as per EU format using latest coding dictionary.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Somatropin
    Reporting group description
    		 The children were randomized into a treated group receiving 0.068 mg/kg/day (0.48 mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation. Dose adjustments were made at 6 month intervals.

    Reporting group title
    Control Arm
    Reporting group description
    		 The children were randomized into control group and after 1 year underwent Growth Hormone (GH) therapy, with 0.068 mg/kg/day (0.48mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation. Dose adjustments were made at 6 month intervals.

    Serious adverse events
    		 Somatropin Control Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 18 (27.78%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         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
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Somatropin Control Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    11 / 15 (73.33%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Tooth disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Arthritis allergic
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nuchal rigidity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Scoliosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 15 (13.33%)
         occurrences all number
    3
    3
    Bronchitis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 15 (13.33%)
         occurrences all number
    1
    3
    Ear infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Erythema infectiosum
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Febrile infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    2
    4
    Oral herpes
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 15 (6.67%)
         occurrences all number
    6
    1
    Otitis media acute
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Scarlet fever
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    Tooth abscess
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    4
    4
    Varicella
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2005
    Amendment was made to specific study procedures, subject selection and laboratory assessments.

    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.
    Result values for the primary outcome measures were revised at the final analysis due to programmatic corrections: age rounded up if >6 months past last birthday. Height and height SDS not rounded for final analysis; rounded only for the reports.
    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.

    European Medicines Agency © 1995-Sat Apr 20 08:17:33 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA