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    Clinical Trial Results:
    A two-year multi-centre, randomized two arm study of Genotropin treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN)

    Summary
    EudraCT number
    		 2007-003949-32
    Trial protocol
    		 SE   CZ   BE   ES   AT   GB   FR   IT   DE   NL  
    Global end of trial date
    30 Dec 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    A6281287
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00627523
    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., 001-800 718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001-800 718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of 24 months of treatment with growth hormone (GH) therapy at a dose of 0.035 milligram per kilogram per day (mg/kg/d) on height in short small for gestational age (SGA) children starting treatment at 24-30 months of age, compared to untreated controls, in randomized subjects.
    Protection of trial subjects
    The study was in compliance with with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Feb 2008
    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
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Switzerland: 6
    Worldwide total number of subjects
    43
    EEA total number of subjects
    37
    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)
    18
    Children (2-11 years)
    25
    Adolescents (12-17 years)
    0
    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
    		 This randomized controlled trial enrolled small for gestational age (SGA) children at 16 centers in 8 countries. In total, 52 subjects were screened for the study, of these, 9 subjects were considered screen failures. The remaining 43 subjects were randomized to receive either study drug (Genotropin) or were not treated (Control).

    Pre-assignment
    Screening details
    		 Subjects aged between 19 to 29 months at Screening visit, born SGA (birth length and/or weight less than (<) 2 standard deviations (SD) for gestational age, using country specific standards), height below -2.5 SD at Screening (19-29 months of age),and had at least one measurement of length between 12 and 18 months of age were enrolled in this study

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Genotropin
    Arm description
    		 Subjects received Genotropin at a dose of 0.035 mg/kg/d for 24 months. The dose was calculated based on the actual body weight, and the closest dosing step of the 5 mg pen used. The starting dose for the first 2 weeks was 1/3 of the calculated dose. After 2 weeks the dose was increased to 2/3 of the calculated dose. After 4 weeks the daily dose was the dose calculated on body weight at randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Genotropin at a dose of 0.035 mg/kg/d for 24 months.

    Arm title
    		 Control
    Arm description
    		 This group was the untreated control group and was not administered placebo.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Genotropin Control
    Started
    21
    22
    Completed
    19
    20
    Not completed
    2
    2
         'Not specified '
    1
    -
         Withdrawal by Subject
    -
    2
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genotropin
    Reporting group description
    		 Subjects received Genotropin at a dose of 0.035 mg/kg/d for 24 months. The dose was calculated based on the actual body weight, and the closest dosing step of the 5 mg pen used. The starting dose for the first 2 weeks was 1/3 of the calculated dose. After 2 weeks the dose was increased to 2/3 of the calculated dose. After 4 weeks the daily dose was the dose calculated on body weight at randomization.

    Reporting group title
    Control
    Reporting group description
    		 This group was the untreated control group and was not administered placebo.

    Reporting group values
    		 Genotropin Control Total
    Number of subjects
    		 21 22 43
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 24.91 ± 3.262 24.44 ± 3.324 -
    Gender categorical
    Units: Subjects
        Female
    		 13 11 24
        Male
    		 8 11 19

    End points

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    End points reporting groups
    Reporting group title
    Genotropin
    Reporting group description
    		 Subjects received Genotropin at a dose of 0.035 mg/kg/d for 24 months. The dose was calculated based on the actual body weight, and the closest dosing step of the 5 mg pen used. The starting dose for the first 2 weeks was 1/3 of the calculated dose. After 2 weeks the dose was increased to 2/3 of the calculated dose. After 4 weeks the daily dose was the dose calculated on body weight at randomization.

    Reporting group title
    Control
    Reporting group description
    		 This group was the untreated control group and was not administered placebo.

    Primary: Change From Baseline in Height Standard Deviation Score (SDS) at Month 24

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    End point title
    		 Change From Baseline in Height Standard Deviation Score (SDS) at Month 24
    End point description
    Height SDS was calculated at the relevant visit by means of the following formula:Height SDS=(subject height)-(normal height)/normal height standard deviation. Where subject height refers to the subject’s height at the relevant visit, and normal height and the normal height standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. The change from Baseline value for height SDS was calculated as the difference between the parameter values at a specific visit, and the Baseline parameter values. The scores were centred around 0. Negative score indicated a subject was smaller for their age/gender.Full Analysis Set (FAS) included subjects who were randomized to treatment and completed at least 1 post-baseline efficacy measure. Missing values were imputed using LOCF method. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control for safety analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Month 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
        least squares mean (standard error)
    1.63 ± 0.13
    0.43 ± 0.13
    Statistical analysis title
    		 Genotropin, Control
    Statistical analysis description
    The null hypothesis was that there was no difference in the mean change from Baseline after 24 months in height SDS between the Genotropin® and the untreated control groups. The alternative hypothesis was that there was a difference between the treatment groups.
    Comparison groups
    Genotropin v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Notes
    [1] - Analysis of covariance (ANCOVA) model, fitting treatment as a factor, and the baseline parameter value as covariate was used. All hypotheses were tested at a 5% level of significance.No adjustments were made for multiple comparisons.

    Secondary: Change From Baseline in Growth Velocity SDS at Month 24

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    End point title
    		 Change From Baseline in Growth Velocity SDS at Month 24
    End point description
    The growth velocity SDS was calculated at the relevant visit by means of the following formula: Growth velocity SDS = (subject growth velocity) - (normal growth velocity)/normal growth velocity standard deviation. Where, subject growth velocity refers to the subject's growth velocity at the relevant visit, and normal growth velocity and the normal growth velocity standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. The change from baseline value for growth velocity SDS was calculated as the difference between the parameter values at a specific visit, and the Baseline parameter values. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. Missing values were imputed using LOCF method.1 subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
        least squares mean (standard error)
    0.74 ± 0.57
    -0.03 ± 0.57
    Statistical analysis title
    		 Genotropin®, Control
    Statistical analysis description
    The null hypothesis was that there was no difference between the Genotropin® and the untreated control group in terms of the relevant secondary endpoints. The alternative hypothesis was that a difference existed.
    Comparison groups
    Genotropin v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.348
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 2.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.81
    Notes
    [2] - ANCOVA model, fitting treatment as a factor, and the baseline parameter value as covariate was used. All hypotheses were tested at a 5% level of significance. No adjustments were made for multiple comparisons.

    Secondary: Change From Baseline in Height SDS at Month 12

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    End point title
    		 Change From Baseline in Height SDS at Month 12
    End point description
    Height SDS was calculated at the relevant visit by means of the following formula: Height SDS = (subject height) - (normal height)/normal height standard deviation. Where subject height refers to the subject's height at the relevant visit, and normal height and the normal height standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. The change from baseline value for height SDS was calculated as the difference between the parameter values at a specific visit, and the baseline parameter values. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. Missing values were imputed using LOCF method. 1 subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
        least squares mean (standard error)
    1.03 ± 0.12
    0.14 ± 0.12
    Statistical analysis title
    		 Genotropin, Control
    Statistical analysis description
    The null hypothesis was that there was no difference between the Genotropin and the untreated control group in terms of the relevant secondary endpoints. The alternative hypothesis was that a difference existed.
    Comparison groups
    Genotropin v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [3] - ANCOVA model, fitting treatment as a factor, and the baseline parameter value as covariate was used. All hypotheses were tested at a 5% level of significance. No adjustments were made for multiple comparisons.

    Secondary: Change From Baseline in Growth Velocity SDS at Month 12

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    End point title
    		 Change From Baseline in Growth Velocity SDS at Month 12
    End point description
    The growth velocity SDS was calculated at the relevant visit by means of the following formula: Growth velocity SDS = (subject growth velocity) - (normal growth velocity)/normal growth velocity standard deviation. Where, subject growth velocity refers to the subject's growth velocity at the relevant visit, and normal growth velocity and the normal growth velocity standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. The change from Baseline value for growth velocity SDS was calculated as the difference between the parameter values at a specific visit, and the Baseline parameter values. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. Missing values were imputed using LOCF method. 1 subject was randomized to Genotropin® but did not receive any treatment. This subject was excluded from FAS but included in Control for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
        least squares mean (standard error)
    1.65 ± 0.56
    -1.59 ± 0.56
    Statistical analysis title
    		 Genotropin®, Control
    Statistical analysis description
    The null hypothesis was that there was no difference between the Genotropin® and the untreated control group in terms of the relevant secondary endpoints. The alternative hypothesis was that a difference existed.
    Comparison groups
    Genotropin v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.63
         upper limit
    		 4.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [4] - ANCOVA model, fitting treatment as a factor, and the baseline parameter value as covariate was used. All hypotheses were tested at a 5% level of significance. No adjustments were made for multiple comparisons.

    Secondary: Change From Baseline in Mental Development Using the Mental Development Index (MDI) of Bayley Scale at Month 12

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    End point title
    		 Change From Baseline in Mental Development Using the Mental Development Index (MDI) of Bayley Scale at Month 12
    End point description
    The Bayley Scale of Infant Development (BSID-II) measured the mental and motor development and test behavior of subjects from 1 to 42 months of age. The scale was used to describe the current developmental functioning of infants and to assist in diagnosis and treatment planning for infants with developmental delays or disabilities. The BSID-II provided the mental raw score which was used to calculate the MDI score. Possible MDI scores ranged from 50-150. The MDI score of 69 and below indicated significantly delayed performance, 70 to 84 indicated mildly delayed performance, 85 to 114 indicated normal limit, and 115 and above indicated accelerated performance. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: Units on a scale
        least squares mean (standard error)
    10.97 ± 5.34
    8.55 ± 4.74
    Statistical analysis title
    		 Genotropin®, Control
    Statistical analysis description
    The null hypothesis was that there was no difference between the Genotropin® and the untreated control group in terms of the relevant secondary endpoints. The alternative hypothesis was that a difference existed.ANCOVA model, fitting treatment as a factor, and the baseline parameter value, age, and gender as covariates were used. All hypotheses were tested at a 5% level of significance.No adjustments were made for multiple comparisons.
    Comparison groups
    Genotropin v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.738
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.27
         upper limit
    		 17.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.19

    Secondary: Change From Baseline in Psychomotor Development Using the Psychomotor Development Index (PDI) of Bayley Scale at Month 12

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    End point title
    		 Change From Baseline in Psychomotor Development Using the Psychomotor Development Index (PDI) of Bayley Scale at Month 12
    End point description
    BSID-II measured the mental and motor development and test behavior of subjects from 1 to 42 months of age. The scale was used to describe the current developmental functioning of infants and to assist in diagnosis and treatment planning for infants with developmental delays or disabilities. The BSID-II provided the psychomotor raw score which was used to calculate the PDI score. The PDI score of 69 and below indicated significantly delayed performance, 70 to 84 indicated mildly delayed performance, 85 to 114 indicated normal limit, and 115 and above indicated accelerated performance. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: Units on a scale
        least squares mean (standard error)
    4.04 ± 3.04
    8.55 ± 2.84
    Statistical analysis title
    		 Genotropin, Control
    Statistical analysis description
    The null hypothesis was that there was no difference between the Genotropin and the untreated control group in terms of the relevant secondary endpoints. The alternative hypothesis was that a difference existed.
    Comparison groups
    Control v Genotropin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.301
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.27
         upper limit
    		 4.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.27
    Notes
    [5] - ANCOVA model, fitting treatment as a factor, and the baseline parameter value, age, and gender as covariates were used. All hypotheses were tested at a 5% level of significance. No adjustments were made for multiple comparisons.

    Secondary: Head Circumference SDS at Months 3, 6, 12, 18 and 24

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    End point title
    		 Head Circumference SDS at Months 3, 6, 12, 18 and 24
    End point description
    Head circumference SDS was calculated by means of the following formula = (Subject head circumference) - (Normal head circumference) / Normal head circumference standard deviation. Where subject head circumference refers to the subject's head circumference at the relevant visit, and normal head circumference and the normal head circumference standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 12, 18 and 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
    arithmetic mean (standard deviation)
        Month 3 (n = 21, 19)
    -0.93 ± 1.217
    -1.37 ± 1.122
        Month 6 (n = 21, 19)
    -1.2 ± 1.31
    -1.72 ± 1.077
        Month 12 (n = 20, 18)
    -0.87 ± 1.33
    -1.84 ± 1.158
        Month 18 (n = 20, 19)
    -0.56 ± 1.89
    -1.76 ± 1.153
        Month 24 (n = 20, 20)
    -0.75 ± 1.384
    -1.65 ± 1.227
    No statistical analyses for this end point

    Secondary: Change From Baseline in Head Circumference SDS at Months 3, 6, 12, 18 and 24

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    End point title
    		 Change From Baseline in Head Circumference SDS at Months 3, 6, 12, 18 and 24
    End point description
    Head circumference SDS was calculated by means of the following formula = (Subject head circumference)-(Normal head circumference)/Normal head circumference standard deviation. Where subject head circumference refers to the subject's head circumference at the relevant visit, and normal head circumference and the normal head circumference standard deviation equals the population mean and standard deviation values for subjects of a similar age and gender. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin® but did not receive any treatment. This subject was excluded from FAS but included in Control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 12, 18 and 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: SDS
    arithmetic mean (standard deviation)
        Month 3 (n = 21, 19)
    0.27 ± 0.977
    0.36 ± 0.693
        Month 6 (n = 21, 19)
    0 ± 0.423
    0.07 ± 0.495
        Month 12 (n = 20, 18)
    0.26 ± 0.516
    0.02 ± 0.587
        Month 18 (n = 20, 19)
    0.57 ± 1.094
    0.04 ± 0.506
        Month 24 (n = 20, 20)
    0.39 ± 0.638
    0.08 ± 0.602
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight at Months 3, 6, 12, 18, and 24

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    End point title
    		 Change From Baseline in Body Weight at Months 3, 6, 12, 18, and 24
    End point description
    Body weight was measured at all the relevant visits. The change from Baseline in body weight was calculated as the difference between the parameter values at each visit, and the Baseline parameter values. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 12, 18, and 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Month 3 (n = 21, 19)
    0.57 ± 0.154
    0.53 ± 0.406
        Month 6 (n = 21, 20)
    1.08 ± 0.269
    1.01 ± 0.659
        Month 12 (n = 20, 19)
    2.34 ± 0.389
    1.66 ± 0.397
        Month 18 (n = 20, 19)
    3.48 ± 0.669
    2.41 ± 0.709
        Month 24 (n = 20, 20)
    4.79 ± 0.814
    3.19 ± 0.601
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI) at Months 3, 6, 12, 18, and 24

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    End point title
    		 Change From Baseline in Body Mass Index (BMI) at Months 3, 6, 12, 18, and 24
    End point description
    BMI was calculated for all visits by means of the following formula: BMI Kilogram per meters square (kg/m^2) = Weight Kilogram per height meters square (kg) / (Height[m])^2. The change from baseline BMI was calculated as the difference between the parameter values at each visit, and the baseline parameter values. FAS included subjects who were randomized to treatment and completed at least one post-baseline efficacy measure. One subject was randomized to Genotropin but did not receive any treatment. This subject was excluded from FAS but included in Control group for safety analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 12, 18, and 24
    End point values
    		 Genotropin Control
    Number of subjects analysed
    21
    21
    Units: Kilogram/meters^2
    arithmetic mean (standard deviation)
        Month 3 (n = 21, 19)
    -0.28 ± 0.419
    -0.05 ± 0.811
        Month 6 (n = 21, 20)
    -0.57 ± 0.537
    0.08 ± 1.013
        Month 12 (n = 20, 19)
    -0.62 ± 0.65
    -0.29 ± 0.683
        Month 18 (n = 20, 19)
    -0.78 ± 0.93
    -0.25 ± 0.806
        Month 24 (n = 20, 20)
    -0.58 ± 0.823
    -0.55 ± 0.776
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from screening (Visit 1) until the follow-up visit for subjects in both treatment groups.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v16.1
    Reporting groups
    Reporting group title
    Genotropin
    Reporting group description
    		 Subjects received Genotropin at a dose of 0.035 mg/kg/d for 24 months. The dose was calculated based on the actual body weight, and the closest dosing step of the 5 mg pen used. The starting dose for the first 2 weeks was 1/3 of the calculated dose. After 2 weeks the dose was increased to 2/3 of the calculated dose. After 4 weeks the daily dose was the dose calculated on body weight at randomization.

    Reporting group title
    Control
    Reporting group description
    		 This group was the untreated control group and was not administered placebo.

    Serious adverse events
    		 Genotropin Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    2 / 22 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Conductive deafness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hordeolum
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (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: 4%
    Non-serious adverse events
    		 Genotropin Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    18 / 22 (81.82%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    9 / 21 (42.86%)
    4 / 22 (18.18%)
         occurrences all number
    13
    7
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Milk allergy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Asthma
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    2
    Bronchial dysplasia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    Increased bronchial secretion
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Respiratory disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Tympanic membrane disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 22 (0.00%)
         occurrences all number
    8
    0
    Dysphagia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Regurgitation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    4 / 21 (19.05%)
    4 / 22 (18.18%)
         occurrences all number
    6
    5
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Lipoatrophy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Growing pains
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 21 (28.57%)
    6 / 22 (27.27%)
         occurrences all number
    12
    11
    Bronchopneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Exanthema subitum
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    3
    2
    Gastroenteritis viral
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Hordeolum
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    Molluscum contagiosum
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 21 (42.86%)
    6 / 22 (27.27%)
         occurrences all number
    23
    9
    Otitis media
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    Otitis media acute
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Pharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    4
    4
    Scarlet fever
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 21 (38.10%)
    1 / 22 (4.55%)
         occurrences all number
    23
    5
    Varicella
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Viral infection
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2007
    Amended to include updated Pfizer standard wording for SAE reporting.
    22 Feb 2012
    Revision of safety and Hy’s law sections.
    22 Feb 2012
    Revision of AE reporting.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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