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    Clinical Trial Results:
    Long-term phase IV multicenter study on the safety and efficacy of Omnitrope® (rhGH) in short children born Small for Gestational Age (SGA)

    Summary
    EudraCT number
    		 2006-002506-58
    Trial protocol
    		 HU   DE   CZ   PL   BE  
    Global end of trial date
    25 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CEP00-401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00537914
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    25 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term effect of growth hormone treatment on the development of diabetes in short children born SGA during treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 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
    Poland: 213
    Country: Number of subjects enrolled
    Georgia: 20
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Belgium: 1
    Worldwide total number of subjects
    278
    EEA total number of subjects
    258
    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)
    253
    Adolescents (12-17 years)
    25
    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
    		 Study was carried out in 31 centers in 7 countries (Poland, Romania, Hungary, Czech Republic, Germany, Belgium and Georgia).

    Pre-assignment
    Screening details
    		 This study was not randomized. All enrolled patients received Omnitrope

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

    Arms
    Arm title
    		 Omnitrope
    Arm description
    		 All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    EP2000
    Other name
    Omnitrope
    Pharmaceutical forms
    Solution for injection, Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.

    Number of subjects in period 1
    		Omnitrope
    Started
    278
    Full analysis set (FAS)
    278
    Safety analysis set (SAS)
    277
    Completed
    166
    Not completed
    112
         Adverse event, serious fatal
    1
         Treatment failure
    10
         Adverse event, non-fatal
    7
         patients documented other
    16
         Lost to follow-up
    19
         Withdrawal of informed consent
    59

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Omnitrope
    Reporting group description
    		 All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.

    Reporting group values
    		 Omnitrope Total
    Number of subjects
    		 278 278
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 253 253
        Adolescents (12-17 years)
    		 25 25
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.36 ± 2.70 -
    Sex: Female, Male
    Units: Participants
        Female
    		 130 130
        Male
    		 148 148
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 276 276
        Oriental
    		 1 1
        Mixed ethnic origin (Arabic/ Caucasian)
    		 1 1
        Black
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Omnitrope
    Reporting group description
    		 All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.

    Primary: Number of participants with development of diabetes in short children born SGA during treatment

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    End point title
    		 Number of participants with development of diabetes in short children born SGA during treatment [1]
    End point description
    The development of diabetes in short children born SGA during treatment was evaluated based on the carbohydrate metabolism parameters FPG, HbA1c and OGTT (basal and 2-h plasma glucose). Only cases which were confirmed by the investigator were included.
    End point type
    Primary
    End point timeframe
    throughout the study, approximately 13 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were performed for this outcome
    End point values
    		 Omnitrope
    Number of subjects analysed
    277
    Units: Participants
    0
    No statistical analyses for this end point

    Secondary: Mean change in Height (H) (cm) from baseline

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    End point title
    		 Mean change in Height (H) (cm) from baseline
    End point description
    Mean change in Height from baseline for all patients was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 year, 2 years, 5 years and 9 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: cm
    arithmetic mean (confidence interval 95%)
        1 year
    9.08 (8.89 to 9.27)
        2 years
    16.52 (16.22 to 16.82)
        5 years
    35.10 (34.48 to 35.72)
        9 years
    58.07 (56.83 to 59.30)
    No statistical analyses for this end point

    Secondary: Mean change in Height standard deviation score over time (H SDS) from baseline

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    End point title
    		 Mean change in Height standard deviation score over time (H SDS) from baseline
    End point description
    Mean change in Height standard deviation score over time (H SDS) from baseline was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: cm
    arithmetic mean (confidence interval 95%)
        3 months
    0.30 (0.28 to 0.33)
        0.5 year
    0.51 (0.47 to 0.54)
        9 months
    0.68 (0.64 to 0.72)
        1 year
    0.81 (0.76 to 0.86)
        1.25 years
    0.93 (0.87 to 0.98)
        1.5 years
    1.04 (0.98 to 1.10)
        1.75 years
    1.16 (1.09 to 1.22)
        2 years
    1.25 (1.18 to 1.31)
        3 years
    1.50 (1.42 to 1.58)
        4 years
    1.67 (1.57 to 1.77)
        5 years
    1.82 (1.70 to 1.94)
        6 years
    1.94 (1.81 to 2.07)
        7 years
    2.07 (1.92 to 2.22)
        8 years
    2.19 (2.03 to 2.35)
        9 years
    2.18 (1.99 to 2.37)
        10 years
    2.21 (2.00 to 2.43)
        11 years
    2.38 (2.13 to 2.63)
        12 years
    2.39 (1.81 to 2.97)
        12.5 years
    3.01 (1.78 to 4.24)
    No statistical analyses for this end point

    Secondary: Mean change in Height velocity (HV) (cm/year) over time from baseline

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    End point title
    		 Mean change in Height velocity (HV) (cm/year) over time from baseline
    End point description
    Mean change in Height velocity (HV) (cm/year) over time from baseline was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 year, 2 years, 5 years and 9 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: cm/year
    arithmetic mean (confidence interval 95%)
        1 year
    4.71 (4.47 to 4.96)
        2 years
    3.02 (2.80 to 3.25)
        5 years
    1.37 (1.01 to 1.73)
        9 years
    0.10 (-0.53 to 0.74)
    No statistical analyses for this end point

    Secondary: Mean change in Height velocity standard deviation score (HV SDS) over time from baseline

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    End point title
    		 Mean change in Height velocity standard deviation score (HV SDS) over time from baseline
    End point description
    Mean change in Height velocity standard deviation score (HV SDS) over time from baseline was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: cm/year
    arithmetic mean (confidence interval 95%)
        3 months
    8.41 (7.76 to 9.07)
        0.5 year
    7.27 (6.83 to 7.71)
        9 months
    6.69 (6.31 to 7.06)
        1 year
    6.26 (5.92 to 6.59)
        1.25 years
    5.29 (4.99 to 5.60)
        1.5 years
    4.85 (4.55 to 5.15)
        1.75 years
    4.59 (4.28 to 4.91)
        2 years
    4.35 (4.02 to 4.68)
        3 years
    3.62 (3.23 to 4.00)
        4 years
    3.08 (2.68 to 3.47)
        5 years
    2.99 (2.50 to 3.49)
        6 years
    2.63 (2.14 to 3.13)
        7 years
    2.43 (1.95 to 2.92)
        8 years
    1.37 (0.75 to 1.98)
        9 years
    0.85 (0.14 to 1.55)
        10 years
    0.62 (-0.24 to 1.47)
        11 years
    1.60 (0.36 to 2.84)
        12 years
    1.34 (-0.50 to 3.18)
        12.5 years
    1.98 (1.74 to 2.22)
    No statistical analyses for this end point

    Secondary: Mean change in serum IGF-1 level (nmol/L) from baseline

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    End point title
    		 Mean change in serum IGF-1 level (nmol/L) from baseline
    End point description
    Mean change in serum IGF-1 level (nmol/L) from baseline was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 year, 2 years, 5 years and 9 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: nmol/L
    arithmetic mean (confidence interval 95%)
        1 year
    20.58 (18.77 to 22.39)
        2 years
    30.64 (28.16 to 33.12)
        5 years
    44.87 (41.33 to 48.40)
        9 years
    75.72 (69.59 to 81.85)
    No statistical analyses for this end point

    Secondary: Mean change in IGFBP-3 levels (nmol/L) from baseline

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    End point title
    		 Mean change in IGFBP-3 levels (nmol/L) from baseline
    End point description
    Mean change in IGFBP-3 levels (nmol/L) from baseline was reported.
    End point type
    Secondary
    End point timeframe
    Baseline, 1 year, 2 years, 5 years and 9 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    278
    Units: nmol/L
    arithmetic mean (confidence interval 95%)
        1 year
    30.48 (27.04 to 33.92)
        2 years
    48.48 (44.51 to 52.45)
        5 years
    92.94 (87.65 to 98.23)
        9 years
    139.12 (126.12 to 152.12)
    No statistical analyses for this end point

    Secondary: Number of participants with the development of anti-rhGH antibodies during Omnitrope treatment

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    End point title
    		 Number of participants with the development of anti-rhGH antibodies during Omnitrope treatment
    End point description
    Number of participants with the development of anti-rhGH antibodies with positive test result were reported.
    End point type
    Secondary
    End point timeframe
    throughout the study, approximately 13 years
    End point values
    		 Omnitrope
    Number of subjects analysed
    277
    Units: Participants
    23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to end of the study i.e. up to 13 years.
    Adverse event reporting additional description
    Any signs or symptoms were collected from first dose of study treatment to end of the study i.e. up to 13 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Omnitrope
    Reporting group description
    		 All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.

    Serious adverse events
    		 Omnitrope
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 277 (26.71%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pachydermodactyly
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Face oedema
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Obstruction
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Acquired hydrocele
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Varicocele
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    7 / 277 (2.53%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    Asthma
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nasal septum perforation
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Behaviour disorder
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Enuresis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac murmur
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Alcohol poisoning
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Head injury
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Joint dislocation
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Internal injury
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ligament sprain
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Multiple injuries
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Procedural complication
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Radius fracture
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Road traffic accident
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skull fracture
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sternal fracture
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Toxicity to various agents
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Traumatic shock
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Upper limb fracture
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Congenital, familial and genetic disorders
    Congenital arterial malformation
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Developmental hip dysplasia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gilbert's syndrome
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coma
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intellectual disability
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Seizure
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Headache
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    Syncope
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Anaemia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Abdominal pain upper
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Aphthous ulcer
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chronic gastritis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Duodenal ulcer
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dysphagia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Eosinophilic oesophagitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastritis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Malabsorption
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Vomiting
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vitiligo
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Urethral fistula
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haematuria
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urinary incontinence
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urinary retention
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urethral stenosis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Scoliosis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Osteonecrosis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    4 / 277 (1.44%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Bronchitis
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Bacterial sepsis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ear infection
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Epididymitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Giardiasis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Helicobacter infection
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Infectious mononucleosis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Laryngitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Orchitis
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Otitis media
         subjects affected / exposed
    4 / 277 (1.44%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Otitis media acute
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Otitis media chronic
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pharyngitis
         subjects affected / exposed
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Rhinitis
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Omnitrope
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    210 / 277 (75.81%)
    Investigations
    Insulin-like growth factor increased
         subjects affected / exposed
    9 / 277 (3.25%)
         occurrences all number
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 277 (9.75%)
         occurrences all number
    49
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    23 / 277 (8.30%)
         occurrences all number
    42
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    11 / 277 (3.97%)
         occurrences all number
    16
    Seasonal allergy
         subjects affected / exposed
    9 / 277 (3.25%)
         occurrences all number
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 277 (3.61%)
         occurrences all number
    18
    Abdominal pain upper
         subjects affected / exposed
    10 / 277 (3.61%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    21 / 277 (7.58%)
         occurrences all number
    27
    Vomiting
         subjects affected / exposed
    13 / 277 (4.69%)
         occurrences all number
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 277 (7.22%)
         occurrences all number
    56
    Rhinorrhoea
         subjects affected / exposed
    14 / 277 (5.05%)
         occurrences all number
    26
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    12 / 277 (4.33%)
         occurrences all number
    15
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    27 / 277 (9.75%)
         occurrences all number
    32
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    12 / 277 (4.33%)
         occurrences all number
    12
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    58 / 277 (20.94%)
         occurrences all number
    104
    Ear infection
         subjects affected / exposed
    14 / 277 (5.05%)
         occurrences all number
    22
    Gastroenteritis
         subjects affected / exposed
    11 / 277 (3.97%)
         occurrences all number
    12
    Influenza
         subjects affected / exposed
    11 / 277 (3.97%)
         occurrences all number
    12
    Laryngitis
         subjects affected / exposed
    9 / 277 (3.25%)
         occurrences all number
    15
    Nasopharyngitis
         subjects affected / exposed
    78 / 277 (28.16%)
         occurrences all number
    302
    Otitis media
         subjects affected / exposed
    19 / 277 (6.86%)
         occurrences all number
    35
    Otitis media acute
         subjects affected / exposed
    9 / 277 (3.25%)
         occurrences all number
    13
    Pharyngitis
         subjects affected / exposed
    92 / 277 (33.21%)
         occurrences all number
    310
    Rhinitis
         subjects affected / exposed
    20 / 277 (7.22%)
         occurrences all number
    33
    Respiratory tract infection
         subjects affected / exposed
    25 / 277 (9.03%)
         occurrences all number
    39
    Pneumonia
         subjects affected / exposed
    17 / 277 (6.14%)
         occurrences all number
    21
    Scarlet fever
         subjects affected / exposed
    11 / 277 (3.97%)
         occurrences all number
    12
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 277 (16.97%)
         occurrences all number
    119
    Tonsillitis
         subjects affected / exposed
    35 / 277 (12.64%)
         occurrences all number
    86
    Sinusitis
         subjects affected / exposed
    15 / 277 (5.42%)
         occurrences all number
    17
    Urinary tract infection
         subjects affected / exposed
    17 / 277 (6.14%)
         occurrences all number
    20
    Varicella
         subjects affected / exposed
    37 / 277 (13.36%)
         occurrences all number
    38
    Viral infection
         subjects affected / exposed
    18 / 277 (6.50%)
         occurrences all number
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2007
    - Change from EP2000 5 mg/ml lyophilized powder for solution for injection to EP2000 5 mg/1.5ml solution for injection - Reduction of blood glucose measurements - Recording of historical IGF-1 and IGFBP-3
    27 Nov 2008
    - Inclusion of subgroup analysis for different formulations - Allowing treatment of overweight children with SGA (deletion of exclusion criterion 7) - Safety reporting for device related events - Clarification of BA determination procedure
    22 Mar 2012
    - Introduction of a higher Omnitrope dose strength (10 mg/1.5 mL) - Discontinuation of anti-HCP antibody assessment
    24 Aug 2017
    - Addition of instructions for female patients of childbearing potential - Changes due to implementation of new processes and a new protocol template by the sponsor - Removal of the per-protocol population from analysis
    07 Feb 2020
    - The post-treatment observation EP00-402 (for patients who had been treated within this study, EP00-401) was terminated in 2018. All references to study EP00-402 were removed Clarification of the lost to follow up definition to limit protocol deviations and facilitate compliance to visit schedule

    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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