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    Clinical Trial Results:
    An open, multicenter, randomized, controlled trial to evaluate the correlation between spontaneous catch-up growth, clinical response to Saizen® (recombinant human growth hormone, r-hGH) and gene expression profiling in children small for gestational age (SGA)

    Summary
    EudraCT number
    		 2015-001681-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Jul 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    23681
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01067352
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.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
    10 Jul 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2009
    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 correlation between gene expression and catch-up growth (either spontaneous or drug-induced after one year of treatment) in SGA children. A secondary objective was to evaluate the percentage of patients who were not treated, but who showed a spontaneous catch-up growth during two years of observation. Safety objectives included the safety and tolerability of Saizen (recombinant human growth hormone, r-hGH) in SGA children.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 2004
    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
    Italy: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    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
    		 Subjects were recruited in 12 study centers in Italy from 20 Feb 2004 to 10 Jul 2009.

    Pre-assignment
    Screening details
    		 in total, 25 subject enrolled in this study

    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
    		 Group A, less than third percentile (Saizen)
    Arm description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human growth hormone (r-hGH)
    Investigational medicinal product code
    Other name
    Saizen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Recombinant human GH were administered subcutaneously at the daily dose of 0.067 mg/kg of body weight to Group A1.

    Arm title
    		 Group A2, less than third percentile (No treatment)
    Arm description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group B, more than third percentile (No treatment)
    Arm description
    		 Subjects with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Started
    9
    6
    10
    Completed
    8
    3
    9
    Not completed
    1
    3
    1
         Consent withdrawn by subject
    1
    2
    1
         Physician decision
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A, less than third percentile (Saizen)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.

    Reporting group title
    Group A2, less than third percentile (No treatment)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Reporting group title
    Group B, more than third percentile (No treatment)
    Reporting group description
    		 Subjects with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Reporting group values
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment) Total
    Number of subjects
    		 9 6 10 25
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.7 ( 1.2 ) 5 ( 0.7 ) 5.2 ( 0.4 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 4 4 5 13
        Male
    		 5 2 5 12

    End points

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    End points reporting groups
    Reporting group title
    Group A, less than third percentile (Saizen)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.

    Reporting group title
    Group A2, less than third percentile (No treatment)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Reporting group title
    Group B, more than third percentile (No treatment)
    Reporting group description
    		 Subjects with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Primary: Correlation between gene expression profiling and catch-up growth in small for gestational age (SGA) children

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    End point title
    		 Correlation between gene expression profiling and catch-up growth in small for gestational age (SGA) children [1]
    End point description
    Gene expression profiling:analysis of ribonucleic acid (RNA) extracted from body tissue or fluids using Clontech Atlas Human Array to study level of activation of genes in tissue analyzed. Analysis was performed to identify possible correlation between catch-up growth (either spontaneous or drug-induced after Week 48) and therapeutic response to rhGH. Spontaneous catch up growth:shown by SGA subjects having length more than third percentile at Week 96 without any treatment;drug induced growth was by SGA subjects having length more than third percentile at Week 96 with drug treatment. Gene expression profiling was not performed due to RNA degradation in nearly all of the blood samples and hence no comparison between gene expression and growth was made.
    End point type
    Primary
    End point timeframe
    Baseline and Week 48
    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: Gene expression profiling was not performed due to RNA degradation in nearly all of the blood samples and hence no comparison between gene expression and growth was made.
    End point values
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: correlation factor
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [2] - Comparison between gene expression and growth could not be done as gene profiling could not be done.
    [3] - Comparison between gene expression and growth could not be done as gene profiling could not be done.
    [4] - Comparison between gene expression and growth could not be done as gene profiling could not be done.
    No statistical analyses for this end point

    Secondary: Percentage of untreated subjects who showed a spontaneous catch-up growth

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    End point title
    		 Percentage of untreated subjects who showed a spontaneous catch-up growth
    End point description
    Spontaneous catch up growth was the growth shown by SGA subjects having length more than third percentile at Week 96 without any study drug treatment. Data was not analyzed due to small number of evaluable participants.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Percentage of subjects
        number (not applicable)
    Notes
    [5] - Data was not analyzed due to small number of evaluable subjects.
    [6] - Data was not analyzed due to small number of evaluable subjects.
    [7] - Data was not analyzed due to small number of evaluable subjects.
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs) and AEs leading to study drug discontinuation

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    End point title
    		 Number of subjects with adverse events (AEs), serious adverse events (SAEs) and AEs leading to study drug discontinuation
    End point description
    AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug , SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Subjects who discontinued from the study due to AE were also recorded. This endpoint was assessed in safety analysis population which included all randomized subjectss with at least 1 post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Number of subjects analysed
    8
    4
    10
    Units: subjects
    number (not applicable)
        AEs
    6
    4
    9
        SAEs
    0
    0
    0
        Discontinuation due to AEs
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected on an ongoing basis from day of written informed consent. All new AEs were recorded until the post-treatment safety, on Day 30 post-drug administration.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    MedDRA (U
    Reporting groups
    Reporting group title
    Group A, less than third percentile (Saizen)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.

    Reporting group title
    Group A2, less than third percentile (No treatment)
    Reporting group description
    		 Subjects with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Reporting group title
    Group B, more than third percentile (No treatment)
    Reporting group description
    		 Subjects with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.

    Serious adverse events
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A, less than third percentile (Saizen) Group A2, less than third percentile (No treatment) Group B, more than third percentile (No treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    4 / 4 (100.00%)
    9 / 10 (90.00%)
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    6 / 8 (75.00%)
    2 / 4 (50.00%)
    4 / 10 (40.00%)
         occurrences all number
    15
    6
    6
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    4
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Lipoprotein (a) abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Blood insulin decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Microcytic anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Acute generalised exanthematous pustulosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    3 / 10 (30.00%)
         occurrences all number
    2
    1
    4
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 4 (50.00%)
    2 / 10 (20.00%)
         occurrences all number
    4
    2
    2
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    1
    Varicella
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 4 (50.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Enterocolitis infectious
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    0
    3
    Laryngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The primary and secondary efficacy objectives were not met because of poor subject enrollment and no quality RNA samples obtained to evaluate (RNA degradation in nearly all of the blood samples).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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