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    Clinical Trial Results:
    A Phase 2, Randomized, Open-Label, Safety and Dose-Finding Study Comparing 3 Different Doses of Weekly TV-1106 and Daily Recombinant Human Growth Hormone (Genotropin®) Therapy in Treatment-Naive, Pre-Pubertal, Growth Hormone-Deficient Children

    Summary
    EudraCT number
    2013-004468-69
    Trial protocol
    HU   CZ   RO   GR   BG   ES   PL  
    Global end of trial date
    29 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Nov 2016
    First version publication date
    16 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV1106-IMM-20001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02092077
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd.
    Sponsor organisation address
    5 Bazel Street, Petach Tikva, Israel,
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info.era-clinical@teva.de
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the safety and tolerability of 3 different weekly doses of TV-1106 and a daily dose of Genotropin® in paediatric patients. EARLY TERMINATION: the Sponsor Teva Pharmaceuticals Ltd. reassessed the benefit/risk balance of TV-1106 and the likelihood of regulatory success for TV-1106. As a consequence of this reassessment, the Sponsor took the decision to terminate the development of TV-1106 and stop all ongoing clinical trials. Notably, no new safety issues were identified with the administration of TV-1106.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 11, 50, 54, 56, 312, and 314; European Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all patients and parent(s) or other legally acceptable representative(s) in a language understandable by the patients and parent(s) or other legally acceptable representative(s). The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each parent(s) or other legally acceptable representative(s) and an oral or signed and dated (where applicable) assent form was obtained from each applicable minor patient before any study procedures or assessments were done. It was explained to the patients and parent(s) or other legally acceptable representative(s) that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each investigator kept the original consent and assent forms, and copies were given to the patients/parent(s)/other legally acceptable representative(s).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Belarus: 1
    Country: Number of subjects enrolled
    Georgia: 5
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 14
    Worldwide total number of subjects
    65
    EEA total number of subjects
    8
    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)
    65
    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
    -

    Pre-assignment
    Screening details
    A total of 148 pediatric patients with isolated idiopathic GH insufficiency, GH insufficiency as part of multiple pituitary hormone deficiencies, or organic GH insufficiency (eg, due to pituitary tumor, pituitary or brain surgery, intracranial radiation therapy) were screened for enrollment into this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    TV-1106 0.554 mg/kg/week
    Arm description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-1106
    Investigational medicinal product code
    Other name
    long-acting growth hormone
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All patients randomized to any one of the TV 1106 treatment arms began with a dose of 0.554 mg/kg/week. Two weeks after this initial dose, the patients who were assigned to the 0.554 mg/kg/week dose group continued on that dose for the remainder of the core period of the study. The remaining patients randomized to TV 1106 received the next higher dose, 0.924 mg/kg/week, for the next 2 weeks. After completing 2 weeks at this dose (4 weeks since beginning treatment), the patients assigned to the 0.924 mg/kg/week dose group continued on that dose until the end of the core period, and the patients assigned to the 1.20 mg/kg/week dose group began taking 1.20 mg/kg/week and continued with that dose until the end of the core period (6 months total). Patients who continued into the core extension period of the study for an additional 6 months and the later 12 month safety period continued on the same treatment and dose of TV-1106. Adjustments could be made as agreed by DMC and sponsor.

    Arm title
    TV-1106 0.924 mg/kg/week
    Arm description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks and then titrated up to 0.924 mg/kg/week for 5.5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-1106
    Investigational medicinal product code
    Other name
    long-acting growth hormone
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All patients randomized to any one of the TV 1106 treatment arms began with a dose of 0.554 mg/kg/week. Two weeks after this initial dose, the patients who were assigned to the 0.554 mg/kg/week dose group continued on that dose for the remainder of the core period of the study. The remaining patients randomized to TV 1106 received the next higher dose, 0.924 mg/kg/week, for the next 2 weeks. After completing 2 weeks at this dose (4 weeks since beginning treatment), the patients assigned to the 0.924 mg/kg/week dose group continued on that dose until the end of the core period, and the patients assigned to the 1.20 mg/kg/week dose group began taking 1.20 mg/kg/week and continued with that dose until the end of the core period (6 months total). Patients who continued into the core extension period of the study for an additional 6 months and the later 12 month safety period continued on the same treatment and dose of TV-1106. Adjustments could be made as agreed by DMC and sponsor.

    Arm title
    TV-1106 1.2 mg/kg/week
    Arm description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks, followed by TV-1106 0.924 mg/kg/week for study weeks 3-4, followed by the assigned dose of TV-1106 1.2 mg/kg/week for 5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-1106
    Investigational medicinal product code
    Other name
    long-acting growth hormone
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All patients randomized to any one of the TV 1106 treatment arms began with a dose of 0.554 mg/kg/week. Two weeks after this initial dose, the patients who were assigned to the 0.554 mg/kg/week dose group continued on that dose for the remainder of the core period of the study. The remaining patients randomized to TV 1106 received the next higher dose, 0.924 mg/kg/week, for the next 2 weeks. After completing 2 weeks at this dose (4 weeks since beginning treatment), the patients assigned to the 0.924 mg/kg/week dose group continued on that dose until the end of the core period, and the patients assigned to the 1.20 mg/kg/week dose group began taking 1.20 mg/kg/week and continued with that dose until the end of the core period (6 months total). Patients who continued into the core extension period of the study for an additional 6 months and the later 12 month safety period continued on the same treatment and dose of TV-1106. Adjustments could be made as agreed by DMC and sponsor.

    Arm title
    Genotropin 0.033 mg/kg/day
    Arm description
    Participants were administered genotropin subcutaneously at a dosage of 0.033 mg/kg/day for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were made for safety reasons (e.g. dose decrease if the IGF-1 SDS for 2 consecutive peak IGF-1 levels exceeded +2.5 SDS), or as agreed by the DMC and sponsor.
    Arm type
    Active comparator

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    rhGH, recombinant human growth hormone
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    A subcutaneous dose of 0.033 mg/kg/day for GENOTROPIN was chosen because it is the standard GENOTROPIN dose for the age of patients included. Injections were given in the evening at bedtime (between 1800 and 2200), except on days of in clinic visits when injections were given as part of the study procedures.

    Number of subjects in period 1
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Started
    16
    15
    17
    17
    Safety Analysis Set
    16
    15
    17
    16
    Completed
    0
    0
    0
    0
    Not completed
    16
    15
    17
    17
         Protocol deviation
    -
    -
    -
    1
         Lack of efficacy
    1
    -
    -
    -
         Adverse event, non-fatal
    3
    2
    3
    1
         Consent withdrawn by subject
    -
    -
    2
    -
         primarily termination of study
    11
    13
    12
    15
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TV-1106 0.554 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV-1106 0.924 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks and then titrated up to 0.924 mg/kg/week for 5.5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV-1106 1.2 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks, followed by TV-1106 0.924 mg/kg/week for study weeks 3-4, followed by the assigned dose of TV-1106 1.2 mg/kg/week for 5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    Genotropin 0.033 mg/kg/day
    Reporting group description
    Participants were administered genotropin subcutaneously at a dosage of 0.033 mg/kg/day for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were made for safety reasons (e.g. dose decrease if the IGF-1 SDS for 2 consecutive peak IGF-1 levels exceeded +2.5 SDS), or as agreed by the DMC and sponsor.

    Reporting group values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day Total
    Number of subjects
    16 15 17 17 65
    Age categorical
    Units: Subjects
        <7 years
    9 10 9 9 37
        >=7 years
    7 5 8 8 28
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.1 ± 2.47 5.8 ± 1.9 6.5 ± 2.1 6.4 ± 2.57 -
    Gender categorical
    Units: Subjects
        Female
    9 7 6 4 26
        Male
    7 8 11 13 39
    Race
    Units: Subjects
        White
    16 15 16 17 64
        Other
    0 0 1 0 1
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    15.8 ± 1.67 15.8 ± 1.4 15.6 ± 1.97 15.8 ± 1.39 -
    Gestation Age
    Units: weeks
        arithmetic mean (standard deviation)
    39.4 ± 1.37 39.1 ± 0.53 38.2 ± 2.11 38.8 ± 1.23 -
    Birth weight
    Units: kg
        arithmetic mean (standard deviation)
    3.3 ± 0.4 3.2 ± 0.34 3 ± 0.66 3.2 ± 0.56 -
    Birth height
    Units: cm
        arithmetic mean (standard deviation)
    51.2 ± 1.97 50.5 ± 1.68 49.8 ± 2.7 50.7 ± 2.85 -
    Height standard deviation score
    H-SDS
    Units: standard deviations
        arithmetic mean (standard deviation)
    -3.1 ± 0.81 -3.1 ± 0.99 -3.2 ± 1.04 -3.3 ± 0.75 -
    Height velocity
    Units: cm/year
        arithmetic mean (standard deviation)
    3.5 ± 1.73 3.5 ± 1.7 3.7 ± 2.75 3.6 ± 1.2 -
    Height velocity standard deviation score
    Units: standard deviation
        arithmetic mean (standard deviation)
    -2.7 ± 1.85 -3 ± 1.62 -2.3 ± 3.12 -2.5 ± 1.25 -
    Insulin-like growth factor-1 standard deviation score
    IGF-1-SDS
    Units: standard deviation
        arithmetic mean (standard deviation)
    -2.1 ± 0.87 -1.7 ± 0.73 -1.7 ± 0.8 -1.7 ± 0.99 -

    End points

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    End points reporting groups
    Reporting group title
    TV-1106 0.554 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV-1106 0.924 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks and then titrated up to 0.924 mg/kg/week for 5.5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV-1106 1.2 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks, followed by TV-1106 0.924 mg/kg/week for study weeks 3-4, followed by the assigned dose of TV-1106 1.2 mg/kg/week for 5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    Genotropin 0.033 mg/kg/day
    Reporting group description
    Participants were administered genotropin subcutaneously at a dosage of 0.033 mg/kg/day for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were made for safety reasons (e.g. dose decrease if the IGF-1 SDS for 2 consecutive peak IGF-1 levels exceeded +2.5 SDS), or as agreed by the DMC and sponsor.

    Primary: Height Velocity (HV) At Baseline and After 6 Months of Treatment

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    End point title
    Height Velocity (HV) At Baseline and After 6 Months of Treatment [1]
    End point description
    Height measurements were performed as follows: the patient was measured standing without shoes with head, shoulders, buttocks, and heels in contact with the vertical surface of the wall mounted stadiometer and the back as straight as possible. With the child looking straight ahead, the head projection of the stadiometer was placed at the crown of the head. At each determination, the measurement was performed in triplicate by the same person, and the 3 measurements were recorded. HV at baseline computed as [(mean height at baseline - mean height at pre-study measurement)/interval (baseline - pre-study measurement)] *365.25 HV at 6 months computed as [(mean height at study visit - mean height at baseline)/interval (study visit - baseline)]*365.25
    End point type
    Primary
    End point timeframe
    Pre-study (-6 weeks), Baseline (Day 1), Month 6
    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: Due to the early termination of the study, no paediatric patients completed the study according to the protocol; thus limited efficacy analyses were completed and no conclusions can be drawn from these data. Thus no statistical analyses were performed.
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [2]
    15 [3]
    16 [4]
    17 [5]
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (n=16, 15, 16, 17)
    3.5 ± 1.73
    3.5 ± 1.7
    3.7 ± 2.75
    3.6 ± 1.2
        Month 6 (n=13, 12, 12, 15)
    11 ± 3.34
    12.8 ± 3.23
    16 ± 5.02
    13.4 ± 3.98
    Notes
    [2] - Randomized patients (ITT) with data at the timepoint.
    [3] - Randomized patients (ITT) with data at the timepoint.
    [4] - Randomized patients (ITT) with data at the timepoint.
    [5] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Secondary: Height Velocity After 12 Months of Treatment

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    End point title
    Height Velocity After 12 Months of Treatment
    End point description
    Height measurements were performed as follows: the patient was measured standing without shoes with head, shoulders, buttocks, and heels in contact with the vertical surface of the wall mounted stadiometer and the back as straight as possible. With the child looking straight ahead, the head projection of the stadiometer was placed at the crown of the head. At each determination, themeasurement was performed in triplicate by the same person, and the 3 measurements were recorded. HV at 12 months computed as [(mean height at study visit - mean height at baseline)/interval (study visit - baseline)]*365.25
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Month 12
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    1 [6]
    4 [7]
    7 [8]
    3 [9]
    Units: cm/year
        arithmetic mean (standard deviation)
    8.1 ± 0
    10.8 ± 2.37
    11.9 ± 3.5
    8.6 ± 2.32
    Notes
    [6] - Randomized patients (ITT) with data at the timepoint.
    [7] - Randomized patients (ITT) with data at the timepoint.
    [8] - Randomized patients (ITT) with data at the timepoint.
    [9] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Secondary: Height Velocity Standard Deviation Score (HV-SDS) after 6 and 12 Months of Treatment

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    End point title
    Height Velocity Standard Deviation Score (HV-SDS) after 6 and 12 Months of Treatment
    End point description
    HV at 6 and 12 months was computed as [(mean height at study visit - mean height at baseline)/interval (study visit - baseline)]*365.25 HV-SDS was based on Swiss Growth Reference Standard by Prader et al. 1989.
    End point type
    Secondary
    End point timeframe
    Months 6 and 12
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [10]
    15 [11]
    17 [12]
    17 [13]
    Units: standard deviation score
    arithmetic mean (standard deviation)
        Month 6 (n=13, 12, 12, 15)
    5.2 ± 4.08
    7.2 ± 3.08
    11.4 ± 5.9
    7.6 ± 4.4
        Month 12 (n=1, 4, 7, 3)
    1.9 ± 0
    4.1 ± 1.77
    6.2 ± 4.14
    3.2 ± 2.07
    Notes
    [10] - Randomized patients (ITT) with data at the timepoint.
    [11] - Randomized patients (ITT) with data at the timepoint.
    [12] - Randomized patients (ITT) with data at the timepoint.
    [13] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Height Standard Deviation Score (H-SDS) After 6 and 12 Months of Treatment

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    End point title
    Change from Baseline in Height Standard Deviation Score (H-SDS) After 6 and 12 Months of Treatment
    End point description
    Height measurements were performed as follows: the patient was measured standing without shoes with head, shoulders, buttocks, and heels in contact with the vertical surface of the wall mounted stadiometer and the back as straight as possible. With the child looking straight ahead, the head projection of the stadiometer was placed at the crown of the head. At each determination, the measurement was performed in triplicate by the same person, and the 3 measurements were recorded. H-SDS was based on CDC (2000) Growth Charts by Kuczmarski RJ et. al.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Months 6 and 12
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [14]
    15 [15]
    17 [16]
    17 [17]
    Units: standard deviation score
    arithmetic mean (standard deviation)
        Month 6 (n=13, 12, 12, 15)
    0.6 ± 0.41
    0.8 ± 0.37
    1.1 ± 0.46
    0.9 ± 0.46
        Month 12 (n=1, 4, 7, 3)
    0.4 ± 0
    1 ± 0.55
    1.3 ± 0.58
    0.8 ± 0.37
    Notes
    [14] - Randomized patients (ITT) with data at the timepoint.
    [15] - Randomized patients (ITT) with data at the timepoint.
    [16] - Randomized patients (ITT) with data at the timepoint.
    [17] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Secondary: Participants with Adverse Events

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    End point title
    Participants with Adverse Events
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 84
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [18]
    15 [19]
    17 [20]
    16 [21]
    Units: participants
        >=1 adverse event
    11
    12
    11
    8
        Severe adverse event
    2
    0
    2
    0
        Treatment-related adverse event
    7
    8
    9
    2
        Death
    0
    0
    0
    0
        Other serious adverse event
    0
    1
    0
    1
        Withdrawn from study due to adverse event
    3
    2
    2
    1
    Notes
    [18] - Safety analysis population
    [19] - Safety analysis population
    [20] - Safety analysis population
    [21] - Safety analysis population
    No statistical analyses for this end point

    Secondary: Participants with Potentially Clinically Significant Abnormal Serum Chemistry, Hematology and Urinalysis Results

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    End point title
    Participants with Potentially Clinically Significant Abnormal Serum Chemistry, Hematology and Urinalysis Results
    End point description
    Significance criteria for parameters showing potentially clinically significant abnormal results are: - Lactate Dehydrogenase High (U/L): >=3* upper limit of normal - Hemoglobin Low Female (G/L): <=95 - Hemoglobin Low Male (G/L): <=115 - Hematocrit Low Male (1): <0.37 - Hematocrit Low Female (1): < 0.32 - Eosinophils//Leukocytes High (%): >=10.0 - Urine Ketones High: >=2 unit increase from baseline - Urine Protein High: >=2 unit increase from baseline
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 84
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [22]
    15 [23]
    17 [24]
    16 [25]
    Units: participants
        Lactate Dehydrogenase High
    1
    0
    0
    0
        Hemoglobin Low Female
    0
    2
    0
    0
        Hemoglobin Low Male
    4
    0
    3
    4
        Hematocrit Low Male
    5
    1
    5
    5
        Hematocrit Low Female
    0
    2
    0
    0
        Eosinophils//Leukocytes High
    1
    4
    2
    0
        Urine Ketones High
    2
    0
    0
    0
        Urine Protein High
    0
    0
    1
    0
    Notes
    [22] - Safety analysis population
    [23] - Safety analysis population
    [24] - Safety analysis population
    [25] - Safety analysis population
    No statistical analyses for this end point

    Secondary: Patients with Positive Anti-drug Antibodies (ADA) at Various Timepoints

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    End point title
    Patients with Positive Anti-drug Antibodies (ADA) at Various Timepoints
    End point description
    For TV-1106 randomized patients, blood samples for immunogenicity were taken on Day 7 after the last study drug administration, and prior to the next administration, to avoid interference of the treatment with the assay. Counts indicate participants with positive ADA results. Values of 999 = not applicable
    End point type
    Secondary
    End point timeframe
    Week 2, Months 3, 6, 10, 12, 15, 18
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [26]
    15 [27]
    17 [28]
    17 [29]
    Units: participants
        Week 2 (n=5, 3, 4, 13)
    5
    3
    4
    0
        Month 3 (n=8, 9, 13, 11)
    8
    9
    13
    0
        Month 6 (n=11, 7, 11, 12)
    11
    7
    11
    0
        Month 10 (n=4, 5, 7, 1)
    4
    5
    7
    0
        Month 12 (n=1, 1, 4, 2)
    1
    1
    4
    0
        Month 15 (n=0, 1, 3, 0)
    9999
    1
    3
    9999
        Month 18 (n=0, 0, 0, 1)
    9999
    9999
    9999
    0
    Notes
    [26] - Randomized patients (ITT) with data at the timepoint.
    [27] - Randomized patients (ITT) with data at the timepoint.
    [28] - Randomized patients (ITT) with data at the timepoint.
    [29] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Other pre-specified: Insulin-like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) at Timepoints up to Month 12

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    End point title
    Insulin-like Growth Factor-1 Standard Deviation Score (IGF-1 SDS) at Timepoints up to Month 12
    End point description
    Peak IGF-I levels were collected on Day 3 following TV-1106 dose at Weeks 4, 6, 8, and Months 4, 5, and 8. Trough IGF-I levels were taken on Day 7 following TV 1106 dose at Week 2, Months 3, 6, 10, 12. For Genotropin®, samples were drawn at least 12 hours after the previous Genotropin® dose.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1) to Month 12
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [30]
    15 [31]
    17 [32]
    17 [33]
    Units: standard deviation score
    arithmetic mean (standard deviation)
        Baseline (n=12, 12, 16, 16)
    -2.1 ± 0.87
    -1.7 ± 0.73
    -1.7 ± 0.8
    -1.7 ± 0.99
        Week 2 (n=14, 13, 15, 8)
    -2 ± 0.81
    -1.6 ± 0.92
    -1.4 ± 0.78
    -1.5 ± 1.09
        Week 4 (n=15, 14, 15, 14)
    -0.3 ± 1.2
    0.5 ± 1.29
    0.5 ± 1.8
    -0.7 ± 1.27
        Week 6 (n=15, 14, 15, 13)
    -0.9 ± 0.96
    0.6 ± 1.28
    0.8 ± 1.44
    -0.9 ± 1.28
        Week 8 (n=14, 13, 15, 13)
    -0.5 ± 1.11
    0.8 ± 1.32
    0.9 ± 1.23
    -0.8 ± 1.11
        Month 3 (n=13, 13, 13, 15)
    -1.5 ± 0.86
    -1.1 ± 0.95
    -1.1 ± 0.61
    -0.9 ± 1.21
        Month 4 (n=15, 14, 15, 14)
    -0.1 ± 1.17
    0.4 ± 1.34
    0.6 ± 0.84
    -0.8 ± 0.8
        Month 5 (n=12, 14, 13, 14)
    -0.5 ± 1.07
    0.3 ± 1.52
    0.5 ± 1.37
    -0.5 ± 1.35
        Month 6 (n=13, 11, 12, 14)
    -1.8 ± 0.68
    -1.4 ± 0.49
    -1.3 ± 1.09
    -0.6 ± 1.42
        Month 8 (n=10, 9, 10, 11)
    -0.5 ± 1.25
    0.8 ± 1.18
    1.3 ± 1.09
    -0.5 ± 1.8
        Month 10 (n=6, 7, 8, 8)
    -1.4 ± 1.09
    -0.4 ± 1.53
    0.7 ± 1.6
    0.1 ± 2.34
        Month 12 (n=1, 4, 7, 3)
    -0.3 ± 0
    -1.3 ± 0.94
    -1.5 ± 0.63
    -1.2 ± 1.72
    Notes
    [30] - Randomized patients (ITT) with data at the timepoint.
    [31] - Randomized patients (ITT) with data at the timepoint.
    [32] - Randomized patients (ITT) with data at the timepoint.
    [33] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Other pre-specified: Peak Serum Concentration of TV-1106 at Week 4 and 6 and Month 15

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    End point title
    Peak Serum Concentration of TV-1106 at Week 4 and 6 and Month 15
    End point description
    Sampling times for peak serum concentrations of TV-1106 were taken approximately 72 hours (Day 3) after TV-1106 was administered. All pharmacokinetic (PK) blood samples were drawn during clinic visits at approximately the same time every morning between 6:00 and 10:00 AM (+ 4 hours). Values of 9999 indicate 'not applicable'.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 4 and 6, Month 15
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [34]
    15 [35]
    17 [36]
    0 [37]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4 (n=16, 14, 14, 0)
    221.81 ± 277.96
    598.3 ± 767.06
    494.61 ± 679.31
    ±
        Week 6 (n=16, 15, 15, 0)
    342.29 ± 483.26
    537.93 ± 648.46
    1351.53 ± 990.35
    ±
        Month 15 (n=0, 1, 3, 0)
    9999 ± 9999
    50 ± 0
    1529.53 ± 1341.08
    ±
    Notes
    [34] - Randomized patients (ITT) with data at the timepoint.
    [35] - Randomized patients (ITT) with data at the timepoint.
    [36] - Randomized patients (ITT) with data at the timepoint.
    [37] - Genotropin samples not collected at these timepoints.
    No statistical analyses for this end point

    Other pre-specified: Trough Serum Concentrations at Various Timepoints

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    End point title
    Trough Serum Concentrations at Various Timepoints
    End point description
    Sampling times for trough serum concentrations for TV-2206 were taken approximately 152 to 160 hours (Day 7) after the previous TV-1106 dose and prior to the next dose. Sample times for serum concentrations of Genotropin were at least 12 hours after the previous Genotropin® dose. All pharmacokinetic (PK) blood samples were drawn during clinic visits at approximately the same time every morning between 6:00 and 10:00 AM (+ 4 hours). Values of 9999 indicate 'not applicable'.
    End point type
    Other pre-specified
    End point timeframe
    Week 2, Months 3, 6, 12 and 18
    End point values
    TV-1106 0.554 mg/kg/week TV-1106 0.924 mg/kg/week TV-1106 1.2 mg/kg/week Genotropin 0.033 mg/kg/day
    Number of subjects analysed
    16 [38]
    15 [39]
    17 [40]
    17 [41]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 2 (n=5, 3, 4, 13)
    25 ± 26.63
    7.8 ± 2.66
    6.98 ± 1.56
    3.8 ± 8.22
        Month 3 (n=8, 9, 13,11)
    33.18 ± 21.46
    35.28 ± 31.14
    27.38 ± 29.09
    1.37 ± 0.81
        Month 6 (n=11, 7, 11, 12)
    55.92 ± 39.36
    34.04 ± 33.02
    164.95 ± 354.66
    0.9 ± 0.33
        Month 12 (n=1, 1, 4, 2)
    33.2 ± 0
    19.6 ± 0
    36.43 ± 17.37
    1.89 ± 0.82
        Month 18 (n=0, 0, 0, 1)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    0.7 ± 0
    Notes
    [38] - Randomized patients (ITT) with data at the timepoint.
    [39] - Randomized patients (ITT) with data at the timepoint.
    [40] - Randomized patients (ITT) with data at the timepoint.
    [41] - Randomized patients (ITT) with data at the timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 84
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    TV1106 0.554 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV1106 0.924 mg/kg/week
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks and then titrated up to 0.924 mg/kg/week for 5.5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    TV1106 1.2 mg/kg/eek
    Reporting group description
    Participants were administered TV-1106 subcutaneously at a dosage of 0.554 mg/kg/week for 2 weeks, followed by TV-1106 0.924 mg/kg/week for study weeks 3-4, followed by the assigned dose of TV-1106 1.2 mg/kg/week for 5 months (core period), and remained at the assigned dose for an additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were allowed for low HV and/or new information showing clear benefit or risk of any specific dosage.

    Reporting group title
    Genotropin
    Reporting group description
    Participants were administered genotropin subcutaneously at a dosage of 0.033 mg/kg/day for 6 months (core period), and additional 6 months (core extension period), and a 12 month safety period. Dose adjustments were made for safety reasons (e.g. dose decrease if the IGF-1 SDS for 2 consecutive peak IGF-1 levels exceeded +2.5 SDS), or as agreed by the DMC and sponsor.

    Serious adverse events
    TV1106 0.554 mg/kg/week TV1106 0.924 mg/kg/week TV1106 1.2 mg/kg/eek Genotropin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TV1106 0.554 mg/kg/week TV1106 0.924 mg/kg/week TV1106 1.2 mg/kg/eek Genotropin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 16 (62.50%)
    12 / 15 (80.00%)
    11 / 17 (64.71%)
    6 / 16 (37.50%)
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    2
    Fatigue
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    2 / 17 (11.76%)
    0 / 16 (0.00%)
         occurrences all number
    16
    18
    12
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    1
    8
    3
    0
    Injection site swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    2 / 17 (11.76%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    5
    0
    Injection site warmth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    11
    1
    0
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site pain
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    2 / 17 (11.76%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    3
    3
    Irritability
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    0
    1
    Psychiatric disorders
    Fear of injection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Skin injury
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Animal bite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Drug specific antibody present
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 15 (33.33%)
    2 / 17 (11.76%)
    0 / 16 (0.00%)
         occurrences all number
    2
    5
    2
    0
    Neutralising antibodies positive
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Red blood cell target cells present
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Red blood cell elliptocytes present
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Sinus arrhythmia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Congenital, familial and genetic disorders
    Odontogenic cyst
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Tachypnoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Asthma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Posture abnormal
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    1 / 17 (5.88%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    1
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyoderma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Acute tonsillitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Varicella
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    3 / 17 (17.65%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    4
    1
    Bronchitis
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2014
    Amendment 1 (dated 09 April 2014) to the protocol was issued before any patients were enrolled into the study. The following changes (not all-inclusive) were made to the protocol: • The addition of 2 health-related quality of life scales, in order to assess other QoL aspects in this patient population. • References to growth standards for H-SDS and HV-SDS were added.
    15 Jul 2014
    Amendment 2 (dated 15 July 2014) to the protocol was issued before any patients were enrolled into the study. The following changes (not all-inclusive) were made to the protocol: • The addition of alternative sites for injections in order to emphasize the importance of rotating injection sites • Removal of in-clinic administration of TV 1106 where the weekly dosing did not coincide with the visit schedule.
    19 Nov 2015
    Amendment 3 (dated 19 November 2015) to the protocol was issued after 65 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. This amendment was issued as a follow-up to the notification, dated 06 July 2015, submitted to all concerned Health Authorities concerning the identification of increased antibody response (ADA) in 11 pediatric patients treated with TV-1106 in this ongoing study. The following changes were made to the protocol: • The addition of extra visits to monitor immunogenicity. • Treatment discontinuation criteria were revised following expert advice and increased frequency of monitoring of nAb, if required. • The local amendment (described above) concerning the request to have only 1 single venipuncture was incorporated into the global amendment.

    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.
    As the study was terminated early, no paediatric patients completed the study according to the protocol. Thus limited efficacy analyses were completed and no conclusions can be drawn from these data. The focus of the clinical trial summary is safety.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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