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    Clinical Trial Results:
    A 64-Week (12-week core phase and 52-week safety extension), Phase II, Multicenter, Randomized, Open Label Study to Evaluate the Safety, Tolerability and Efficacy of Weekly TV-1106 in Adults with Growth Hormone Deficiency

    Summary
    EudraCT number
    2012-004975-37
    Trial protocol
    HU   CZ   SK   GR   SI   DE   SE  
    Global end of trial date
    23 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    14 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV1106-GHD-201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01811576
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd.
    Sponsor organisation address
    5 Bazel St., Petach Tikva, Israel,
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the clinical effect of weekly doses of Albutropin (TV-1106), as measured by the change from baseline in insulin-like growth factor 1 (IGF-I), in growth hormone deficient (GHD) adults following 12 weeks of treatment.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on 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 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 GCP 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 in a language understandable by the patients. 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 patient before any study procedures or assessments were done. It was explained to the patients 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 patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Aug 2013
    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
    Slovakia: 12
    Country: Number of subjects enrolled
    Slovenia: 4
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Serbia: 3
    Worldwide total number of subjects
    52
    EEA total number of subjects
    46
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    49
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 93 patients with GHD were screened for enrollment into this study. Of the 93 patients screened, 52 patients at 16 centers in Europe, the Middle East and the US met entry criteria.

    Pre-assignment
    Screening details
    Of the 41 patients not enrolled, 32 were excluded due to inclusion/exclusion criteria, 3 withdrew consent, 2 were lost to follow-up before the baseline visit, 1 experienced an AE, and 3 were excluded for ‘other’ reasons. Eligible patients were randomized on a 4:1 basis to either albutropin or genotropin.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Albutropin
    Arm description
    Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin.
    Arm type
    Experimental

    Investigational medicinal product name
    Albutropin
    Investigational medicinal product code
    TV-1106
    Other name
    human serum albumin-human growth hormone (HSA-hGH)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose and titration dose levels of Albutropin were up to 50 mg given as weekly subcutaneous (sc) injections in the formulation buffer. Doses in excess of 50 mg were not allowed for titration and resulted in early termination. Except on in-clinic visit days, the patient was responsible for injections of the specified dose of Albutropin once weekly between 6:00 and 10:00 AM in the abdomen or thigh, rotating the site with each injection. The starting Albutropin dose was 60% of the albutropin dose considered ‘comparable’ to the dose of rhGH previously administered. Dose adjustments were accomplished using a titration algorithm based on IGF-1 levels evaluated by a central reader who directed the investigator in choosing the titration dose. Ultimately, the investigator was responsible for making the final decision regarding the dose administered.

    Arm title
    Genotropin
    Arm description
    The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin.
    Arm type
    Active comparator

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    somatropin (rDNA origin), rhGH (recombinant human Growth Hormone)
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients injected their specified dose of Genotropin once daily between 6:00 and 10:00 AM except on days of in-clinic visits when the dose was injected in the arm by a qualified site staff member after the planned activities were performed by the site staff. The dose levels available for achieving the appropriate final daily dose ranged from 0.2 mg to 1.8 mg and were administered using a variable, multi-dose injection device.

    Number of subjects in period 1
    Albutropin Genotropin
    Started
    41
    11
    Completed
    41
    11
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Albutropin
    Arm description
    At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin for an additional 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Albutropin
    Investigational medicinal product code
    TV-1106
    Other name
    human serum albumin-human growth hormone (HSA-hGH)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose and titration dose levels of Albutropin were up to 50 mg given as weekly subcutaneous (sc) injections in the formulation buffer. Except on in-clinic visit days, the patient was responsible for injections of the specified dose of Albutropin once weekly between 6:00 and 10:00 AM in the abdomen or thigh, rotating the site with each injection.

    Arm title
    Genotropin
    Arm description
    At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin for an additional 52 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    somatropin (rDNA origin), rhGH (recombinant human Growth Hormone)
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients injected their specified dose of Genotropin once daily between 6:00 and 10:00 AM except on days of in-clinic visits when the dose was injected in the arm by a qualified site staff member after the planned activities were performed by the site staff. The dose levels available for achieving the appropriate final daily dose ranged from 0.2 mg to 1.8 mg and were administered using a variable, multi-dose injection device.

    Number of subjects in period 2
    Albutropin Genotropin
    Started
    41
    11
    Completed
    33
    9
    Not completed
    8
    2
         Noncompliance
    1
    -
         Lack of efficacy
    1
    -
         Not specified
    1
    -
         Adverse event, non-fatal
    1
    1
         Consent withdrawn by subject
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Albutropin
    Reporting group description
    Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin.

    Reporting group title
    Genotropin
    Reporting group description
    The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin.

    Reporting group values
    Albutropin Genotropin Total
    Number of subjects
    41 11 52
    Age categorical
    Units: Subjects
        20 to <=40
    16 4 20
        >40 to <=60
    18 6 24
        >60
    7 1 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    45.9 ± 13.11 44 ± 13.08 -
    Gender categorical
    Units: Subjects
        Female
    15 5 20
        Male
    26 6 32
    Race
    Units: Subjects
        White
    41 11 52
        Not White
    0 0 0
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    41 11 52
        Hispanic or Latino
    0 0 0
    Normal IGF SDS
    Range: -1.5 to 2.0
    Units: Subjects
        Yes
    41 11 52
        No
    0 0 0
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    80.5 ± 17.42 72.5 ± 19.04 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    170.1 ± 11.38 165.1 ± 10.94 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.6 ± 4.45 26.3 ± 4.51 -
    Insulin-like Growth Factor 1 (IGF-1)
    Units: ng/mL
        arithmetic mean (standard deviation)
    167.83 ± 50.563 198.82 ± 42.211 -
    IGF-1 Standard Deviation Score (SDS) Level
    Units: SDS level
        arithmetic mean (standard deviation)
    0.32 ± 0.622 0.67 ± 0.593 -
    Fasting blood glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.65 ± 0.429 4.77 ± 0.39 -
    Triiodothyronine
    Units: pmol/L
        arithmetic mean (standard deviation)
    1404.57 ± 299.862 1490.91 ± 430.011 -
    Triiodothyronine, Free
    Units: pmol/L
        arithmetic mean (standard deviation)
    15.64 ± 3.334 15.56 ± 3.112 -
    Thyroid stimulating hormones
    Units: mU/L
        arithmetic mean (standard deviation)
    0.27 ± 0.602 0.79 ± 1.46 -
    Cortisol, serum random
    Units: nmol/L
        arithmetic mean (standard deviation)
    317.74 ± 276.846 311.6 ± 214.783 -

    End points

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    End points reporting groups
    Reporting group title
    Albutropin
    Reporting group description
    Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin.

    Reporting group title
    Genotropin
    Reporting group description
    The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for Albutropin, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin.
    Reporting group title
    Albutropin
    Reporting group description
    At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin for an additional 52 weeks.

    Reporting group title
    Genotropin
    Reporting group description
    At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of Genotropin for an additional 52 weeks.

    Subject analysis set title
    Albutropin: Baseline
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A paired t-test in Albutropin subjects to assess the magnitude of change from baseline to maximum IGF-1 SDS (Cmax) value during week 12. Baseline data are reported in this column.

    Subject analysis set title
    Albutropin: Cmax at Week 12
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    A paired t-test in Albutropin subjects to assess the magnitude of change from baseline to maximum IGF-1 SDS (Cmax) value during week 12. IGF-1 SDS data at maximum concentration during Week 12 are reported in this column.

    Primary: Insulin-Like Growth Factor 1 (IGF-1) Standard Deviation Score (SDS) at Baseline and Cmax Level During Week 12

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    End point title
    Insulin-Like Growth Factor 1 (IGF-1) Standard Deviation Score (SDS) at Baseline and Cmax Level During Week 12
    End point description
    The study hypotheses are defined as follows:  H0: μD = 0  H1: μD ≠ 0  Where μD = expected value of IGF-1 SDS difference (Cmax at week 12 - baseline) in Albutropin group. Observed values are reported here. The statistical analysis was based on the within-subject change from baseline to Cmax during week 12.
    End point type
    Primary
    End point timeframe
    Baseline (Day 0), Week 12; samples drawn between 6:00 and 10:00 AM prior to dosing on Days 0, 78, 79, 80, 81 and 84
    End point values
    Albutropin: Baseline Albutropin: Cmax at Week 12
    Number of subjects analysed
    41
    41
    Units: standard deviation score
        arithmetic mean (standard error)
    -1.5 ± 0.14
    0.8 ± 0.12
    Statistical analysis title
    IGF-1 SDS Change Baseline to Cmax Week 12
    Statistical analysis description
    The null hypothesis was tested based on a paired t – test with n-1 degrees of freedom, where n refers to the total number of subjects in the Albutropin group with baseline and Cmax at week 12. n=41 since this is a within subject change.
    Comparison groups
    Albutropin: Baseline v Albutropin: Cmax at Week 12
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [1] - The significance level of the paired t-test was 5% (2-sided).

    Secondary: Percentage of Patients Whose Week 12 Trough IGF-1 SDS Value Is Within +/- 0.5 of screening IGF-1 SDS Value and Cmax <+2.0

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    End point title
    Percentage of Patients Whose Week 12 Trough IGF-1 SDS Value Is Within +/- 0.5 of screening IGF-1 SDS Value and Cmax <+2.0
    End point description
    Percentage of patients who meet both conditions: 1) Week 12 trough IGF-1 SDS within +/- 0.5 of screening IGF-1 SDS 2) Cmax Level During Week 12 Is Below +2.0 SDS. Both protocol and SAP document that 95% CI ranges will only be calculated for the Albutropin group. Values of 9999 indicate values were not calculated.
    End point type
    Secondary
    End point timeframe
    Screening (Weeks -8 to -5), Week 12
    End point values
    Albutropin Genotropin
    Number of subjects analysed
    41 [2]
    11 [3]
    Units: percentage of patients
        number (confidence interval 95%)
    37 (22.12 to 53.06)
    36 (-9999 to 9999)
    Notes
    [2] - ITT
    [3] - ITT
    No statistical analyses for this end point

    Secondary: Patients with Adverse Events (AE)

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    End point title
    Patients with Adverse Events (AE)
    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 64
    End point values
    Albutropin Genotropin
    Number of subjects analysed
    41 [4]
    11 [5]
    Units: patients
        Any AE
    26
    5
        Severe AE
    2
    1
        Treatment-related AE
    10
    1
        Deaths
    0
    0
        Other serious AE
    7
    1
        Withdrawn from study due to AE
    1
    1
    Notes
    [4] - Safety
    [5] - Safety
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint in Lipid Profile

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    End point title
    Change from Baseline to Endpoint in Lipid Profile
    End point description
    Change from baseline to endpoint values are offered for total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Endpoint in this context is referring to the last observed, post-baseline value for each patient.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0), Endpoint (up to Week 64)
    End point values
    Albutropin Genotropin
    Number of subjects analysed
    41 [6]
    11 [7]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Total cholesterol
    -0.1 ± 0.83
    0 ± 1.04
        VLDL cholesterol
    0 ± 0.2
    0 ± 0.28
        LDL cholesterol
    -0.1 ± 0.64
    -0.1 ± 0.81
        HDL cholesterol
    0 ± 0.24
    0 ± 0.23
        Triglycerides
    0 ± 0.88
    0 ± 0.6
    Notes
    [6] - ITT
    [7] - ITT
    No statistical analyses for this end point

    Secondary: Patients with Treatment-Emergent Anti-drug Antibodies (ADA)

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    End point title
    Patients with Treatment-Emergent Anti-drug Antibodies (ADA)
    End point description
    The testing scheme for patients treated with Albutropin (TV-1106) was multi-tiered, with testing for inhibition by TV-1106, by human growth hormone (hGH), and by human serum albumin (HSA). Confirmed positive assays were titered and tested for neutralizing antibodies (NAbs). All patients treated with Genotropin were tested for anti- recombinant human growth hormone (anti-rhGH) ADA. Values of 9999 = not applicable
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 64
    End point values
    Albutropin Genotropin
    Number of subjects analysed
    29 [8]
    11 [9]
    Units: patients
        ADA response
    13
    0
        Anti-TV-1106 NAb response
    1
    9999
    Notes
    [8] - PK analysis set
    [9] - PK analysis set
    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 64
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Albutropin
    Reporting group description
    Patients began with a starting weekly dose of Albutropin based on the conversion calculations (previous daily rhGH dose ×28 ×0.6). Up or down titration was allowed based on the IGF-1 SDS obtained on day 7 of weeks 3, 6, and 9 with the goal for each patient to achieve an IGF-1 SDS by the time of trough level during week 12 that was within ±0.5 SDS of the patient’s pre-washout IGF-1 SDS and a Cmax IGF-1 SDS level during week 12 that was below +2.0 SDS. Doses increased or decreased by 2.8 mg if the current dose was < 15 mg, and adjusted by 5.8 mg otherwise. At the end of week 12, patients were expected to continue into the extension phase on their current dose of weekly Albutropin.

    Reporting group title
    Genotropin
    Reporting group description
    The initial dose of Genotropin was based on the previous daily rhGH dose in use prior to washout. Up and down titrations were performed at the same time points and according to the same algorithm as that described for TV-1106, using either 0.2 mg/day of the Genotropin if the current dose of Genotropin was greater than 0.5 mg/day or 0.1 mg/day if the current dose of Genotropin was less than or equal to 0.5 mg/day. At the end of week 12, patients were expected to continue into the extension phase on their current daily dose of genotropin.

    Serious adverse events
    Albutropin Genotropin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 41 (17.07%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutralising antibodies positive
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Albutropin Genotropin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 41 (36.59%)
    5 / 11 (45.45%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 11 (18.18%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Injection site atrophy
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 11 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 11 (0.00%)
         occurrences all number
    8
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 11 (9.09%)
         occurrences all number
    5
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    Amendment 1 (dated 04 March 2013) to the protocol was issued before any patients were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  Added monitoring procedures (MRI/CT imaging)  Clarified the inclusion/exclusion criteria  Clarified the study design  Clarified study drug dosing
    21 Jul 2013
    Amendment 2 (dated 21 July 2013) to the protocol was issued before any 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. The following major procedural changes (not all-inclusive) were made to the protocol:  Modified inclusion criterion d: the intent of inclusion criterion d was to establish that patients with GHD had been receiving stable rhGH therapy. However, patients with GHD that had been clinically stable over an extended period of time may have had infrequent monitoring of their IGF-1 levels, and still have been an appropriate clinical candidate for the study. Therefore, clarification of this criterion was necessary to reduce patient burden in terms of time and inconvenience of additional blood draws, as well as to clarify to investigators how to proceed with patients with long standing GHD in whom frequent monitoring was not indicated.  Modified / amended exclusion criteria Electrocardiography was modified so that the methodology of ECG collection could support further development work for QT analysis. Digital ECGs with a central reader were used for the core phase of the study. For the safety extension phase, traditional ECGs were performed with investigator interpretation. Lipid profile was changed from a secondary endpoint to a safety endpoint .  Clarified that the MRI/CT scan should have been performed prior to baseline (visit 3) so that the results could have been obtained prior to the baseline visit, in which the first dose of study drug was administered.

    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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