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    Clinical Trial Results:
    A phase II, randomized, active controlled, open label study of safety and efficacy of HM10560A a Long-acting rhGH-HMC001 conjugate in treatment of subjects suffering from adult growth hormone deficiency (AGHD)

    Summary
    EudraCT number
    2011-001826-61
    Trial protocol
    HU   PL   BG  
    Global end of trial date
    29 Jun 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    11‐HM10560A‐201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    HANMI Pharmaceutical Co., Ltd.
    Sponsor organisation address
    14, Wiryeseong-daero, Songpa-gu, Seoul, Korea, Republic of, 138-724
    Public contact
    Executive Director, HANMI Pharmaceutical Co., Ltd., +82 24109041, jhkang@hanmi.co.kr
    Scientific contact
    Executive Director, HANMI Pharmaceutical Co., Ltd., +82 24109041, jhkang@hanmi.co.kr
    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
    18 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.To assess the safety, tolerability and Pharmacokinetic/ Pharmacodynamic (PK/PD) profile of three doses of HM10560A on an every week (EW) regime and one dose on every other week(EOW) regime administered for a period of 24 weeks initial study 2.To select the optimal dose and dosing regimen of HM10560A for the subsequent phase III study on the basis of the safety and PK/PD profile after 24 weeks of treatment 3.To assess the long term safety of HM10560A when administered in optimal dose range and dose frequency for additional 48 weeks (followed with 2 weeks safety follow up)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Nov 2011
    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: 15
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Serbia: 8
    Worldwide total number of subjects
    69
    EEA total number of subjects
    39
    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)
    69
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial took place at 16 centres in 8 countries: Poland-3 sites, Romania-3 sites, Ukraine-3 sites, Hungary-2 sites, Russia-2 sites, Bulgaria-1 site, Korea-1 site, and Serbia-1 site. The first subject was enrolled on 21 November 2011 and the last study visit occurred on 29 June 2015.

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    169 [1]
    Number of subjects completed
    69

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Screen failure: 97
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    Consent withdrawn by subject: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: It is the number of subjects screened indicated as starters of the pre-assignment period and the number of subjects treated as the worldwide number of subjects, therefore the difference.
    Period 1
    Period 1 title
    24-week dose finding period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    HM10560A 0.03 mg/kg EW
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HM10560A 0.03 mg/kg EW. Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 2
    Arm description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 20 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 20 weeks. Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 3
    Arm description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 4 weeks then 0.10 mg/kg EW for 16 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 4 weeks then 0.10 mg/kg EW for 16 weeks. Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 4
    Arm description
    HM10560A 0.04 mg/kg EOW for 4 weeks then 0.08 mg/kg EOW for 4 weeks then 0.12 mg/kg EOW for 16 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HM10560A 0.04 mg/kg EOW for 4 weeks then 0.08 mg/kg EOW for 4 weeks then 0.12 mg/kg EOW for 16 weeks. Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 5
    Arm description
    standard daily rhGH
    Arm type
    Active comparator

    Investigational medicinal product name
    Genotropin®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Genotropin® was administered at a dose of 0.04 mg/kg/week (0.006 mg/kg/day), divided and administered as a daily SC dose (7X/week), at bedtime, and that dose was then adjusted on every 4 weeks with 25% increments or decrements (0.01 mg/kg/week) up to the maximal dose of 0.08 mg/kg/week, with the aim to stabilize IGF-1 levels between 0 and +2 SDS (standard deviation score).

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
    Started
    15
    14
    14
    12
    14
    Completed
    13
    14
    14
    11
    14
    Not completed
    2
    0
    0
    1
    0
         Military actions
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    1
    -
    Period 2
    Period 2 title
    Long-term safety: 48 weeks treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1 SFU
    Arm description
    0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum insulin-like growth factor- 1 (IGF-1) as follows: IGF-1 < -0.5 SDS dose increased 50% IGF-1 between -0.5 and +1.5 SDS dose maintained IGF-1 > 1.5 SDS dose decreased 25% IGF-1 >2 SDS dose decreased 50%.
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum insulin-like growth factor- 1 (IGF-1) as follows: IGF-1 < -0.5 SDS dose increased 50% IGF-1 between -0.5 and +1.5 SDS dose maintained IGF-1 > 1.5 SDS dose decreased 25% IGF-1 >2 SDS dose decreased 50%. Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 2 SFU
    Arm description
    0.06 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.06 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU). Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 3 SFU
    Arm description
    0.10 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.10 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU) Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 4 SFU
    Arm description
    0.12 mg/kg EOW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.12 mg/kg EOW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU). Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Arm title
    Cohort 5 SFU
    Arm description
    Switched from Genotropin to 0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Switched from Genotropin to 0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1). Study treatment was administered as SC injections in the region of right or left thigh and right or left lower abdominal wall, always alternating the injection site. Dose calculation was adjusted to the subject’s body weight at each regularly scheduled visit.

    Number of subjects in period 2
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU
    Started
    13
    14
    14
    11
    14
    Completed
    13
    12
    14
    10
    12
    Not completed
    0
    2
    0
    1
    2
         Growth of an intracranial tumor during study
    -
    -
    -
    -
    1
         Own reasons
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    -
    -
    1
         Personal reasons
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    1
    -
    -
    -
    Period 3
    Period 3 title
    Single dose PK/PD run-in period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1 PK-PD
    Arm description
    Single dose 0.04 mg/kg HM10560A (total body weight)
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose 0.04 mg/kg HM10560A (total body weight). Subjects received a single dose administered in the abdominal wall.

    Arm title
    Cohort 2 PK-PD
    Arm description
    Single dose 0.08 mg/kg HM10560A
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose 0.08 mg/kg HM10560A (total body weight). Subjects received a single dose administered in the abdominal wall.

    Arm title
    Cohort 3 PK-PD
    Arm description
    Single dose 0.12 mg/kg HM10560A
    Arm type
    Experimental

    Investigational medicinal product name
    HM10560A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose 0.12 mg/kg HM10560A (total body weight). Subjects received a single dose administered in the abdominal wall.

    Number of subjects in period 3 [2]
    Cohort 1 PK-PD Cohort 2 PK-PD Cohort 3 PK-PD
    Started
    3
    3
    3
    Completed
    3
    3
    3
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The PK-PD substudy was conducted in a subgroup of patients prior to the dose finding period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    HM10560A 0.03 mg/kg EW

    Reporting group title
    Cohort 2
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 20 weeks

    Reporting group title
    Cohort 3
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 4 weeks then 0.10 mg/kg EW for 16 weeks

    Reporting group title
    Cohort 4
    Reporting group description
    HM10560A 0.04 mg/kg EOW for 4 weeks then 0.08 mg/kg EOW for 4 weeks then 0.12 mg/kg EOW for 16 weeks

    Reporting group title
    Cohort 5
    Reporting group description
    standard daily rhGH

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Total
    Number of subjects
    15 14 14 12 14 69
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    15 14 14 12 14 69
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.2 ± 12.01 38.6 ± 12.73 36.2 ± 9.74 41.7 ± 11.42 37.4 ± 9.29 -
    Gender categorical
    Units: Subjects
        Female
    5 6 6 6 6 29
        Male
    10 8 8 6 8 40
    Race
    Units: Subjects
        Asian
    0 0 0 0 1 1
        Caucasian
    15 14 14 12 13 68
    GHD history
    Units: Subjects
        Childhood onset
    7 7 7 6 5 32
        Adult onset
    8 7 7 6 9 37
    IGF-1
    Units: μg/l
        arithmetic mean (standard deviation)
    50.5 ± 30.35 52.5 ± 28.79 61.9 ± 33.43 44.3 ± 27.91 44.6 ± 28.73 -
    IGF-1 SDS
    Units: SDS
        arithmetic mean (standard deviation)
    -2.84 ± 1.57 -2.72 ± 1.275 -2.49 ± 1.452 -2.97 ± 1.58 -3.14 ± 1.264 -
    IGFBP3 SDS
    Units: SDS
        arithmetic mean (standard deviation)
    -2.21 ± 1.932 -2.36 ± 1.505 -2.26 ± 1.539 -2.69 ± 1.992 -2.55 ± 1.595 -
    Body fat mass
    Units: kg
        arithmetic mean (standard deviation)
    22.591 ± 6.0256 23.243 ± 6.7088 23.188 ± 4.0353 24.335 ± 8.4133 29.113 ± 9.5614 -
    Lean body mass
    Units: kg
        arithmetic mean (standard deviation)
    43.677 ± 8.5766 41.88 ± 13.201 41.201 ± 10.4357 41.73 ± 15.4269 44.261 ± 12.5819 -
    Trunk fat mass
    Units: kg
        arithmetic mean (standard deviation)
    12.715 ± 3.6182 12.747 ± 3.5907 12.353 ± 2.3455 13.827 ± 4.6946 15.847 ± 5.8307 -
    Bone mineral density
    Units: g/cm2
        arithmetic mean (standard deviation)
    1.086 ± 0.1613 1.087 ± 0.1611 1.094 ± 0.116 1.076 ± 0.1523 1.126 ± 0.1798 -
    Subject analysis sets

    Subject analysis set title
    SAS
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized subjects who had received at least one dose of the active treatment

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized subjects who had received at least one dose of the active treatment and who provided any follow-up data for the primary target variables

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects with major protocol deviations in the dose-finding period were excluded.

    Subject analysis set title
    SAS-SFU
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Includes all randomized patients who have completed the dose finding period and have received at least one dose of active treatment in the safety follow-up period.

    Subject analysis set title
    FAS-SFU
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all randomized patients who have completed the dose finding period, and who have received at least one dose of active treatment in the safety follow-up period and who provide any follow-up data for the primary target variables in the safety follow-up period.

    Subject analysis sets values
    SAS FAS PP SAS-SFU FAS-SFU
    Number of subjects
    69
    69
    58
    66
    65
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    69
    69
    58
    66
    65
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.3 ± 10.93
    38.3 ± 10.93
    38.8 ± 11.19
    38.5 ± 10.99
    38.5 ± 11.08
    Gender categorical
    Units: Subjects
        Female
    29
    29
    26
    27
    26
        Male
    40
    40
    32
    39
    39
    Race
    Units: Subjects
        Asian
    1
    1
    1
    1
    1
        Caucasian
    68
    68
    57
    65
    64
    GHD history
    Units: Subjects
        Childhood onset
    32
    32
    29
    30
    30
        Adult onset
    37
    37
    29
    36
    35
    IGF-1
    Units: μg/l
        arithmetic mean (standard deviation)
    51 ± 29.78
    51 ± 29.78
    50.2 ± 27.92
    ±
    ±
    IGF-1 SDS
    Units: SDS
        arithmetic mean (standard deviation)
    -2.83 ± 1.407
    -2.83 ± 1.407
    -2.83 ± 1.35
    ±
    ±
    IGFBP3 SDS
    Units: SDS
        arithmetic mean (standard deviation)
    -2.4 ± 1.675
    -2.4 ± 1.675
    -2.42 ± 1.658
    ±
    ±
    Body fat mass
    Units: kg
        arithmetic mean (standard deviation)
    24.49 ± 7.3842
    24.49 ± 7.3842
    24.288 ± 6.8127
    ±
    ±
    Lean body mass
    Units: kg
        arithmetic mean (standard deviation)
    42.61 ± 11.8294
    42.61 ± 11.8294
    42.033 ± 11.6529
    ±
    ±
    Trunk fat mass
    Units: kg
        arithmetic mean (standard deviation)
    13.493 ± 4.2566
    13.493 ± 4.2566
    13.259 ± 3.7528
    ±
    ±
    Bone mineral density
    Units: g/cm2
        arithmetic mean (standard deviation)
    1.094 ± 0.1525
    1.094 ± 0.1525
    1.087 ± 0.1552
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    HM10560A 0.03 mg/kg EW

    Reporting group title
    Cohort 2
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 20 weeks

    Reporting group title
    Cohort 3
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 4 weeks then 0.10 mg/kg EW for 16 weeks

    Reporting group title
    Cohort 4
    Reporting group description
    HM10560A 0.04 mg/kg EOW for 4 weeks then 0.08 mg/kg EOW for 4 weeks then 0.12 mg/kg EOW for 16 weeks

    Reporting group title
    Cohort 5
    Reporting group description
    standard daily rhGH
    Reporting group title
    Cohort 1 SFU
    Reporting group description
    0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum insulin-like growth factor- 1 (IGF-1) as follows: IGF-1 < -0.5 SDS dose increased 50% IGF-1 between -0.5 and +1.5 SDS dose maintained IGF-1 > 1.5 SDS dose decreased 25% IGF-1 >2 SDS dose decreased 50%.

    Reporting group title
    Cohort 2 SFU
    Reporting group description
    0.06 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 3 SFU
    Reporting group description
    0.10 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 4 SFU
    Reporting group description
    0.12 mg/kg EOW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 5 SFU
    Reporting group description
    Switched from Genotropin to 0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).
    Reporting group title
    Cohort 1 PK-PD
    Reporting group description
    Single dose 0.04 mg/kg HM10560A (total body weight)

    Reporting group title
    Cohort 2 PK-PD
    Reporting group description
    Single dose 0.08 mg/kg HM10560A

    Reporting group title
    Cohort 3 PK-PD
    Reporting group description
    Single dose 0.12 mg/kg HM10560A

    Subject analysis set title
    SAS
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized subjects who had received at least one dose of the active treatment

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomized subjects who had received at least one dose of the active treatment and who provided any follow-up data for the primary target variables

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects with major protocol deviations in the dose-finding period were excluded.

    Subject analysis set title
    SAS-SFU
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Includes all randomized patients who have completed the dose finding period and have received at least one dose of active treatment in the safety follow-up period.

    Subject analysis set title
    FAS-SFU
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all randomized patients who have completed the dose finding period, and who have received at least one dose of active treatment in the safety follow-up period and who provide any follow-up data for the primary target variables in the safety follow-up period.

    Primary: Period 1: Change in IGF-1 over time (FAS)

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    End point title
    Period 1: Change in IGF-1 over time (FAS)
    End point description
    95% confidence intervals (CIs) for least-square mean (LSM) changes from baseline (coupled with standard error (SE) and degrees of freedom) at Week 24 in IGF-1 levels were calculated within a repeated mixed model analysis (MMRM) with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 level, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Primary
    End point timeframe
    Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [1]
    Units: μg/l
    least squares mean (standard error)
        Week 2
    24.02 ± 10.31
    27.5 ± 10.234
    25.33 ± 10.31
    5.4 ± 11.105
    86.47 ± 10.384
    ±
        Week 4
    23.02 ± 9.182
    24.38 ± 9.097
    11.74 ± 9.182
    7.52 ± 10.074
    98.15 ± 9.266
    ±
        Week 8
    31.64 ± 8.855
    47.21 ± 8.674
    32.23 ± 8.763
    14.92 ± 9.428
    110.65 ± 8.85
    ±
        Week 12
    34.52 ± 10.262
    50.11 ± 10.186
    57.38 ± 10.262
    12.6 ± 11.053
    91.49 ± 10.337
    ±
        Week 16
    37.57 ± 8.993
    44.83 ± 8.905
    61.11 ± 8.993
    17.91 ± 9.677
    115.23 ± 9.077
    ±
        Week 20
    39.37 ± 10.273
    43.84 ± 10.011
    61.1 ± 10.089
    15.17 ± 11.107
    104 ± 10.165
    ±
        Week 24
    37.25 ± 9.643
    44.35 ± 9.439
    75.85 ± 9.521
    23.51 ± 10.416
    96.99 ± 9.602
    ±
    Notes
    [1] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohort 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -59.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -86.87
         upper limit
    -32.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.559
    Notes
    [2] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with standard error of the mean [SEM], 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohort 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -52.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -79.6
         upper limit
    -25.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.475
    Notes
    [3] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohorts 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.125
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -21.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -48.32
         upper limit
    6.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.584
    Notes
    [4] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -73.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -101.82
         upper limit
    -45.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.167
    Notes
    [5] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with standard error of the mean [SEM], 95% CI and p value).

    Primary: Period 1: Change in IGF-1 over time (PP)

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    End point title
    Period 1: Change in IGF-1 over time (PP)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in IGF-1 levels were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 level, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Primary
    End point timeframe
    Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 PP
    Number of subjects analysed
    12
    14
    11
    8
    13
    0 [6]
    Units: μg/l
    least squares mean (standard error)
        Week 2
    24.38 ± 10.574
    27.22 ± 9.736
    12.27 ± 11.282
    2.3 ± 13.008
    81.91 ± 10.377
    ±
        Week 4
    22.74 ± 9.683
    24.1 ± 8.906
    9.11 ± 10.372
    4.07 ± 11.922
    91.6 ± 9.541
    ±
        Week 8
    31.37 ± 9.766
    46.94 ± 8.984
    26.67 ± 10.457
    10.17 ± 12.024
    107.65 ± 9.619
    ±
        Week 12
    33.98 ± 11.139
    49.84 ± 10.261
    53.76 ± 11.859
    11.69 ± 13.697
    93.05 ± 10.909
    ±
        Week 16
    37.48 ± 9.565
    44.56 ± 8.796
    53.41 ± 10.252
    15.17 ± 11.778
    112.68 ± 9.43
    ±
        Week 20
    40.13 ± 9.994
    43.57 ± 9.196
    43.29 ± 10.689
    12.63 ± 12.301
    109.74 ± 9.832
    ±
        Week 24
    37.97 ± 9.929
    44.07 ± 9.135
    64.2 ± 10.623
    20.59 ± 12.222
    102.29 ± 9.771
    ±
    Notes
    [6] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohort 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -64.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -92.14
         upper limit
    -36.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.847
    Notes
    [7] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -58.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -85.19
         upper limit
    -31.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.424
    Notes
    [8] - Comparison of LSMs across treatment groups (Cohort 2vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohorts 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.014
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -38.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -67.96
         upper limit
    -8.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.865
    Notes
    [9] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -81.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -113.32
         upper limit
    -50.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.733
    Notes
    [10] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Primary: Period 2: Change in IGF-1 from Week 24 to 74 (FAS-SFU)

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    End point title
    Period 2: Change in IGF-1 from Week 24 to 74 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an analysis of covariance (ANCOVA) model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Primary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [11]
    Units: μg/l
        least squares mean (standard error)
    9.06 ± 12.103
    9.13 ± 12.083
    14.57 ± 11.543
    -8.64 ± 14.226
    -50.92 ± 13.305
    ±
    Notes
    [11] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 change from Week 24 to Week 72 between Cohorts 1-4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 5 SFU v Cohort 1 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.002
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    59.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.37
         upper limit
    96.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.238
    Notes
    [12] - Comparison of LSMs across treatment groups (Cohort 1-4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 change from Week 24 to Week 72 between Cohorts 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.002
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    59.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.37
         upper limit
    96.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.238
    Notes
    [13] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 change from Week 24 to Week 72 between Cohorts 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    65.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.69
         upper limit
    99.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    16.835
    Notes
    [14] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 change from Week 24 to Week 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.044
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    42.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.24
         upper limit
    83.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    20.439
    Notes
    [15] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Primary: Period 3: Change in IGF-1 over time (FAS)

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    End point title
    Period 3: Change in IGF-1 over time (FAS) [16]
    End point description
    Actual change in IGF-1 over time (observed cases)
    End point type
    Primary
    End point timeframe
    0 hours to 672 hours
    Notes
    [16] - 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: This is a Phase II study of exloratory nature, therefore statistical analysis of each endpoint is not completely necessary. However, statistical analyses of the same measured variable (IGF-1) are ready in other study periods.
    End point values
    Cohort 1 PK-PD Cohort 2 PK-PD Cohort 3 PK-PD FAS
    Number of subjects analysed
    3
    3
    3
    0 [17]
    Units: μ/l
    arithmetic mean (standard deviation)
        0.5-1.5 hours
    -4.7 ± 6.79
    -3.6 ± 1.23
    -0.5 ± 2.16
    ±
        2-4 hours
    -3.6 ± 4.48
    -3.1 ± 4.83
    -2.9 ± 4.54
    ±
        7-12 hours
    4.5 ± 7.09
    12 ± 4.78
    23.5 ± 9.24
    ±
        16-30 hours
    21.9 ± 16.21
    69.9 ± 7.71
    80.8 ± 31.12
    ±
        30-60 hours
    34 ± 22.14
    91.2 ± 12.76
    109.7 ± 48.58
    ±
        72-100 hours
    37.7 ± 26.8
    73.5 ± 44.77
    84.3 ± 64.37
    ±
        120-150 hours
    25.2 ± 16.35
    61.2 ± 29.75
    53.2 ± 53.34
    ±
        200-250 hours
    19.5 ± 5.75
    40.1 ± 19.54
    18.3 ± 25.37
    ±
        400-450 hours
    -7 ± 11.03
    8.1 ± 12.28
    0.1 ± 9.98
    ±
        600-672 hours
    -4.2 ± 8.85
    3.4 ± 5.49
    -4.1 ± 8.7
    ±
    Notes
    [17] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    No statistical analyses for this end point

    Secondary: Period 1: Change in IGF-1 SDS (FAS)

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    End point title
    Period 1: Change in IGF-1 SDS (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in IGF-1 SDS were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [18]
    Units: SDS
    least squares mean (standard error)
        Week 2
    1.01 ± 0.265
    0.87 ± 0.263
    0.98 ± 0.264
    0.06 ± 0.285
    2.55 ± 0.267
    ±
        Week 4
    1.02 ± 0.229
    1.01 ± 0.227
    0.61 ± 0.229
    0.13 ± 0.252
    2.84 ± 0.232
    ±
        Week 8
    1.27 ± 0.244
    1.52 ± 0.238
    1.28 ± 0.24
    0.45 ± 0.259
    3.17 ± 0.243
    ±
        Week 12
    1.35 ± 0.288
    1.7 ± 0.286
    1.87 ± 0.287
    0.35 ± 0.31
    2.52 ± 0.289
    ±
        Week 16
    1.39 ± 0.255
    1.52 ± 0.253
    2 ± 0.254
    0.69 ± 0.275
    3.24 ± 0.257
    ±
        Week 20
    1.41 ± 0.253
    1.56 ± 0.247
    2 ± 0.248
    0.46 ± 0.273
    3.19 ± 0.251
    ±
        Week 24
    1.37 ± 0.241
    1.52 ± 0.235
    2.35 ± 0.237
    0.8 ± 0.259
    2.97 ± 0.24
    ±
    Notes
    [18] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 SDS change from baseline to Week 24 between Cohorts 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.28
         upper limit
    -0.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.338
    Notes
    [19] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 SDS change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.12
         upper limit
    -0.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.336
    Notes
    [20] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 SDS change from baseline to Week 24 between Cohorts 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    = 0.071
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.338
    Notes
    [21] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGF-1 SDS change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.88
         upper limit
    -1.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.354
    Notes
    [22] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Change in IGFBP3 SDS (FAS)

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    End point title
    Period 1: Change in IGFBP3 SDS (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in IGFBP3 SDS were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 2, 4, 8, 12, 16, 20 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [23]
    Units: SDS
    least squares mean (standard error)
        Week 2
    0.58 ± 0.197
    0.53 ± 0.195
    0.55 ± 0.196
    0.08 ± 0.212
    1.61 ± 0.197
    ±
        Week 4
    0.55 ± 0.168
    0.45 ± 0.166
    0.26 ± 0.167
    -0.1 ± 0.185
    1.65 ± 0.169
    ±
        Week 8
    0.7 ± 0.173
    0.64 ± 0.169
    0.47 ± 0.169
    0.12 ± 0.183
    1.53 ± 0.171
    ±
        Week 12
    0.59 ± 0.202
    0.8 ± 0.2
    0.9 ± 0.2
    0.05 ± 0.217
    1.4 ± 0.202
    ±
        Week 16
    0.53 ± 0.176
    0.7 ± 0.174
    0.99 ± 0.174
    0.36 ± 0.189
    1.76 ± 0.176
    ±
        Week 20
    0.56 ± 0.178
    0.75 ± 0.172
    1 ± 0.173
    0.18 ± 0.192
    1.8 ± 0.175
    ±
        Week 24
    0.8 ± 0.19
    0.63 ± 0.184
    1.09 ± 0.185
    0.4 ± 0.205
    1.67 ± 0.186
    ±
    Notes
    [23] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGFBP3 SDS change from baseline to Week 24 between cohorts
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    P-value
    = 0.002
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.41
         upper limit
    -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.266
    Notes
    [24] - Comparison of LSMs across treatment groups (Cohort 1-4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGFBP3 SDS change from baseline to Week 24 between cohorts
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.57
         upper limit
    -0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.262
    Notes
    [25] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGFBP3 SDS change from baseline to Week 24 between cohorts
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [26]
    P-value
    = 0.028
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.11
         upper limit
    -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.262
    Notes
    [26] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in IGFBP3 SDS change from baseline to Week 24 between cohorts
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.83
         upper limit
    -0.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.277
    Notes
    [27] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Change in lean body mass (LBM) (FAS)

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    End point title
    Period 1: Change in lean body mass (LBM) (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in LBM were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [28]
    Units: kg
    least squares mean (standard error)
        Week 12
    0.575 ± 0.4054
    1.749 ± 0.3868
    0.436 ± 0.4021
    0.599 ± 0.4192
    1.709 ± 0.3895
    ±
        Week 24
    1.078 ± 0.4408
    1.675 ± 0.4239
    1.286 ± 0.4405
    1.1 ± 0.4739
    2.357 ± 0.4263
    ±
    Notes
    [28] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in LBM change from baseline to Week 24 between Cohort 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [29]
    P-value
    = 0.04
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.279
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.497
         upper limit
    -0.061
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6086
    Notes
    [29] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in LBM change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [30]
    P-value
    = 0.26
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.682
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.882
         upper limit
    0.519
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5997
    Notes
    [30] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in LBM change from baseline to Week 24 between Cohort 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [31]
    P-value
    = 0.085
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.293
         upper limit
    0.151
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6106
    Notes
    [31] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in LBM change from baseline to Week 24 between Cohort 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [32]
    P-value
    = 0.054
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.257
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.538
         upper limit
    0.024
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6399
    Notes
    [32] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Change in body fat mass (FM) (FAS)

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    End point title
    Period 1: Change in body fat mass (FM) (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in FM were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [33]
    Units: kg
    least squares mean (standard error)
        Week 12
    -0.713 ± 0.5672
    -0.956 ± 0.5452
    0.923 ± 0.5671
    -0.506 ± 0.5913
    -1.418 ± 0.5675
    ±
        Week 24
    -0.468 ± 0.7144
    -1.337 ± 0.6944
    1.137 ± 0.7216
    -0.599 ± 0.7648
    -0.831 ± 0.712
    ±
    Notes
    [33] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in FM change from baseline to Week 24 between Cohort 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [34]
    P-value
    = 0.722
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.363
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.67
         upper limit
    2.396
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0156
    Notes
    [34] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in FM change from baseline to Week 24 between Cohort 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [35]
    P-value
    = 0.615
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.506
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.511
         upper limit
    1.498
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0012
    Notes
    [35] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in FM change from baseline to Week 24 between Cohort 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [36]
    P-value
    = 0.058
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.968
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.071
         upper limit
    4.007
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0187
    Notes
    [36] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in FM change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [37]
    P-value
    = 0.826
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.232
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.87
         upper limit
    2.334
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0502
    Notes
    [37] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Relative change in body fat mass (FM) (FAS)

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    End point title
    Period 1: Relative change in body fat mass (FM) (FAS)
    End point description
    95% CIs for LSM % changes from baseline (coupled with SE and degrees of freedom) at Week 24 in FM were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [38]
    Units: percent
    least squares mean (standard error)
        Week 12
    -1.173 ± 0.61
    -1.922 ± 0.5884
    0.467 ± 0.6124
    -0.964 ± 0.6418
    -1.98 ± 0.6219
    ±
        Week 24
    -1.164 ± 0.7327
    -2.175 ± 0.7134
    0.244 ± 0.7418
    -1.21 ± 0.7896
    -2.081 ± 0.7412
    ±
    Notes
    [38] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change in FM from baseline to Week 24 between Cohorts 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [39]
    P-value
    = 0.383 [40]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.917
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.169
         upper limit
    3.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0418
    Notes
    [39] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    [40] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change in FM from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [41]
    P-value
    = 0.927
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.152
         upper limit
    1.963
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0277
    Notes
    [41] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change in FM from baseline to Week 24 between Cohorts 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [42]
    P-value
    = 0.03
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.325
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.233
         upper limit
    4.416
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0449
    Notes
    [42] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change in FM from baseline to Week 24 between Cohort 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [43]
    P-value
    = 0.425
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.296
         upper limit
    3.036
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0821
    Notes
    [43] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Change in trunk fat (FAS)

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    End point title
    Period 1: Change in trunk fat (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in trunk fat were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [44]
    Units: kg
    least squares mean (standard error)
        Week 12
    -0.898 ± 0.3781
    -0.803 ± 0.3651
    0.115 ± 0.3814
    -0.571 ± 0.3955
    -1.249 ± 0.3751
    ±
        Week 24
    -0.595 ± 0.4354
    -1.178 ± 0.4236
    0.111 ± 0.4417
    -0.771 ± 0.4675
    -0.804 ± 0.4322
    ±
    Notes
    [44] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in trunk fat change from baseline to Week 24 between Cohort 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.735
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.209
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.022
         upper limit
    1.441
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6151
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in trunk fat change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [45]
    P-value
    = 0.543
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.373
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.594
         upper limit
    0.847
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6096
    Notes
    [45] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in trunk fat change from baseline to Week 24 between Cohort 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.147
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.915
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.332
         upper limit
    2.162
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6229
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in trunk fat change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [46]
    P-value
    = 0.959
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.244
         upper limit
    1.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6381
    Notes
    [46] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Relative change in trunk fat (FAS)

    Close Top of page
    End point title
    Period 1: Relative change in trunk fat (FAS)
    End point description
    95% CIs for LSM % changes from baseline (coupled with SE and degrees of freedom) at Week 24 in trunk fat were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [47]
    Units: percent
    least squares mean (standard error)
        Week 12
    -2.012 ± 0.7492
    -2.516 ± 0.7226
    -0.124 ± 0.7532
    -1.463 ± 0.7904
    -2.94 ± 0.754
    ±
        Week 24
    -1.799 ± 0.8373
    -3.184 ± 0.8135
    -0.574 ± 0.8472
    -1.932 ± 0.9063
    -2.847 ± 0.8416
    ±
    Notes
    [47] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change from baseline to Week 24 between Cohorts 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.379
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.317
         upper limit
    3.413
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1816
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [48]
    P-value
    = 0.775
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.337
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.68
         upper limit
    2.007
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1708
    Notes
    [48] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change from baseline to Week 24 between Cohorts 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.063
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.273
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.124
         upper limit
    4.671
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1979
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in relative change from baseline to Week 24 between Cohort 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [49]
    P-value
    = 0.46
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.916
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.548
         upper limit
    3.379
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2307
    Notes
    [49] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 1: Change in bone mineral density (BMD) (FAS)

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    End point title
    Period 1: Change in bone mineral density (BMD) (FAS)
    End point description
    95% CIs for LSM changes from baseline (coupled with SE and degrees of freedom) at Week 24 in BMD were calculated within a MMRM with random subject effect, class variables: cohort, gender, and GHD onset type (Childhood or Adult), and continuous covariates: baseline IGF-1 SDS, age at screening (in years). An unstructured covariance structure was assumed.
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 FAS
    Number of subjects analysed
    15
    14
    14
    12
    14
    0 [50]
    Units: kg
    least squares mean (standard error)
        Week 12
    -0.003 ± 0.006
    0.004 ± 0.0058
    -0.006 ± 0.006
    0.013 ± 0.0063
    -0.006 ± 0.0058
    ±
        Week 24
    0 ± 0.0053
    -0.005 ± 0.005
    -0.002 ± 0.0052
    0.002 ± 0.0057
    -0.01 ± 0.0051
    ±
    Notes
    [50] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in BMD change from baseline to Week 24 between Cohorts 1 and Cohort 5
    Comparison groups
    Cohort 1 v Cohort 5
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    other [51]
    P-value
    = 0.187
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.024
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0073
    Notes
    [51] - Comparison of LSMs across treatment groups (Cohort 1 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in BMD change from baseline to Week 24 between Cohorts 2 and Cohort 5
    Comparison groups
    Cohort 2 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [52]
    P-value
    = 0.521
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.019
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0071
    Notes
    [52] - Comparison of LSMs across treatment groups (Cohort 2 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in BMD change from baseline to Week 24 between Cohort 3 and Cohort 5
    Comparison groups
    Cohort 3 v Cohort 5
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other [53]
    P-value
    = 0.275
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.023
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0073
    Notes
    [53] - Comparison of LSMs across treatment groups (Cohort 3 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 24
    Statistical analysis description
    Difference in BMD change from baseline to Week 24 between Cohorts 4 and Cohort 5
    Comparison groups
    Cohort 4 v Cohort 5
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    other [54]
    P-value
    = 0.152
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0077
    Notes
    [54] - Comparison of LSMs across treatment groups (Cohort 4 vs. Cohort 5) using the same MMRM (with SEM, 95% CI and p value).

    Secondary: Period 2: Change in IGF-1 SDS from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in IGF-1 SDS from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [55]
    Units: SDS
        least squares mean (standard error)
    0.36 ± 0.301
    0.22 ± 0.301
    0.58 ± 0.286
    -0.09 ± 0.358
    -1.3 ± 0.33
    ±
    Notes
    [55] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 SDS change from Week 24 to 72 between Cohorts 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [56]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    2.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45
    Notes
    [56] - Comparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 SDS change from Week 24 to 72 between Cohorts 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [57]
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.446
    Notes
    [57] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 SDS change from Week 24 to 72 between Cohorts 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [58]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    2.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.421
    Notes
    [58] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGF-1 SDS change from Week 24 to 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [59]
    P-value
    = 0.022
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    2.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.511
    Notes
    [59] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Change in IGFBP3 SDS from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in IGFBP3 SDS from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [60]
    Units: SDS
        least squares mean (standard error)
    0.32 ± 0.23
    0.31 ± 0.236
    0.83 ± 0.22
    0.04 ± 0.272
    -0.44 ± 0.255
    ±
    Notes
    [60] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGFBP3 SDS change from Week 24 to 72 between Cohorts 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [61]
    P-value
    = 0.028
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.338
    Notes
    [61] - Comparison of LSMs across treatment groups (Cohort 1-4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGFBP3 SDS change from Week 24 to 72 between Cohort 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [62]
    P-value
    = 0.033
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    1.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.345
    Notes
    [62] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGFBP3 SDS change from Week 24 to 72 between Cohort 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [63]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.332
    Notes
    [63] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in IGFBP3 SDS change from Week 24 to 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [64]
    P-value
    = 0.215
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    1.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.384
    Notes
    [64] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Change in lean body mass (LBM) from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in lean body mass (LBM) from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [65]
    Units: kg
        least squares mean (standard error)
    0.26 ± 0.612
    0.18 ± 0.608
    0.92 ± 0.58
    0.75 ± 0.682
    0.31 ± 0.617
    ±
    Notes
    [65] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in LBM change from Week 24 to 72 between Cohort 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [66]
    P-value
    = 0.951
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.75
         upper limit
    1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.845
    Notes
    [66] - Comparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in LBM change from Week 24 to 72 between Cohorts 1-4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [67]
    P-value
    = 0.872
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.86
         upper limit
    1.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.856
    Notes
    [67] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in LBM change from Week 24 to 72 between Cohorts 1-4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [68]
    P-value
    = 0.465
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    2.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.829
    Notes
    [68] - Comparison of LSMs across treatment groups (Cohort 1-4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in LBM change from Week 24 to 72 between Cohort 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [69]
    P-value
    = 0.644
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.44
         upper limit
    2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.932
    Notes
    [69] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Change in body fat mass (FM) from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in body fat mass (FM) from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [70]
    Units: kg
        least squares mean (standard error)
    0.88 ± 0.863
    -1.32 ± 0.885
    -0.47 ± 0.815
    0.46 ± 0.986
    0.94 ± 0.901
    ±
    Notes
    [70] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in body FM change from Week 24 to 72 between Cohorts 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [71]
    P-value
    = 0.965
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.55
         upper limit
    2.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.246
    Notes
    [71] - Comparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in body FM change from Week 24 to 72 between Cohorts 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [72]
    P-value
    = 0.081
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.8
         upper limit
    0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.269
    Notes
    [72] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in body FM change from Week 24 to 72 between Cohort 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [73]
    P-value
    = 0.246
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.81
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.199
    Notes
    [73] - Comparison of LSMs across treatment groups (Cohort 1-4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in body FM change from Week 24 to 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [74]
    P-value
    = 0.728
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.17
         upper limit
    2.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.346
    Notes
    [74] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Relative change in body fat mass (FM) from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Relative change in body fat mass (FM) from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM % changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [75]
    Units: percent
        least squares mean (standard error)
    0.75 ± 0.9
    -1.54 ± 0.929
    -0.85 ± 0.883
    0.09 ± 1.043
    0.86 ± 0.959
    ±
    Notes
    [75] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in FM relative change from Week 24 to 72 between Cohort 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [76]
    P-value
    = 0.93
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.71
         upper limit
    2.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.292
    Notes
    [76] - Comparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in FM relative change from Week 24 to 72 between Cohorts 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [77]
    P-value
    = 0.078
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.09
         upper limit
    0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.337
    Notes
    [77] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in FM relative change from Week 24 to 72 between Cohort 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [78]
    P-value
    = 0.179
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.24
         upper limit
    0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.258
    Notes
    [78] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in FM relative change from Week 24 to 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [79]
    P-value
    = 0.592
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.62
         upper limit
    2.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.423
    Notes
    [79] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Change in trunk fat from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in trunk fat from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [80]
    Units: kg
        least squares mean (standard error)
    0.44 ± 0.486
    -0.61 ± 0.503
    -0.22 ± 0.462
    0.18 ± 0.56
    0.18 ± 0.508
    ±
    Notes
    [80] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in trunk fat change from Week 24 to 72 between Cohort 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [81]
    P-value
    = 0.71
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.14
         upper limit
    1.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.698
    Notes
    [81] - Comparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in trunk fat change from Week 24 to 72 between Cohort 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [82]
    P-value
    = 0.276
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.718
    Notes
    [82] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in trunk fat change from Week 24 to 72 between Cohorts 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [83]
    P-value
    = 0.554
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.77
         upper limit
    0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.681
    Notes
    [83] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in trunk fat change from Week 24 to 72 between Cohorts 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [84]
    P-value
    = 1
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.53
         upper limit
    1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.761
    Notes
    [84] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Relative change in trunk fat from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Relative change in trunk fat from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM % changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU FAS-SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    0 [85]
    Units: percent
        least squares mean (standard error)
    0.79 ± 1.086
    -1.75 ± 1.126
    -1.27 ± 1.047
    -0.05 ± 1.262
    0.02 ± 1.149
    ±
    Notes
    [85] - It is not reasonable to summarize results across cohorts (except for baseline, reported separately).
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in relative change in trunk fat from Week 24 to 72 between Cohort 1 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [86]
    P-value
    = 0.622
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.34
         upper limit
    3.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.548
    Notes
    [86] - Comparison of LSMs across treatment groComparison of LSMs across treatment groups (Cohort 1 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).ups (Cohort 1-4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in relative change in trunk fat from Week 24 to 72 between Cohorts 2 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other [87]
    P-value
    = 0.278
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.02
         upper limit
    1.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.616
    Notes
    [87] - Comparison of LSMs across treatment groups (Cohort 2 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in relative change in trunk fat from Week 24 to 72 between Cohort 3 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other [88]
    P-value
    = 0.401
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.33
         upper limit
    1.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.518
    Notes
    [88] - Comparison of LSMs across treatment groups (Cohort 3 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Statistical analysis description
    Difference in relative change in trunk fat from Week 24 to 72 between Cohort 4 SFU and Cohort 5 SFU
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other [89]
    P-value
    = 0.97
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    3.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71
    Notes
    [89] - Comparison of LSMs across treatment groups (Cohort 4 SFU vs Cohort 5 SFU) using the same ANCOVA model (with SEM, 95% CI and p-value).

    Secondary: Period 2: Change in bone mineral density (BMD) from Week 24 to 72 (FAS-SFU)

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    End point title
    Period 2: Change in bone mineral density (BMD) from Week 24 to 72 (FAS-SFU)
    End point description
    95% CIs for LSM changes from Week 24 (coupled with SE and degrees of freedom) at Week 72 were evaluated in an ANCOVA model with class variables: cohort, gender and GHD onset type (Childhood or Adult), and continuous covariates: change in HM10560A dose, week 24 result, age at screening (in years).
    End point type
    Secondary
    End point timeframe
    Weeks 24 to 72
    End point values
    Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU
    Number of subjects analysed
    13
    11
    13
    10
    9
    Units: g/cm2
        least squares mean (standard error)
    0 ± 0.01
    -0.01 ± 0.01
    0 ± 0.01
    0.01 ± 0.012
    0 ± 0.01
    Statistical analysis title
    Cohort 1 vs Cohort 5 at Week 72
    Comparison groups
    Cohort 1 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.802
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    Cohort 2 vs Cohort 5 at Week 72
    Comparison groups
    Cohort 2 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.354
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.04
         upper limit
    0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015
    Statistical analysis title
    Cohort 3 vs Cohort 5 at Week 72
    Comparison groups
    Cohort 3 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.898
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Statistical analysis title
    Cohort 4 vs Cohort 5 at Week 72
    Comparison groups
    Cohort 4 SFU v Cohort 5 SFU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.366
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected beginning after starting the study treatment and continued until 2 weeks after the subject received the last dose of the study treatment. SAEs, reporting started after the subject had provided IC until the same timeframe as AEs.
    Adverse event reporting additional description
    Reported AEs(SAEs) are Treatment-emergent adverse events(TEAEs). TEAEs are summarized by the following study periods: Single Dose Run-in and 24-week Dose Finding Periods (Periods 3 and 1) pooled, and for the 48+2 weeks Long-term Safety Period (Period 2).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    HM10560A 0.03 mg/kg EW

    Reporting group title
    Cohort 2
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 20 weeks

    Reporting group title
    Cohort 3
    Reporting group description
    HM10560A 0.03 mg/kg EW for 4 weeks then 0.06 mg/kg EW for 4 weeks then 0.10 mg/kg EW for 16 weeks

    Reporting group title
    Cohort 4
    Reporting group description
    HM10560A 0.04 mg/kg EOW for 4 weeks then 0.08 mg/kg EOW for 4 weeks then 0.12 mg/kg EOW for 16 weeks

    Reporting group title
    Cohort 5
    Reporting group description
    standard daily rhGH

    Reporting group title
    Cohort 1 SFU
    Reporting group description
    0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum insulin-like growth factor- 1 (IGF-1) as follows: IGF-1 < -0.5 SDS dose increased 50% IGF-1 between -0.5 and +1.5 SDS dose maintained IGF-1 > 1.5 SDS dose decreased 25% IGF-1 >2 SDS dose decreased 50%.

    Reporting group title
    Cohort 2 SFU
    Reporting group description
    0.06 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 3 SFU
    Reporting group description
    0.10 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 4 SFU
    Reporting group description
    0.12 mg/kg EOW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Reporting group title
    Cohort 5 SFU
    Reporting group description
    Switched from Genotropin to 0.03 mg/kg HM10560A EW initially then adjusted up to 6 times following monthly visits, according to subjects’ age and gender-adjusted serum IGF-1 (as detailed for cohort 1 SFU).

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric volvulus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 1 SFU Cohort 2 SFU Cohort 3 SFU Cohort 4 SFU Cohort 5 SFU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 15 (40.00%)
    11 / 14 (78.57%)
    8 / 14 (57.14%)
    4 / 12 (33.33%)
    8 / 14 (57.14%)
    4 / 13 (30.77%)
    12 / 14 (85.71%)
    8 / 14 (57.14%)
    4 / 11 (36.36%)
    5 / 14 (35.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour recurrent
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Injection site atrophy
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    2 / 12 (16.67%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    5 / 14 (35.71%)
    3 / 14 (21.43%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    2
    5
    0
    2
    8
    9
    1
    0
    Injection site erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    1
    0
    0
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Injection site induration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Injection site nodule
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    2 / 13 (15.38%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    3
    1
    4
    0
    9
    0
    2
    2
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    3 / 14 (21.43%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    3
    0
    3
    0
    1
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    1
    1
    1
    0
    0
    Psychiatric disorders
    Food aversion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Thyroxine free decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    1
    0
    0
    Thyroxine increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    2
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    2 / 14 (14.29%)
    0 / 11 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    2
    0
    3
    4
    0
    2
    3
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    2
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
    2 / 14 (14.29%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    3
    2
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Blister
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Diabetic dermopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Dry skin
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Dyshidrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    2
    0
    1
    2
    1
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    2 / 12 (16.67%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Osteoporosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Osteoarthritis