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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

11‐HM10560A‐201

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

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?

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

Independent data monitoring committee (IDMC) involvement?

Yes

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

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

Screening details

Number of subjects started

169 ^[1]

Number of subjects completed

Reason: Number of subjects

Adverse event, non-fatal: 1

Reason: Number of subjects

Consent withdrawn by subject: 2

Reason: Number of subjects

Screen failure: 97

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 title

24-week dose finding period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

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.

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.

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.

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.

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
Consent withdrawn by subject	1	-	-	1	-
Military actions	1	-	-	-	-

Period 2 title

Long-term safety: 48 weeks treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1 SFU

Arm description

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.

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.

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.

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.

Cohort 5 SFU

Arm description

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
Personal reasons	-	1	-	-	-
Consent withdrawn by subject	-	-	-	-	1
Own reasons	-	-	-	1	-
Lost to follow-up	-	1	-	-	-
Growth of an intracranial tumor during study	-	-	-	-	1

Period 3 title

Single dose PK/PD run-in period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

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.

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.

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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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 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

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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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

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

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

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

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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

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

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).

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

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

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

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)

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).

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

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

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

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).

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

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

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

End point title

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

End point description

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).

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

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).

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

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).

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

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).

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

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)

Top of page

End point title

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

End point description

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).

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

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).

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

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).

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

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).

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

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)

Top of page

End point title

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

End point description

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).

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

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).

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

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).

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

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

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).

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

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)

Top of page

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).

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

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).

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

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).

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

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).

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

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)

Top of page

End point title

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

End point description

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).

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

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).

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

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).

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

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).

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

Analysis specification

Pre-specified

Analysis type

other ^[84]

P-value

= 1

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

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)

Top of page

End point title

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

End point description

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).

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

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).

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

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).

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

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).

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

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)

Top of page

End point title

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

End point description

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

Cohort 1 vs Cohort 5 at Week 72

Comparison groups

Cohort 1 SFU v Cohort 5 SFU

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.802

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

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

Cohort 2 vs Cohort 5 at Week 72

Comparison groups

Cohort 2 SFU v Cohort 5 SFU

Number of subjects included in analysis

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

Cohort 3 vs Cohort 5 at Week 72

Comparison groups

Cohort 3 SFU v Cohort 5 SFU

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.898

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

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

Cohort 4 vs Cohort 5 at Week 72

Comparison groups

Cohort 4 SFU v Cohort 5 SFU

Number of subjects included in analysis

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

Top of page

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 name

MedDRA

Dictionary version

14.1

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

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

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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Endocrine disorders
Hypercorticoidism
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
Hyperthyroidism
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
Hypothyroidism
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%)	1 / 14 (7.14%)	0 / 11 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0	1	1	0	0
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%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	0	2	0	0	4
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
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
Pain in extremity
subjects affected / exposed	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 12 (8.33%)	1 / 14 (7.14%)	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	1	2	2	0	0	0	0
Tendonitis
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
Infections and infestations
Bacterial 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%)	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
Bronchitis
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
Gastroenteritis
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
Gastroenteritis viral
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
Influenza
subjects affected / exposed	1 / 15 (6.67%)	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	1	0	0	0	2	0	1	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 15 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 12 (8.33%)	2 / 14 (14.29%)	1 / 13 (7.69%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 11 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	2	0	1	1	1	2	1	0	1
Pharyngitis
subjects affected / exposed	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 12 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 11 (9.09%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	2	0
Respiratory tract infection
subjects affected / exposed	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 12 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	3	0	0	1	0	4	0	0	0
Rhinitis
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
Salpingo-oophoritis
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%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 11 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 12 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 11 (9.09%)	0 / 14 (0.00%)
occurrences all number	0	1	2	0	2	0	0	2	1	0
Viral upper respiratory tract infection
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
Viral 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%)	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
Sinusitis
subjects affected / exposed	0 / 15 (0.00%)	2 / 14 (14.29%)	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
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 all number	0	0	0	0	0	0	1	0	0	0
Metabolism and nutrition disorders
Hyperglycaemia
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

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Mar 2012

The protocol was revised to reflect the fact that the run-in period had been completed. The number and timing of blood samples for PK/PD analysis was revised Cohorts 1-4. The protocol was amended to address the change of the dose within 24-week-dose finding period after data obtained from single dose PK/PD run-in period. However, this change is addressed only to Cohorts 1-4. Pregnancy and breast-feeding were added to the exclusion criteria and it was clarified that fertile females had to use contraceptives for the duration of study and 20 days after the last dose of study medication. Cohort 5 SFU dose was revised from starting at 0.02-0.04 HM10560A to starting at 0.03 mg/kg EW. The protocol was amended to expand and clarify details of the Interim Analysis and the Final Analysis. Typographic, administrative and clarification changes were also made.

04 Jun 2013

Raised the upper age permitted for inclusion from 60 to 65 years. Changed methods for measurement of IGF-I and IGFBP3 with addition of IDS iSYS assay. Clarified that in case of severe or serious lipoatrophy a dermatologist should be consulted. Typographic and administrative changes were also made.

25 Mar 2014

Added a new interim analysis to be performed upon completion of Week 12 Visit of the 24-week-dose finding period.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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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)