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Clinical Trial Results:
RECOMBINANT HUMAN GROWTH HORMONE (RHGH) AND RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-1 (RHIGF-1) COMBINATION THERAPY IN CHILDREN WITH SHORT STATURE ASSOCIATED WITH IGF-1 DEFICIENCY: A SIX-YEAR, RANDOMIZED, MULTI-CENTER, OPEN LABEL, PARALLEL-GROUP, ACTIVE TREATMENT CONTROLLED, DOSE SELECTION TRIAL.

Summary
EudraCT number	2019-000843-29
Trial protocol	Outside EU/EEA
Global end of trial date	01 Mar 2012

Results information
Results version number	v1(current)
This version publication date	22 Sep 2019
First version publication date	22 Sep 2019
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

MS316

ISRCTN number

US NCT number

NCT00572156

WHO universal trial number (UTN)

Sponsor organisation name

Ipsen Pharma

Sponsor organisation address

65 Quai Georges Gorse, Boulogne Billancourt, France, 92100

Public contact

Medical Director, Ipsen Pharma, clinical.trials@ipsen.com

Scientific contact

Medical Director, Ipsen Pharma, clinical.trials@ipsen.com

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?

Yes

Analysis stage

Final

Date of interim/final analysis

01 Mar 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Mar 2012

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective was to assess the efficacy and safety of three combinations of recombinant human growth hormone (rhGH) and recombinant human insulin-like growth factor-1 (rhIGF-1) compared to that of rhGH alone in the treatment of short stature associated with IGF-1 deficiency.

Protection of trial subjects

The study was conducted in accordance with Good Clinical Practice, the ethical principles that have their origins in the Declaration of Helsinki, and applicable national and local regulatory requirements.

Background therapy

Evidence for comparator

Under standard United States (US) clinical practice, children in this study could expect to be prescribed long-term rhGH treatment following a diagnosis of idiopathic short stature. The use of a placebo group would be unethical where a viable treatment option exists; hence rhGH monotherapy (45 micrograms per kilogram [μg/kg] per day) was included as a comparator in this study.

Actual start date of recruitment

01 Jan 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 106

Worldwide total number of subjects

106

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

This was a Phase II, multicenter, randomized, open-label, parallel-group, active treatment controlled, dose selection study in prepubertal children, aged ≥5 years, with short stature associated with low IGF-1 and normal stimulated GH response. The study was conducted at 27 centers in the US from January 2008 to March 2012.

Screening details

Eligible subjects were randomized to one of four treatment groups, stratified by age ≤9 years and IGF-1 standard deviation score (SDS) ≤-2, in a 1:1:1:1 ratio. The planned treatment duration for each subject was six years, however, the study was prematurely terminated by the Sponsor after the last subject completed Year 3.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

45 μg/kg rhGH Alone

Arm description

Subjects received 45 μg/kg rhGH alone, administered once daily by injection. Treatment commenced on Day 1 (Visit 2) at 50% of the assigned dose. Full doses commenced on the day immediately following Day 15 (Visit 3).

Arm type

Active comparator

Investigational medicinal product name

rhGH

Investigational medicinal product code

Other name

Somatropin, Nutropin AQ®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received subcutaneous injections of rhGH once daily. Injections were to be administered shortly before or shortly after (20 minutes) breakfast into the upper thigh, upper arm, abdomen or buttock. Subjects were instructed to rotate the injection sites daily to minimize the potential for injection site reactions.

45 μg/kg rhGH + 50 μg/kg rhIGF-1

Arm description

Subjects received 45 μg/kg rhGH and 50 μg/kg rhIGF-1, administered once daily as separate injections. Treatment commenced on Day 1 (Visit 2) at 50% of the assigned dose. Full doses commenced on the day immediately following Day 15 (Visit 3).

Arm type

Experimental

Investigational medicinal product name

rhGH

Investigational medicinal product code

Other name

Somatropin, Nutropin AQ®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received subcutaneous injections of rhGH once daily. Injections were to be administered shortly before or shortly after (20 minutes) breakfast into the upper thigh, upper arm, abdomen or buttock. Subjects were instructed to inject each drug (rhGH and rhIGF-1) into opposite sides of the body, and the injection sites were rotated daily to minimize the potential for injection site reactions.

Investigational medicinal product name

rhIGF-1

Investigational medicinal product code

Other name

Mecasermin, Increlex®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received subcutaneous injections of rhIGF-1 once daily. Injections were to be administered shortly before or shortly after (20 minutes) breakfast into the upper thigh, upper arm, abdomen or buttock. Subjects were instructed to inject each drug (rhGH and rhIGF-1) into opposite sides of the body, and the injection sites were rotated daily to minimize the potential for injection site reactions.

45 μg/kg rhGH + 100 μg/kg rhIGF-1

Arm description

Subjects received 45 μg/kg rhGH and 100 μg/kg rhIGF-1, administered once daily as separate injections. Treatment commenced on Day 1 (Visit 2) at 50% of the assigned dose. Full doses commenced on the day immediately following Day 15 (Visit 3).

Arm type

Experimental

Investigational medicinal product name

rhGH

Investigational medicinal product code

Other name

Somatropin, Nutropin AQ®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received subcutaneous injections of rhGH once daily. Injections were to be administered shortly before or shortly after (20 minutes) breakfast into the upper thigh, upper arm, abdomen or buttock. Subjects were instructed to inject each drug (rhGH and rhIGF-1) into opposite sides of the body, and the injection sites were rotated daily to minimize the potential for injection site reactions.

Investigational medicinal product name

rhIGF-1

Investigational medicinal product code

Other name

Mecasermin, Increlex®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

45 μg/kg rhGH + 150 μg/kg rhIGF-1

Arm description

Subjects received 45 μg/kg rhGH and 150 μg/kg rhIGF-1, administered once daily as separate injections. Treatment commenced on Day 1 (Visit 2) at 50% of the assigned doses. Full doses commenced on the day immediately following Day 15 (Visit 3).

Arm type

Experimental

Investigational medicinal product name

rhGH

Investigational medicinal product code

Other name

Somatropin, Nutropin AQ®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received subcutaneous injections of rhGH once daily. Injections were to be administered shortly before or shortly after (20 minutes) breakfast into the upper thigh, upper arm, abdomen or buttock. Subjects were instructed to inject each drug (rhGH and rhIGF-1) into opposite sides of the body, and the injection sites were rotated daily to minimize the potential for injection site reactions.

Investigational medicinal product name

rhIGF-1

Investigational medicinal product code

Other name

Mecasermin, Increlex®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 1	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Started	26	27	27	26
Completed	0	1	0	1
Not completed	26	26	27	25
Adverse event, non-fatal	3	1	5	1
Subject/Parent Decision	1	6	4	3
Sponsor Decision	20	16	17	19
Lost to follow-up	1	1	1	-
Protocol deviation	1	2	-	2

Baseline characteristics

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Reporting group title

45 μg/kg rhGH Alone

Reporting group description

Reporting group title

45 μg/kg rhGH + 50 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 100 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 150 μg/kg rhIGF-1

Reporting group description

Reporting group values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1	Total
Number of subjects	26	27	27	26
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	9.2 ( 2.0 )	8.4 ( 2.0 )	9.0 ( 2.2 )	8.8 ( 2.3 )	-
Gender categorical
Units: Subjects
Female	5	5	7	4	21
Male	21	22	20	22	85
Race
Units: Subjects
Asian	2	4	1	1	8
Black	1	1	1	0	3
Hispanic	4	1	3	2	10
White	17	20	19	23	79
Hispanic/White	1	1	3	0	5
Hawaiian or Pacific Islander/ White	1	0	0	0	1

End points

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Reporting group title

45 μg/kg rhGH Alone

Reporting group description

Reporting group title

45 μg/kg rhGH + 50 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 100 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 150 μg/kg rhIGF-1

Reporting group description

Primary: Height Velocity During the First Year of Treatment

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End point title

Height Velocity During the First Year of Treatment

End point description

Height was measured standing, without shoes, as the average of three measurements (the subject being repositioned each time) by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer which was calibrated prior to measurement of each subject and a calibration log kept. Height was evaluated at each study visit from screening up to the end-of-year-one visit. First-year height velocity (growth in centimeters [cm]) is presented for the Modified Intent-To-Treat (MITT) population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. Missing end-of-year-one height measurements were imputed using the last observation carried forward (LOCF) method.

End point type

Primary

End point timeframe

Baseline (Day 1) and at Year 1 (Week 52).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: cm/year
arithmetic mean (standard deviation)	9.3 ( 1.7 )	10.1 ( 1.3 )	9.7 ( 2.5 )	11.2 ( 2.1 )

45 rhGH + 50 rhIGF-1 vs 45 rhGH Alone

Statistical analysis description

Comparison of 45 μg/kg rhGH + 50 μg/kg rhIGF-1 combination treatment versus 45 μg/kg rhGH monotherapy using an analysis of covariance (ANCOVA), with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH Alone v 45 μg/kg rhGH + 50 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.243 ^[1]

Method

ANCOVA

Parameter type

Least squares (LS) mean difference

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

1.91

Notes
[1] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s test.

45 rhGH + 100 rhIGF-1 vs 45 rhGH Alone

Statistical analysis description

Comparison of 45 μg/kg rhGH + 100 μg/kg rhIGF-1 combination treatment versus 45 μg/kg rhGH monotherapy using ANCOVA, with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH Alone v 45 μg/kg rhGH + 100 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.722 ^[2]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.5

Notes
[2] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s test.

45 rhGH + 150 rhIGF-1 vs 45 rhGH Alone

Statistical analysis description

Comparison of 45 μg/kg rhGH + 150 μg/kg rhIGF-1 combination treatment versus 45 μg/kg rhGH monotherapy using ANCOVA, with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH Alone v 45 μg/kg rhGH + 150 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[3]

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

3.01

Notes
[3] - The two-sided p-values for the comparisons are adjusted for multiple comparisons using Dunnett’s method.

45 rhGH + 100 rhIGF-1 vs 45 rhGH + 50 rhIGF-1

Statistical analysis description

Comparison of 45 μg/kg rhGH + 100 μg/kg rhIGF-1 versus 45 μg/kg rhGH + 50 μg/kg rhIGF-1 combination treatments using ANCOVA, with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH + 50 μg/kg rhIGF-1 v 45 μg/kg rhGH + 100 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.427

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-1.44

upper limit

0.61

45 rhGH + 150 rhIGF-1 vs 45 rhGH + 50 rhIGF-1

Statistical analysis description

Comparison of 45 μg/kg rhGH + 150 μg/kg rhIGF-1 versus 45 μg/kg rhGH + 50 μg/kg rhIGF-1 combination treatments using ANCOVA, with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH + 50 μg/kg rhIGF-1 v 45 μg/kg rhGH + 150 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

2.12

45 rhGH + 150 rhIGF-1 vs 45 rhGH + 100 rhIGF-1

Statistical analysis description

Comparison of 45 μg/kg rhGH + 150 μg/kg rhIGF-1 versus 45 μg/kg rhGH + 100 μg/kg rhIGF-1 combination treatments using ANCOVA, with Year 1 height velocity as the dependent variable and with randomization strata defined by baseline age and IGF-1 SDS as covariates.

Comparison groups

45 μg/kg rhGH + 100 μg/kg rhIGF-1 v 45 μg/kg rhGH + 150 μg/kg rhIGF-1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

2.54

Secondary: Height Velocity During the Second, Third and Fourth Year of Treatment

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End point title

Height Velocity During the Second, Third and Fourth Year of Treatment

End point description

Height was measured standing, without shoes, as the average of three measurements (the subject being repositioned each time) by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer which was calibrated prior to measurement of each subject and a calibration log kept. Height was evaluated at each study visit from screening up to end of study. Second, third and fourth-year height velocity (growth in cm) is presented for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. Missing end-of-year height measurements were imputed for Years 2, 3 and 4 only if a subject had at least one height value recorded in the specified year (imputation by LOCF method). n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 2, 3 and 4 (Weeks 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: cm/year
arithmetic mean (standard deviation)
Year 2 (n=24,25,22,24)	8.4 ( 1.3 )	9.1 ( 1.2 )	9.4 ( 1.6 )	10.1 ( 1.8 )
Year 3 (n=22,22,20,22)	8.0 ( 1.1 )	8.4 ( 1.0 )	8.9 ( 1.3 )	9.2 ( 1.5 )
Year 4 (n=17,16,15,16)	7.7 ( 0.9 )	8.1 ( 0.8 )	8.4 ( 1.2 )	8.3 ( 1.3 )

No statistical analyses for this end point

Secondary: Cumulative Change in Height SDS During the First, Second, Third and Fourth Year of Treatment

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End point title

Cumulative Change in Height SDS During the First, Second, Third and Fourth Year of Treatment

End point description

Height was measured standing, without shoes, as the average of three measurements (the subject being repositioned each time) by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer which was calibrated prior to measurement of each subject and a calibration log kept. Height was evaluated at each study visit from screening up to end of study. Height SDS was calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. Mean change from baseline in height SDS at Years 1, 2, 3 and 4 is presented for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. Missing end-of-year-one height SDS was imputed using last LOCF method; height SDS was imputed for Years 2, 3 and 4 only if a subject had at least one height value recorded in the specified year. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: SDS
arithmetic mean (standard deviation)
Year 1 (n=25,27,27,26)	0.7 ( 0.3 )	0.9 ( 0.2 )	0.8 ( 0.4 )	1.0 ( 0.4 )
Year 2 (n=24,25,22,24)	1.0 ( 0.4 )	1.4 ( 0.4 )	1.4 ( 0.5 )	1.6 ( 0.6 )
Year 3 (n=22,22,20,22)	1.3 ( 0.5 )	1.6 ( 0.4 )	1.8 ( 0.7 )	1.9 ( 0.6 )
Year 4 (n=17,16,15,16)	1.5 ( 0.5 )	1.8 ( 0.5 )	2.1 ( 0.8 )	2.0 ( 0.7 )

No statistical analyses for this end point

Secondary: Predicted Adult Height (PAH) at Years 1, 2, 3 and 4

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End point title

Predicted Adult Height (PAH) at Years 1, 2, 3 and 4

End point description

PAH was calculated by the Roche-Wainer-Thissen (RWT) method, as refined by Khamis and Guo and adjusted for growth after age 18 according to Roche and Davila, and was summarized for subjects completing the year in the context of baseline height SDS and mid-parental target height SDS. The mid-parental target height SDS was defined as: 0.4*(Mother’s height SDS + Father’s height SDS). RWT PAH SDS at baseline (Day 1) and at Years 1, 2, 3 and 4, as well as mid-parental target height SDS, are presented for the completer population, consisting of all subjects that remained in the study until a specific time point (ie, Year 1, Year 2, Year 3 and Year 4). n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: SDS
arithmetic mean (standard deviation)
Baseline (n=25,27,27,26)	-1.67 ( 0.51 )	-1.83 ( 0.58 )	-1.69 ( 0.59 )	-1.76 ( 0.73 )
Year 1 (n=24,25,22,25)	-1.12 ( 0.57 )	-1.22 ( 0.58 )	-0.99 ( 0.55 )	-1.01 ( 0.80 )
Year 2 (n=22,21,20,22)	-0.96 ( 0.56 )	-0.81 ( 0.55 )	-0.66 ( 0.56 )	-0.69 ( 0.91 )
Year 3 (n=21,19,19,20)	-0.78 ( 0.63 )	-0.65 ( 0.60 )	-0.42 ( 0.62 )	-0.64 ( 0.98 )
Year 4 (n=3,4,4,3)	-1.22 ( 0.59 )	-0.44 ( 0.81 )	0.49 ( 0.60 )	-0.07 ( 0.89 )
Mid-parental target height (n=25,27,27,26)	-0.51 ( 0.38 )	-0.64 ( 0.52 )	-0.53 ( 0.50 )	-0.47 ( 0.51 )

No statistical analyses for this end point

Secondary: Total Change from Baseline in Body Mass Index (BMI) SDS at Years 1, 2, 3, 4 and End of Study

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End point title

Total Change from Baseline in Body Mass Index (BMI) SDS at Years 1, 2, 3, 4 and End of Study

End point description

Weight in kilograms (kg) was recorded from a single observation of the subject in light clothing or dressing gown with shoes removed. BMI was calculated by weight divided by height squared and measured as kg per square meter (kg/m^2). Height and weight were evaluated at each study visit from screening up to the end of study. Mean change from baseline in BMI SDS at Years 1, 2, 3 and 4, and at end of study is presented for the completer population, consisting of all subjects that remained in the study until a specific time point (ie, Year 1, Year 2, Year 3 and Year 4). n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: SDS
arithmetic mean (standard deviation)
Change to Year 1 (n=24,25,22,25)	0.24 ( 0.43 )	0.31 ( 0.39 )	0.36 ( 0.41 )	0.54 ( 0.40 )
Change to Year 2 (n=22,21,20,22)	0.31 ( 0.49 )	0.57 ( 0.41 )	0.49 ( 0.44 )	0.59 ( 0.46 )
Change to Year 3 (n=21,19,19,20)	0.35 ( 0.58 )	0.62 ( 0.43 )	0.49 ( 0.59 )	0.71 ( 0.54 )
Change to Year 4 (n=3,5,5,4)	0.27 ( 0.52 )	0.64 ( 0.58 )	0.65 ( 0.90 )	1.20 ( 0.91 )
Change to End of Study (n=25,27,27,26)	0.34 ( 0.54 )	0.45 ( 0.45 )	0.42 ( 0.53 )	0.64 ( 0.60 )

No statistical analyses for this end point

Secondary: Skeletal Maturation (Bone Age) at Years 1, 2, 3 and 4

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End point title

Skeletal Maturation (Bone Age) at Years 1, 2, 3 and 4

End point description

Plain X-rays of the left hand and wrist exposed for bone age appraisal were sent to a central facility for standardized evaluation. Bone age was evaluated at screening and each end-of-year visit up to the end of study. Bone age is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the completer population, consisting of all subjects that remained in the study until a specific time point (ie, Year 1, Year 2, Year 3 and Year 4). n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: years
arithmetic mean (standard deviation)
Baseline (n=25,27,27,26)	7.6 ( 1.8 )	7.3 ( 1.9 )	7.2 ( 2.0 )	7.4 ( 2.0 )
Year 1 (n=24,25,22,25)	9.0 ( 1.9 )	8.5 ( 1.9 )	8.4 ( 2.2 )	8.5 ( 2.1 )
Year 2 (n= 22,21,20,22)	10.3 ( 2.0 )	9.6 ( 2.1 )	9.8 ( 2.4 )	9.9 ( 2.2 )
Year 3 (n=21,19,19,20)	11.4 ( 2.0 )	10.9 ( 2.2 )	11.4 ( 2.4 )	10.9 ( 2.2 )
Year 4 (n=3,4,5,3)	12.4 ( 1.0 )	10.9 ( 1.8 )	12.2 ( 3.0 )	12.5 ( 2.1 )

No statistical analyses for this end point

Secondary: Serum Concentration of GH at Years 1, 2, 3 and 4

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End point title

Serum Concentration of GH at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring GH were evaluated at each study visit from screening up to the end-of-year-four visit. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for GH is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (n=23,25,18,25)	1.1 ( 2.2 )	2.9 ( 8.1 )	2.4 ( 4.5 )	1.9 ( 2.3 )
Year 1 (Trough) (n=23,25,18,25)	1.7 ( 2.1 )	3.5 ( 12.9 )	2.1 ( 3.2 )	1.4 ( 2.1 )
Year 2 (Trough) (n=21,20,16,20)	4.0 ( 6.0 )	2.2 ( 4.2 )	2.7 ( 3.9 )	1.4 ( 1.2 )
Year 3 (Trough) (n=20,18,15,20)	2.8 ( 5.1 )	1.3 ( 1.6 )	1.5 ( 1.4 )	1.9 ( 3.5 )
Year 4 (Trough) (n=3,5,4,3)	1.2 ( 0.3 )	0.5 ( 0.4 )	3.0 ( 2.9 )	1.1 ( 0.6 )

No statistical analyses for this end point

Secondary: Serum Concentration of IGF-1 at Years 1, 2, 3 and 4

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End point title

Serum Concentration of IGF-1 at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring IGF-1 were evaluated at each study visit from screening up to the end of study. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for IGF-1 is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: ng/mL
arithmetic mean (standard deviation)
Baseline (n=24,25,22,25)	108.3 ( 39.8 )	87.1 ( 31.0 )	100.2 ( 41.4 )	96.7 ( 38.8 )
Year 1 (Trough) (n=24,25,22,25)	278.2 ( 95.5 )	326.9 ( 108.9 )	397.8 ( 185.4 )	296.0 ( 126.8 )
Year 2 (Trough) (n=22,21,20,22)	312.8 ( 97.2 )	427.2 ( 178.5 )	539.3 ( 195.9 )	466.4 ( 178.6 )
Year 3 (Trough) (n=21,19,19,20)	335.3 ( 110.0 )	404.9 ( 140.4 )	462.2 ( 156.4 )	441.3 ( 226.0 )
Year 4 (Trough) (n=3,5,5,3)	347.7 ( 130.7 )	363.6 ( 125.4 )	546.2 ( 265.8 )	607.7 ( 65.0 )

No statistical analyses for this end point

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) at Years 1, 2, 3 and 4

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End point title

Serum Concentration of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring IGFBP-1 were evaluated at baseline and various visits during the study. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for IGFBP-1 is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: ng/mL
arithmetic mean (standard deviation)
Baseline (n=24,24,21,24)	87.8 ( 54.5 )	102.5 ( 37.2 )	95.7 ( 50.0 )	122.4 ( 53.7 )
Year 1 (Trough) (n=24,24,21,24)	45.7 ( 38.0 )	63.8 ( 50.1 )	68.2 ( 61.6 )	88.8 ( 47.4 )
Year 2 (Trough) (n=22,21,19,20)	59.4 ( 45.6 )	58.2 ( 47.7 )	53.3 ( 35.3 )	71.7 ( 46.1 )
Year 3 (Trough) (n=21,19,18,19)	46.1 ( 35.2 )	60.4 ( 52.5 )	53.2 ( 34.8 )	84.7 ( 53.5 )
Year 4 (Trough) (n=3,5,5,3)	100.0 ( 60.4 )	46.8 ( 58.0 )	49.2 ( 20.7 )	49.0 ( 26.9 )

No statistical analyses for this end point

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) at Years 1, 2, 3 and 4

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End point title

Serum Concentration of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring IGFBP-3 were evaluated at each study visit from screening up to the end of study. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for IGFBP-3 is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: ng/mL
arithmetic mean (standard deviation)
Baseline (n=24,25,22,25)	2204.2 ( 387.3 )	2160.0 ( 421.3 )	2113.6 ( 486.3 )	2196.0 ( 612.0 )
Year 1 (Trough) (n=24,25,22,25)	2954.2 ( 618.5 )	2784.0 ( 755.9 )	2677.3 ( 548.5 )	2624.0 ( 598.8 )
Year 2 (Trough) (n=22,21,20,22)	2813.6 ( 399.2 )	2942.9 ( 552.8 )	3060.0 ( 703.7 )	2754.5 ( 600.6 )
Year 3 (Trough) (n=21,19,19,20)	3404.8 ( 476.9 )	3431.6 ( 718.1 )	3373.7 ( 479.4 )	3260.0 ( 908.1 )
Year 4 (Trough) (n=3,5,5,3)	3733.3 ( 378.6 )	3260.0 ( 709.2 )	3620.0 ( 957.6 )	3466.7 ( 461.9 )

No statistical analyses for this end point

Secondary: Serum Concentration of Acid-Labile Subunit (ALS) at Years 1, 2, 3 and 4

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End point title

Serum Concentration of Acid-Labile Subunit (ALS) at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring ALS were evaluated at baseline and various visits during the study. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for ALS is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: milligrams per liter
arithmetic mean (standard deviation)
Baseline (n=25,26,26,25)	10.6 ( 3.0 )	10.0 ( 3.4 )	10.9 ( 3.0 )	11.0 ( 4.1 )
Year 1 (Trough) (n=24,24,21,24)	16.0 ( 4.0 )	12.7 ( 2.3 )	14.0 ( 3.9 )	11.5 ( 2.8 )
Year 2 (Trough) (n=22,21,19,20)	15.2 ( 4.3 )	14.3 ( 5.2 )	15.7 ( 4.0 )	13.7 ( 4.5 )
Year 3 (Trough) (n=21,18,18,19)	13.7 ( 2.3 )	13.0 ( 3.2 )	12.9 ( 2.7 )	11.2 ( 4.0 )
Year 4 (Trough) (n=3,5,5,3)	13.7 ( 1.5 )	12.0 ( 2.2 )	12.0 ( 3.0 )	13.7 ( 2.1 )

No statistical analyses for this end point

Secondary: Serum Concentration of Growth Hormone Binding Protein (GHBP) at Years 1, 2, 3 and 4

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End point title

Serum Concentration of Growth Hormone Binding Protein (GHBP) at Years 1, 2, 3 and 4

End point description

Growth factor panels for measuring GHBP were evaluated at baseline and various visits during the study. Samples were assayed at a central laboratory from a single blood sample collected during the appropriate visit. Serum concentration for GHBP is presented at baseline (Day 1) and at Years 1, 2, 3 and 4 for the MITT population, consisting of all subjects who were randomized and had at least one post-baseline height measurement. n = number of subjects with data available for analysis for each indicated timepoint.

End point type

Secondary

End point timeframe

Baseline (Day 1) and at Years 1, 2, 3 and 4 (Weeks 52, 104, 156 and 208, respectively).

End point values	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Number of subjects analysed	25	27	27	26
Units: picomoles per liter
arithmetic mean (standard deviation)
Baseline (n=25,26,25,25)	785.8 ( 291.1 )	735.8 ( 343.5 )	698.8 ( 212.2 )	719.0 ( 261.5 )
Year 1 (Trough) (n=23,24,20,24)	729.4 ( 229.5 )	576.9 ( 211.0 )	598.9 ( 187.3 )	530.5 ( 233.5 )
Year 2 (Trough) (n=22,21,18,21)	725.6 ( 308.4 )	589.3 ( 171.6 )	562.5 ( 184.4 )	564.6 ( 171.9 )
Year 3 (Trough) (n=21,17,17,19)	672.0 ( 224.4 )	646.9 ( 204.1 )	614.3 ( 210.9 )	554.9 ( 197.0 )
Year 4 (Trough) (n=3,5,5,3)	714.0 ( 38.5 )	516.9 ( 252.5 )	798.2 ( 336.1 )	519.7 ( 141.1 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment emergent adverse events were collected from randomization (Day 1) until 30 days after the subject was terminated from the study. Overall timeframe up to a maximum of approximately 4 years.

Adverse event reporting additional description

Safety population consisted of all subjects who were randomized.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

11.0

Reporting group title

45 μg/kg rhGH Alone

Reporting group description

Reporting group title

45 μg/kg rhGH + 50 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 100 μg/kg rhIGF-1

Reporting group description

Reporting group title

45 μg/kg rhGH + 150 μg/kg rhIGF-1

Reporting group description

Serious adverse events	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	2 / 27 (7.41%)	1 / 26 (3.85%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Injury, poisoning and procedural complications
Forearm fracture
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Intracranial pressure increased
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Evans syndrome
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Papilloedema
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Viral infection
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	45 μg/kg rhGH Alone	45 μg/kg rhGH + 50 μg/kg rhIGF-1	45 μg/kg rhGH + 100 μg/kg rhIGF-1	45 μg/kg rhGH + 150 μg/kg rhIGF-1
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 26 (100.00%)	27 / 27 (100.00%)	27 / 27 (100.00%)	26 / 26 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	2 / 27 (7.41%)	4 / 26 (15.38%)
occurrences all number	2	0	3	5
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 26 (34.62%)	15 / 27 (55.56%)	4 / 27 (14.81%)	13 / 26 (50.00%)
occurrences all number	17	27	22	19
Injection site pain
subjects affected / exposed	4 / 26 (15.38%)	1 / 27 (3.70%)	0 / 27 (0.00%)	4 / 26 (15.38%)
occurrences all number	4	2	0	6
Malaise
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	2 / 27 (7.41%)	4 / 26 (15.38%)
occurrences all number	1	0	2	4
Injection site bruising
subjects affected / exposed	4 / 26 (15.38%)	4 / 27 (14.81%)	4 / 27 (14.81%)	3 / 26 (11.54%)
occurrences all number	4	5	4	5
Injection site hypertrophy
subjects affected / exposed	0 / 26 (0.00%)	6 / 27 (22.22%)	7 / 27 (25.93%)	3 / 26 (11.54%)
occurrences all number	0	8	13	4
Injection site induration
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	2 / 27 (7.41%)	3 / 26 (11.54%)
occurrences all number	0	1	2	4
Influenza like illness
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	2	0	0	2
Injection site erythema
subjects affected / exposed	0 / 26 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	2	0	3
Injection site urticaria
subjects affected / exposed	2 / 26 (7.69%)	3 / 27 (11.11%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	3	3	2	5
Fatigue
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	0 / 27 (0.00%)	1 / 26 (3.85%)
occurrences all number	1	3	0	1
Feeling hot
subjects affected / exposed	0 / 26 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	0	2	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	1	1	0	2
Seasonal allergy
subjects affected / exposed	2 / 26 (7.69%)	3 / 27 (11.11%)	3 / 27 (11.11%)	0 / 26 (0.00%)
occurrences all number	2	4	3	0
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	2 / 27 (7.41%)	1 / 26 (3.85%)
occurrences all number	1	0	2	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 26 (23.08%)	14 / 27 (51.85%)	9 / 27 (33.33%)	10 / 26 (38.46%)
occurrences all number	7	18	16	14
Pharyngolaryngeal pain
subjects affected / exposed	3 / 26 (11.54%)	7 / 27 (25.93%)	7 / 27 (25.93%)	5 / 26 (19.23%)
occurrences all number	3	11	10	5
Nasal congestion
subjects affected / exposed	2 / 26 (7.69%)	2 / 27 (7.41%)	3 / 27 (11.11%)	3 / 26 (11.54%)
occurrences all number	2	2	6	3
Asthma
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	3 / 27 (11.11%)	2 / 26 (7.69%)
occurrences all number	0	1	4	2
Epistaxis
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	5	0	1	4
Rhinitis allergic
subjects affected / exposed	3 / 26 (11.54%)	2 / 27 (7.41%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	3	2	1	1
Rhinorrhoea
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	2 / 27 (7.41%)	1 / 26 (3.85%)
occurrences all number	0	1	2	1
Tonsillar hypertrophy
subjects affected / exposed	2 / 26 (7.69%)	2 / 27 (7.41%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	2	2	1	1
Adenoidal hypertrophy
subjects affected / exposed	2 / 26 (7.69%)	1 / 27 (3.70%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	1	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	1	0	1	2
Attention deficit/hyperactivity disorder
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	0	0	2	0
Attention
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	0	0	2	0
Investigations
Insulin-like growth factor increased
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	0	0	1	4
Body temperature increased
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	3 / 27 (11.11%)	1 / 26 (3.85%)
occurrences all number	1	4	3	1
Hepatic enzyme increased
subjects affected / exposed	1 / 26 (3.85%)	2 / 27 (7.41%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	2	0	0
Thyroxine free decreased
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	0	0	2	0
Weight decreased
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0	0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	1 / 27 (3.70%)	3 / 26 (11.54%)
occurrences all number	1	0	1	3
Arthropod sting
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	0	2
Contusion
subjects affected / exposed	2 / 26 (7.69%)	1 / 27 (3.70%)	0 / 27 (0.00%)	1 / 26 (3.85%)
occurrences all number	3	2	0	1
Skin laceration
subjects affected / exposed	2 / 26 (7.69%)	2 / 27 (7.41%)	0 / 27 (0.00%)	1 / 26 (3.85%)
occurrences all number	2	2	0	1
Upper limb fracture
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	2	0	1	1
Concussion
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0	0
Joint sprain
subjects affected / exposed	1 / 26 (3.85%)	2 / 27 (7.41%)	3 / 27 (11.11%)	0 / 26 (0.00%)
occurrences all number	1	2	4	0
Limb injury
subjects affected / exposed	0 / 26 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	0	2	0	0
Orthodontic appliance complication
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	0	0	2	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	0	0	1	2
Nervous system disorders
Headache
subjects affected / exposed	14 / 26 (53.85%)	14 / 27 (51.85%)	17 / 27 (62.96%)	18 / 26 (69.23%)
occurrences all number	40	43	39	50
Dizziness
subjects affected / exposed	1 / 26 (3.85%)	2 / 27 (7.41%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	1	4	0	3
Migraine
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	3 / 27 (11.11%)	1 / 26 (3.85%)
occurrences all number	2	3	3	7
Tremor
subjects affected / exposed	0 / 26 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	2	0	1
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	4 / 26 (15.38%)	1 / 27 (3.70%)	3 / 27 (11.11%)	1 / 26 (3.85%)
occurrences all number	7	1	3	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 26 (7.69%)	2 / 27 (7.41%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	2	2	1	2
Eye disorders
Eye pain
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	1	0	2
Myopia
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	1 / 26 (3.85%)
occurrences all number	0	0	2	1
Vision blurred
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	2	0	1	1
Conjunctivitis
subjects affected / exposed	2 / 26 (7.69%)	4 / 27 (14.81%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	4	0	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	9 / 26 (34.62%)	5 / 27 (18.52%)	6 / 27 (22.22%)	12 / 26 (46.15%)
occurrences all number	17	6	12	19
Abdominal pain upper
subjects affected / exposed	7 / 26 (26.92%)	5 / 27 (18.52%)	3 / 27 (11.11%)	7 / 26 (26.92%)
occurrences all number	11	8	7	11
Diarrhoea
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	2 / 27 (7.41%)	6 / 26 (23.08%)
occurrences all number	1	4	2	6
Nausea
subjects affected / exposed	4 / 26 (15.38%)	4 / 27 (14.81%)	4 / 27 (14.81%)	6 / 26 (23.08%)
occurrences all number	10	5	7	11
Abdominal pain
subjects affected / exposed	1 / 26 (3.85%)	4 / 27 (14.81%)	4 / 27 (14.81%)	2 / 26 (7.69%)
occurrences all number	1	4	6	2
Dyspepsia
subjects affected / exposed	0 / 26 (0.00%)	3 / 27 (11.11%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	3	0	4
Stomach discomfort
subjects affected / exposed	1 / 26 (3.85%)	2 / 27 (7.41%)	3 / 27 (11.11%)	2 / 26 (7.69%)
occurrences all number	1	2	4	2
Abdominal discomfort
subjects affected / exposed	2 / 26 (7.69%)	2 / 27 (7.41%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	2	0	0
Toothache
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis contact
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	1 / 27 (3.70%)	3 / 26 (11.54%)
occurrences all number	1	2	1	6
Skin hypertrophy
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)	3 / 26 (11.54%)
occurrences all number	0	2	0	3
Urticaria
subjects affected / exposed	2 / 26 (7.69%)	1 / 27 (3.70%)	3 / 27 (11.11%)	3 / 26 (11.54%)
occurrences all number	2	1	6	3
Eczema
subjects affected / exposed	1 / 26 (3.85%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	1	0	1	2
Keratosis pilaris
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	0	0	1	2
Alopecia
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	1 / 26 (3.85%)
occurrences all number	0	0	2	1
Hair texture abnormal
subjects affected / exposed	0 / 26 (0.00%)	1 / 27 (3.70%)	2 / 27 (7.41%)	1 / 26 (3.85%)
occurrences all number	0	1	2	1
Renal and urinary disorders
Enuresis
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	1	1	2	0
Pollakiuria
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	0 / 26 (0.00%)
occurrences all number	0	0	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 26 (26.92%)	4 / 27 (14.81%)	5 / 27 (18.52%)	6 / 26 (23.08%)
occurrences all number	8	7	5	12
Pain in extremity
subjects affected / exposed	4 / 26 (15.38%)	8 / 27 (29.63%)	7 / 27 (25.93%)	5 / 26 (19.23%)
occurrences all number	7	11	8	12
Back pain
subjects affected / exposed	3 / 26 (11.54%)	5 / 27 (18.52%)	1 / 27 (3.70%)	4 / 26 (15.38%)
occurrences all number	4	5	1	4
Musculoskeletal stiffness
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	0	2
Neck pain
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	2	0	1	2
Scoliosis
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)	2 / 26 (7.69%)
occurrences all number	0	0	2	2
Muscle spasms
subjects affected / exposed	0 / 26 (0.00%)	3 / 27 (11.11%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	0	4	2	1
Myalgia
subjects affected / exposed	1 / 26 (3.85%)	2 / 27 (7.41%)	1 / 27 (3.70%)	1 / 26 (3.85%)
occurrences all number	2	4	1	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	10 / 26 (38.46%)	10 / 27 (37.04%)	9 / 27 (33.33%)	13 / 26 (50.00%)
occurrences all number	23	19	31	37
Otitis media
subjects affected / exposed	4 / 26 (15.38%)	5 / 27 (18.52%)	3 / 27 (11.11%)	9 / 26 (34.62%)
occurrences all number	4	7	5	19
Viral infection
subjects affected / exposed	6 / 26 (23.08%)	3 / 27 (11.11%)	6 / 27 (22.22%)	8 / 26 (30.77%)
occurrences all number	10	6	6	21
Gastroenteritis
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	5 / 27 (18.52%)	6 / 26 (23.08%)
occurrences all number	2	3	9	10
Pharyngitis streptococcal
subjects affected / exposed	5 / 26 (19.23%)	12 / 27 (44.44%)	7 / 27 (25.93%)	6 / 26 (23.08%)
occurrences all number	13	17	9	14
Gastroenteritis viral
subjects affected / exposed	6 / 26 (23.08%)	3 / 27 (11.11%)	2 / 27 (7.41%)	4 / 26 (15.38%)
occurrences all number	7	9	4	4
Influenza
subjects affected / exposed	2 / 26 (7.69%)	3 / 27 (11.11%)	5 / 27 (18.52%)	4 / 26 (15.38%)
occurrences all number	2	4	6	4
Ear infection
subjects affected / exposed	3 / 26 (11.54%)	2 / 27 (7.41%)	4 / 27 (14.81%)	3 / 26 (11.54%)
occurrences all number	5	4	6	4
Otitis externa
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	0 / 27 (0.00%)	3 / 26 (11.54%)
occurrences all number	1	1	0	3
Molluscum contagiosum
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	0 / 27 (0.00%)	3 / 26 (11.54%)
occurrences all number	2	0	0	3
Bronchitis
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	2 / 27 (7.41%)	2 / 26 (7.69%)
occurrences all number	1	3	4	2
Nasopharyngitis
subjects affected / exposed	3 / 26 (11.54%)	4 / 27 (14.81%)	4 / 27 (14.81%)	2 / 26 (7.69%)
occurrences all number	4	5	15	3
Pharyngitis
subjects affected / exposed	0 / 26 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	3	0	2
Sinusitis
subjects affected / exposed	5 / 26 (19.23%)	7 / 27 (25.93%)	3 / 27 (11.11%)	2 / 26 (7.69%)
occurrences all number	25	14	5	2
Urinary tract infection
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)	2 / 26 (7.69%)
occurrences all number	0	0	3	2
Varicella
subjects affected / exposed	0 / 26 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	0	2
Tonsillitis
subjects affected / exposed	1 / 26 (3.85%)	1 / 27 (3.70%)	3 / 27 (11.11%)	0 / 26 (0.00%)
occurrences all number	1	1	3	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 26 (3.85%)	3 / 27 (11.11%)	0 / 27 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	3	0	0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	2 / 26 (7.69%)	0 / 27 (0.00%)	0 / 27 (0.00%)	7 / 26 (26.92%)
occurrences all number	3	0	0	8

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Were there any global substantial amendments to the protocol? Yes

25 Jul 2008

• The adiponectin test was deleted after failure to validate that assay; • The number of sites was increased to 30; • Language regarding the use of gonadotropin agonists (e.g., Lupron®) was clarified; • Safety lab follow up for subjects with sustained IGF-1 SDS +4 was added; • The possibility to use single injections of combination rhGH and rhIGF-1 during the first year was deleted; • Addition of serum chemistry panel at Visit 4; • Addition of gamma glutamyl transferase and creatine phosphokinase to the safety laboratory assessments, and additional growth factors as needed; • Additional language added to risk management and reduction section regarding intracranial hypertension symptoms.

11 Aug 2010

Amendment came into effect after all subjects had completed 1 year of treatment and following the availability of the first year height data contained in the interim report. • The study duration for individual subjects was extended from 3 to 6 years to provide safety and efficacy data on longer-term use of combination rhGH and rhIGF-1. Updates to the protocol were made to reflect the extension to a six-year study; • Minor changes were made to the wording of some of the study’s secondary objectives. • The primary efficacy endpoint of the study was clarified to only comprise the first year of the study and secondary efficacy endpoints for the subsequent years of the study were added; • A new table of study assessments was added to reflect the extension to a six-year study. Insulin testing was removed from all future visits and collection of month and year of first menarche was added; • The growth factor panel to be evaluated was modified to also include IGF-2 and insulin–like growth factor binding proteins other than IGFBP-1; • The composition of the Data Monitoring Committee was changed; • Text regarding resumption of study treatment after generalised allergic reaction, intracranial hypertension, hypoglycemia and subject monitoring was added to the Risk Management and reduction section; • Protocol sections describing study assessments for each visit were modified in that pubertal status was added and specification of growth factors was replaced by “growth factor panel”; • Two additional protocol sections describing the study assessments to be performed at Visits 15 to 23 were added; • Description of statistical method for assessment of total treatment effect for subjects with data beyond Year 1 and text regarding handling of missing data were added.

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.

The study was prematurely terminated once the last subject had completed 3 years of treatment (compared to the 6 years planned) for strategic reasons.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Height Velocity During the First Year of Treatment

Primary: Height Velocity During the First Year of Treatment

Secondary: Height Velocity During the Second, Third and Fourth Year of Treatment

Secondary: Height Velocity During the Second, Third and Fourth Year of Treatment

Secondary: Cumulative Change in Height SDS During the First, Second, Third and Fourth Year of Treatment

Secondary: Cumulative Change in Height SDS During the First, Second, Third and Fourth Year of Treatment

Secondary: Predicted Adult Height (PAH) at Years 1, 2, 3 and 4

Secondary: Predicted Adult Height (PAH) at Years 1, 2, 3 and 4

Secondary: Total Change from Baseline in Body Mass Index (BMI) SDS at Years 1, 2, 3, 4 and End of Study

Secondary: Total Change from Baseline in Body Mass Index (BMI) SDS at Years 1, 2, 3, 4 and End of Study

Secondary: Skeletal Maturation (Bone Age) at Years 1, 2, 3 and 4

Secondary: Skeletal Maturation (Bone Age) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of GH at Years 1, 2, 3 and 4

Secondary: Serum Concentration of GH at Years 1, 2, 3 and 4

Secondary: Serum Concentration of IGF-1 at Years 1, 2, 3 and 4

Secondary: Serum Concentration of IGF-1 at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Acid-Labile Subunit (ALS) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Acid-Labile Subunit (ALS) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Growth Hormone Binding Protein (GHBP) at Years 1, 2, 3 and 4

Secondary: Serum Concentration of Growth Hormone Binding Protein (GHBP) at Years 1, 2, 3 and 4

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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