Clinical Trial Results:
A 12-month, open-labelled, randomised, parallel-group, multi-centre, interventional trial to evaluate the efficacy and safety of recombinant human growth hormone (hGH) (Norditropin® Nordilet®) therapy on height velocity (Ht-V) in patients with idiopathic short stature in Korea.
|
Summary
|
|
EudraCT number |
2015-002613-30 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
18 Dec 2014
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
02 Jul 2017
|
First version publication date |
02 Jul 2017
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
GH-3899
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01778023 | ||
WHO universal trial number (UTN) |
U1111-1125-4790 | ||
|
Sponsors
|
|||
Sponsor organisation name |
Novo Nordisk A/S
|
||
Sponsor organisation address |
Novo Allé, Bagsværd, Denmark, 2880
|
||
Public contact |
Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
|
||
Scientific contact |
Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
05 Feb 2016
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
18 Dec 2014
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
18 Dec 2014
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To evaluate the efficacy of recombinant human growth hormone (hGH) (Norditropin® Nordilet®) therapy compared with untreated group assessed by height velocity after 6 months of treatment in patients with idiopathic short stature (ISS) in Korea.
|
||
Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996).
|
||
Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
18 Jan 2013
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Korea, Republic of: 51
|
||
Worldwide total number of subjects |
51
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
51
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
The trial was conducted at 10 sites in South Korea. | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
Not applicable | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
Overall Study (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Not blinded | |||||||||
Blinding implementation details |
Not applicable
|
|||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
Group A: 12-month Growth Hormone Treatment | |||||||||
Arm description |
For 12 months, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Somatropin
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
Norditropin® Nordilet®
|
|||||||||
Pharmaceutical forms |
Solution for injection in pre-filled pen
|
|||||||||
Routes of administration |
Subcutaneous use
|
|||||||||
Dosage and administration details |
Somatropin (recombinant deoxyribonucleic acid [rDNA] origin) 0.469 mg per kg of body weight was injected subcutaneously (s.c.; under the skin) in the evening in 7 days per week using the Norditropin® Nordilet® pen.
|
|||||||||
|
Arm title
|
Group B: 6-month Untreated + 6-month Growth Hormone Treatment | |||||||||
Arm description |
Subjects participated in the trial for 12 months. For the first six months of the trial period, subjects were untreated. For the last six months of the trial period, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Somatropin
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
Norditropin® Nordilet®
|
|||||||||
Pharmaceutical forms |
Solution for injection in pre-filled pen
|
|||||||||
Routes of administration |
Subcutaneous use
|
|||||||||
Dosage and administration details |
Somatropin (rDNA origin) 0.469 mg per kg of body weight was injected s.c. in the evening in 7 days per week using the Norditropin® Nordilet® pen.
|
|||||||||
|
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group A: 12-month Growth Hormone Treatment
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
For 12 months, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B: 6-month Untreated + 6-month Growth Hormone Treatment
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects participated in the trial for 12 months. For the first six months of the trial period, subjects were untreated. For the last six months of the trial period, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Group A: 12-month Growth Hormone Treatment
|
||
Reporting group description |
For 12 months, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | ||
Reporting group title |
Group B: 6-month Untreated + 6-month Growth Hormone Treatment
|
||
Reporting group description |
Subjects participated in the trial for 12 months. For the first six months of the trial period, subjects were untreated. For the last six months of the trial period, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | ||
|
|||||||||||||
End point title |
Height velocity (Ht-V) | ||||||||||||
End point description |
Height velocity (Ht-V) (cm/year) is the change in height per year (after 6 months of treatment). Three sort of Ht-V was calculated from height data at Visit 2 (day 0), Visit 4 (6 months ± 7 days) and Visit 6 (12 months ± 7 days ), as follows: Between Visits 2 and 4, between Visit 4 and 6 and between Visit 2 and 6. Ht-V was calculated by Novo Nordisk. The analysis was performed on the full analysis set (FAS), which included all randomised subjects in Group A, who received at least one dose of the trial product and all randomised subjects in Group B.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
After 6-month of treatment
|
||||||||||||
|
|||||||||||||
| Notes [1] - Out of 36 exposed subjects, 4 subjects had missing values for height at baseline visit. |
|||||||||||||
Statistical analysis title |
Group A: 12-month GH Treatment, Group | ||||||||||||
Statistical analysis description |
"D" represents a mean difference of the primary endpoint between group A and group B. Null hypothesis H0: D = 0 vs. alternative H1: D ≠ 0 will be statistically tested by an ANOVA model.
|
||||||||||||
Comparison groups |
Group A: 12-month Growth Hormone Treatment v Group B: 6-month Untreated + 6-month Growth Hormone Treatment
|
||||||||||||
Number of subjects included in analysis |
47
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Treatment-Contrast | ||||||||||||
Point estimate |
5.15
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
4.09 | ||||||||||||
upper limit |
6.21 | ||||||||||||
| Notes [2] - The Ht-V after 6 months of treatment was analysed using an analysis of variance (ANOVA) method with group and sex as fixed effects, and age as a covariate. |
|||||||||||||
|
|||||||||||||
End point title |
Change in Ht-SDS (Height Standard Deviation Score) | ||||||||||||
End point description |
HSDS were calculated using Korean growth data (reported by the Korea Centre for Disease Control and Prevention). The mean normal range for HSDS is from - 2 to +2. Negative scores below -2 indicate a height below normal range, whereas positive scores above +2 indicate a height above normal. The analysis was performed on the FAS, which included all randomised subjects in Group A, who received at least one dose of the trial product and all randomised subjects in Group B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the baseline to 6-month of treatment.
|
||||||||||||
|
|||||||||||||
| Notes [3] - Out of 36 exposed subjects, 4 subjects had missing values for height at baseline visit. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in IGF Related Factors: IGF-I (Insulin-like Growth Factor-I) | ||||||||||||
End point description |
IGF-I was measured at Visit 1 (screening), Visit 3 (3 months ± 7 days ), Visit 4 (6 months ± 7 days), Visit 5 (9 months ± 7 days ) and Visit 6 (12 months ± 7 days ). Change of IGF-I from baseline to 6-month of treatment was calculated. The analysis was performed on the FAS, which included all randomised subjects in Group A, who received at least one dose of the trial product and all randomised subjects in Group B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the baseline to 6-month of treatment.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in IGF Related Factors: IGFBP-3 (Insulin-like Growth Factor Binding Protein-3) | ||||||||||||
End point description |
IGFBP-3 was measured at visit 1(screening), visit 3 (3 months ± 7 days ), visit 4 (6 months ± 7 days), visit 5 (9 months ± 7 days ) and visit 6 ( 12 months ± 7 days). Change of IGFBP-3 from baseline to 6-month of treatment were calculated. The analysis was performed on the FAS, which included all randomised subjects in Group A, who received at least one dose of the trial product and all randomised subjects in Group B.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the baseline to 6-month of treatment.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
Ht-V (Height Velocity) [4] | ||||||||
End point description |
Height velocity (Ht-V) (cm/year) is the change in height per year (after 6 months of treatment). Three sort of Ht-V was calculated from height data at visit 2 (day 0), visit 4 (6 months ± 7 days) and visit 6 (12 months ± 7 days), as follows: Between visits 2 and 4, between visits 4 and 6 and between visit 2 and 6. Ht-V was calculated by Novo Nordisk. It is the difference between Ht-V for the last 6 months and Ht-V for the first 6 months of treatment in group A. The analysis was performed on the FAS, which included all randomised subjects in Group A, who received at least one dose of the trial product and all randomised subjects in Group B.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
At the first 6 months and the last 6 months in group A
|
||||||||
| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated only for the treatment arm, ‘Group A: 12-month Growth Hormone Treatment’ as per the trial protocol. |
|||||||||
|
|||||||||
| Notes [5] - Out of 36 exposed subjects, 4 subjects had missing values for height at baseline visit. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
||||||||||
End point title |
Occurrence of Adverse Events (AEs) | |||||||||
End point description |
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All AEs mentioned here are treatment emergent. For Group A, a treatment emergent adverse event (TEAE) was defined as an event that has onset date on or after the first day of exposure to GH treatment (day 0) and no later than the last day of randomised treatment (month 12). For Group B, a TEAE was defined as an event that has onset date on or after Visit 2 (day 0) and no later than the last visit date (Visit 6 [month 12] for completers and withdrawal date for withdrawals). The analysis was performed on the safety analysis set (SAS), which included all subjects in Group A receiving at least one dose of the trial product and all subjects in Group B who had any available data after visit 2 (day 0).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Throughout the trial (12 months).
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||
End point title |
Change in Bone Age | ||||||||||||||||||
End point description |
Plain X-rays of the left hand and wrist ex-posed for bone age appraisal were obtained at Visit 1 (screening), visit 4 (month 6) and 6 (month 12). For both group A and group B, change in bone age was evaluated from baseline to 6-month of treatment and from baseline to 12-month of treatment. The analysis was performed on the SAS, which included all subjects in Group A receiving at least one dose of the trial product and all subjects in Group B who had any available data after visit 2 (day 0).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From baseline to 6-month of treatment and 12-month of treatment, respectively.
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||
End point title |
Change in Bone Age; for Group B only [6] | ||||||||
End point description |
Plain X-rays of the left hand and wrist ex-posed for bone age appraisal were obtained at Visit 1 (screening), visit 4 (month 6) and 6 (month 12). For group B, change in bone age was evaluated from 6 months to 12 months (i.e., last 6-month of treatment period). The analysis was performed on the SAS, which included all subjects in Group A receiving at least one dose of the trial product and all subjects in Group B who had any available data after visit 2 (day 0).
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For group B: From 6 months to 12 months.
|
||||||||
| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated only for the treatment arm, ‘Group B: 6-month Untreated + 6-month Growth Hormone Treatment’ as per the trial protocol. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Throughout the trial (12 months).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety analysis set included all subjects in Group A receiving at least one dose of the trial product and all subjects in Group B who had any available data after visit 2 (day 0). All AEs mentioned here are treatment emergent, i.e., TEAEs.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group A: 12-month Growth Hormone Treatment
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
For 12 months, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B: 6-month Untreated + 6-month Growth Hormone Treatment
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects participated in the trial for 12 months. For the first six months of the trial period, subjects were untreated. For the last six months of the trial period, a weekly dosage of 0.469 mg of somatropin (hGH) per kg body weight was injected subcutaneously in the evening in seven (7) days per week using the Norditropin® Nordilet®. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Apr 2012 |
The change was the revision of height measurement method, statistical method (per protocol (PP) analysis to be conducted, 1st, 2nd exploratory purpose to be included in the secondary purpose.), In/Exclusion criteria (‘Bone age ≤ 12 years’ was added in the inclusion criteria and ‘Bone age is advanced over chronological age more than 3 years (inclusive)’ was added in the exclusion criteria). |
||
31 Oct 2012 |
The change was the revision of IGF-I/ IGFBP-3, addition of withdrawal criterion, sample size adjustment, exclusion criteria, change of dose regimen, change of screening period, paper CRF, data management, central laboratory assessment, monitoring procedures and trial sites. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
