Clinical Trial Results:
A multicentre, multinational, randomised, open-labelled, parallel-group, active-controlled trial to compare the safety of once-weekly dosing of somapacitan (NNC0195-0092) with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated adults with growth hormone deficiency
Summary
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EudraCT number |
2014-000290-39 |
Trial protocol |
SE DK GB |
Global end of trial date |
04 Jan 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jan 2017
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First version publication date |
19 Jan 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
nn8640-4043
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02382939 | ||
WHO universal trial number (UTN) |
U1111-1152-3664 | ||
Other trial identifiers |
Japanese trial registration number: JapicCTI-152850 | ||
Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, 2880
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Public contact |
Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Jun 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Jan 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Jan 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the clinical safety of once-weekly dosing of somapacitan during 26 weeks of treatment in Adults with growth hormone deficiency subjects previously treated with daily human growth hormone.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and ICH Good Clinical Practice (GCP) (May 1996), ISO 14155 and FDA 21 CFR 312.120.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
12 Feb 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Denmark: 22
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Country: Number of subjects enrolled |
France: 20
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
Japan: 17
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Country: Number of subjects enrolled |
Sweden: 8
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Worldwide total number of subjects |
92
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EEA total number of subjects |
75
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
73
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From 65 to 84 years |
19
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted at 26 sites in 6 countries. All 26 sites screened and randomised/ assigned patients to treatment. Denmark: 3 sites; France: 5 sites; Germany: 3 sites; Sweden: 3 sites; United Kingdom: 5 sites; Japan: 7 sites. | |||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects, who were diagnosed with adults with growth hormone deficiency ≥ 6 months (defined as 180 days) prior to screening and receiving treatment with human growth hormone at least 6 months (defined as 180 days) at screening, were enrolled. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Norditropin | |||||||||||||||||||||
Arm description |
Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg). | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Somatropin
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Investigational medicinal product code |
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Other name |
Norditropin FlexPro 10 mg
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
All subjects were trained in the use of the pen-injector and to inject themselves with trial drug under the supervision of the site staff. Norditropin® FlexPro® subjects injected themselves daily s.c. in the evening (standard treatment practice), except during observed trial administrations (where injections were
done in the morning (up to 12 PM noon) and at least 12 hours after injection the evening.
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Arm title
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Somapacitan | |||||||||||||||||||||
Arm description |
Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Somapacitan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
All subjects were trained in the use of the pen-injector and to inject themselves with trial drug under the supervision of the site staff. Somapacitan subjects injected themselves once-weekly s.c. in the morning (no later than 10 am to ensure consistency of PK/PD with previous trials). On site visit days this could be extended until 12 PM (noon).
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Baseline characteristics reporting groups
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Reporting group title |
Norditropin
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Reporting group description |
Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Somapacitan
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Reporting group description |
Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Norditropin
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Reporting group description |
Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg). | ||
Reporting group title |
Somapacitan
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Reporting group description |
Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg. |
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End point title |
Incidence of adverse events [1] | |||||||||
End point description |
An adverse event can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. Total number of adverse events are reported. Analysis was performed on safety analysis set (all randomised subjects that received at least one dose of randomised treatment).
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End point type |
Primary
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End point timeframe |
From baseline to the end of the treatment period (26 weeks)
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Notes [1] - 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: As this is a safety endpoint, no statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Incidence of injection site reactions [2] | |||||||||
End point description |
Number of total injection site reactions. Analysis was performed on safety analysis set.
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End point type |
Primary
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End point timeframe |
From baseline to the end of the treatment period (26 weeks)
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Notes [2] - 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: As this is a safety endpoint, no statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Occurrence of anti-NNC0195-0092 antibodies [3] | ||||||
End point description |
Number of subjects with anti-somapacitan (NNC0195-0092) antibodies. Analysis was performed on safety analysis set (subjects who received somapacitan only).
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End point type |
Secondary
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End point timeframe |
From baseline (randomisation) to end of treatment period (26 weeks)
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Notes [3] - 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: The endpoint was assessed in subjects who received only somapacitan. Hence, no results for Norditropin arm are reported. |
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No statistical analyses for this end point |
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End point title |
Change in Treatment Satisfaction Questionnaire for Medication (TSQM) scores (effectiveness, convenience, and global satisfaction scores) | |||||||||||||||||||||
End point description |
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. Items are rated on a 5- or 7- point scale according to subjects’ experience with the medication. Each domain score can vary from 0 to 100 with higher scores indicating higher effectiveness of treatment, more convenient use of medication and overall greater satisfaction with the treatment. Analysis was performed on full analysis set (all randomised subjects that received at least one dose of randomised treatment). Here, 'n' specifies the number of subjects with data available for specified category.
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End point type |
Secondary
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End point timeframe |
From baseline (randomisation) to end of treatment period (26 weeks)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Baseline to week 26
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Adverse event reporting additional description |
Subjects in the safety analysis set contributed to the evaluation of adverse events.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Norditropin
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Reporting group description |
Subjects received s.c. injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at Week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Somapacitan
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Reporting group description |
Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at Week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 Jan 2015 |
Two typing errors in the visit flow chart were corrected. No impact on subject safety or trial procedures: 1) The timing of visit 1 changed to ‘minimum 1 day prior to visit 2’. 2) Attend visit fasting: should read ‘No’ for visit 3 and ‘yes’ for visit 4. The master PI/informed consent was updated accordingly. |
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27 Jan 2015 |
Changes requested by the Voluntary Harmonisation Procedure were addressed: The guideline for the United Kingdom investigators concerning contraception requirements for study subjects to be identical to the one applicable for the Denmark investigators. |
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11 May 2015 |
Updates of procedures as well as clarifications of relevant sections in the protocol:
1) Local tolerability assessments: external review by a dermatologist was added to ensure that the clinical validity of photos supported the AE description.
2) Antibody analysis: process for follow up after last patient last visit of subjects with 2 consecutive positive antidrug antibody results.
3) French health authority: any immediate adverse effects on kidney function (eGFR creatinine ≤60 mL/min/1.73m2) to be reported as a critical laboratory alert.
4)Homeostasis model assessment calculation.
5) Process for tryptase sampling in case of severe hypersensitivity. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |