Clinical Trial Results:
A 26-week, Multinational, Multi-centre, Open-Labelled, Randomised, Parallel, Efficacy and Safety Comparison of Insulin Degludec and Insulin Detemir in children and adolescents 1 to less than 18 years with type 1 Diabetes Mellitus on a basal-bolus regimen with insulin aspart as bolus insulin followed by a 26-week extension investigating long term safety.
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Summary
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EudraCT number |
2011-003148-39 |
Trial protocol |
NL FI DE BG GB IT |
Global end of trial date |
30 Jul 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2016
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First version publication date |
28 Jul 2015
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Other versions |
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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 |
NN1250-3561
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01513473 | ||
WHO universal trial number (UTN) |
U1111-1122-4758 | ||
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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, clinicatrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicatrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000412-PIP01-08 EMEA-000479-PIP01-08 EMEA-000456-PIP01-08 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Jul 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Feb 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jul 2013
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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 confirm the efficacy of insulin degludec (IDeg) administered once daily plus mealtime insulin aspart in controlling glycaemia with respect to change from baseline in HBA1c after 26 weeks of treatment. This is done by comparing the difference in change in HbA1c between insulin degludec (IDeg) + insulin aspart (IAsp) and insulin detemir (IDet) + insulin aspart(IAsp) to a non-inferiority limit of 0.4%, and if non-inferiority is confirmed, to a superiority limit of 0%.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice.
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Background therapy |
Not Applicable | ||
Evidence for comparator |
Not Applicable | ||
Actual start date of recruitment |
16 Jan 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Netherlands: 16
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Country: Number of subjects enrolled |
United Kingdom: 15
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Country: Number of subjects enrolled |
Bulgaria: 30
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Country: Number of subjects enrolled |
Finland: 16
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 14
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Country: Number of subjects enrolled |
Italy: 15
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Country: Number of subjects enrolled |
Japan: 55
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Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 16
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Country: Number of subjects enrolled |
Russian Federation: 51
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Country: Number of subjects enrolled |
South Africa: 12
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Country: Number of subjects enrolled |
United States: 101
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Worldwide total number of subjects |
350
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EEA total number of subjects |
115
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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) |
4
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Children (2-11 years) |
219
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Adolescents (12-17 years) |
127
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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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 72 sites in 12 countries as follows: Bulgaria (2), Finland (5), France (4), Germany (3), Italy (2), Japan (15), Netherlands (5), Republic of Macedonia (2), Russian Federation (6), South Africa (2), United Kingdom (4), United States (22). | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Not Applicable | ||||||||||||||||||||||||
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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 |
This is an open-label, randomised trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Insulin Degludec (IDeg) + Insulin Aspart (IAsp) | ||||||||||||||||||||||||
Arm description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDeg OD as basal insulin treatment. IDeg was administered subcutaneously OD as basal insulin. IAsp was given as mealtime bolus insulin. 170 subjects completed the main trial,152 subjects included in the extension. 18 subjects did not consent to participate in the extension trial. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
IDeg
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Investigational medicinal product code |
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Other name |
Insulin Degludec
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The basal insulin was to be administered with NovoPen® Echo (blue for basal) and in Japan NovoPen® 300 Demi Lime and in the US NovoPen® Junior. In Finland and the UK only, NovoPen® 4 (blue/silver) was used for administration of higher basal insulin doses.IDeg was given once a day at approximately the same time of the day.
Basal insulin titration was done according to the lowest pre-breakfast SMPG value measured on the three days prior to the visit/ phone contact for IDeg.
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Investigational medicinal product name |
IAsp
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Investigational medicinal product code |
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Other name |
Insulin Aspart
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The bolus insulin was to be administered with NovoPen® Echo (red for bolus), in Japan NovoPen®°300 Demi Apricot and in the US NovoPen® Junior. It was given as mealtime insulin. IAsp titration was done once weekly based on the lowest of three SMPG values measured prior to
the next meal and bedtime on the three days prior to the visit/phone contact.
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Arm title
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Insulin Detemir (IDet) + Insulin Aspart (IAsp) | ||||||||||||||||||||||||
Arm description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDet OD or BID (twice daily) as basal insulin treatment and used IAsp as mealtime bolus insulin. 165 subjects completed the main trial, 128 included in the extension trial. 37 subjects did not consent to participate in the extension trial. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
IDet
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Investigational medicinal product code |
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Other name |
Insulin Detemir
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects randomised into the IDet treatment arm continued with their pre-trial dosing scheme (OD or BID). Subjects randomised into the IDet treatment arm were allowed to switch from OD to BID dosing according to Protocol.The basal insulin was to be administered with NovoPen® Echo (blue for basal) and in Japan NovoPen® 300 Demi Lime and in the US NovoPen® Junior. In Finland and the UK only, NovoPen® 4 (blue/silver) was used for administration of higher basal insulin doses.Basal insulin titration was done according to the lowest pre-breakfast SMPG value measured on the
three days prior to the visit/ phone contact for IDet OD. For IDet BID the morning dose adjustment was to be based on the lowest pre-dinner SMPG value measured on the three days prior to the visit/phone contact.
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Investigational medicinal product name |
IAsp
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Investigational medicinal product code |
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Other name |
Insulin Aspart
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The bolus insulin was to be administered with NovoPen® Echo (red for bolus), in Japan NovoPen®°300 Demi Apricot and in the US NovoPen® Junior. It was given as mealtime insulin.IAsp titration was done once weekly based on the lowest of three SMPG values measured prior to the next meal and bedtime on the three days prior to the visit/phone contact.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Insulin Degludec (IDeg) + Insulin Aspart (IAsp)
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Reporting group description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDeg OD as basal insulin treatment. IDeg was administered subcutaneously OD as basal insulin. IAsp was given as mealtime bolus insulin. 170 subjects completed the main trial,152 subjects included in the extension. 18 subjects did not consent to participate in the extension trial. | ||
Reporting group title |
Insulin Detemir (IDet) + Insulin Aspart (IAsp)
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Reporting group description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDet OD or BID (twice daily) as basal insulin treatment and used IAsp as mealtime bolus insulin. 165 subjects completed the main trial, 128 included in the extension trial. 37 subjects did not consent to participate in the extension trial. | ||
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End point title |
Change from baseline in HbA1c (%) | ||||||||||||
End point description |
Change from baseline in HbA1c (%) after 26 weeks of treatment .
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End point type |
Primary
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End point timeframe |
After 26 weeks of treatment
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Statistical analysis title |
Change from baseline in HbA1c | ||||||||||||
Comparison groups |
Insulin Degludec (IDeg) + Insulin Aspart (IAsp) v Insulin Detemir (IDet) + Insulin Aspart (IAsp)
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Number of subjects included in analysis |
350
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Treatment- Contrast | ||||||||||||
Point estimate |
0.15
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.03 | ||||||||||||
upper limit |
0.32 | ||||||||||||
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End point title |
Change from baseline in fasting plasma glucose (FPG) | ||||||||||||
End point description |
Change from baseline in FPG after 26 weeks of treatment.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of treatment emergent adverse events (TEAEs) | |||||||||
End point description |
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
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End point type |
Secondary
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End point timeframe |
After 26 weeks weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of hypoglycaemic episodes | |||||||||
End point description |
Episodes of severe hypoglycaemia or episodes with plasma glucose (PG) ≤3.9mmol/L (70mg/dL) with or without symptoms of hypoglycaemia)during the trial. The number of episodes described in the results section is the sum of the above classifications.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of nocturnal hypoglycaemic episodes | |||||||||
End point description |
Episodes of severe hypoglycaemia or episodes with plasma glucose (PG) ≤3.9mmol/L (70mg/dL) with or without symptoms of hypoglycaemia)during the trial. Nocturnal hypoglycaemia- Hypoglycaemic episodes from 11pm-7.00am noted in the subjects.The number of episodes described in the results section is the sum of the above classifications.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of self-measured hyperglycaemia | |||||||||
End point description |
Episodes of PG >11.1mmol/L (200mg/dL)
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of self measured blood ketones >1.5 mmol/L-capillary blood ketone measurement to be performed if self- measured plasma glucose (SMPG) exceeds 14.0 mmol/L (250 mg/dL) | |||||||||
End point description |
Blood ketones > 1.5mmol/L (Capillary blood ketone measurement to be performed if self measured plasma glucose (SMPG) exceeds 14.0mmol/L (250mg/dL) )after 26 weeks of treatment.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Steady state plasma concentrations of insulin degludec and insulin detemir | |||||||||||||||||||||
End point description |
Steady state plasma concentrations of insulin degludec and insulin detemir on three different visits (three different weeks) during the trial.
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End point type |
Secondary
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End point timeframe |
During the first 26 weeks of treatment
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Change from baseline in HbA1c (%) | ||||||||||||
End point description |
Change from baseline in HbA1c (%) after 52 weeks of treatments.
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline in fasting plasma glucose (FPG) | ||||||||||||
End point description |
Change from baseline in FPG after 52 weeks of treatment
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End point type |
Secondary
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End point timeframe |
At 52 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of treatment emergent adverse events (TEAEs) | |||||||||
End point description |
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of hypoglycaemic episodes | |||||||||
End point description |
Episodes of severe hypoglycaemia or episodes with plasma glucose (PG) ≤3.9mmol/L (70mg/dL) with or without symptoms of hypoglycaemia)during the trial. The number of episodes described in the results section is the sum of the above classifications.
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of nocturnal hypoglycaemic episodes | |||||||||
End point description |
Episodes of severe hypoglycaemia or episodes with plasma glucose (PG) ≤3.9mmol/L (70mg/dL) with or without symptoms of hypoglycaemia)during the trial. Nocturnal hypoglycaemia- Hypoglycaemic episodes from 11pm-7.00am noted in the subjects. The number of episodes described in the results section is the sum of the above classifications.
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of self measured blood ketones >1.5 mmol/L-capillary blood ketone measurement to be performed if self-measured plasma glucose (SMPG) exceeds 14.0 mmol/L (250 mg/dL) | |||||||||
End point description |
Blood ketones > 1.5mmo/L (Capillary blood ketone measurement to be performed if self measured plasma glucose (SMPG) exceeds 14.0mmol/L (250mg/dL) ) after 52 weeks of treatment.
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Insulin Aspart specific antibodies | ||||||||||||
End point description |
Antibody measurements : the values presented are week 26 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Insulin Aspart specific antibodies | ||||||||||||
End point description |
Antibody measurements : the values presented are week 52 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Insulin Detemir specific antibodies | ||||||||||||
End point description |
Antibody measurements : the values presented are week 26 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| Notes [1] - The analysis was done for the subjects taking insulin detemir only |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Insulin Detemir specific antibodies | ||||||||||||
End point description |
Antibody measurements : the values presented are week 52 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| Notes [2] - The antibody analysis was for subjects taking insulin detemir only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Insulin Degludec specific antibodies | ||||||||||||
End point description |
Antibody measurements : the values presented are of week 26 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| Notes [3] - The antibody analysis was for the subjects who took insulin degludec only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Insulin Degludec specific antibodies | ||||||||||||
End point description |
Antibody measurements :the presented values are week 52 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| Notes [4] - The antibody analysis was done for subjects taking insulin degludec only |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Cross -reacting insulin antibodies to human insulin | ||||||||||||
End point description |
Antibody measurements : the values presented are week 26 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Cross-reacting insulin antibodies to human insulin | ||||||||||||
End point description |
Antibody measurements : the values pressnted are week 52 (LOCF)
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of self-measured hyperglycaemia | |||||||||
End point description |
Episodes of PG >11.1mmol/L (200mg/dL)
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End point type |
Secondary
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End point timeframe |
After 52 weeks of treatment
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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 |
treatment emergent events (after first trial product administration and no later than 7 days after last trial product administration)
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16
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Reporting groups
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Reporting group title |
Insulin Detemir+Insulin Aspart
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Reporting group description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDet OD or BID (twice daily) as basal insulin treatment and used IAsp as mealtime bolus insulin. 165 subjects completed the main trial and 37 subjects did not consent to participate in the extension trial. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Insulin Degludec +Insulin Aspart
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Reporting group description |
Subjects from 1 to less than 18 years of age were randomised into treatment arms, receiving IDeg OD as basal insulin treatment. IDeg was administered subcutaneously OD as basal insulin. IAsp was given as mealtime bolus insulin. 170 subjects completed the main trial and 18 subjects did not consent to participate in the extension trial. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Nov 2011 |
The corrections to the text for the definition of confirmed hypoglycaemia and conversion of FPG from mmol/dL to mg/dL. In addition it is stated that Novo Nordisk will supply NPH insulin to Japan, Italy and the US. |
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06 Mar 2012 |
The revisions to the text to further describe and clarify the endpoints measured in the extension period of the trial. All subjects who completed 26 weeks of treatment (main period) were encouraged to continue in an extension of the trial under similar conditions, for an additional 6 months (extension period). Subjects were to continue the 6 month extension period according to the treatment allocation in the main period and all efficacy analyses based on the full 12 months period (two times 26 weeks of treatment) will be regarded as supportive. An informed consent covering the extension period must be obtained prior to any activities related to the extension period. An additional secondary endpoint, measurement of insulin antibodies (IDeg specific, IDet specific, IAsp specific and antibodies cross-reacting to human insulin) after 26 weeks and 52 weeks of treatment was added to fulfil the requirement of monitoring the long term immunogenicity. Substantial amendment 3 was not approved in South Africa due to administrative delay and therefore subjects in South Africa could not continue into the extension period of the trial. |
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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. | |||
| Not Applicable | |||
