Clinical Trial Results:
A trial investigating the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily plus insulin aspart (IAsp) for the remaining meals versus insulin detemir (IDet) once or twice daily plus meal time insulin aspart in children and adolescents with type 1 diabetes mellitus
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Summary
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EudraCT number |
2012-003566-41 |
Trial protocol |
CZ SI ES BE HR |
Global end of trial date |
07 Nov 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
16 Mar 2016
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First version publication date |
21 May 2015
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Other versions |
v1 |
Version creation reason |
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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 |
NN5401-3816
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01835431 | ||
WHO universal trial number (UTN) |
U1111-1133-0958 | ||
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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, Soeborg, 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) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000479-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 |
27 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Nov 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Nov 2014
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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/insulin aspart administered once daily plus meal-time insulin aspart for the remaining meals in controlling glycaemia with respect to change from baseline in HbA1c after 16 weeks of treatment. This is done by comparing the difference in change from baseline in HbA1c between insulin degludec/insulin aspart + meal-time insulin aspart for the remaining meals and insulin detemir + meal-time insulin aspart 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 (Ethical Principles for Medical Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, Fortaleza, Brazil. World Medical Association. 20 A.D) and International Conference on Harmonisation (ICH) Good Clinical Practice (ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice. J Postgrad Med 2001; 47(3):199-203) and 21 Code of Federal Regulations (CFR) 312.120.
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Background therapy |
Not Applicable | ||
Evidence for comparator |
Not Applicable | ||
Actual start date of recruitment |
17 Oct 2013
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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 |
Canada: 11
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Country: Number of subjects enrolled |
Israel: 34
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Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 20
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Country: Number of subjects enrolled |
Russian Federation: 46
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Country: Number of subjects enrolled |
Serbia: 27
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Country: Number of subjects enrolled |
South Africa: 12
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Country: Number of subjects enrolled |
United States: 114
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Country: Number of subjects enrolled |
Brazil: 7
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Country: Number of subjects enrolled |
Poland: 28
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Country: Number of subjects enrolled |
Slovenia: 4
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Country: Number of subjects enrolled |
Spain: 15
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Country: Number of subjects enrolled |
Croatia: 12
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Country: Number of subjects enrolled |
Belgium: 13
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Country: Number of subjects enrolled |
Czech Republic: 19
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Worldwide total number of subjects |
362
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EEA total number of subjects |
91
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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) |
1
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Children (2-11 years) |
203
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Adolescents (12-17 years) |
158
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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 63 sites in 14 countries as follows: Belgium: 3 sites; Brazil: 1 sites; Canada: 3 sites; Czech Republic 3 sites; Croatia: 2 sites; Israel: 6 sites; Macedonia: 2 sites; Poland: 3 sites; Russia: 5 sites; Serbia: 4 sites; Slovenia: 1 sites; South Africa: 2 sites; Spain: 5 sites; and United States: 23 sites. | ||||||||||||||||||||||||
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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 |
Open label 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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IDegAsp OD +IAsp | ||||||||||||||||||||||||
Arm description |
IDegAsp OD with a main meal + IAsp for the remaining meals | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
IDegAsp
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Investigational medicinal product code |
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Other name |
Insulin degludec/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 |
IDegAsp was to be administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen OD in connection with a main meal. The dosing time could be moved to a different main meal at any time during the trial.
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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 |
IAsp was to be administered subcutaneously according to local labelling as mealtime insulin.
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Arm title
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IDet+IAsp | ||||||||||||||||||||||||
Arm description |
IDet once or twice daily + meal‑time IAsp. | ||||||||||||||||||||||||
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 |
IDet was to be administered subcutaneously according to local labelling. Subjects randomised into the IDet treatment group continued with their pre-trial dosing scheme (OD or BID) and were allowed to switch from OD to BID dosing.
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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 |
IAsp was to be administered subcutaneously as mealtime insulin.
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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 |
IDegAsp OD +IAsp
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Reporting group description |
IDegAsp OD with a main meal + IAsp for the remaining meals | ||
Reporting group title |
IDet+IAsp
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Reporting group description |
IDet once or twice daily + meal‑time IAsp. | ||
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End point title |
Change from baseline in HbA1c (%-point) | ||||||||||||
End point description |
Percentage point change in glycosylated haemoglobin A1c (HbA1c) from baseline (week 0) to 16 Weeks.
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End point type |
Primary
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End point timeframe |
After 16 weeks of treatment
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Statistical analysis title |
Change from baseline in HbA1c (%-point) | ||||||||||||
Comparison groups |
IDegAsp OD +IAsp v IDet+IAsp
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Number of subjects included in analysis |
338
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.04
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.23 | ||||||||||||
upper limit |
0.15 | ||||||||||||
| Notes [1] - If non-inferiority was confirmed, superiority of IDegAsp over IDet was investigated for the FAS. Non-inferiority will be considered confirmed if the upper bound of the two-sided 95% confidence interval is below or equal to 0.4% corresponding to one-sided test at the 2.5% level. The subjects in this analysis is 350/362 from FAS who had baseline and atleast one post-baseline assessment. |
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End point title |
Change from baseline in fasting plasma glucose | ||||||||||||
End point description |
FPG was analysed on blood samples from fasting subjects which were analysed centrally.
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End point type |
Secondary
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End point timeframe |
After 16 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Incidence of Treatment Emergent Adverse Events (TEAEs) | |||||||||
End point description |
A Treatment Emergent Adverse Event (TEAE) was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
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End point type |
Secondary
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End point timeframe |
After 16 weeks of treatment.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Treatment emergent confirmed hypoglycaemic episodes | ||||||||||||
End point description |
Treatment emergent hypoglycaemic episodes (PG < 3.1 mmol/L (56 mg/dL) or severe hypoglycaemia).
Confirmed hypoglycaemic episodes were defined as episodes that were either:
1. Severe (i.e. the child is having altered mental status and cannot assist in their care, is semiconscious or unconscious or in coma with or without convulsions and may require parenteral therapy (glucagon or i.v. glucose), or
2. An episode biochemically confirmed by PG value of <3.1 mmol/L (56 mg/dL), with or without
symptoms consistent with hypoglycaemia.
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End point type |
Secondary
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End point timeframe |
After 16 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Treatment emergent nocturnal confirmed hypoglycaemic episodes | ||||||||||||
End point description |
The confirmed hypoglycaemic episodes occurring between 23:00 and 07:00 were considered for this endpoint.
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End point type |
Secondary
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End point timeframe |
After 16 weeks of treatment
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Hyperglycaemic episodes | |||||||||
End point description |
Number of hyperglycaemic episodes (PG > 14.0 mmol/L (250 mg/dL) where subject looks/feels ill.
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End point type |
Secondary
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End point timeframe |
After 16 weeks of treatment
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| No statistical analyses for this end point | ||||||||||
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End point title |
Hyperglycaemic episodes with ketosis | ||||||||||||
End point description |
Number of hyperglycaemic episodes (PG > 14.0 mmol/L (250 mg/dL) where subject looks/feels ill with ketosis (blood ketones > 1.5 mmol/L)
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End point type |
Secondary
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End point timeframe |
After 16 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 |
Onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
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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 |
17
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Reporting groups
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Reporting group title |
IDegAsp OD + IAsp
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Reporting group description |
IDegAsp OD with a main meal + IAsp for the remaining meals | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IDet +IAsp
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Reporting group description |
IDet once or twice daily + meal‑time IAsp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Apr 2013 |
The protocol was updated upon request from FDA; the use of Last observation carried forward (LOCF) in the statistical analyses was discarded in favour of mixed effect model repeat measurement (MMRM). Furthermore, the blood volume needed for blood sampling in the age group below 6 years was updated to a smaller volume due to a miscalculation. Furthermore, the text in the master subject information related to the use of Lantus® was updated. In addition, a few typing errors in Section 17 (Statistical considerations) were discovered and corrected. |
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22 Apr 2014 |
Error corrected regarding definition of the Full Analysis Set (FAS). |
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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 | |||
