Clinical Trial Results:
A 26-week trial comparing efficacy and safety of insulin degludec/insulin aspart BID and insulin degludec OD plus insulin aspart in subjects with type 2 Diabetes Mellitus treated with basal insulin in need of treatment intensification with mealtime insulin.
Summary
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EudraCT number |
2012-002346-20 |
Trial protocol |
AT NO |
Global end of trial date |
09 Jan 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
14 Apr 2016
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First version publication date |
31 Jul 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 |
NN5401-3996
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01713530 | ||
WHO universal trial number (UTN) |
U1111-1130-7135 | ||
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 |
24 Jun 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jan 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jan 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 |
The objective of this trial was to confirm the efficacy of insulin degludec/insulin aspart (IDegAsp) twice daily (BID) in controlling glycaemia after 26 weeks of treatment.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996) and FDA 21 CFR 312.120.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
21 Feb 2013
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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 |
Algeria: 36
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Country: Number of subjects enrolled |
United States: 140
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Country: Number of subjects enrolled |
France: 42
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Country: Number of subjects enrolled |
Norway: 33
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Country: Number of subjects enrolled |
Austria: 23
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Worldwide total number of subjects |
274
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EEA total number of subjects |
98
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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) |
204
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From 65 to 84 years |
70
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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 48 sites in five countries as follows: Algeria (4), Austria (6), France (8), Norway (6), United States (24). In addition, 3 sites (in Austria and US) screened but did not randomise any subjects, and one site in Norway was approved by the institutional review board (IRB) but did not screen any subjects. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
For both treatment arms, diet and exercise counselling was continued as per the standard of care at the investigational site. During the screening and treatment period, it was not allowed to start any other antidiabetic treatment, change the pre-randomisation OAD (except for the SU/glinides which were to be discontinued at randomisation)or OAD dose | ||||||||||||||||||||||||
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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IDegAsp BID | ||||||||||||||||||||||||
Arm description |
IDegAsp is the soluble co-formulation of IDeg (70%) and IAsp (30%). IDegAsp was administered twice daily (BID). | ||||||||||||||||||||||||
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 in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IDegAsp 100 U/mL, 3 mL prefilled pen PDS290, for subcutaneous injection. IDegAsp was administered twice daily (BID); either with breakfast and dinner or with lunch and dinner. IDegAsp was injected subcutaneously in the abdomen, upper arm (deltoid area) or thigh. The injection area was to remain the same throughout the trial, but the site within the area was to be changed for each injection.
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Arm title
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IDeg once daily (OD) + IAsp | ||||||||||||||||||||||||
Arm description |
IDeg was administered once daily (OD) at any time of the day. IAsp was administered with the main meals 2−4 times daily in accordance with local labelling. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
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 in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IDeg 100 U/mL, 3 mL prefilled pen PDS290, for subcutaneous injection. IDeg was administered once daily (OD) subcutaneous injection in the thigh, the upper arm (deltoid area) or the abdominal wall and the chosen area of injection had to be the same throughout 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 in pre-filled pen
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IAsp; NovoRapid®/NovoLog®, 100 U/mL, 3 mL, FlexPen®, for subcutaneous injection. IAsp was administered with the main meals 2−4 times daily in accordance with local labelling. The IAsp was injected subcutaneously preferably into the abdominal wall in accordance with local labelling.
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Baseline characteristics reporting groups
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Reporting group title |
IDegAsp BID
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Reporting group description |
IDegAsp is the soluble co-formulation of IDeg (70%) and IAsp (30%). IDegAsp was administered twice daily (BID). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IDeg once daily (OD) + IAsp
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Reporting group description |
IDeg was administered once daily (OD) at any time of the day. IAsp was administered with the main meals 2−4 times daily in accordance with local labelling. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
IDegAsp BID
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Reporting group description |
IDegAsp is the soluble co-formulation of IDeg (70%) and IAsp (30%). IDegAsp was administered twice daily (BID). | ||
Reporting group title |
IDeg once daily (OD) + IAsp
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Reporting group description |
IDeg was administered once daily (OD) at any time of the day. IAsp was administered with the main meals 2−4 times daily in accordance with local labelling. |
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End point title |
Change from baseline in HbA1c (%) | ||||||||||||
End point description |
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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 |
HbA1c (%) after 26 weeks of treatment | ||||||||||||
Statistical analysis description |
Change from baseline in HbA1c after 26 weeks of treatment was analysed using an Analysis of Variance (ANOVA) method with treatment, anti-diabetic therapy at screening, sex and region as fixed factors, and age and baseline HbA1c as covariates.
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Comparison groups |
IDegAsp BID v IDeg once daily (OD) + IAsp
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Number of subjects included in analysis |
274
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.029 [2] | ||||||||||||
Method |
ANOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.18
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.04 | ||||||||||||
upper limit |
0.41 | ||||||||||||
Notes [1] - The test of mean treatment difference is greater than 0.4%. [2] - Non-inferiority was considered confirmed if the upper bound of the two-sided 95% confidence interval was below or equal to 0.4%. This was equivalent to using a one-sided test of size 2.5%. |
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End point title |
Change from baseline in fasting plasma glucose (FPG) | ||||||||||||
End point description |
Change from baseline in fasting plasma glucose (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 hypoglycaemic episodes according to Novo Nordisk definition of confirmed hypoglycaemic episodes. | |||||||||
End point description |
Novo Nordisk definition for confirmed hypoglycaemic episodes: severe hypoglycaemia and /or a measured plasma glucose (PG)< 3.1 mmol/L (56 mg/dL).
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End point type |
Secondary
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End point timeframe |
During 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 hypoglycaemic episodes according to the American Diabetes Association (ADA) definition | |||||||||||||||||||||||||||
End point description |
Categories of hypoglycaemic episode as per ADA definition:
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L (70 mg/dL).
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of hypoglycaemia are accompanied by a measured PG concentration ≤3.9 mmol/L (70 mg/dL).
Relative hypoglycaemia: An episode during which the person with diabetes mellitus reports any of the typical symptoms of hypoglycaemia, and interprets those as indicative of hypoglycaemia, but with a measured PG concentration >3.9 mmol/L (70 mg/dL).
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are not accompanied by a PG determination (but that was presumably caused by a PG concentration ≤3.9 mmol/L [70 mg/dL]).
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End point type |
Secondary
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End point timeframe |
During 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 nocturnal (00:01-05:59 am) confirmed hypoglycaemic episodes. | |||||||||
End point description |
Nocturnal period is defined as the period between 00:01 and 05:59 a.m. (both included) in which hypoglycaemia can occur.
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End point type |
Secondary
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End point timeframe |
During 26 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 (TEAE). | |||||||||
End point description |
A TEAE was 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 |
During 26 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 |
From the first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period (visit 29).
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Adverse event reporting additional description |
Safety analysis set included all the subjects receiving at least one dose of the investigational product.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0, 16.1
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Reporting groups
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Reporting group title |
IDeg OD + IAsp
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Reporting group description |
IDeg was to be administered OD at any time of the day. It was to be injected subcutaneously in the abdomen, upper arm (deltoid area) or thigh. IAsp was to be administered with the main meals 2−4 times daily in accordance with local labelling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IDegAsp PDS290
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Reporting group description |
IDegAsp was to be administered either with breakfast and dinner or with lunch and dinner. IDegAsp was to be injected subcutaneously in the abdomen, upper arm (deltoid area) or thigh. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Dec 2012 |
Due to unforeseen changes in the regulatory environment, India was removed as
a participating country and Quintiles Laboratory in Mumbai was removed from
Protocol Attachment I.
In order to reflect real life practice, it was clarified that 11 days from visit 1 to
visit 2 were allowed.
The timing of fundoscopy/fundus photography and that subjects were not to
discard unused trial products was clarified.
Due to a change in international trial manager, Protocol Attachment I was
updated.
Minor inconsistencies in Appendix A were corrected
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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 |