Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe and North America. The aim of this trial is to compare the efficacy and safety of adding liraglutide versus addition of insulin aspart with the largest meal to insulin degludec in subjects with type 2 diabetes. Eligible subjects with an HbA1c equal to or above 7% at end of treatment in NN1250-3643 (NCT01193309) trial will be randomised to receive treatment intensification while subjects with an HbA1c below 7% at end of treatment in NN1250-3643 (NCT01193309) may continue to receive insulin degludec treatment. Subjects are to continue their pre-trial metformin treatment.
Interventions
DRUGinsulin degludec
Injected s.c. (under the skin) once daily. The doses will be individually adjusted
DRUGinsulin aspart
Injected s.c. (under the skin) once daily. The doses will be individually adjusted.
DRUGliraglutide
Injected s.c. (under the skin) once daily. The doses will be individually adjusted.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject). * The subject must have completed the end of treatment visit of NN1250-3643 with Insulin degludec once daily + metformin. * Ability and willingness to adhere to the protocol including self measurement of plasma glucose according to the protocol
Exclusion criteria
* Participated in NN1250-3643 and treated with insulin glargine * Previous treatment with glucacon like peptide (GLP-1) receptor agonists (e.g. exenatide, liraglutide) * Impaired liver function, defined as alanine aminotransferase (ALAT) 2.5 times the upper limit of normal at end of treatment in NN1250-3643 * Impaired renal function defined as serum-creatinine = 125 µmol/l (= 1.4 mg/dl) for males and = 110 µmol/L (= 1.3 mg/dl) for females or according to local label for metformin \[For France: glomerular filtration rate below 60 ml/min, calculated by the Cockroft & Gault formula\] at end of treatment in NN1250-3643.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin) | week 0, week 26 | Values for change in HbA1c from baseline to 26 weeks of treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) | week 0, week 26 | Values for change in FPG in mmol/L from baseline to week 26 of randomised period. |
| Change From Baseline in Body Weight | week 0, week 26 | Corresponds to the values of change in body weight in kilograms from baseline to week 26. |
| Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Onset on or after the first day of exposure to investigational product for 26 weeks of treatment period and no later than 7 days after last exposure to investigational product. | Corresponds to number of treatment emergent hypoglycaemic events from onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product. Confirmed hypoglycaemia was defined as the pool of severe hypoglycaemic episodes and minor episodes with a plasma glucose (PG) value \< 3.1 mmol/L (56 mg/dL). |
Countries
Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Norway, Serbia, Spain, United States
Participant flow
Recruitment details
The trial was conducted at 119 sites in 12 countries: Austria (4), Belgium (4), Canada (15), Czech Republic (4), Denmark (6), Finland (6), France (4), Germany (12), Norway (6), Serbia (5), Spain (7) and United States (46). These sites enrolled subjects in the randomised or non-randomised arms of the trial.
Pre-assignment details
Subjects treated with Insulin degludec (IDeg) once daily (OD) + metformin in trial NN1250-3643 (NCT01193309) were eligible for this trial. Eligible subjects with an HbA1c \>/=7.0% at the end of 3643 trial were qualified to enter the extension trial 3948 and be randomised to add either liraglutide/insulin aspart to their prior IDeg + Met treatment.
Participants by arm
| Arm | Count |
|---|---|
| IDeg This non-randomised arm consisted of subjects treated with IDeg + metformin who achieved the target glycosylated haemoglobin (HbA1c) \< 7.0 % at the end of treatment in NN1250-3643. Subjects were treated with once-daily subcutaneous administration of IDeg 100 U/mL prefilled pen along with stable and pre-trial dose of oral antidiabetic drug metformin for 26-weeks. These subjects continued on IDeg + metformin to assess the treatment regimen's ability to sustain long term glycaemic control. No comparisons of endpoints were made between the non-randomised and randomised treatment arms. | 236 |
| IDeg + Liraglutide All subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in a prefilled pen along with once-daily subcutaneous administration of liraglutide (6 mg/mL) in a prefilled pen for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period. | 88 |
| IDeg + IAsp OD Subjects in this arm were randomised to once-daily subcutaneous administration of IDeg 100 U/mL in prefilled pen along with once-daily subcutaneous administration of insulin aspart (IAsp)100 U/mL in a FlexPen® administered just before the largest meal for 26 weeks of treatment. Subjects continued their oral antidiabetic drug metformin at a stable, pre-trial dose throughout the trial period. | 89 |
| Total | 413 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 5 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 2 |
| Overall Study | Unclassified | 0 | 0 | 1 |
| Overall Study | Withdrawal criteria | 12 | 7 | 10 |
Baseline characteristics
| Characteristic | IDeg | IDeg + Liraglutide | IDeg + IAsp OD | Total |
|---|---|---|---|---|
| Age, Continuous | NA years | 61.1 years STANDARD_DEVIATION 9.5 | 60.9 years STANDARD_DEVIATION 8.8 | 61.0 years STANDARD_DEVIATION 9.2 |
| Fasting plasma glucose (FPG) | NA mmol/L | 6.4 mmol/L STANDARD_DEVIATION 2.4 | 6.1 mmol/L STANDARD_DEVIATION 1.7 | 6.7 mmol/L STANDARD_DEVIATION 1.8 |
| Glycosylated haemoglobin (HbA1c) | NA percentage of glycosylated haemoglobin | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 90 Participants | NA Participants | NA Participants | NA Participants |
| Sex: Female, Male Male | NA Participants | 63 Participants | 53 Participants | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 64 / 236 | 40 / 87 | 18 / 86 |
| serious Total, serious adverse events | 11 / 236 | 4 / 87 | 5 / 86 |
Outcome results
Primary
Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin)
Values for change in HbA1c from baseline to 26 weeks of treatment period.
Time frame: week 0, week 26
Population: The FAS and NAS included all randomised and non-randomised subjects respectively, and missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin) | 0.10 percentage of glycosylated haemoglobin | Standard Deviation 0.4 |
| IDeg + Liraglutide | Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin) | -0.74 percentage of glycosylated haemoglobin | Standard Deviation 0.73 |
| IDeg + IAsp OD | Change From Baseline in HbA1c (%) (Glycosylated Haemoglobin) | -0.39 percentage of glycosylated haemoglobin | Standard Deviation 0.72 |
Secondary
Change From Baseline in Body Weight
Corresponds to the values of change in body weight in kilograms from baseline to week 26.
Time frame: week 0, week 26
Population: Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period and missing data was imputed using LOCF. At baseline, the body weight values were missing for 1 subject in IDeg + Liraglutide arm from FAS and 3 subjects in NAS for IDeg arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Body Weight | 0.1 kg | Standard Deviation 2.7 |
| IDeg + Liraglutide | Change From Baseline in Body Weight | -1.0 kg | Standard Deviation 1.3 |
| IDeg + IAsp OD | Change From Baseline in Body Weight | 0.3 kg | Standard Deviation 0.9 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Values for change in FPG in mmol/L from baseline to week 26 of randomised period.
Time frame: week 0, week 26
Population: Both sets of FAS and NAS included all randomised and non-randomised subjects in the treatment period. The FPG values were missing for 7 subjects in FAS (2 subjects with IDeg+ liraglutide; 5 subjects with IDeg+IAsp arm) and 10 subjects in NAS for IDeg arm at baseline. The missing data was imputed using LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Fasting Plasma Glucose (FPG) | -1.23 mmol/L | Standard Deviation 2.03 |
| IDeg + Liraglutide | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.14 mmol/L | Standard Deviation 2.52 |
| IDeg + IAsp OD | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.04 mmol/L | Standard Deviation 2.84 |
Secondary
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes
Corresponds to number of treatment emergent hypoglycaemic events from onset on or after the first day of exposure to investigational product and no later than 7 days after last exposure to investigational product. Confirmed hypoglycaemia was defined as the pool of severe hypoglycaemic episodes and minor episodes with a plasma glucose (PG) value \< 3.1 mmol/L (56 mg/dL).
Time frame: Onset on or after the first day of exposure to investigational product for 26 weeks of treatment period and no later than 7 days after last exposure to investigational product.
Population: The safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Confirmed(severe+minor) | 313 events |
| IDeg | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Severe | 1 events |
| IDeg + Liraglutide | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Confirmed(severe+minor) | 40 events |
| IDeg + Liraglutide | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Severe | 0 events |
| IDeg + IAsp OD | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Confirmed(severe+minor) | 330 events |
| IDeg + IAsp OD | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | Severe | 0 events |