Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe, and North and South America. The aim of this clinical trial is to investigate if the two treatments are equally effective.
Interventions
DRUGinsulin aspart
Insulin aspart added stepwise according to the largest meal following an evaluation of HbA1c. Doses individually adjusted.
DRUGinsulin detemir
Insulin detemir as basal insulin, adminstered once daily. Doses 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
* Type 2 diabetes (diagnosed clinically) for at least 12 months * Basal insulin treatment (NPH once or twice daily, insulin glargine once daily or insulin detemir once daily) for at least 6 months * HbA1c: 7.0-9.0 % (both inclusive) by central laboratory analysis (one retest analysed at the central laboratory within a week is permitted with the result of the last sample being conclusive) * BMI (Body Mass Index) less than 40.0 kg/m\^2
Exclusion criteria
* Previous use of pre-mix or bolus insulin (allowed is previous use of bolus insulin only in case of a hospitalisation or a severe condition requiring intermittent use of bolus insulin for less than 14 consecutive days, but not during the last 6 months prior to screening visit (Visit 1) * Use of GLP-1 (Glucagon-like peptide-1) receptor agonists or pramlintide within the last 6 months prior to prior to screening visit (Visit 1) * Anticipated change in concomitant medication known to interfere significantly with glucose metabolism (e.g. systemic corticosteroids, beta-blockers, MAO (Monoamine oxidase) inhibitors, etc.) * Cardiovascular disease, within the last 12 months prior to screening visit (Visit 1), defined as: stroke; decompensated heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty * Uncontrolled treated/untreated severe hypertension (systolic blood pressure sitting at least 180 millimetre (mm) mercury (Hg) and/or diastolic blood pressure at least 100 mmHg). For Argentina: systolic blood pressure sitting at least 150 mmHg and/or diastolic blood pressure at least 90 mmHg * Impaired liver function, defined as ALAT (Alanine aminotransferase) at least 2.5 times upper limit of normal (one retest analysed at the central laboratory within a week is permitted with the result of the last sample being conclusive) * Impaired renal function defined as serum creatinine above 135 micromol/L (above 1.5 mg/dL) for males and above 110 micromol/L (above 1.2 mg/dL) for females; and, if required by the locally applicable metformin label, glomerular filtration rate below 60 ml/min, calculated by the Cockroft & Gault formula). One retest within a week is permitted with the result of the last sample being conclusive * Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic episode, during the last 12 months) or hypoglycaemic unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months * Proliferative retinopathy or maculopathy requiring treatment according to the Investigator * Treatment with OADs (Oral anti-diabetic drug) contraindicated or unapproved for combination treatment with insulin (according to local OAD label)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32 | Week 0, Week 32 | Estimated mean change from baseline in HbA1c after 32 Weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21 | Week 0, Week 21 | Estimated mean change from baseline in HbA1c after 21 Weeks of treatment |
| Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10 | Week 10 | Proportion of subjects reaching HbA1c below 7.0% at Week 10 |
| Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21 | Week 21 | Proportion of subjects reaching HbA1c below 7.0% at Week 21 |
| Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32 | Week 32 | Proportion of subjects reaching HbA1c below 7.0% at Week 32 |
| Fasting Plasma Glucose (FPG) at Week 10 | Week 10 | Mean FPG at Week 10 |
| Fasting Plasma Glucose (FPG) at Week 21 | Week 21 | Mean FPG at Week 21 |
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10 | Week 0, Week 10 | Estimated mean change from baseline in HbA1c after 10 Weeks of treatment |
| Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10 | Week 10 | Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 10 |
| Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21 | Week 21 | Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 21 |
| Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32 | Week 32 | Estimated mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 32 |
| Body Weight at Week 32 | Week 32 | Estimated mean body weight after 32 Weeks of treatment |
| Body Mass Index (BMI) at Week 32 | Week 32 | Estimated mean BMI after 32 Weeks of treatment |
| Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes) | Week 0 to Week 32 | A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. |
| Fasting Plasma Glucose (FPG) at Week 32 | Week 32 | Estimated Mean FPG at Week 32 |
Countries
Argentina, Brazil, Canada, France, North Macedonia, Slovenia, United States
Participant flow
Recruitment details
The trial was conducted at 69 sites in 7 countries: Argentina (7), Brazil (5), Canada (12), France (7), Macedonia (1), Slovenia (4), and the US (31). Of 12 sites in Canada, one site (Site 303) closed early on 07-Mar-2011.
Pre-assignment details
Subjects on pre-trial metformin and pioglitazone continued their medication.
Participants by arm
| Arm | Count |
|---|---|
| Step-wise In addition to insulin detemir once daily, insulin aspart was added step-wise starting at the randomisation visit (Week 0) with the first bolus before the largest meal, followed by a second bolus at the second largest meal at Week 11 in subjects with HbA1c ≥ 7.0% at Week 10, and a second or third bolus at Week 22 in subjects with HbA1c ≥ 7.0% at Week 21. Subjects on pre-trial metformin and pioglitazone continued their medication. | 201 |
| Basal-bolus In addition to insulin detemir once daily, insulin aspart was added before each of the main meals (breakfast, lunch and dinner) starting at the randomisation visit. Subjects on pre-trial metformin and pioglitazone continued their medication. | 200 |
| Total | 401 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Protocol Violation | 7 | 15 |
| Overall Study | Unclassified | 16 | 22 |
| Overall Study | Withdrawal Criteria | 2 | 13 |
Baseline characteristics
| Characteristic | Step-wise | Basal-bolus | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 9.1 | 59.6 years STANDARD_DEVIATION 9.5 | 59.8 years STANDARD_DEVIATION 9.3 |
| Body Mass Index (BMI) | 31.5 kg/m^2 STANDARD_DEVIATION 4.8 | 30.7 kg/m^2 STANDARD_DEVIATION 4.6 | 31.1 kg/m^2 STANDARD_DEVIATION 4.7 |
| Body weight | 88.9 kg STANDARD_DEVIATION 18.7 | 86.1 kg STANDARD_DEVIATION 15.2 | 87.5 kg STANDARD_DEVIATION 17.1 |
| Fasting plasma glucose (FPG) | 7.0 mmol/L STANDARD_DEVIATION 1.9 | 6.9 mmol/L STANDARD_DEVIATION 1.6 | 6.9 mmol/L STANDARD_DEVIATION 1.8 |
| Gender Female | 97 Participants | 101 Participants | 198 Participants |
| Gender Male | 104 Participants | 99 Participants | 203 Participants |
| Glycosylated haemoglobin (HbA1c) | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 198 | 47 / 199 |
| serious Total, serious adverse events | 18 / 198 | 15 / 199 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32
Estimated mean change from baseline in HbA1c after 32 Weeks of treatment
Time frame: Week 0, Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32 | -0.98 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Basal-bolus | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 32 | -1.12 percentage of glycosylated haemoglobin | Standard Error 0.06 |
p-value: 0.08895% CI: [-0.02, 0.3]Regression, Linear
Secondary
Body Mass Index (BMI) at Week 32
Estimated mean BMI after 32 Weeks of treatment
Time frame: Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 378 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Body Mass Index (BMI) at Week 32 | 31.86 kg/m^2 | Standard Error 0.1 |
| Basal-bolus | Body Mass Index (BMI) at Week 32 | 32.03 kg/m^2 | Standard Error 0.1 |
p-value: 0.22495% CI: [-0.45, 0.11]Regression, Linear
Secondary
Body Weight at Week 32
Estimated mean body weight after 32 Weeks of treatment
Time frame: Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 378 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Body Weight at Week 32 | 89.32 kg | Standard Error 0.28 |
| Basal-bolus | Body Weight at Week 32 | 89.80 kg | Standard Error 0.28 |
p-value: 0.22895% CI: [-1.25, 0.3]Regression, Linear
Secondary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10
Estimated mean change from baseline in HbA1c after 10 Weeks of treatment
Time frame: Week 0, Week 10
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 376 subjects contributed to the statistical analysis at Week 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10 | -0.45 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Basal-bolus | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 10 | -1.00 percentage of glycosylated haemoglobin | Standard Error 0.05 |
p-value: <0.00195% CI: [0.42, 0.69]Regression, Linear
Secondary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21
Estimated mean change from baseline in HbA1c after 21 Weeks of treatment
Time frame: Week 0, Week 21
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 21.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21 | -0.78 percentage of glycosylated haemoglobin | Standard Error 0.06 |
| Basal-bolus | Change in Glycosylated Haemoglobin (HbA1c) From Baseline to Week 21 | -1.15 percentage of glycosylated haemoglobin | Standard Error 0.06 |
p-value: <0.00195% CI: [0.21, 0.53]Regression, Linear
Secondary
Fasting Plasma Glucose (FPG) at Week 10
Mean FPG at Week 10
Time frame: Week 10
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 368 subjects contributed to data at Week 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Fasting Plasma Glucose (FPG) at Week 10 | 7.1 mmol/L | Standard Deviation 1.9 |
| Basal-bolus | Fasting Plasma Glucose (FPG) at Week 10 | 6.7 mmol/L | Standard Deviation 1.9 |
Secondary
Fasting Plasma Glucose (FPG) at Week 21
Mean FPG at Week 21
Time frame: Week 21
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the data at Week 21.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Fasting Plasma Glucose (FPG) at Week 21 | 7.1 mmol/L | Standard Deviation 2.3 |
| Basal-bolus | Fasting Plasma Glucose (FPG) at Week 21 | 7.0 mmol/L | Standard Deviation 2.3 |
Secondary
Fasting Plasma Glucose (FPG) at Week 32
Estimated Mean FPG at Week 32
Time frame: Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Fasting Plasma Glucose (FPG) at Week 32 | 7.12 mmol/L | Standard Error 0.17 |
| Basal-bolus | Fasting Plasma Glucose (FPG) at Week 32 | 7.01 mmol/L | Standard Error 0.17 |
p-value: 0.63595% CI: [-0.37, 0.6]Regression, Linear
Secondary
Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes)
A hypoglycaemic episode was defined as treatment emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment.
Time frame: Week 0 to Week 32
Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator. 397 subjects contributed with data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step-wise | Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes) | 33.47 Episodes /year of patient exposure |
| Basal-bolus | Hypoglycaemic Episodes (Rate of All Treatment Emergent Hypoglycaemia Episodes) | 57.56 Episodes /year of patient exposure |
Secondary
Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10
Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 10
Time frame: Week 10
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 326 subjects contributed to the data at Week 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10 | 2.3 mmol/L | Standard Deviation 2.2 |
| Basal-bolus | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 10 | 1.4 mmol/L | Standard Deviation 2 |
Secondary
Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21
Mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 21
Time frame: Week 21
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 343 subjects contributed to the data at Week 21.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21 | 1.9 mmol/L | Standard Deviation 1.8 |
| Basal-bolus | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 21 | 1.5 mmol/L | Standard Deviation 1.8 |
Secondary
Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32
Estimated mean plasma glucose increment over 3 meals (breakfast, lunch and dinner) at Week 32
Time frame: Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 352 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Step-wise | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32 | 1.64 mmol/L | Standard Deviation 0.12 |
| Basal-bolus | Mean Plasma Glucose Increment Over 3 Meals (Breakfast, Lunch and Dinner) at Week 32 | 1.28 mmol/L | Standard Deviation 0.13 |
p-value: 0.04695% CI: [0.01, 0.71]Regression, Linear
Secondary
Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10
Proportion of subjects reaching HbA1c below 7.0% at Week 10
Time frame: Week 10
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 376 subjects contributed to the statistical analysis at Week 10.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step-wise | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10 | 19.2 percentage (%) of subjects |
| Basal-bolus | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 10 | 56.3 percentage (%) of subjects |
p-value: <0.00195% CI: [4.12, 11.39]Regression, Logistic
Secondary
Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21
Proportion of subjects reaching HbA1c below 7.0% at Week 21
Time frame: Week 21
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 21.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step-wise | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21 | 45.1 percentage (%) of subjects |
| Basal-bolus | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 21 | 65.4 percentage (%) of subjects |
p-value: <0.00195% CI: [1.56, 3.64]Regression, Logistic
Secondary
Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32
Proportion of subjects reaching HbA1c below 7.0% at Week 32
Time frame: Week 32
Population: Full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). 383 subjects contributed to the statistical analysis at Week 32.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Step-wise | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32 | 55.9 percentage (%) of subjects |
| Basal-bolus | Proportion of Subjects Reaching Glycosylated Haemoglobin (HbA1c) Below 7.0% at Week 32 | 63.3 percentage (%) of subjects |
p-value: 0.14695% CI: [0.9, 2.07]Regression, Logistic