Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The trial aims to investigate if the blood glucose control of biphasic insulin aspart 50 is at least as effective as treatment with biphasic insulin aspart 30 both in combination with metformin.
Interventions
DRUGbiphasic insulin aspart 30
Treat-to-target dose titration scheme (dose adjusted individually), s.c. (under the skin) injection before dinner
DRUGmetformin
Tablets, 500 - 2000 mg, once, twice or three times daily
Treat-to-target dose titration scheme (dose adjusted individually), s.c. (under the skin) injection before breakfast and lunch
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 * Currently treated with premix human insulin twice daily with or without oral antidiabetic drugs for at least 3 months * HbA1c (Glycosylated Haemoglobin A1c) between 7.5% - 12.0% (both inclusive) * FPG (Fasting Plasma Glucose) higher than 7.0 mmol/L * BMI (Body Mass Index) 23-40 kg/sq.m (both inclusive)
Exclusion criteria
* Metformin contraindications according to local practice * Systemic use of TZDs (thiazolidinediones) for more than 1 month within 6 months prior to this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin A1c (HbA1c) | week 0, week 16 | Change in glycosylated haemoglobin A1c (HbA1c) from week 0 (baseline) to end of treatment (week 16) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change and Daily Average in 8-point Plasma Glucose | week 0, week 16 | Change in 8-point plasma glucose from baseline (week 0) to at end of treatment (week 16). 8-point plasma glucose was measured at following time points: Before each meal, 120 minutes after the start of each meal, at bedtime, and at 3:00 AM in the morning. Daily average was calculated at the end of treatment. |
| Change and Daily Average in Prandial Plasma Glucose Increment | week 0, week 16 | Change in prandial (mealtime) plasma glucose increment from baseline (week 0) to end of treatment (week 16). Daily average prandial plasma glucose increment was calculated at end of treatment. |
| The Total Increase in Total Daily Insulin Dose Per Body Weight | week 0, week 16 | The total increase in total daily insulin dose per body weight from baseline (week 0) to end of treatment (week 16). |
| The Percentage of Subjects Achieving HbA1c Treatment Targets | week 16 | The percentage of subjects who after 16 weeks of treatment met the glycosylated haemoglobin A1c (HbA1c) treatment targets below 7%, or below or equal to 6.5%. |
| Number of Hypoglycaemic Episodes | weeks 0-16 | Number of hypoglycaemic episodes occurring after baseline (week 0) to the end of treatment (week 16) in each treatment group. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL. |
| Number of Nocturnal Hypoglycaemic Episodes | weeks 0-16 | Number of nocturnal hypoglycaemic episodes occurring after baseline (week 0) to end of treatment (week 16) in each treatment group. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL. |
| Change in Body Weight | week 0, week 16 | Change in body weight from baseline (week 0) to end of treatment (week 16) |
Countries
China
Participant flow
Recruitment details
15 sites in China
Pre-assignment details
Eligible subjects were subjects with type 2 diabetes having an HbA1c (Glycosylated Haemoglobin A1c) between 7.5-12.0 %, and treated with premix human insulin twice daily with or without oral anti-diabetic drugs (OADs) for at least 3 months qualifying for an intensified insulin treatment.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 50-50-30 Individual adjusted dose of biphasic insulin aspart 50 administered before breakfast and lunch and individual adjusted dose of biphasic insulin aspart 30 at dinner in combination with metformin 500-2000 mg, up to three times daily | 219 |
| BIAsp 30-30 Individual adjusted dose of biphasic insulin aspart 30 administered before breakfast and dinner in combination with metformin 500-2000 mg, up to three times daily | 222 |
| Total | 441 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Other | 6 | 8 |
Baseline characteristics
| Characteristic | BIAsp 50-50-30 | BIAsp 30-30 | Total |
|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 8.6 | 55.5 years STANDARD_DEVIATION 8.6 | 55.5 years STANDARD_DEVIATION 8.6 |
| BMI | 26.06 kg/m2 STANDARD_DEVIATION 2.7 | 26.27 kg/m2 STANDARD_DEVIATION 2.73 | 26.17 kg/m2 STANDARD_DEVIATION 2.71 |
| Height | 162.8 cm STANDARD_DEVIATION 7.9 | 163.7 cm STANDARD_DEVIATION 8.4 | 163.2 cm STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 131 Participants | 113 Participants | 244 Participants |
| Sex: Female, Male Male | 88 Participants | 109 Participants | 197 Participants |
| Weight | 69.2 kg STANDARD_DEVIATION 9.8 | 70.5 kg STANDARD_DEVIATION 9.7 | 69.9 kg STANDARD_DEVIATION 9.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 74 / 219 | 68 / 222 |
| serious Total, serious adverse events | 5 / 219 | 9 / 222 |
Outcome results
Primary
Change in Glycosylated Haemoglobin A1c (HbA1c)
Change in glycosylated haemoglobin A1c (HbA1c) from week 0 (baseline) to end of treatment (week 16)
Time frame: week 0, week 16
Population: Intention-to-Treat analysis set (ITT) using LOCF (Last Observation Carried Forward) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50-50-30 | Change in Glycosylated Haemoglobin A1c (HbA1c) | -1.790 percentage (%) of total haemoglobin | Standard Error 0.057 |
| BIAsp 30-30 | Change in Glycosylated Haemoglobin A1c (HbA1c) | -1.517 percentage (%) of total haemoglobin | Standard Error 0.056 |
Secondary
Change and Daily Average in 8-point Plasma Glucose
Change in 8-point plasma glucose from baseline (week 0) to at end of treatment (week 16). 8-point plasma glucose was measured at following time points: Before each meal, 120 minutes after the start of each meal, at bedtime, and at 3:00 AM in the morning. Daily average was calculated at the end of treatment.
Time frame: week 0, week 16
Population: Intention-to-Treat analysis set (ITT) using LOCF (Last Observation Carried Forward) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Breakfast, N= 213, 210 | -3.92 mmol/L | Standard Error 0.17 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | Before Dinner, N= 212, 212 | -3.83 mmol/L | Standard Error 0.16 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | Before Lunch, N= 213, 210 | -2.80 mmol/L | Standard Error 0.13 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Dinner, N= 211, 209 | -3.46 mmol/L | Standard Error 0.18 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | Bedtime, N= 207, 207 | -2.93 mmol/L | Standard Error 0.15 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | 3:00 AM, N= 211, 210 | -1.99 mmol/L | Standard Error 0.13 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | Before Breakfast, N= 213, 213 | -2.52 mmol/L | Standard Error 0.1 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | Average, N= 213, 212 | -3.23 mmol/L | Standard Error 0.1 |
| BIAsp 50-50-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Lunch, N= 213, 211 | -4.37 mmol/L | Standard Error 0.19 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | Average, N= 213, 212 | -2.94 mmol/L | Standard Error 0.1 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Breakfast, N= 213, 210 | -4.00 mmol/L | Standard Error 0.17 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | Before Lunch, N= 213, 210 | -2.71 mmol/L | Standard Error 0.13 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Dinner, N= 211, 209 | -3.37 mmol/L | Standard Error 0.18 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | 2 hours After Lunch, N= 213, 211 | -3.15 mmol/L | Standard Error 0.18 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | Before Dinner, N= 212, 212 | -2.83 mmol/L | Standard Error 0.15 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | Bedtime, N= 207, 207 | -3.09 mmol/L | Standard Error 0.15 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | 3:00 AM, N= 211, 210 | -1.89 mmol/L | Standard Error 0.13 |
| BIAsp 30-30 | Change and Daily Average in 8-point Plasma Glucose | Before Breakfast, N= 213, 213 | -2.43 mmol/L | Standard Error 0.1 |
Secondary
Change and Daily Average in Prandial Plasma Glucose Increment
Change in prandial (mealtime) plasma glucose increment from baseline (week 0) to end of treatment (week 16). Daily average prandial plasma glucose increment was calculated at end of treatment.
Time frame: week 0, week 16
Population: Intention-to-Treat analysis set (ITT) using LOCF (Last Observation Carried Forward) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 50-50-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Breakfast, N= 213, 210 | -1.41 mmol/L | Standard Error 0.16 |
| BIAsp 50-50-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Lunch, N= 213, 210 | -1.57 mmol/L | Standard Error 0.19 |
| BIAsp 50-50-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Dinner, N= 210, 209 | 0.40 mmol/L | Standard Error 0.18 |
| BIAsp 50-50-30 | Change and Daily Average in Prandial Plasma Glucose Increment | Average, N= 213, 211 | -0.88 mmol/L | Standard Error 0.11 |
| BIAsp 30-30 | Change and Daily Average in Prandial Plasma Glucose Increment | Average, N= 213, 211 | -0.84 mmol/L | Standard Error 0.11 |
| BIAsp 30-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Breakfast, N= 213, 210 | -1.58 mmol/L | Standard Error 0.16 |
| BIAsp 30-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Dinner, N= 210, 209 | -0.53 mmol/L | Standard Error 0.18 |
| BIAsp 30-30 | Change and Daily Average in Prandial Plasma Glucose Increment | At Lunch, N= 213, 210 | -0.44 mmol/L | Standard Error 0.19 |
Secondary
Change in Body Weight
Change in body weight from baseline (week 0) to end of treatment (week 16)
Time frame: week 0, week 16
Population: Intention-to-Treat analysis set (ITT) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50-50-30 | Change in Body Weight | 1.188 kg | Standard Error 0.157 |
| BIAsp 30-30 | Change in Body Weight | 0.817 kg | Standard Error 0.155 |
Secondary
Number of Hypoglycaemic Episodes
Number of hypoglycaemic episodes occurring after baseline (week 0) to the end of treatment (week 16) in each treatment group. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL.
Time frame: weeks 0-16
Population: Intention-to-Treat analysis set (ITT) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 50-50-30 | Number of Hypoglycaemic Episodes | Major or Minor | 158 episodes |
| BIAsp 50-50-30 | Number of Hypoglycaemic Episodes | Symptoms Only | 570 episodes |
| BIAsp 50-50-30 | Number of Hypoglycaemic Episodes | Minor | 157 episodes |
| BIAsp 50-50-30 | Number of Hypoglycaemic Episodes | All | 728 episodes |
| BIAsp 30-30 | Number of Hypoglycaemic Episodes | Minor | 198 episodes |
| BIAsp 30-30 | Number of Hypoglycaemic Episodes | Major or Minor | 198 episodes |
| BIAsp 30-30 | Number of Hypoglycaemic Episodes | All | 679 episodes |
| BIAsp 30-30 | Number of Hypoglycaemic Episodes | Symptoms Only | 481 episodes |
Secondary
Number of Nocturnal Hypoglycaemic Episodes
Number of nocturnal hypoglycaemic episodes occurring after baseline (week 0) to end of treatment (week 16) in each treatment group. Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L or 56 mg/dL. Symptoms only if subject was able to treat her/himself and with either no plasma glucose or blood glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L or 56 mg/dL.
Time frame: weeks 0-16
Population: Intention-to-Treat analysis set (ITT) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 50-50-30 | Number of Nocturnal Hypoglycaemic Episodes | All | 134 episodes |
| BIAsp 50-50-30 | Number of Nocturnal Hypoglycaemic Episodes | Major or Minor | 31 episodes |
| BIAsp 50-50-30 | Number of Nocturnal Hypoglycaemic Episodes | Minor | 31 episodes |
| BIAsp 50-50-30 | Number of Nocturnal Hypoglycaemic Episodes | Symptons Only | 103 episodes |
| BIAsp 30-30 | Number of Nocturnal Hypoglycaemic Episodes | Major or Minor | 30 episodes |
| BIAsp 30-30 | Number of Nocturnal Hypoglycaemic Episodes | Symptons Only | 51 episodes |
| BIAsp 30-30 | Number of Nocturnal Hypoglycaemic Episodes | All | 81 episodes |
| BIAsp 30-30 | Number of Nocturnal Hypoglycaemic Episodes | Minor | 30 episodes |
Secondary
The Percentage of Subjects Achieving HbA1c Treatment Targets
The percentage of subjects who after 16 weeks of treatment met the glycosylated haemoglobin A1c (HbA1c) treatment targets below 7%, or below or equal to 6.5%.
Time frame: week 16
Population: Intention-to-Treat analysis set (ITT) using LOCF (Last Observation Carried Forward) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 50-50-30 | The Percentage of Subjects Achieving HbA1c Treatment Targets | Achieving HbA1c <7.0% | 65 percentage (%) of subjects |
| BIAsp 50-50-30 | The Percentage of Subjects Achieving HbA1c Treatment Targets | Achieving HbA1c <=6.5% | 47 percentage (%) of subjects |
| BIAsp 30-30 | The Percentage of Subjects Achieving HbA1c Treatment Targets | Achieving HbA1c <7.0% | 52 percentage (%) of subjects |
| BIAsp 30-30 | The Percentage of Subjects Achieving HbA1c Treatment Targets | Achieving HbA1c <=6.5% | 29 percentage (%) of subjects |
Secondary
The Total Increase in Total Daily Insulin Dose Per Body Weight
The total increase in total daily insulin dose per body weight from baseline (week 0) to end of treatment (week 16).
Time frame: week 0, week 16
Population: Intention-to-Treat analysis set (ITT) is all randomised subjects exposed to at least one dose of trial product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 50-50-30 | The Total Increase in Total Daily Insulin Dose Per Body Weight | 0.963 U/kg | Standard Error 0.016 |
| BIAsp 30-30 | The Total Increase in Total Daily Insulin Dose Per Body Weight | 0.820 U/kg | Standard Error 0.015 |