Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia. The aim of this clinical trial is to investigate the blood sugar lowering effect and the safety profile of biphasic insulin aspart 30 compared to biphasic human insulin 30, both in combination with metformin in Chinese insulin-naive subjects with type 2 diabetes when failing on oral antidiabetic drug (OAD) therapy.
Interventions
DRUGbiphasic insulin aspart 30
The initial doses for BIAsp 30 twice-daily regimen will be recommended to start at a total daily dose of 0.3 U/kg body weight and to be equally divided (1/2:1/2) between pre-breakfast and pre-dinner
The initial doses for BHI 30 twice-daily regimen will be recommended to start at a total daily dose of 0.3 IU/kg body weight and to be divided in the ratio of 2/3:1/3 between pre-breakfast and pre-dinner
DRUGmetformin
Metformin dose must remain the same as that used prior to the trial.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes diagnosed for at least 6 months * Insulin-naive (less than or equal to 1 week of daily use of insulin therapy) * Treatment with metformin as monotherapy or in combination therapy with other OAD(s) for at least 3 months prior to this trial * Currently on metformin greater than or equal to 1000 mg/day for at least 2 weeks * Currently at least one of other OAD(s) reaching at least one-half of the recommended maximum dose for at least 2 weeks * Glycosylated haemoglobin (HbA1c) between 7.5-11.0% * Body Mass Index (BMI) between 18.5 - 35.0 kg/m\^2 * Be able and willing to perform continuous glucose monitoring system (CGMS ) and self-monitored blood glucose (SMBG)
Exclusion criteria
* Known or suspected allergy to trial product(s) or related products * Any contraindication of metformin * Receipt of investigational drug within the last 3 months prior to this trial * Any history of chronic insulin therapy (more than 1 week of daily use) * Systemically treated with thiazolidinediones (TZDs) for more than one month within 6 months prior to this trial * Pregnancy, nursing mother, or unwillingness to use adequate contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in IAUC (Incremental Area Under the Curve) for Postprandial Glucose (0-4 Hours) Over 3 Main Meals | Week 0, week 6 | The blood glucose profiles were monitored by CGMS (Continuous Glucose Monitoring System) for 72 hours at baseline (week 0) and end of treatment (week 6). IAUC was calculated using the trapezoidal method. The arithmetic mean of IAUC (3 meal-specific incremental areas) of day 1 and day 2 was used as the value of IAUC for each CGMS period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean FBG (Fasting Blood Glucose) Assessed by CGMS | Week 6 | The blood glucose profiles were monitored by CGMS for 72 hours at end of treatment (week 6). Mean FBG assessed by CGMS at 6 weeks. FBG was read on the CGMS glucose curves at 06:00 each morning over the 72 hours. The arithmetic mean of day 1 and day 2 was used as the value of mean FBG for each CGMS period. |
| Change in Mean FBG Assessed by CGMS | Week 0, week 6 | The blood glucose profiles were monitored by CGMS for 72 hours at baseline (week 0) and at end of treatment (week 6). Change in mean FBG from baseline (week 0) was assessed. FBG was read on the CGMS glucose curves at 06:00 each morning over the 72 hours. The arithmetic mean of day 1 and day 2 was used as the value of mean FBG for each CGMS period. |
| Change in FPG (Fasting Plasma Glucose) | Week 0, Week 6 | FPG was analysed by local laboratories at baseline (week 0) and end of treatment (week 6). Change in FPG at end of treatment (week 6) from baseline (week 0) was to be assessed. |
| Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Week 0, Week 6 | Subjects were asked to perform 8-point SMBG profiles using the provided blood glucose meter on one day within 72 hours CGMS monitoring period at week 0 and week 6. Change in blood glucose level at end of treatment (week 6) from baseline (week 0) at each time point was to be assessed respectively. Blood glucose levels were measured at the following 8 time points: Before each meal (breakfast, lunch and dinner), 120 minutes after the start of each meal, at bedtime and at 3 am in the morning. |
| Change in Prandial Blood Glucose Increment | Week 0, Week 6 | Subjects were asked to perform 8-point SMBG profiles using the provided blood glucose meter on one day within 72 hours CGMS monitoring period at week 0 and week 6 respectively. Prandial increment was the difference between the blood glucose (BG) value measured 120 minutes after meal and the BG value measured before meal. |
| Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Week 0, Week 6 | The blood glucose profiles were monitored by CGMS for 72 hours at baseline (week 0) and end of treatment (week 6). IAUC (0-4 hours) after each meal at 6 weeks and change in IAUC (0-4 hours) from baseline (week 0) after each meal were to be assessed. The arithmetic mean of day 1 and day 2 for each meal-specific incremental area (breakfast, lunch, dinner) was calculated. |
| Change in GA (Glycated Albumin) | Week -2, week 6 | Glycated Albumin is used as a general glycaemic control parameter. Analysed by laboratory. GA was measured at baseline (week 0) and end of treatment (week 6). Change in GA at end of treatment (week 6) from baseline (week 0) was assessed. |
| Change in Glycosylated Haemoglobin (HbA1c) | Week -2, week 6 | — |
| Duration of Hypoglycaemic Events Based on CGMS | 72-hour monitoring period at Week 0 and Week 6 | The CGMS device recorded blood glucose levels every 10 seconds then stored a smoothed average over 5 minutes. The range of blood glucose detection was 2.2-22 mmol/l. Hypoglycaemia was defined as blood glucose readings below 3.5 mmol/l or below 2.5 mmol/l, respectively. The duration of the hypoglycaemic episodes was quantified by accumulating the total time the CGMS profiles stays below the defined threshold (i.e. below 3.5 mmol/l or below 2.5 mmol/l, respectively). |
| Hypoglycaemia Based on Self-reported Episodes | Weeks 0-6 | Total number of hypoglycaemic episodes occurring in the trial after baseline (week 0) until the end of treatment (week 6). Hypoglycaemic episodes are classified 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 self monitored blood glucose (SMBG) was below 2.8 mmol/L; symptoms only if subject was able to treat her/himself and with no blood glucose measurement or SMBG higher than or equal to 2.8 mmol/L. |
| Change in MAGE (Mean Amplitude of Glycaemic Excursions) Assessed by CGMS | Week 0, Week 6 | MAGE is a parameter to monitor the intraday blood glucose excursions. It was calculated using CGMS data and as the arithmetic mean of glycaemic excursion with the criterion that both segments (ascending and descending parts) of the glycaemic excursion exceed of the value of one standard deviation of respective 24-hour blood glucose value. The direction of calculation (peak-to-nadir or nadir-to-peak) was established by the direction of the first excursion. The arithmetic mean of the glycaemic excursion of day 1 and day 2 was the value of MAGE for each CGMS |
Countries
China
Participant flow
Recruitment details
A total of 10 sites across China
Pre-assignment details
All eligible subjects had their baseline blood glucose profiles monitored by continuous glucose monitoring system (CGMS) for 72 hours. Following CGMS uninstall and discontinuation of all previous oral anti-diabetic drug (OAD) treatment, subjects were randomised to one of two treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| BIAsp 30 BIAsp 30 (biphasic insulin aspart 30) administered subcutaneously (under the skin) twice daily (before breakfast and dinner) + metformin. Initial total daily dose of 0.3 U or IU/kg body weight followed by individual dose adjustment for BIAsp 30 was performed over the first 4 weeks (titration period) to achieve the pre-meal blood glucose target of 4.4-6.1 mmol/l. The achieved dose was maintained for the last 2 weeks of treatment unless hypoglycaemia occurred. | 71 |
| BHI 30 BHI 30 (biphasic human insulin 30) administered subcutaneously (under the skin) twice daily (30 minutes before breakfast and dinner) + metformin. Initial total daily dose of 0.3 U or IU/kg body weight followed by individual dose adjustment for BHI 30 was performed over the first 4 weeks (titration period) to achieve the pre-meal blood glucose target of 4.4-6.1 mmol/l. The achieved dose was maintained for the last 2 weeks of treatment unless hypoglycaemia occurred. | 73 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | CGMS data collection failed | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | BIAsp 30 | Total | BHI 30 |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9 | 55.5 years STANDARD_DEVIATION 9.8 | 54.4 years STANDARD_DEVIATION 10.4 |
| BMI (Body Mass Index) | 24.68 kg/m^2 STANDARD_DEVIATION 3 | 24.71 kg/m^2 STANDARD_DEVIATION 3 | 24.74 kg/m^2 STANDARD_DEVIATION 3 |
| Duration of diagnosed diabetes | 7.74 years STANDARD_DEVIATION 5.5 | 7.36 years STANDARD_DEVIATION 5.3 | 7 years STANDARD_DEVIATION 5.2 |
| HbA1c at screening | 9.19 percentage of total haemoglobin STANDARD_DEVIATION 1.05 | 9.13 percentage of total haemoglobin STANDARD_DEVIATION 1.06 | 9.08 percentage of total haemoglobin STANDARD_DEVIATION 1.08 |
| Height at screening | 1.634 m STANDARD_DEVIATION 0.09 | 1.628 m STANDARD_DEVIATION 0.09 | 1.623 m STANDARD_DEVIATION 0.09 |
| Metformin monotherapy or combination therapy at randomisation Metformin Combination Therapy | 51 participants | 106 participants | 55 participants |
| Metformin monotherapy or combination therapy at randomisation Metformin Monotherapy | 20 participants | 38 participants | 18 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 144 Participants | 73 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 33 Participants | 72 Participants | 39 Participants |
| Sex: Female, Male Male | 38 Participants | 72 Participants | 34 Participants |
| Weight | 66.28 kg STANDARD_DEVIATION 12 | 65.88 kg STANDARD_DEVIATION 11.7 | 65.49 kg STANDARD_DEVIATION 11.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 71 | 0 / 73 |
| serious Total, serious adverse events | 1 / 71 | 3 / 73 |
Outcome results
Primary
Change in IAUC (Incremental Area Under the Curve) for Postprandial Glucose (0-4 Hours) Over 3 Main Meals
The blood glucose profiles were monitored by CGMS (Continuous Glucose Monitoring System) for 72 hours at baseline (week 0) and end of treatment (week 6). IAUC was calculated using the trapezoidal method. The arithmetic mean of IAUC (3 meal-specific incremental areas) of day 1 and day 2 was used as the value of IAUC for each CGMS period
Time frame: Week 0, week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in IAUC (Incremental Area Under the Curve) for Postprandial Glucose (0-4 Hours) Over 3 Main Meals | -1.99 mmol/L | Standard Error 0.49 |
| BHI 30 | Change in IAUC (Incremental Area Under the Curve) for Postprandial Glucose (0-4 Hours) Over 3 Main Meals | -1.977 mmol/L | Standard Error 0.517 |
Comparison: The null hypothesis (H0) was:~H0: Change in mean IAUC(0-4hours) of BIAsp 30 after 6 weeks of treatment-Change in mean IAUC(0-4hours) of BHI 30 after 6 weeks of treatment greater than or equal to 0 mol\*h/L against the alternative hypothesis(H1): H1: Change in mean IAUC (0-4hours) of BIAsp 30 after 6 weeks of treatment-Change in mean IAUC(0-4hours) of BHI 30 after 6 weeks of treatment less than 0 mol\*h/L95% CI: [-1.332, 1.306]ANCOVA
Secondary
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles
Subjects were asked to perform 8-point SMBG profiles using the provided blood glucose meter on one day within 72 hours CGMS monitoring period at week 0 and week 6. Change in blood glucose level at end of treatment (week 6) from baseline (week 0) at each time point was to be assessed respectively. Blood glucose levels were measured at the following 8 time points: Before each meal (breakfast, lunch and dinner), 120 minutes after the start of each meal, at bedtime and at 3 am in the morning.
Time frame: Week 0, Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Breakfast, N=69, 69 | -3.99 mmol/L | Standard Error 0.41 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Dinner, N=70, 69 | -4.57 mmol/L | Standard Error 0.36 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Lunch, N=70, 69 | -2.24 mmol/L | Standard Error 0.38 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Bedtime, N=71, 68 | -3.84 mmol/L | Standard Error 0.3 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before Lunch, N=71, 68 | -3.46 mmol/L | Standard Error 0.3 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 3AM, N=68, 66 | -2.62 mmol/L | Standard Error 0.21 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before dinner, N=70, 69 | -2.59 mmol/L | Standard Error 0.36 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Average, N=71, 69 | -3.16 mmol/L | Standard Error 0.18 |
| BIAsp 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before Breakfast, N=71, 68 | -2.27 mmol/L | Standard Error 0.2 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Average, N=71, 69 | -3.43 mmol/L | Standard Error 0.19 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before Breakfast, N=71, 68 | -2.38 mmol/L | Standard Error 0.2 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Breakfast, N=69, 69 | -5.22 mmol/L | Standard Error 0.41 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before Lunch, N=71, 68 | -3.73 mmol/L | Standard Error 0.31 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Lunch, N=70, 69 | -2.41 mmol/L | Standard Error 0.39 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Before dinner, N=70, 69 | -2.32 mmol/L | Standard Error 0.37 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 2 hours after Dinner, N=70, 69 | -4.1 mmol/L | Standard Error 0.36 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | Bedtime, N=71, 68 | -4.03 mmol/L | Standard Error 0.31 |
| BHI 30 | Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles | 3AM, N=68, 66 | -3.39 mmol/L | Standard Error 0.22 |
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.67695% CI: [-0.41, 0.63]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.02695% CI: [0.15, 2.31]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.595% CI: [-0.53, 1.08]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.74795% CI: [-0.86, 1.19]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.58195% CI: [-1.23, 0.69]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.32695% CI: [-1.42, 0.48]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.64395% CI: [-0.61, 0.99]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.00895% CI: [0.21, 1.33]ANCOVA
Comparison: For each endpoint of SMBG :The null hypothesis (H0) was:~H0: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in BG of BIAsp 30 after 6 weeks of treatment-Change in BG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.27495% CI: [-0.22, 0.75]ANCOVA
Secondary
Change in FPG (Fasting Plasma Glucose)
FPG was analysed by local laboratories at baseline (week 0) and end of treatment (week 6). Change in FPG at end of treatment (week 6) from baseline (week 0) was to be assessed.
Time frame: Week 0, Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) (if a measurement on the withdrawal visit was available) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in FPG (Fasting Plasma Glucose) | -2.961 mmol/L | Standard Error 0.185 |
| BHI 30 | Change in FPG (Fasting Plasma Glucose) | -3.456 mmol/L | Standard Error 0.188 |
Comparison: The null hypothesis (H0) was:~H0: Change in FPG of BIAsp 30 after 6 weeks of treatment-Change in FPG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in FPG of BIAsp 30 after 6 weeks of treatment-Change in FPG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.047295% CI: [0.006, 0.984]ANCOVA
Secondary
Change in GA (Glycated Albumin)
Glycated Albumin is used as a general glycaemic control parameter. Analysed by laboratory. GA was measured at baseline (week 0) and end of treatment (week 6). Change in GA at end of treatment (week 6) from baseline (week 0) was assessed.
Time frame: Week -2, week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) (if a measurement on the withdrawal visit was available) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in GA (Glycated Albumin) | -6.147 percentage point change | Standard Error 0.428 |
| BHI 30 | Change in GA (Glycated Albumin) | -6.474 percentage point change | Standard Error 0.438 |
Comparison: The null hypothesis (H0) was:~H0: Change in GA of BIAsp 30 after 6 weeks of treatment-Change in GA of BHI 30 after 6 weeks of treatment =0 % against the alternative hypothesis(H1): H1: Change in GA of BIAsp 30 after 6 weeks of treatment-Change in GA of BHI 30 after 6 weeks of treatment≠0 %p-value: 0.570695% CI: [-0.813, 1.468]ANCOVA
Secondary
Change in Glycosylated Haemoglobin (HbA1c)
Time frame: Week -2, week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) (if a measurement on the withdrawal visit was available) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in Glycosylated Haemoglobin (HbA1c) | -1.647 percentage point change | Standard Error 0.083 |
| BHI 30 | Change in Glycosylated Haemoglobin (HbA1c) | -1.667 percentage point change | Standard Error 0.086 |
Comparison: The null hypothesis (H0) was:~H0: Change in HbA1c of BIAsp 30 after 6 weeks of treatment-Change in HbA1c of BHI 30 after 6 weeks of treatment =0 % against the alternative hypothesis(H1): H1: Change in HbA1c of BIAsp 30 after 6 weeks of treatment-Change in HbA1c of BHI 30 after 6 weeks of treatment≠0%p-value: 0.859895% CI: [-0.243, 0.243]ANCOVA
Secondary
Change in MAGE (Mean Amplitude of Glycaemic Excursions) Assessed by CGMS
MAGE is a parameter to monitor the intraday blood glucose excursions. It was calculated using CGMS data and as the arithmetic mean of glycaemic excursion with the criterion that both segments (ascending and descending parts) of the glycaemic excursion exceed of the value of one standard deviation of respective 24-hour blood glucose value. The direction of calculation (peak-to-nadir or nadir-to-peak) was established by the direction of the first excursion. The arithmetic mean of the glycaemic excursion of day 1 and day 2 was the value of MAGE for each CGMS
Time frame: Week 0, Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in MAGE (Mean Amplitude of Glycaemic Excursions) Assessed by CGMS | -0.499 mmol/L | Standard Error 0.273 |
| BHI 30 | Change in MAGE (Mean Amplitude of Glycaemic Excursions) Assessed by CGMS | -0.686 mmol/L | Standard Error 0.284 |
Comparison: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.p-value: 0.614995% CI: [-0.547, 0.921]ANCOVA
Secondary
Change in Mean FBG Assessed by CGMS
The blood glucose profiles were monitored by CGMS for 72 hours at baseline (week 0) and at end of treatment (week 6). Change in mean FBG from baseline (week 0) was assessed. FBG was read on the CGMS glucose curves at 06:00 each morning over the 72 hours. The arithmetic mean of day 1 and day 2 was used as the value of mean FBG for each CGMS period.
Time frame: Week 0, week 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Change in Mean FBG Assessed by CGMS | -2.114 mmol/L | Standard Error 0.193 |
| BHI 30 | Change in Mean FBG Assessed by CGMS | -2.561 mmol/L | Standard Error 0.2 |
Secondary
Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS
The blood glucose profiles were monitored by CGMS for 72 hours at baseline (week 0) and end of treatment (week 6). IAUC (0-4 hours) after each meal at 6 weeks and change in IAUC (0-4 hours) from baseline (week 0) after each meal were to be assessed. The arithmetic mean of day 1 and day 2 for each meal-specific incremental area (breakfast, lunch, dinner) was calculated.
Time frame: Week 0, Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Dinner, N=69, 65 | -4.775 mmol/L | Standard Error 0.539 |
| BIAsp 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Breakfast, N=68, 64 | -3.094 mmol/L | Standard Error 0.725 |
| BIAsp 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Lunch, N=69, 66 | 1.651 mmol/L | Standard Error 0.897 |
| BHI 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Breakfast, N=68, 64 | -4.272 mmol/L | Standard Error 0.765 |
| BHI 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Lunch, N=69, 66 | 1.969 mmol/L | Standard Error 0.93 |
| BHI 30 | Change in Mean IAUC for Postprandial Glucose (0-4 Hours) After Each Meal (Breakfast, Lunch, Dinner) Assessed by CGMS | Dinner, N=69, 65 | -4.026 mmol/L | Standard Error 0.566 |
Comparison: Null hypothesis and alternative hypothesis for breakfast:~The null hypothesis (H0) was:~H0: Change in mean IAUC(0-4h) of BIAsp 30 for breakfast after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for breakfast after 6 weeks of treatment =0 mol\*h/L against the alternative hypothesis(H1): H1: Change in mean IAUC (0-4h) of BIAsp 30 for breakfast after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for breakfast after 6 weeks of treatment≠0 mol\*h/Lp-value: 0.241295% CI: [-0.802, 3.157]ANCOVA
Comparison: Null hypothesis and alternative hypothesis for lunch:~The null hypothesis (H0) was:~H0: Change in mean IAUC(0-4h) of BIAsp 30 for lunch after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for lunch after 6 weeks of treatment =0 mol\*h/L against the alternative hypothesis(H1): H1: Change in mean IAUC (0-4h) of BIAsp 30 for lunch after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for lunch after 6 weeks of treatment≠0 mol\*h/Lp-value: 0.79495% CI: [-2.724, 2.087]ANCOVA
Comparison: Null hypothesis and alternative hypothesis for dinner:~The null hypothesis (H0) was:~H0: Change in mean IAUC(0-4h) of BIAsp 30 for dinner after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for dinner after 6 weeks of treatment =0 mol\*h/L against the alternative hypothesis(H1): H1: Change in mean IAUC (0-4h) of BIAsp 30 for dinner after 6 weeks of treatment-Change in mean IAUC(0-4h) of BHI 30 for dinner after 6 weeks of treatment≠0 mol\*h/Lp-value: 0.309395% CI: [-2.2, 0.703]ANCOVA
Secondary
Change in Prandial Blood Glucose Increment
Subjects were asked to perform 8-point SMBG profiles using the provided blood glucose meter on one day within 72 hours CGMS monitoring period at week 0 and week 6 respectively. Prandial increment was the difference between the blood glucose (BG) value measured 120 minutes after meal and the BG value measured before meal.
Time frame: Week 0, Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Change in Prandial Blood Glucose Increment | Breakfast, N=69, 68 | -1.82 mmol/L | Standard Error 0.39 |
| BIAsp 30 | Change in Prandial Blood Glucose Increment | Lunch, N=70, 68 | 1.32 mmol/L | Standard Error 0.44 |
| BIAsp 30 | Change in Prandial Blood Glucose Increment | Dinner, N=69, 69 | -1.91 mmol/L | Standard Error 0.42 |
| BIAsp 30 | Change in Prandial Blood Glucose Increment | Average, N=70, 68 | -0.81 mmol/L | Standard Error 0.21 |
| BHI 30 | Change in Prandial Blood Glucose Increment | Average, N=70, 68 | -1.1 mmol/L | Standard Error 0.22 |
| BHI 30 | Change in Prandial Blood Glucose Increment | Breakfast, N=69, 68 | -2.82 mmol/L | Standard Error 0.4 |
| BHI 30 | Change in Prandial Blood Glucose Increment | Dinner, N=69, 69 | -1.85 mmol/L | Standard Error 0.42 |
| BHI 30 | Change in Prandial Blood Glucose Increment | Lunch, N=70, 68 | 1.27 mmol/L | Standard Error 0.45 |
Comparison: For each endpoint of Prandial Blood Glucose Increment :The null hypothesis (H0) was:~H0: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.06295% CI: [-0.05, 2.04]ANCOVA
Comparison: For each endpoint of Prandial Blood Glucose Increment :The null hypothesis (H0) was:~H0: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.93395% CI: [-1.12, 1.22]ANCOVA
Comparison: For each endpoint of Prandial Blood Glucose Increment :The null hypothesis (H0) was:~H0: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.92295% CI: [-1.16, 1.05]ANCOVA
Comparison: For each endpoint of Prandial Blood Glucose Increment :The null hypothesis (H0) was:~H0: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in prandial BG increment of BIAsp 30 after 6 weeks of treatment-Change in prandial BG increment of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.31395% CI: [-0.28, 0.85]ANCOVA
Secondary
Duration of Hypoglycaemic Events Based on CGMS
The CGMS device recorded blood glucose levels every 10 seconds then stored a smoothed average over 5 minutes. The range of blood glucose detection was 2.2-22 mmol/l. Hypoglycaemia was defined as blood glucose readings below 3.5 mmol/l or below 2.5 mmol/l, respectively. The duration of the hypoglycaemic episodes was quantified by accumulating the total time the CGMS profiles stays below the defined threshold (i.e. below 3.5 mmol/l or below 2.5 mmol/l, respectively).
Time frame: 72-hour monitoring period at Week 0 and Week 6
Population: Safety analysis set consists of all randomised subjects who were exposed to at least one dose of trial product(s).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BIAsp 30 | Duration of Hypoglycaemic Events Based on CGMS | Blood glucose < 3.5 mmol/L, N=70, 68 | 0.304 Hours | Standard Error 0.094 |
| BIAsp 30 | Duration of Hypoglycaemic Events Based on CGMS | Blood glucose < 2.5 mmol/L, N=70, 68 | 0.048 Hours | Standard Error 0.028 |
| BHI 30 | Duration of Hypoglycaemic Events Based on CGMS | Blood glucose < 3.5 mmol/L, N=70, 68 | 0.358 Hours | Standard Error 0.097 |
| BHI 30 | Duration of Hypoglycaemic Events Based on CGMS | Blood glucose < 2.5 mmol/L, N=70, 68 | 0.06 Hours | Standard Error 0.029 |
Comparison: The null hypothesis (H0) was:~H0: Duration of Hypoglycaemic Events Based on CGMS of BIAsp 30 after 6 weeks of treatment-Duration of Hypoglycaemic Events Based on CGMS of BHI 30 after 6 weeks of treatment =0 hours against the alternative hypothesis(H1): H1: Duration of Hypoglycaemic Events Based on CGMS of BIAsp 30 after 6 weeks of treatment-Duration of Hypoglycaemic Events Based on CGMS of BHI 30 after 6 weeks of treatment≠0 hoursp-value: 0.67195% CI: [-0.307, 0.198]ANCOVA
Comparison: The null hypothesis (H0) was:~H0: Duration of Hypoglycaemic Events Based on CGMS of BIAsp 30 after 6 weeks of treatment-Duration of Hypoglycaemic Events Based on CGMS of BHI 30 after 6 weeks of treatment =0 hours against the alternative hypothesis(H1): H1: Duration of Hypoglycaemic Events Based on CGMS of BIAsp 30 after 6 weeks of treatment-Duration of Hypoglycaemic Events Based on CGMS of BHI 30 after 6 weeks of treatment≠0 hoursp-value: 0.754495% CI: [-0.088, 0.064]ANCOVA
Secondary
Hypoglycaemia Based on Self-reported Episodes
Total number of hypoglycaemic episodes occurring in the trial after baseline (week 0) until the end of treatment (week 6). Hypoglycaemic episodes are classified 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 self monitored blood glucose (SMBG) was below 2.8 mmol/L; symptoms only if subject was able to treat her/himself and with no blood glucose measurement or SMBG higher than or equal to 2.8 mmol/L.
Time frame: Weeks 0-6
Population: Safety analysis set consists of all randomised subjects who were exposed to at least one dose of trial product(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIAsp 30 | Hypoglycaemia Based on Self-reported Episodes | All | 63 episodes |
| BIAsp 30 | Hypoglycaemia Based on Self-reported Episodes | Major | 3 episodes |
| BIAsp 30 | Hypoglycaemia Based on Self-reported Episodes | Minor | 9 episodes |
| BIAsp 30 | Hypoglycaemia Based on Self-reported Episodes | Symptoms only | 51 episodes |
| BHI 30 | Hypoglycaemia Based on Self-reported Episodes | Symptoms only | 42 episodes |
| BHI 30 | Hypoglycaemia Based on Self-reported Episodes | All | 55 episodes |
| BHI 30 | Hypoglycaemia Based on Self-reported Episodes | Minor | 10 episodes |
| BHI 30 | Hypoglycaemia Based on Self-reported Episodes | Major | 3 episodes |
Secondary
Mean FBG (Fasting Blood Glucose) Assessed by CGMS
The blood glucose profiles were monitored by CGMS for 72 hours at end of treatment (week 6). Mean FBG assessed by CGMS at 6 weeks. FBG was read on the CGMS glucose curves at 06:00 each morning over the 72 hours. The arithmetic mean of day 1 and day 2 was used as the value of mean FBG for each CGMS period.
Time frame: Week 6
Population: The full analysis set using LOCF (Last Observation Carried Forward) consists of all randomised subjects who had been exposed to at least one dose of the trial products.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BIAsp 30 | Mean FBG (Fasting Blood Glucose) Assessed by CGMS | 6.861 mmol/L | Standard Error 0.193 |
| BHI 30 | Mean FBG (Fasting Blood Glucose) Assessed by CGMS | 6.414 mmol/L | Standard Error 0.2 |
Comparison: The null hypothesis (H0) was:~H0: Change in mean FBG of BIAsp 30 after 6 weeks of treatment-Change in mean FBG of BHI 30 after 6 weeks of treatment =0 mmol/L against the alternative hypothesis(H1): H1: Change in mean FBG of BIAsp 30 after 6 weeks of treatment-Change in mean FBG of BHI 30 after 6 weeks of treatment≠0 mmol/Lp-value: 0.089195% CI: [-0.069, 0.964]ANCOVA