Trial Outcomes & Findings for Comparing the Efficacy and Safety of Biphasic Insulin Aspart 30 and Biphasic Human Insulin 30 on Blood Sugar Control in Subjects With Type 2 Diabetes (NCT NCT00807092)

NCT ID: NCT00807092

Last Updated: 2015-03-04

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 145 participants
• Primary outcome timeframe: Week 0, week 6
• Results posted on: 2015-03-04

Participant Flow

A total of 10 sites across China

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.

Participant milestones

Measure	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.	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.
Overall Study STARTED	72	73
Overall Study Exposed to Drug	71	73
Overall Study COMPLETED	71	69
Overall Study NOT COMPLETED	1	4

Reasons for withdrawal

Measure	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.	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.
Overall Study Adverse Event	0	1
Overall Study Protocol Violation	0	2
Overall Study Withdrawal by Subject	1	0
Overall Study CGMS data collection failed	0	1

Baseline Characteristics

Comparing the Efficacy and Safety of Biphasic Insulin Aspart 30 and Biphasic Human Insulin 30 on Blood Sugar Control in Subjects With Type 2 Diabetes

Baseline characteristics by cohort

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.	Total n=144 Participants Total of all reporting groups
Age, Continuous	56.5 years STANDARD_DEVIATION 9 • n=5 Participants	54.4 years STANDARD_DEVIATION 10.4 • n=7 Participants	55.5 years STANDARD_DEVIATION 9.8 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants	39 Participants n=7 Participants	72 Participants n=5 Participants
Sex: Female, Male Male	38 Participants n=5 Participants	34 Participants n=7 Participants	72 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	71 Participants n=5 Participants	73 Participants n=7 Participants	144 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Weight	66.28 kg STANDARD_DEVIATION 12 • n=5 Participants	65.49 kg STANDARD_DEVIATION 11.4 • n=7 Participants	65.88 kg STANDARD_DEVIATION 11.7 • n=5 Participants
Height at screening	1.634 m STANDARD_DEVIATION 0.09 • n=5 Participants	1.623 m STANDARD_DEVIATION 0.09 • n=7 Participants	1.628 m STANDARD_DEVIATION 0.09 • n=5 Participants
BMI (Body Mass Index)	24.68 kg/m^2 STANDARD_DEVIATION 3 • n=5 Participants	24.74 kg/m^2 STANDARD_DEVIATION 3 • n=7 Participants	24.71 kg/m^2 STANDARD_DEVIATION 3 • n=5 Participants
Duration of diagnosed diabetes	7.74 years STANDARD_DEVIATION 5.5 • n=5 Participants	7 years STANDARD_DEVIATION 5.2 • n=7 Participants	7.36 years STANDARD_DEVIATION 5.3 • n=5 Participants
HbA1c at screening	9.19 percentage of total haemoglobin STANDARD_DEVIATION 1.05 • n=5 Participants	9.08 percentage of total haemoglobin STANDARD_DEVIATION 1.08 • n=7 Participants	9.13 percentage of total haemoglobin STANDARD_DEVIATION 1.06 • n=5 Participants
Metformin monotherapy or combination therapy at randomisation Metformin Monotherapy	20 participants n=5 Participants	18 participants n=7 Participants	38 participants n=5 Participants
Metformin monotherapy or combination therapy at randomisation Metformin Combination Therapy	51 participants n=5 Participants	55 participants n=7 Participants	106 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Measure	BIAsp 30 n=67 Participants 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.	BHI 30 n=63 Participants 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.
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	-1.977 mmol/L Standard Error 0.517

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.
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	-4.272 mmol/L Standard Error 0.765
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	1.969 mmol/L Standard Error 0.93
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	-4.026 mmol/L Standard Error 0.566

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	BIAsp 30 n=69 Participants 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.	BHI 30 n=66 Participants 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.
Mean FBG (Fasting Blood Glucose) Assessed by CGMS	6.861 mmol/L Standard Error 0.193	6.414 mmol/L Standard Error 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	BIAsp 30 n=69 Participants 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.	BHI 30 n=66 Participants 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.
Change in Mean FBG Assessed by CGMS	-2.114 mmol/L Standard Error 0.193	-2.561 mmol/L Standard Error 0.2

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	BIAsp 30 n=70 Participants 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.	BHI 30 n=68 Participants 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.
Change in FPG (Fasting Plasma Glucose)	-2.961 mmol/L Standard Error 0.185	-3.456 mmol/L Standard Error 0.188

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles Before Breakfast, N=71, 68	-2.27 mmol/L Standard Error 0.2	-2.38 mmol/L Standard Error 0.2
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	-5.22 mmol/L Standard Error 0.41
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles Before Lunch, N=71, 68	-3.46 mmol/L Standard Error 0.3	-3.73 mmol/L Standard Error 0.31
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	-2.41 mmol/L Standard Error 0.39
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles Before dinner, N=70, 69	-2.59 mmol/L Standard Error 0.36	-2.32 mmol/L Standard Error 0.37
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	-4.1 mmol/L Standard Error 0.36
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles Bedtime, N=71, 68	-3.84 mmol/L Standard Error 0.3	-4.03 mmol/L Standard Error 0.31
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles 3AM, N=68, 66	-2.62 mmol/L Standard Error 0.21	-3.39 mmol/L Standard Error 0.22
Change in 8-point SMBG (Self-monitored Blood Glucose) Profiles Average, N=71, 69	-3.16 mmol/L Standard Error 0.18	-3.43 mmol/L Standard Error 0.19

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.
Change in Prandial Blood Glucose Increment Breakfast, N=69, 68	-1.82 mmol/L Standard Error 0.39	-2.82 mmol/L Standard Error 0.4
Change in Prandial Blood Glucose Increment Lunch, N=70, 68	1.32 mmol/L Standard Error 0.44	1.27 mmol/L Standard Error 0.45
Change in Prandial Blood Glucose Increment Dinner, N=69, 69	-1.91 mmol/L Standard Error 0.42	-1.85 mmol/L Standard Error 0.42
Change in Prandial Blood Glucose Increment Average, N=70, 68	-0.81 mmol/L Standard Error 0.21	-1.1 mmol/L Standard Error 0.22

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	BIAsp 30 n=69 Participants 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.	BHI 30 n=69 Participants 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.
Change in MAGE (Mean Amplitude of Glycaemic Excursions) Assessed by CGMS	-0.499 mmol/L Standard Error 0.273	-0.686 mmol/L Standard Error 0.284

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	BIAsp 30 n=70 Participants 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.	BHI 30 n=68 Participants 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.
Change in GA (Glycated Albumin)	-6.147 percentage point change Standard Error 0.428	-6.474 percentage point change Standard Error 0.438

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=68 Participants 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.
Change in Glycosylated Haemoglobin (HbA1c)	-1.647 percentage point change Standard Error 0.083	-1.667 percentage point change Standard Error 0.086

SECONDARY outcome

Timeframe: 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).

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).

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.
Duration of Hypoglycaemic Events Based on CGMS Blood glucose < 3.5 mmol/L, N=70, 68	0.304 Hours Standard Error 0.094	0.358 Hours Standard Error 0.097
Duration of Hypoglycaemic Events Based on CGMS Blood glucose < 2.5 mmol/L, N=70, 68	0.048 Hours Standard Error 0.028	0.06 Hours Standard Error 0.029

SECONDARY outcome

Timeframe: Weeks 0-6

Population: Safety analysis set consists of all randomised subjects who were exposed to at least one dose of trial product(s).

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.

Outcome measures

Measure	BIAsp 30 n=71 Participants 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.	BHI 30 n=73 Participants 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.
Hypoglycaemia Based on Self-reported Episodes All	63 episodes	55 episodes
Hypoglycaemia Based on Self-reported Episodes Major	3 episodes	3 episodes
Hypoglycaemia Based on Self-reported Episodes Minor	9 episodes	10 episodes
Hypoglycaemia Based on Self-reported Episodes Symptoms only	51 episodes	42 episodes

Adverse Events

BIAsp 30

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

BHI 30

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	BIAsp 30 n=71 participants at risk 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.	BHI 30 n=73 participants at risk 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.
Musculoskeletal and connective tissue disorders Loose body in joint	1.4% 1/71 • Number of events 1 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).	0.00% 0/73 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer metastatic	0.00% 0/71 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).	1.4% 1/73 • Number of events 1 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/71 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).	1.4% 1/73 • Number of events 1 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
Nervous system disorders Hypoglycaemic coma	0.00% 0/71 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).	2.7% 2/73 • Number of events 2 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).
Injury, poisoning and procedural complications Soft tissue injury	0.00% 0/71 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).	1.4% 1/73 • Number of events 1 • The adverse events were collected in a time span of 6 weeks (starting from the start of treatment to the end of treatment plus one day) The safety analysis set contains all randomised subjects exposed to at least one dose of trial drug(s).

Other adverse events

Adverse event data not reported

Additional Information

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