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

Study Overview
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Brief Summary
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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.

Official Title
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Comparison of the Efficacy on Glycaemic Control and Safety Profile of Biphasic Insulin Aspart 30 and Biphasic Human Insulin 30 Both in Combination With Metformin in Insulin-naïve Subjects With Type 2 Diabetes Mellitus Inadequately Controlled on Oral Antidiabetic Drugs (OADs) Therapy

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: biphasic insulin aspart 30
* Drug: biphasic human insulin 30
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIAsp 30<br>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. | Drug: biphasic insulin aspart 30<br>* 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<br>Drug: metformin<br>* Metformin dose must remain the same as that used prior to the trial.<br>|
| Experimental: BHI 30<br>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. | Drug: biphasic human insulin 30<br>* 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<br>Drug: metformin<br>* Metformin dose must remain the same as that used prior to the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Week 0, week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 0, Week 6 | 
| 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. | Week 6 | 
| 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. | Week 0, week 6 | 
| 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. | Week 0, Week 6 | 
| 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. | Week 0, Week 6 | 
| 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. | Week 0, Week 6 | 
| 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 | Week 0, Week 6 | 
| 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. | Week -2, week 6 | 
| Change in Glycosylated Haemoglobin (HbA1c) |  | Week -2, week 6 | 
| 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). | 72-hour monitoring period at Week 0 and Week 6 | 
| 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. | Weeks 0-6 |