Comparison of Insulin Detemir, Insulin Aspart and Biphasic Insulin Aspart 30 With OAD Treatment in Type 2 Diabetes

Study Overview
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Brief Summary
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This trial is conducted in Europe. The aim of this research study is to compare the efficacy (reduction in HbA1c and in blood glucose levels) of insulin detemir, insulin aspart and biphasic insulin aspart 30, when added to current OAD (oral anti-diabetic drug) treatment in subjects with type 2 diabetes and to verify the safety of use (number and severity of episodes of hypoglycaemia, body weight and side effects).

Official Title
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A 36-month, Multi-centre, Open-label, Randomised, Parallel-group Trial Comparing the Safety, Efficacy and Durability of Adding a Basal Insulin Versus a Twice Daily Insulin Mixture Versus a Meal-time Rapid-Acting Insulin in Subjects With Type 2 Diabetes Inadequately Controlled on Therapy With Oral Agents, and Assessing the Requirement for More Complex Insulin Regimens to Achieve and Maintain Glycaemic Control, Their Efficacy and Durability

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: biphasic insulin aspart
* Drug: insulin detemir
* Drug: insulin aspart


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes Insulin naive On OAD treatment for at least 4 months with metformin, a sulphonylurea or a combination Body Mass Index (BMI) below or equal to 40.0 kg/m2 HbA1c (glycosylated haemoglobin): 7.0%-10% (both inclusive) Exclusion Criteria: Proliferative retinopathy Recurrent major hypoglycaemia Cardial problems Uncontrolled hypertension Impaired hepatic or renal function

Ages Eligible for Study
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Minimum Age: 18 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: Insulin detemir (basal insulin)<br>Individually adjusted insulin detemir injected subcutaneously once daily before bed and administered in combination with current OAD treatment. Subjects had the option to add a second pre-breakfast basal insulin analogue injection if pre-breakfast but not pre-dinner meal plasma glucose targets were met. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin detemir once (or twice) daily were asked to add insulin aspart three times daily with meals i.e. a basal-bolus insulin analogue regimen. | Drug: insulin detemir<br>* Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, once or twice daily plus option for insulin aspart<br>|
| Active Comparator: Insulin aspart (prandial insulin)<br>Individually adjusted insulin aspart injected subcutaneously at meal-times (breakfast, lunch and dinner) and administered in combination with current OAD treatment. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to insulin aspart three times a day with meals were asked to add insulin detemir once or twice daily i.e. a basal-bolus insulin analogue regimen. | Drug: biphasic insulin aspart<br>* Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, once or twice daily plus option for insulin aspart<br>|
| Active Comparator: Biphasic insulin aspart 30 (biphasic insulin)<br>Individually adjusted biphasic insulin aspart 30 injected subcutaneously twice daily with meals (breakfast and dinner) and administered in combination with current OAD treatment. In the second and third years, a second insulin formulation was added if subjects failed to achieve or to maintain good glycaemic control, defined as two consecutive HbA1c measurements exceeding 6.5% or a single measurement exceeding 7.5%. Subjects randomised to biphasic insulin aspart twice daily were asked to add insulin aspart at lunchtime (midday) i.e. an augmented pre-mixed insulin analogue regimen. | Drug: insulin aspart<br>* Treat-to-target (individually adjusted dose), subcutaneously (under the skin) injection, twice daily plus option for insulin detemir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c (Glycosylated Haemoglobin) at Month 12 | HbA1c values offer evidence of the efficacy and durability of the insulin regimens. | Baseline, Month 12 | 
| HbA1c (Glycosylated Haemoglobin) at Month 36 | HbA1c values offer evidence of the efficacy and durability of the insulin regimens. | Baseline, Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants (Total Participants and the Subset of Participants Who Did Not Have an Hypoglycaemic Episode) Achieving a Month 12 Value in HbA1c Below or Equal to 6.5% | Two participant counts are listed. The first is the percentage of total participants who achieved the target (HbA1c below or equal to 6.5%) at Month 12. The second is the percentage of subset of participants who achieved the target and did not have either minor or major hypoglycaemic episode within the four weeks prior to the month 12 exam. Minor hypoglycaemic episode is an episode in which the participant was able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major hypoglycaemic episode is an episode in which the participant was unable to treat her/himself. | Month 12 | 
| Percentage of Participants Achieving a Month 36 Value in HbA1c Below or Equal to 6.5% | Percentage of participants who achieved the target (HbA1c below or equal to 6.5%) at Month 36 | Month 36 | 
| Number of Hypoglycaemic Events Per Participant Per Year at Month 12 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5% | Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%. | Month 12 | 
| Number of Hypoglycaemic Events Per Participant Per Year at Month 36 for All Participants and the Subset Who Achieved Target HbA1c Below or Equal to 6.5% | Rate of hypoglycaemic events was calculated as the median number of events per participant per year, defined as grade 1 (symptoms only), 2 (minor) and 3 (major). Symptoms only if self-measured plasma glucose level of 3.1 mmol/L (56 mg/dL) or more. Minor (grade 2) if able to treat her/himself and plasma glucose was below 3.1 mmol/L (56 mg/dL). Major (grade 3) if unable to treat her/himself. Rates are reported for all participants and for the subset of participants who achieved target HbA1c below or equal to 6.5%. | Month 36 | 
| Percentage of Participants Who Required A Second Insulin Therapy by Month 12 | Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens. | Month 12 | 
| Percentage of Participants Who Required A Second Insulin Therapy by Month 36 | Percentage of participants who required a second insulin formulation to be added to their treatment. This outcome offers evidence to the efficacy and durability of the insulin regimens. | Month 36 | 
| Change From Baseline in Body Weight at Month 12 |  | Week 0 (baseline), month 12 | 
| Change From Baseline in Body Weight at Month 36 |  | Week 0 (baseline), month 36 | 
| Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 12 Months | For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group. | Baseline, month 12 | 
| Change in Eight-point Capillary Plasma Glucose Profiles (Self-measured) at 36 Months | For each visit and telephone contact, participants were asked to perform in advance three capillary glucose profiles (using blood glucose metre provided for the trial) obtained before breakfast and before the evening meal for participants in the biphasic and basal groups and before meals and two hours after meals and at bedtime in the prandial group. | Baseline, month 36 | 
| Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 12 Months | The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death. | Month 12 | 
| Quality of Life as Measured by the EuroQol Group 5-Dimension Self-Report Questionnaire Score (EQ5D) at 36 Months | The EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ5D) is a standardised instrument for use as a measure of health outcome in medical research. Responses can be used to generate a single numerical value associated with a given health state. The scale of values is graded from -0.59 to 1.00, with lower scores indicating a poorer health status. A score of 0 represents no quality of life and scores less than 0 represent states perceived by the respondent to be worse than death. | Month 36 | 
| Number of Participants Having an 'Other' Adverse Event |  | Up to month 37 (36 months of treatment plus 1 month follow-up) |