Effect of Different Insulin Administrations, All in Combination With Metformin, on Glycaemic Control in Subjects With Type 2 Diabetes Inadequately Controlled by Oral Anti-diabetic Drugs

Study Overview
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Brief Summary
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This trial is conducted in Africa. The aim of this clinical trial is to investigate the effect of 50 weeks of treatment with different intensified insulin administrations (all in combination with a fixed dose of metformin) on blood sugar control in subjects with type 2 diabetes inadequately controlled by oral anti-diabetic drugs (OADs).

Official Title
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Effect of 50-week Treatment With Stepwise Insulin Intensification of Basal-bolus Insulin Analogues (Insulin Detemir and Aspart) or Biphasic Insulin Aspart 30 (NovoMix 30) All in Combination With Fixed Dose of Metformin on Glycaemic Control (Measured as HbA1c) in Subjects With Type 2 Diabetes. Open Labelled, Randomized, Two-arm, Parallel Group, Multi-centre, Multi-national Trial

Conditions
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Diabetes, Diabetes Mellitus, Type 2

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject) Diagnosed type 2 diabetes (WHO 1999 criteria) Currently treated with suboptimal daily dose of OADs (mono or combination therapy) for at least 6 months Male or female age at least 18 years old HbA1c at least 7.0 % and maximum 11.0% for subjects treated with metformin mono-therapy, or maximum 10% for subjects treated with OAD combination therapy BMI maximum 40 kg/m^2 Able and willing to perform self-monitoring of plasma glucose according to the protocol and to keep a diary Able and willing to be treated with up to 4 insulin injections per day Exclusion Criteria: Known or suspected allergy to trial product(s) or related products Previous participation in this trial. Participation is defined as randomisation Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice) Participated in another clinical trial and received an investigational drug within the last weeks prior to the present trial Impaired hepatic function defined as alanine aminotransferase (ALT) or alkaline phosphatase (ALP) at least 2.5 times upper referenced limit Impaired renal function defined as serum-creatinine at least 1.3 mg/dL (at least 115 mmol/L) for males and at least 1.2 mg/dL (at least 106 mmol/L) for females Subject has a clinically significant, active (or over the past 12 months) cardiovascular history (including a history of myocardial infarction (MI), arrhythmias or conduction delays on ECG, unstable angina, or decompensated heart failure (New York Heart Association class III and IV) Severe uncontrolled treated or untreated hypertension (sitting systolic blood pressure at least 180 mmHg or sitting diastolic blood pressure at least 100 mmHg) Proliferative retinopathy or macular oedema requiring acute treatment Metformin contraindications according to the package insert Current treatment with systemic corticosteroids Subject has a history of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering study drug to the subject Current addiction to alcohol or other addictive substances as determined by the Investigator Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation in the study or use of the glucose monitor History of hypoglycaemic unawareness and/or two or more severe hypoglycaemic episodes in the past year as judged by the Investigator

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 |
| --- | --- |
| Active Comparator: Detemir + Met<br>Individually adjusted insulin detemir (Detemir) was given subcutaneoulsy (s.c.) at bedtime in the thigh at an initial dose of 0.1 U/kg once daily for 50 weeks in combination with 1000-2000 mg/day metformin (Met). Pending evaluation of HbA1c every 3 months, individually adjusted insulin aspart was added to the insulin detemir treatment (up to three doses daily for maximum 36 weeks, injected s.c. [under the skin]) if treatment target of HbA1c below 7.0% was not reached. | Drug: insulin detemir<br>* Initial dose of 0.1 U/kg once daily, injected s.c. (under the skin).<br>Drug: insulin aspart<br>* Pending evaluation of HbA1c every 3 months, insulin aspart was added to the insulin detemir treatment (up to three does daily, injected s.c. (under the skin)<br>Drug: metformin<br>* 1000-2000 mg/day in combination with insulin treatment<br>|
| Active Comparator: BIAsp 30 + Met<br>Individually adjusted biphasic insulin aspart 30 (BIAsp 30) was given subcutaneously (s.c.) in the abdomen at dinner at an initial dose of 0.1 U/kg once daily for 50 weeks in combination with 1000-2000 mg/day metformin (Met). Pending evaluation of HbA1c every 3 months, the dose was intensified up to 3 doses daily, injected s.c. (under the skin) if treatment target of HbA1c below 7.0% was not reached. | Drug: biphasic insulin aspart 30<br>* Initial dose of 0.1 U/kg once daily, injected s.c. (under the skin). Pending evaluation of HbA1c every 3 months, the dose will intensified up to 3 doses daily<br>Drug: metformin<br>* 1000-2000 mg/day in combination with insulin treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycosylated Haemoglobin (HbA1c) | Estimated mean difference in HbA1c after 50 weeks of treatment | Week 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated Haemoglobin (HbA1c) After 14 Weeks of Treatment | Observed mean change from baseline in HbA1c at Week 14 (visit 11) | Week 0, Week 14 | 
| Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | Observed mean change in from baseline in HbA1c at Week 26 (visit 18) | Week 0, Week 26 | 
| Change in Glycosylated Haemoglobin (HbA1c) After 38 Weeks of Treatment | Observed mean change from baseline in HbA1c at Week 38 (visit 25) | Week 0, Week 38 | 
| Change in Glycosylated Haemoglobin (HbA1c) at Week 50 | Observed mean change from baseline in HbA1c at Week 50 (visit 32) | Week 0, Week 50 | 
| Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 14 Weeks of Treatment | Number of subjects achieving HbA1c below 7.0% after 14 weeks of treatment (visit 11) | Week 14 | 
| Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 26 Weeks of Treatment | Number of subjects achieving HbA1c below 7.0% after 26 weeks of treatment (visit 18) | Week 26 | 
| Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 38 Weeks of Treatment | Number of subjects achieving HbA1c below 7.0% after 38 weeks of treatment (visit 25) | Week 38 | 
| Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 50 Weeks of Treatment | Number of subjects achieving HbA1c below 7.0% after 50 weeks of treatment (visit 32) | Week 50 | 
| Mean of Prandial Plasma Glucose (PG) Increment After 14 Weeks of Treatment | Observed overall mean of PG increment after 14 weeks of treatment (Visit 11). Mean PG Increment was calculated using the average of difference between the Post Prandial and Pre Prandial Glucose values {ie .average of (Post Breakfast - Pre Breakfast), (Post Lunch - Pre Lunch) and (Post Dinner - Pre Dinner)} | Week 14 | 
| Mean of Prandial Plasma Glucose (PG) Increment After 26 Weeks of Treatment | Observed overall mean of PG increment after 26 weeks of treatment (visit 18). Mean PG Increment was calculated using the average of difference between the Post Prandial and Pre Prandial Glucose values {ie .average of (Post Breakfast - Pre Breakfast), (Post Lunch - Pre Lunch) and (Post Dinner - Pre Dinner)} | Week 26 | 
| Mean of Prandial Plasma Glucose (PG) Increment After 38 Weeks of Treatment | Observed overall mean of PG increment after 38 weeks of treatment (visit 25). Mean PG Increment was calculated using the average of difference between the Post Prandial and Pre Prandial Glucose values {ie .average of (Post Breakfast - Pre Breakfast), (Post Lunch - Pre Lunch) and (Post Dinner - Pre Dinner)}. | Week 38 | 
| Mean of Prandial Plasma Glucose (PG) Increment After 50 Weeks of Treatment | Observed overall mean of PG increment after 50 weeks of treatment (visit 32). Mean PG Increment was calculated using the average of difference between the Post Prandial and Pre Prandial Glucose values {ie .average of (Post Breakfast - Pre Breakfast), (Post Lunch - Pre Lunch) and (Post Dinner - Pre Dinner)}. | Week 50 | 
| Mean of 8-point Plasma Glucose (PG) Profile After 14 Weeks of Treatment | Observed overall mean of 8-point PG profile after 14 weeks of treatment (visit 11) | Week 14 | 
| Mean of 8-point Plasma Glucose (PG) Profile After 26 Weeks of Treatment | Observed overall mean of 8-point PG profile after 26 weeks of treatment (visit 18) | Week 26 | 
| Mean of 8-point Plasma Glucose (PG) Profile After 38 Weeks of Treatment | Observed overall mean of 8-point PG profile after 38 weeks of treatment (visit 25) | Week 38 | 
| Mean of 8-point Plasma Glucose (PG) Profile After 50 Weeks of Treatment | Observed overall mean of 8-point PG profile after 50 weeks of treatment (visit 32) | Week 50 |