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

Phase 4

Completed

Conditions: Diabetes
Diabetes Mellitus, Type 2

Interventions: Drug: biphasic insulin aspart 30
Drug: insulin detemir
Drug: insulin aspart
Drug: metformin

Registration Number: NCT01068652

Lead Sponsor: Novo Nordisk A/S

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 403

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BIAsp 30 + Met	biphasic insulin aspart 30	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.
Detemir + Met	insulin detemir	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.
Detemir + Met	insulin aspart	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.
Detemir + Met	metformin	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.
BIAsp 30 + Met	metformin	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.

Primary Outcome Measures

Name	Time	Method
Glycosylated Haemoglobin (HbA1c)	Week 50	Estimated mean difference in HbA1c after 50 weeks of treatment

Secondary Outcome Measures

Name	Time	Method
Change in Glycosylated Haemoglobin (HbA1c) After 14 Weeks of Treatment	Week 0, Week 14	Observed mean change from baseline in HbA1c at Week 14 (visit 11)
Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 26 Weeks of Treatment	Week 26	Number of subjects achieving HbA1c below 7.0% after 26 weeks of treatment (visit 18)
Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 50 Weeks of Treatment	Week 50	Number of subjects achieving HbA1c below 7.0% after 50 weeks of treatment (visit 32)
Mean of 8-point Plasma Glucose (PG) Profile After 50 Weeks of Treatment	Week 50	Observed overall mean of 8-point PG profile after 50 weeks of treatment (visit 32)
Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment	Week 0, Week 26	Observed mean change in from baseline in HbA1c at Week 26 (visit 18)
Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 14 Weeks of Treatment	Week 14	Number of subjects achieving HbA1c below 7.0% after 14 weeks of treatment (visit 11)
Change in Glycosylated Haemoglobin (HbA1c) After 38 Weeks of Treatment	Week 0, Week 38	Observed mean change from baseline in HbA1c at Week 38 (visit 25)
Change in Glycosylated Haemoglobin (HbA1c) at Week 50	Week 0, Week 50	Observed mean change from baseline in HbA1c at Week 50 (visit 32)
Number of Subjects Achieving Glycosylated Haemoglobin (HbA1c) Below 7.0% After 38 Weeks of Treatment	Week 38	Number of subjects achieving HbA1c below 7.0% after 38 weeks of treatment (visit 25)
Mean of Prandial Plasma Glucose (PG) Increment After 26 Weeks of Treatment	Week 26	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)}
Mean of 8-point Plasma Glucose (PG) Profile After 26 Weeks of Treatment	Week 26	Observed overall mean of 8-point PG profile after 26 weeks of treatment (visit 18)
Mean of 8-point Plasma Glucose (PG) Profile After 38 Weeks of Treatment	Week 38	Observed overall mean of 8-point PG profile after 38 weeks of treatment (visit 25)
Mean of Prandial Plasma Glucose (PG) Increment After 14 Weeks of Treatment	Week 14	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)}
Mean of Prandial Plasma Glucose (PG) Increment After 38 Weeks of Treatment	Week 38	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)}.
Mean of Prandial Plasma Glucose (PG) Increment After 50 Weeks of Treatment	Week 50	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)}.
Mean of 8-point Plasma Glucose (PG) Profile After 14 Weeks of Treatment	Week 14	Observed overall mean of 8-point PG profile after 14 weeks of treatment (visit 11)