The Effect of Insulin Detemir in Combination With Liraglutide and Metformin Compared to Liraglutide and Metformin in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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This trial is conducted in Europe and North America. The aim of this clinical trial is to assess and compare the effect of insulin detemir in combination with liraglutide and metformin versus liraglutide and metformin in subjects with type 2 diabetes. Subjects will continue their own pre-trial metformin treatment during the trial.

Official Title
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The Effect of Insulin Detemir in Combination With Liraglutide and Metformin Compared to Liraglutide and Metformin in Subjects With Type 2 Diabetes. A 26 Week, Randomised, Open-label, Parallel-group, Multicentre, Multinational Trial With a 26 Week Extension

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: liraglutide
* Drug: insulin detemir
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects diagnosed with type 2 diabetes, insulin naïve and treated with metformin as monotherapy for at least 3 months prior to screening, at a stable dose of at least 1500 mg/day or metformin (at least 1500 mg/day) and a sulfonylurea (less than or equal to half of the maximum approved dose), both at a stable dose for at least 3 months prior to screening. Previous short-term insulin treatment in connection with intercurrent illness is allowed at the discretion of the Investigator HbA1c 7.0-10.0% (both inclusive) for subjects on metformin monotherapy HbA1c 7.0-8.5% (both inclusive) for subjects on metformin in combination with a sulphonylurea Exclusion Criteria: Previous treatment with insulin (except for short-term treatment in connection with intercurrent illness at the discretion of the Investigator) Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria in a period of 3 months prior to screening Recurrent major hypoglycaemia or hypoglycaemic unawareness as judged by the Investigator Impaired kidney function Impaired liver function Uncontrolled treated/untreated hypertension Cancer or any clinically significant disease or disorder as judged by the Investigator Previous participation in the run-in phase of this trial. Re-screening is allowed once History of chronic pancreatitis or idiopathic pancreatitis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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: Lira 1.8<br>Subcutaneous administration of liraglutide 1.8 mg once daily in a forced 12 week run-in period + subject's own pre-trial metformin treatment at an unchanged dose and frequency (at least 1500 mg daily). Initial dose of liraglutide 0.6 mg/day with weekly increments of 0.6 mg until final dose of 1.8 mg/day was reached. Subjects were randomised to continue to receive liraglutide 1.8 mg once daily + metformin for 26 weeks plus 26 weeks extension, when the HbA1c assessment after run-in period was at least 7.0% | Drug: liraglutide<br>* Liraglutide 1.8 mg/day for subcutaneous (under the skin) injection.<br>Drug: metformin<br>* Metformin tablets, at least 1500 mg/day<br>|
| Experimental: Insulin detemir + Lira 1.8<br>Subcutaneous administration of liraglutide 1.8 mg once daily in a forced 12 week run-in period + subject's own pre-trial metformin treatment at an unchanged dose and frequency (at least 1500 mg daily). Initial dose of liraglutide 0.6 mg/day with weekly increments of 0.6 mg until final dose of 1.8 mg/day was reached. Subjects were randomised to continue to receive liraglutide 1.8 mg once daily + metformin in addition to individually adjusted insulin detemir for 26 weeks plus 26 weeks extension, when the HbA1c assessment after run-in period was at least 7.0% | Drug: liraglutide<br>* Liraglutide 1.8 mg/day for subcutaneous (under the skin) injection.<br>Drug: insulin detemir<br>* Insulin detemir subcutaneous (under the skin) injection once daily. Dose will be titrated (individually adjusted) based on fasting self-measured plasma glucose levels according to a pre-specified algorithm<br>Drug: metformin<br>* Metformin tablets, at least 1500 mg/day<br>|
| Experimental: Non-Randomised Lira 1.8<br>Subcutaneous administration of liraglutide 1.8 mg once daily in a forced 12 week run-in period + subject's own pre-trial metformin treatment at an unchanged dose and frequency (at least 1500 mg daily). Initial dose of liraglutide 0.6 mg/day with weekly increments of 0.6 mg until final dose of 1.8 mg/day was reached. Subjects continued to receive liraglutide 1.8 mg once daily + metformin for 26 weeks plus 26 weeks extension, when the HbA1c assessment after run-in period was below 7.0% | Drug: liraglutide<br>* Liraglutide 1.8 mg/day for subcutaneous (under the skin) injection.<br>Drug: metformin<br>* Metformin tablets, at least 1500 mg/day<br>|
| Other: Early Withdrawals Lira 1.8<br>Subcutaneous administration of liraglutide 1.8 mg once daily in a forced 12 week run-in period + subject's own pre-trial metformin treatment at an unchanged dose and frequency (at least 1500 mg daily). Initial dose of liraglutide 0.6 mg/day with weekly increments of 0.6 mg until final dose of 1.8 mg/day was reached. Due to withdrawals in the run-in period, subjects did not receive any further treatment in trial | Drug: liraglutide<br>* Liraglutide 1.8 mg/day for subcutaneous (under the skin) injection.<br>Drug: metformin<br>* Metformin tablets, at least 1500 mg/day<br>|
| Other: Intensified group<br>Intensification of treatment with insulin detemir was offered at Weeks 26 and 38 for subjects with an HbA1c ≥ 8.0% in the randomised Lira 1.8 group and non-randomised liraglutide treatment group. | Drug: liraglutide<br>* Liraglutide 1.8 mg/day for subcutaneous (under the skin) injection.<br>Drug: insulin detemir<br>* Insulin detemir subcutaneous (under the skin) injection once daily. Dose will be titrated (individually adjusted) based on fasting self-measured plasma glucose levels according to a pre-specified algorithm<br>Drug: metformin<br>* Metformin tablets, at least 1500 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Randomisation in Glycosylated Haemoglobin A1c (HbA1c) at Week 26. |  | Week 0 (Randomisation), week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Randomisation in Glycosylated Haemoglobin A1c (HbA1c) at Week 52 (for Intensified Subjects in Original Treatment Group) |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Glycosylated Haemoglobin A1c (HbA1c) at Week 52 (Values Before Intensification as LOCF) |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Fasting Plasma Glucose at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Fasting Plasma Glucose at Week 52 |  | Week 0, Week 52 | 
| Mean Change From Randomisation in 7-point Plasma Glucose Profile (Self-measured) at Week 26 | Calculated as an estimate of the change in mean prandial increment of plasma glucose after breakfast, lunch and dinner (from baseline/randomisation (week 0) to 26 weeks), respectively. Prandial increments of plasma glucose were calculated as the difference between glucose values measured before and after each of these three meals, respectively. | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in 7-point Plasma Glucose Profile (Self-measured) at Week 52 | Calculated as an estimate of the change in mean prandial increment of plasma glucose after breakfast, lunch and dinner (from baseline (week 0) to 52 weeks), respectively. Prandial increments of plasma glucose were calculated as the difference between glucose values measured before and after each of these three meals, respectively. | Week 0, Week 52 | 
| Mean Change From Randomisation in Fasting Insulin at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Fasting Insulin at Week 52 |  | Week 0 (Randomisation), Week 52 | 
| Mean Change From Randomisation in Fasting Pro-insulin at Week 26. |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Fasting Pro-insulin at Week 52 |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Fasting C-peptide at Week 26. |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Fasting C-peptide at Week 52. |  | Week 0, Week 52 | 
| Mean Changes From Randomisation in Cholesterol Lipids at Week 26. | Cholesterol Lipids cover: Total Cholesterol, Low-density Lipoprotein Cholesterol (LDL-C), Very Low Density Lipoprotein Cholesterol (VLDL-C), High Density Lipoprotein Cholesterol (HDL-C) | Week 0 (Randomisation), Week 26 | 
| Mean Changes From Randomisation in Cholesterol Lipids at Week 52. | Cholesterol Lipids cover: Total Cholesterol, Low-density Lipoprotein Cholesterol (LDL-C), Very Low Density Lipoprotein Cholesterol (VLDL-C), High Density Lipoprotein Cholesterol (HDL-C) | Week 0, Week 52 | 
| Mean Change From Randomisation in Lipids: Triglycerides at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Lipids: Triglycerides at Week 52 |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Lipids: Free Fatty Acids (FFA) at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Lipids: Free Fatty Acids (FFA) at Week 52 |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Body Weight at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Body Weight at Week 52 |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Waist Circumference at Week 26. |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Waist Circumference at Week 52. |  | Week 0, Week 52 | 
| Mean Change From Randomisation in Hip Circumference at Week 26 |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Hip Circumference at Week 52 |  | Week 0, week 52 | 
| Mean Change From Randomisation in Waist to Hip Ratio at Week 26 | Waist to Hip Ratio is calculated by dividing Waist circumference with Hip circumference | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Waist to Hip Ratio at Week 52 | Waist to Hip Ratio is calculated by dividing Waist circumference with Hip circumference | Week 0, Week 52 | 
| Mean Change From Randomisation in Blood Pressure (Systolic and Diastolic) at Week 26. |  | Week 0 (Randomisation), Week 26 | 
| Mean Change From Randomisation in Blood Pressure (Systolic and Diastolic) at Week 52. |  | Week 0, Week 52 | 
| Adverse Events From Run-in (Week -12) to Week 52 |  | Run-in (week -12) to Week 52 | 
| Hypoglycaemic Episodes (Excluding Outlier Subject), Weeks 0-26 | Number of hypoglycaemic episodes from Week 0 to Week 26, defined as major, minor, or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. | weeks 0-26 | 
| Hypoglycaemic Episodes Weeks 0-52 | Number of hypoglycaemic episodes from Week 0 to Week 52, defined as major, minor, or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. | Week 0-52 |