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

Phase 3

Completed

Conditions: Diabetes
Diabetes Mellitus, Type 2

Interventions: Drug: liraglutide
Drug: insulin detemir
Drug: metformin

Registration Number: NCT00856986

Lead Sponsor: Novo Nordisk A/S

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 987

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intensified group	metformin	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.
Lira 1.8	liraglutide	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%
Lira 1.8	metformin	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%
Insulin detemir + Lira 1.8	insulin detemir	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%
Insulin detemir + Lira 1.8	liraglutide	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%
Insulin detemir + Lira 1.8	metformin	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%
Non-Randomised Lira 1.8	liraglutide	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%
Early Withdrawals Lira 1.8	liraglutide	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
Non-Randomised Lira 1.8	metformin	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%
Intensified group	liraglutide	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.
Early Withdrawals Lira 1.8	metformin	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
Intensified group	insulin detemir	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.

Primary Outcome Measures

Name	Time	Method
Mean Change From Randomisation in Glycosylated Haemoglobin A1c (HbA1c) at Week 26.	Week 0 (Randomisation), week 26

Secondary Outcome Measures

Name	Time	Method
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 Insulin at Week 52	Week 0 (Randomisation), Week 52
Mean Change From Randomisation in Waist Circumference at Week 26.	Week 0 (Randomisation), Week 26
Mean Change From Randomisation in Blood Pressure (Systolic and Diastolic) at Week 26.	Week 0 (Randomisation), Week 26
Mean Change From Randomisation in Fasting C-peptide at Week 26.	Week 0 (Randomisation), Week 26
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 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	Week 0 (Randomisation), 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.
Mean Change From Randomisation in 7-point Plasma Glucose Profile (Self-measured) at Week 52	Week 0, 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.
Mean Change From Randomisation in Fasting Insulin at Week 26	Week 0 (Randomisation), Week 26
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 Lipids: Free Fatty Acids (FFA) at Week 52	Week 0, Week 52
Mean Change From Randomisation in Fasting C-peptide at Week 52.	Week 0, Week 52
Mean Changes From Randomisation in Cholesterol Lipids at Week 52.	Week 0, 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)
Mean Change From Randomisation in Body Weight at Week 52	Week 0, Week 52
Mean Change From Randomisation in Hip Circumference at Week 52	Week 0, week 52
Mean Changes From Randomisation in Cholesterol Lipids at Week 26.	Week 0 (Randomisation), 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)
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 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 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	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.
Mean Change From Randomisation in Waist to Hip Ratio at Week 26	Week 0 (Randomisation), Week 26	Waist to Hip Ratio is calculated by dividing Waist circumference with Hip circumference
Mean Change From Randomisation in Waist to Hip Ratio at Week 52	Week 0, Week 52	Waist to Hip Ratio is calculated by dividing Waist circumference with Hip circumference
Mean Change From Randomisation in Lipids: Free Fatty Acids (FFA) at Week 26	Week 0 (Randomisation), Week 26
Mean Change From Randomisation in Body Weight at Week 26	Week 0 (Randomisation), Week 26
Hypoglycaemic Episodes Weeks 0-52	Week 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.