The Effect of Liraglutide Compared to Sitagliptin, Both in Combination With Metformin on Glycaemic Control in Subjects With Type 2 Diabetes Mellitus

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 trial is to compare the effect on blood sugar control of liraglutide or sitagliptin, both in combination with metformin, in subjects with type 2 diabetes inadequately controlled with metformin alone. The trial has been extended by 52 weeks. The extension will consist of two 26-week periods: Week 27-52 after randomisation - All subjects will continue receiving sitagliptin or liraglutide at unchanged dose and dosing regimen. Week 53-78 after randomisation Subjects receiving sitagliptin at the end of week 52 after randomisation will discontinue sitagliptin and will be randomised 1:1 to liraglutide 1.2 mg/day or liraglutide 1.8 mg/day. Liraglutide will be initiated at a dose of 0.6 mg/day, and increased to 1.2 mg/day or 1.8 mg/day in weekly intervals. Subjects receiving liraglutide 1.2 mg/day or 1.8 mg/day at the end of week 52 after randomisation will continue the treatment at unchanged dose and dosing regimen. Trial completion is planned for June 2010.

Official Title
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The Effect of Liraglutide Compared to Sitagliptin, Both in Combination With Metformin in Subjects With Type 2 Diabetes. A 26-week, Randomised, Open-label, Active Comparator, Three-armed, Parallel-group, Multi-centre, Multinational Trial With a 52-week Extension

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: liraglutide
* Drug: sitagliptin
* Drug: metformin
* Drug: liraglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes Treatment with metformin alone for at least three months HbA1c (glycosylated haemoglobin A1c) 7.5-10.0% (both inclusive) Body Mass Index (BMI) less than or equal to 45.0 Exclusion Criteria: Previous treatment with insulin, glucagon like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors Treatment with anti-diabetic drugs other than metformin within the last three months Any serious medical condition Females who are pregnant, have the intention of becoming pregnant or are breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 1.2 mg -> Lira 1.2 mg -> Lira 1.2 mg<br>Once-daily subcutaneous dose of liraglutide 1.2 mg with at least 1500 mg metformin/day (tablets) for 26 weeks. First week for up-titration of liraglutide from 0.6 mg to 1.2 mg. Subjects continued to receive liraglutide 1.2 mg once daily in extension period 1 (weeks 26-52) and extension period 2 (weeks 52-78). | Drug: liraglutide<br>* 1.2 mg once daily, subcutaneous (under the skin) injection<br>Drug: metformin<br>* Tablets, minimum 1500 mg daily<br>|
| Experimental: Lira 1.8 mg -> Lira 1.8 mg -> Lira 1.8 mg<br>Once-daily subcutaneous dose of liraglutide 1.8 mg with at least 1500 mg metformin/day (tablets) for 26 weeks. First 2 weeks for up-titration of liraglutide from 0.6 mg to 1.8 mg. Subjects continued to receive liraglutide 1.8 mg once daily in extension period 1 (weeks 26-52) and extension period 2 (weeks 52-78). | Drug: metformin<br>* Tablets, minimum 1500 mg daily<br>Drug: liraglutide<br>* 1.8 mg once daily, subcutaneous (under the skin) injection<br>|
| Active Comparator: Sita -> Sita<br>Once-daily dose of sitagliptin 100 mg (tablets) with at least 1500 mg metformin/day (tablets) for 26 weeks. Subjects continued to receive 100 mg sitagliptin once daily in extension period 1 (weeks 26-52). | Drug: sitagliptin<br>* Tablets, 100 mg daily<br>Drug: metformin<br>* Tablets, minimum 1500 mg daily<br>|
| Experimental: Sita -> Sita -> Lira 1.2 mg<br>Once-daily dose of sitagliptin 100 mg (tablets) with at least 1500 mg metformin/day (tablets) for 26 weeks. Subjects continued to receive 100 mg sitagliptin once daily in extension period 1 (weeks 26-52). In extension period 2 (weeks 52-78), subjects were randomised to liraglutide 1.2 mg + metformin. | Drug: liraglutide<br>* 1.2 mg once daily, subcutaneous (under the skin) injection<br>Drug: sitagliptin<br>* Tablets, 100 mg daily<br>Drug: metformin<br>* Tablets, minimum 1500 mg daily<br>|
| Experimental: Sita -> Sita -> Lira 1.8 mg<br>Once-daily dose of sitagliptin 100 mg (tablets) with at least 1500 mg metformin/day (tablets) for 26 weeks. Subjects continued to receive 100 mg sitagliptin once daily in extension period 1 (weeks 26-52). In extension period 2 (weeks 52-78), subjects were randomised to liraglutide 1.8 mg + metformin. | Drug: sitagliptin<br>* Tablets, 100 mg daily<br>Drug: metformin<br>* Tablets, minimum 1500 mg daily<br>Drug: liraglutide<br>* 1.8 mg once daily, subcutaneous (under the skin) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 26 | Calculated as an estimate of the mean change from baseline in glycosylated haemoglobin A1c (HbA1c) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 52 | Calculated as an estimate of the mean change from baseline in glycosylated haemoglobin A1c (HbA1c) at Week 52. | Week 0, Week 52 | 
| Mean Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 78 | Calculated as an estimate of the mean change from baseline in glycosylated haemoglobin A1c (HbA1c) at Week 78. | Week 0, Week 78 | 
| Mean Change in Glycosylated Haemoglobin A1c (HbA1c) From Week 52 to Week 78 | Mean Change in Glycosylated Haemoglobin A1c (HbA1c) from Week 52 to Week 78 | Week 52, Week 78 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Achieving Treatment Target of HbA1c < 7.0% at Week 26 | Calculated as the percentage of subjects achieving treatment target of HbA1c < 7.0% at Week 26 | Week 0, Week 26 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c < 7.0% at Week 52 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c < 7.0% at Week 52 | Week 0, Week 52 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c < 7.0% at Week 78 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c < 7.0% at Week 78. Based on the FAS. | Week 0, Week 78 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c < 7.0% at Week 78 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c < 7.0% at Week 78. Based on the extension 2 FAS. | Week 0, Week 78 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c =< 6.5% at Week 26 | Calculated as the percentage of subjects achieving treatment target of HbA1c =< 6.5% at Week 26 | Week 0, Week 26 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c =< 6.5% at Week 52 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c =< 6.5% at Week 52 | Week 0, Week 52 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c =< 6.5% at Week 78 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c =< 6.5% at Week 78. Based on the FAS. | Week 0, Week 78 | 
| Percentage of Subjects Achieving Treatment Target of HbA1c =< 6.5% at Week 78 | Calculated as an estimate of the percentage of subjects achieving treatment target of HbA1c =< 6.5% at Week 78. Based on the extension 2 FAS. | Week 0, Week 78 | 
| Mean Change From Baseline in Body Weight at Week 26 | Calculated as an estimate of the mean change from baseline in body weight at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Body Weight at Week 52 | Calculated as an estimate of the mean change from baseline in body weight at Week 52. | Week 0, Week 52 | 
| Mean Change in Body Weight From Week 52 to Week 78 | Mean change in body weight from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Calculated as an estimate of the mean change from baseline in fasting plasma glucose (FPG) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52 | Calculated as an estimate of the mean change from baseline in fasting plasma glucose (FPG) at Week 52. | Week 0, Week 52 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 78 | Calculated as an estimate of the mean change in fasting plasma glucose (FPG) from baseline to Week 78. | Week 0, Week 78 | 
| Mean Change in Fasting Plasma Glucose (FPG) From Week 52 to Week 78 | Mean change in fasting plasma glucose (FPG) Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Beta-cell Function at Week 26 | Calculated as an estimate of the mean change from baseline in beta-cell function at Week 26. Derived from fasting plasma glucose (FPG) and fasting insulin using the homeostatic model assessment (HOMA) method with the assumption that normal-weight subjects aged under 35 years have a 100% beta-cell function (HOMA-B). | Week 0, Week 26 | 
| Mean Change From Baseline in Beta-cell Function at Week 52 | Calculated as an estimate of the mean change from baseline in beta-cell function at Week 52. Derived from fasting plasma glucose (FPG) and fasting insulin using the homeostatic model assessment (HOMA) method with the assumption that normal-weight subjects aged under 35 years have a 100% beta-cell function (HOMA-B). | Week 0, Week 52 | 
| Mean Change in Beta-cell Function From Week 52 to Week 78 | Mean change in beta-cell function from Week 52 to Week 78. Derived from fasting plasma glucose (FPG) and fasting insulin using the homeostatic model assessment (HOMA) method with the assumption that normal-weight subjects aged under 35 years have a 100% beta-cell function (HOMA-B). | Week 52, Week 78 | 
| Mean Change From Baseline in Total Cholesterol at Week 26 | Calculated as an estimate of the mean change from baseline in total cholesterol at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Total Cholesterol at Week 52 | Calculated as an estimate of the mean change from baseline in total cholesterol at Week 52. | Week 0, Week 52 | 
| Mean Change in Total Cholesterol From Week 52 to Week 78 | Mean change in total cholesterol from Week 52 to Week 78 | Week 52, Week 78 | 
| Mean Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C) at Week 26 | Calculated as an estimate of the mean change in low-density lipoprotein-cholesterol (LDL-C) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C) at Week 52 | Calculated as an estimate of the mean change in low-density lipoprotein-cholesterol (LDL-C) at Week 52. | Week 0, Week 52 | 
| Mean Change in Low-density Lipoprotein-cholesterol (LDL-C) From Week 52 to Week 78 | Mean change in low-density lipoprotein-cholesterol (LDL-C) from week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in High-density Lipoprotein-cholesterol (HDL-C) at Week 26 | Calculated as an estimate of the mean change from baseline in high-density lipoprotein-cholesterol (HDL-C) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in High-density Lipoprotein-cholesterol (HDL-C) at Week 52 | Calculated as an estimate of the mean change from baseline in high-density lipoprotein-cholesterol (HDL-C) at Week 52. | Week 0, Week 52 | 
| Mean Change in High-density Lipoprotein-cholesterol (HDL-C) From Week 52 to Week 78 | Mean change in high-density lipoprotein-cholesterol (HDL-C) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) at Week 26 | Calculated as an estimate of the change from baseline in very low-density lipoprotein-cholesterol (VLDL-C) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Very Low-density Lipoprotein-cholesterol (VLDL-C) at Week 52 | Calculated as an estimate of the change from baseline in very low-density lipoprotein-cholesterol (VLDL-C) at Week 52. | Week 0, Week 52 | 
| Mean Change in Very Low-density Lipoprotein-cholesterol (VLDL-C) at Week 52 to Week 78 | Mean change in very low-density lipoprotein-cholesterol (VLDL-C) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Triglycerides (TG) at Week 26 | Calculated as an estimate of the change from baseline in triglycerides (TG) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Triglycerides (TG) at Week 52 | Calculated as an estimate of the change from baseline in triglycerides (TG) at Week 52. | Week 0, Week 52 | 
| Mean Change in Triglycerides (TG) From Week 52 to Week 78 | Mean change in triglycerides (TG) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Free Fatty Acids (FFA) at Week 26 | Calculated as an estimate of the change from baseline in free fatty acids (FFA) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Free Fatty Acids (FFA) at Week 52 | Calculated as an estimate of the change from baseline in free fatty acids (FFA) at Week 52. | Week 0, Week 52 | 
| Mean Change in Free Fatty Acids (FFA) From Week 52 to Week 78 | Mean change in free fatty acids (FFA) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Apolipoprotein B at Week 26 | Calculated as an estimate of the change from baseline in apolipoprotein B (ApoB) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Apolipoprotein B at Week 52 | Calculated as an estimate of the change from baseline in apolipoprotein B (ApoB) at Week 52. | Week 0, Week 52 | 
| Mean Change in Apolipoprotein B From Week 52 to Week 78 | Mean change in apolipoprotein B (ApoB) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Highly Sensitive C-reactive Protein (hsCRP) at Week 26 | Calculated as an estimate of the mean change from baseline in highly sensitive C-reactive protein (hsCRP) at week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at Week 26. | Calculated as an estimate of the mean change from baseline in plasminogen activator inhibitor-1 (PAI-1) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Interleukin-6 (IL-6) at Week 26. | Calculated as an estimate of the mean change from baseline in interleukin-6 (IL-6) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Week 26. | Calculated as an estimate of the mean change from baseline in N-terminal pro B-type Natriuretic Peptide (NT-proBNP) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Adiponectin at Week 26. | Calculated as an estimate of the mean change from baseline in Adiponectin at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Tumour Necrosis Factor Alpha (TNF-alpha) at Week 26. | Calculated as an estimate of the mean change from baseline in Tumour Necrosis Factor Alpha (TNF-alpha) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Von Willebrand Factor (vWf) at Week 26. | Calculated as an estimate of the mean change from baseline in von Willebrand Factor (vWf) at Week 26. vWf is a blood glycoprotein involved in haemostasis. | Week 0, Week 26 | 
| Mean Change From Baseline in Waist to Hip Ratio at Week 26. | Calculated as an estimate of the mean change from baseline in Waist to Hip Ratio at Week 26. The measure is assessed as the circumference of the waist divided by the circumference of the hip. | Week 0, Week 26 | 
| Mean Change From Baseline in Waist to Hip Ratio at Week 52 | Calculated as an estimate of the mean change from baseline in Waist to Hip Ratio at Week 52. The measure is assessed as the circumference of the waist divided by the circumference of the hip. | Week 0, Week 52 | 
| Mean Change in Waist to Hip Ratio From Week 52 to Week 78 | Mean change in Waist to Hip Ratio from Week 52 to Week 78. The measure is assessed as the circumference of the waist divided by the circumference of the hip. | Week 52, Week 78 | 
| Mean Change From Baseline in Waist Circumference at Week 26. | Calculated as an estimate of the mean change from baseline in Waist Circumference at Week 26 | Week 0, Week 26 | 
| Mean Change From Baseline in Waist Circumference at Week 52 | Calculated as an estimate of the mean change from baseline in Waist Circumference at Week 52. | Week 0, Week 52 | 
| Mean Change in Waist Circumference From Week 52 to Week 78 | Mean change in Waist Circumference from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Systolic Blood Pressure (SBP) at Week 26 | Calculated as an estimate of the mean change from baseline in Systolic Blood Pressure (SBP) at Week 26 | Week 0, Week 26 | 
| Mean Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 | Calculated as an estimate of the mean change from baseline in systolic blood pressure (SBP) at Week 52. | Week 0, Week 52 | 
| Mean Change in Systolic Blood Pressure (SBP) From Week 52 to Week 78 | Mean change in systolic blood pressure (SBP) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Diastolic Blood Pressure (DBP) at Week 26 | Calculated as an estimate of the mean change from baseline in diastolic blood pressure (DBP) at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Diastolic Blood Pressure (DBP) at Week 52 | Calculated as an estimate of the mean change from baseline in diastolic blood pressure (DBP) at Week 52. | Week 0, Week 52 | 
| Mean Change in Diastolic Blood Pressure (DBP) From Week 52 to Week 78 | Mean change in diastolic blood pressure (DBP) from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Pulse at Week 26 | Calculated as an estimate of the mean change from baseline in pulse at Week 26. | Week 0, Week 26 | 
| Mean Change From Baseline in Pulse at Week 52 | Calculated as an estimate of the mean change from baseline in pulse at Week 52. | Week 0, Week 52 | 
| Mean Change in Pulse From Week 52 to Week 78 | Mean change in pulse from Week 52 to Week 78. | Week 52, Week 78 | 
| Mean Change From Baseline in Overall Treatment Satisfaction (OTS) at Week 26 | The Overall Treatment Satisfaction is a sum of 6 items from the Diabetes Treatment Satisfaction Questionnaire, which is a self-assessment of treatment satisfaction. The scale of each sub-item goes from 0 (lowest satisfaction) to 6 (highest satisfaction) and the overall scale of OTS therefore goes from 0 to 36. | Week 0, Week 26 | 
| Mean Change From Baseline in Overall Treatment Satisfaction (OTS) at Week 52 | The Overall Treatment Satisfaction is a sum of 6 items from the Diabetes Treatment Satisfaction Questionnaire, which is a self-assessment of treatment satisfaction. The scale of each sub-item goes from 0 (lowest satisfaction) to 6 (highest satisfaction) and the overall scale of OTS therefore goes from 0 to 36. | Week 0, Week 52 | 
| Mean Change in Overall Treatment Satisfaction (OTS) From Week 52 to Week 78 | The Overall Treatment Satisfaction is a sum of 6 items from the Diabetes Treatment Satisfaction Questionnaire, which is a self-assessment of treatment satisfaction. The scale of each sub-item goes from 0 (lowest satisfaction) to 6 (highest satisfaction) and the overall scale of OTS therefore goes from 0 to 36. | Week 52, Week 78 | 
| Hypoglyceamic Episodes, 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 (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 | 
| Hypoglyceamic 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. | Weeks 0-52 | 
| Hypoglycaemic Episodes (Excluding Outlier Subject), 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. | Weeks 0-52 | 
| Hypoglyceamic Episodes, Weeks 0-78 | Number of hypoglycaemic episodes from Week 0 to Week 78, 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 0-78 | 
| Hypoglycaemic Episodes (Excluding Outlier Subject), Weeks 0-78 | Number of hypoglycaemic episodes from Week 0 to Week 78, 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 0-78 | 
| Hypoglycaamic Episodes, Weeks 52-78 | Number of hypoglycaemic episodes from Week 52 to Week 78, 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 52-78 |