To Compare the Effect of Liraglutide When Given Together With Metformin With the Effect of Metformin Given Alone and With the Effect of Glimepiride and Metformin Given Together

Study Overview
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Brief Summary
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This trial is conducted in Europe, Oceania, Africa, Asia and South America. This trial is designed to show the effect of treatment with liraglutide when adding to existing metformin therapy and to compare it with the effects of metformin monotherapy and combination therapy of metformin and glimepiride. Two trial periods: A 6 month (26 weeks) randomised, double-blinded period followed by an 18 months open-label extension, in total 2 years (104 weeks).

Official Title
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Liraglutide Effect and Action in Diabetes (LEAD-2): Effect on Glycaemic Control After Once Daily Administration of Liraglutide in Combination With Metformin Versus Metformin Monotherapy Versus Metformin and Glimepiride Combination Therapy in Subjects With Type 2 Diabetes

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: liraglutide
* Drug: metformin
* Drug: glimepiride
* Drug: placebo
* Drug: placebo
* Drug: liraglutide
* Drug: liraglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects diagnosed with type 2 diabetes and treated with oral anti-diabetic drugs (OADs) for at least 3 months HbA1c: 7.0-11.0 % (both incl.) in subjects on OAD monotherapy. 7.0-10.0 % (both incl.) in subjects on OAD combination therapy Body Mass Index (BMI) less than or equal 40 kg/m2 Exclusion Criteria: Subjects treated with insulin within the last three months Subjects with any serious medical condition Females of child bearing potential who are pregnant, breast-feeding or have the intention of becoming pregnant or not using adequate contraceptive methods Subjects using any drug (except for OADs), which in the Investigator's opinion could interfere with the glucose level (e.g. systemic corticosteroids)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lira 0.6 + Met<br>Liraglutide 0.6 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day | Drug: liraglutide<br>* 0.6 mg for s.c. (under the skin) injection.<br>Drug: metformin<br>* 1.5-2.0 g tablets<br>Drug: placebo<br>* Glimepiride placebo 1 mg and 2 mg tablets<br>|
| Experimental: Lira 1.2 + Met<br>Liraglutide 1.2 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day | Drug: metformin<br>* 1.5-2.0 g tablets<br>Drug: placebo<br>* Glimepiride placebo 1 mg and 2 mg tablets<br>Drug: liraglutide<br>* 1.2 mg for s.c. (under the skin) injection<br>|
| Experimental: Lira 1.8 + Met<br>Liraglutide 1.8 mg/day + glimepiride placebo + metformin 1.5-2.0 g/day | Drug: metformin<br>* 1.5-2.0 g tablets<br>Drug: placebo<br>* Glimepiride placebo 1 mg and 2 mg tablets<br>Drug: liraglutide<br>* 1.8 mg for s.c. (under the skin) injection<br>|
| Active Comparator: Met Mono<br>Metformin 1.5-2.0 g/day + liraglutide placebo + glimepiride placebo | Drug: metformin<br>* 1.5-2.0 g tablets<br>Drug: placebo<br>* Glimepiride placebo 1 mg and 2 mg tablets<br>Drug: placebo<br>* Liraglutide placebo 1-3 mL for s.c. (under the skin) injection<br>|
| Active Comparator: Met + Glim<br>Glimepiride 4 mg/day + metformin 1.5-2.0 g/day + liraglutide placebo | Drug: metformin<br>* 1.5-2.0 g tablets<br>Drug: glimepiride<br>* 4 mg tablets<br>Drug: placebo<br>* Liraglutide placebo 1-3 mL for s.c. (under the skin) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated A1c (HbA1c) at Week 26 | Percentage point change in Glycosylated A1c (HbA1c) from baseline (week 0) to 26 weeks (end of randomisation) | week 0, week 26 | 
| Change in Glycosylated A1c (HbA1c) at Week 104 | Change in glycosylated A1c (HbA1c) baseline (week 0) to 104 weeks (end of randomisation) | week 0, week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight at Week 26 | Change in body weight from baseline (week 0) to 26 weeks (end of randomisation) | week 0, week 26 | 
| Change in Body Weight at Week 104 | Change in body weight from baseline (week 0) to 104 weeks (end of treatment) | week 0, week 104 | 
| Change in Fasting Plasma Glucose (FPG) at Week 26 | Change in fasting plasma glucose (FPG) from baseline (week 0) to 26 weeks (end of randomisation) | week 0, week 26 | 
| Change in Fasting Plasma Glucose (FPG) at Week 104 | Change in Fasting plasma glucose (FPG) from baseline (week 0) to 104 weeks (end of treatment) | week 0, week 104 | 
| Change in Mean Prandial Increments of Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 26 | Change in mean prandial increments of plasma glucose based on self-measured 7-point plasma glucose profiles from baseline (week 0) to 26 weeks (end of randomisation). The 7 time points for self-measurements were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner) and at bedtime. Mean prandial increments of plasma glucose were calculated as the sum of the plasma glucose differences between values measured before and after a meal (breakfast, lunch and dinner) divided by three. | week 0, week 26 | 
| Change in Mean Prandial Increments of Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 104 | Change in mean prandial increments of plasma glucose based on self-measured 7-point plasma glucose profiles from baseline (week 0) to 104 weeks (end of treatment). The 7 time points for self-measurements were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner) and at bedtime. Mean prandial increments of plasma glucose were calculated as the sum of the plasma glucose differences between values measured before and after a meal (breakfast, lunch and dinner) divided by three. | week 0, week 104 | 
| Change in Mean Post Prandial Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 26 | Change in mean post prandial plasma glucose from baseline (Week 0) to 26 weeks (end of randomisation). The 7 time points for self-measurements were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner) and at bedtime. Mean post prandial plasma glucose were calculated as the sum of the post pradial plasma glucose values divided by three. | week 0, week 26 | 
| Change in Mean Post Prandial Plasma Glucose Based on Self-measured 7-point Plasma Glucose Profiles at Week 104 | Change in mean post prandial plasma glucose from baseline (Week 0) to 104 weeks (end of treatment) The 7 time points for self-measurements were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner) and at bedtime. Mean post prandial plasma glucose were calculated as the sum of the post pradial plasma glucose values divided by three. | week 0, week 104 | 
| Change in Beta-cell Function at Week 26 | Change in beta cell function from baseline (week 0) to 16 weeks (end of treatment). Beta-cell function was derived from fasting plasma glucose (FPG) and fasting insulin concentrations using the homeostasic model assessment (HOMA) method which uses the assumption that normal-weight normal subjects aged under 35 years have a 100% beta-cell function (HOMA-B). Beta-cell function: HOMA-B (%) = 20∙fasting insulin[uU/mL] divided by (FPG mmol/L]-3.5). | week 0, week 26 | 
| Change in Beta-cell Function at Week 104 | Change in beta cell function from baseline (week 0) to 16 weeks (end of treatment). Beta-cell function was derived from fasting plasma glucose (FPG) and fasting insulin concentrations using the homeostasic model assessment (HOMA) method which uses the assumption that normal-weight normal subjects aged under 35 years have a 100% beta-cell function (HOMA-B). Beta-cell function: HOMA-B (%) = 20∙fasting insulin[uU/mL] divided by (FPG mmol/L]-3.5). | week 0, week 104 | 
| Hypoglycaemic Episodes at Week 26 | Total number of hypoglycaemic episodes occuring after baseline (week 0) until week 26 (end of randomisation). Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. | weeks 0-26 | 
| Hypoglycaemic Episodes at Week 104 | Total number of hypoglycaemic episodes occuring after baseline (week 0) until 104 weeks (end of treatment). Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. | weeks 0-104 |