To Evaluate the Effect of Liraglutide Versus Glimepiride (Amaryl®) on Haemoglobin A1c

Study Overview
=================
Brief Summary
-----------------
This trial is conducted in North America (the United States of America (USA) and Mexico). The trial is designed to evaluate the effects of treatment with liraglutide versus glimepiride in subjects with type 2 diabetes. The trial is a 52-week randomised, double-blind trial period plus a 52-week open-label extension (week 104) followed by an additional 156-week continued open-label extension. The total duration of the treatment period is planned to be 260 weeks (5 years).

Official Title
-----------------
Liraglutide Effect and Action in Diabetes (LEAD-3): Effect on Glycemic Control of Liraglutide Versus Glimepiride in Type 2 Diabetes

Conditions
-----------------
Diabetes, Diabetes Mellitus, Type 2

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetes TTreatment with diet/exercise or with not more than half maximal dose of oral anti-diabetic drugs alone for at least 2 months Diet/exercise treated subjects with HbA1c between 7.0% and 11%, inclusive OAD (oral anti-diabetic drug) treated subjects with HbA1c between 7.0% and 10%, inclusive Body Mass Index (BMI) less than or equal to 45 kg/m^2 Exclusion Criteria: Treatment with insulin for the last 3 months, except short-term treatment for intercurrent illness Treatment with any drug that could interfere with the glucose level (besides use of a single anti-diabetic compound) Any serious medical condition

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lira 1.8<br>Liraglutide 1.8 mg once daily + glimepiride placebo 8 mg once daily, weeks 0-52 (double-blinded period) and open-label liraglutide 1.8 mg once daily in the extension periods (weeks 52-195). | Drug: liraglutide<br>* 1.8 mg for s.c. (under the skin) injection<br>Drug: placebo<br>* Glimepiride placebo, 8mg capsule<br>|
| Experimental: Lira 1.2<br>Liraglutide 1.2 mg once daily + glimepiride placebo 8 mg once daily, weeks 0-52 (double-blinded period) and open-label liraglutide 1.2 mg once daily in the extension periods (weeks 52-195). | Drug: liraglutide<br>* 1.2 mg for s.c. (under the skin) injection<br>Drug: placebo<br>* Glimepiride placebo, 8mg capsule<br>|
| Active Comparator: Glimepiride - 1<br>Glimepiride 8 mg once daily + liraglutide placebo 200 mcl, weeks 0-52 (double-blinded period) and open-label glimepiride 8 mg once daily in the extension periods (weeks 52-195). | Drug: glimepiride<br>* 8 mg capsule<br>Drug: placebo<br>* Liraglutide placebo, 200 mcl<br>|
| Active Comparator: Glimepiride - 2<br>Glimepiride 8 mg once daily + liraglutide placebo 300 mcl, weeks 0-52 (double-blinded period) and open-label glimepiride 8 mg once daily in the extension periods (weeks 52-195). | Drug: glimepiride<br>* 8 mg capsule<br>Drug: placebo<br>* Liraglutide placebo, 300 mcl<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycosylated Haemoglobin A1c (HbA1c) at Week 52 | Percentage point change in Glycosylated Haemoglobin A1c (HbA1c) from baseline (week 0) to 52 weeks (end of double-blind period) | week 0, week 52 | 
| Change in Glycosylated Haemoglobin A1c (HbA1c) at Week 104 | Percentage point change in Glycosylated Haemoglobin A1c (HbA1c) from baseline (week 0) to 104 weeks (end of 52-week extension) | week 0, week 104 | 
| Change in Glycosylated Haemoglobin A1c (HbA1c) at Week 156 | Percentage point change in Glycosylated Haemoglobin A1c (HbA1c) from baseline (week 0) to 156 weeks | week 0, week 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight at Week 52 | Change in body weight from baseline (week 0) to 52 weeks (end of double-blind period) | week 0, week 52 | 
| Change in Body Weight at Week 104 | Change in body weight from baseline (week 0) to 104 weeks (end of 52-week extension) | week 0, week 104 | 
| Change in Body Weight at Week 156 | Change in body weight from baseline (week 0) to 156 weeks | week 0, week 156 | 
| Change in Fasting Plasma Glucose at Week 52 | Change in fasting plasma glucose (FPG) from baseline (week 0) to 52 weeks (end of double-blind period) | week 0, week 52 | 
| Change in Fasting Plasma Glucose at Week 104 | Change in fasting plasma glucose (FPG) from baseline (week 0) to 104 weeks (end of 52-week extension) | week 0, week 104 | 
| Change in Fasting Plasma Glucose at Week 156 | Change in fasting plasma glucose (FPG) from baseline (week 0) to 156 weeks | week 0, week 156 | 
| Change in Mean Postprandial Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 52 | Change in mean postprandial glucose (PPG) based on self-measured 8-point plasma glucose profiles from baseline (week 0) to 52 weeks (end of double-blind period). The 8 time points for self-measurements of plasma glucose were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. | week 0, week 52 | 
| Change in Mean Postprandial Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 104 | Change in mean postprandial glucose (PPG) based on self-measured 8-point plasma glucose profiles from baseline (week 0) to 104 weeks (end of 52-week extension). The 8 time points for self-measurements of plasma glucose were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. | week 0, week 104 | 
| Change in Mean Postprandial Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 156 | Change in mean postprandial glucose (PPG) based on self-measured 8-point plasma glucose profiles from baseline (week 0) to 156 weeks. The 8 time points for self-measurements of plasma glucose were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. | week 0, week 156 | 
| Change in Prandial Increments of Plasma Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 52 | Change in mean prandial increments of plasma glucose from baseline (week 0) to 52 weeks (end of double-blind period). The 8 time points for self-measured 8-point plasma glucose profiles were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. Mean prandial increments of plasma glucose were calculated as the sum of the plasma glucose differences between post- and pre-meal values (for breakfast, lunch and dinner) divided by three. | week 0, week 52 | 
| Change in Prandial Increments of Plasma Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 104 | Change in mean prandial increments of plasma glucose from baseline (week 0) to 104 weeks (end of 52-week extension). The 8 time points for self-measured 8-point plasma glucose profiles were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. Mean prandial increments of plasma glucose were calculated as the sum of the plasma glucose differences between post- and pre-meal values (for breakfast, lunch and dinner) divided by three. | week 0, week 104 | 
| Change in Prandial Increments of Plasma Glucose Based on Self-measured 8-point Plasma Glucose Profiles at Week 156 | Change in mean prandial increments (incr.) of plasma glucose from baseline (week 0) to 156 weeks. The 8 time points for self-measured 8-point plasma glucose profiles were: before each meal (breakfast, lunch and dinner), at 90 min after start of each meal (breakfast, lunch and dinner), at bedtime, and at 3:00 AM ± 30 min. Mean prandial increments of plasma glucose were calculated as the sum of the plasma glucose differences between post- and pre-meal values (for breakfast, lunch and dinner) divided by three. | week 0, week 156 | 
| Hypoglycaemic Episodes | Total number of hypoglycaemic episodes occuring from baseline (week 0) to 104 weeks (end of the 52-week extension). 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 56 mg/dL. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 56 mg/dL. | weeks 0-104 | 
| Hypoglycaemic Episodes | Total number of hypoglycaemic episodes occuring from week 104 to end of trial (week 195). 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 56 mg/dL. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 56 mg/dL. | weeks 104-195 |