Efficacy and Safety of BI 1356 in Combination With Metformin in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5.0 mg daily) compared to glimepiride given for 104 weeks as add-on therapy to preferably > 1500 mg metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control

Official Title
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A Randomised Double-blind, Active-controlled Parallel Group Efficacy and Safety Study of BI 1356 ( 5.0 mg, Administered Orally Once Daily) Compared to Glimepiride Over Two Years in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite Metformin Therapy

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo identical to BI 1356 5mg
* Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg
* Drug: BI 1356
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female patients with a diagnosis of type 2 diabetes mellitus and previously treated with metformin alone or with metformin and one other oral antidiabetic drug Glycosylated haemoglobin (HbA1c) 6.0 - 9.0% at screening for patients treated with metformin and one other oral antidiabetic drug HbA1c 6.5 - 10.0% at screening for patients treated with metformin alone HbA1c 6.5 - 10.0% at beginning of the placebo run-in phase Exclusion criteria: Myocardial infarction, stroke or transient ischemic attack (TIA) Impaired hepatic function Renal failure or renal impairment Treatment with rosiglitazone or pioglitazone within 6 months prior to screening Treatment with insulin or glucagon-like peptide 1 (GLP-1) analogue/antagonists within 3 months prior to screening

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: BI 1356 5mg, once daily<br>patient to receive a tablet containing 5mg BI 1356 plus one (two in US) inactive placebo capsule matching Glimepiride | Drug: Placebo identical to Glimepiride 1mg or 2mg or 3mg or 4 mg<br>* Placebo tablets once daily<br>Drug: BI 1356<br>* 5mg, once daily in the morning for 104 weeks<br>|
| Active Comparator: Glimepiride<br>patient to receive 1mg or 2mg or 3mg (not in US) or 4mg Glimepiride capsule plus one inactive placebo tablet matching BI 1356 (plus one inactive placebo capsule in US) | Drug: Placebo identical to BI 1356 5mg<br>* Placebo tablet once daily<br>Drug: Glimepiride<br>* 1mg or 2mg or 3mg or 4mg in the morning for 104 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline at Week 52 | This co-primary endpoint, change from baseline, reflects the Week 52 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications. | Baseline and week 52 | 
| HbA1c Change From Baseline at Week 104 | This co-primary endpoint, change from baseline, reflects the Week 104 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and the number of previous anti-diabetic medications. | Baseline and week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight Change From Baseline at Week 52 | This key secondary endpoint, change from baseline, reflects the Week 52 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications. | Baseline and week 52 | 
| Body Weight Change From Baseline at Week 104 | This key secondary endpoint, change from baseline, reflects the Week 104 body weight minus the baseline body weight. Means are treatment adjusted for baseline HbA1c, baseline weight and the number of previous antidiabetic-medications. | Baseline and week 104 | 
| Incidence of Hypoglycaemic Events up to 52 Weeks | A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a home blood glucose monitoring (HBGM) of below 55 mg/dl (3.1 mmol/L) | Week 52 | 
| Incidence of Hypoglycaemic Events up to 104 Weeks | A hypoglycaemic event is defined as patient showing clinical signs suggestive of low blood glucose confirmed by a HBGM of below 55 mg/dl (3.1 mmol/L) | Week 104 | 
| Fasting Plasma Glucose (FPG) Change From Baseline at Week 52 | This change from baseline reflects the Week 52 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and the number of previous anti-diabetic medications. | Baseline and week 52 | 
| Fasting Plasma Glucose (FPG) Change From Baseline at Week 104 | This change from baseline reflects the Week 104 FPG minus the Baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and number of previous anti-diabetic medications. | Baseline and week 104 | 
| Percentage of Patients With HbA1c <7.0% at Week 52 | The percentage of patients with an HbA1c value below 7.0% at week 52, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications. | Week 52 | 
| Percentage of Patients With HbA1c <7.0% at Week 104 | The percentage of patients with an HbA1c value below 7.0% at week 104, based upon patients with baseline HbA1c >= 7%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 7.0%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications. | Week 104 | 
| Percentage of Patients With HbA1c <6.5% at Week 52 | The percentage of patients with an HbA1c value below 6.5% at week 52, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 52 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications. | Week 52 | 
| Percentage of Patients With HbA1c <6.5% at Week 104 | The percentage of patients with an HbA1c value below 6.5% at week 104, based upon patients with baseline HbA1c >= 6.5%. If a patient did not have an HbA1c value at week 104 they were considered a failure, so HbA1c >= 6.5%. The logistic regression is treatment adjusted for baseline HbA1c and number of previous anti-diabetic medications. | Week 104 | 
| Percentage of Patients With HbA1c Lowering by 0.5% at Week 104 | Occurrence of relative efficacy response, defined as a lowering of 0.5% HbA1c at week 104 | Week 104 | 
| 2 hr Postprandial Glucose (PPG) Change From Baseline at Week 104 | This change from baseline reflects the Week 104 2 hr PPG minus the Baseline 2hr PPG. Means are treatment adjusted for baseline HbA1c, baseline 2hr PPG and number of previous anti-diabetic medications. | Baseline and week 104 | 
| HbA1c Change at Week 4 | Difference of base percent value [Week x(%) - baseline (%)] | Baseline and week 4 | 
| HbA1c Change at Week 8 |  | Baseline and week 8 | 
| HbA1c Change at Week 12 |  | Baseline and week 12 | 
| HbA1c Change at Week 16 |  | Baseline and week 16 | 
| HbA1c Change at Week 28 |  | Baseline and week 28 | 
| HbA1c Change at Week 40 |  | Baseline and week 40 | 
| HbA1c Change at Week 52 |  | Baseline and week 52 | 
| HbA1c Change at Week 65 |  | Baseline and week 65 | 
| HbA1c Change at Week 78 |  | Baseline and week 78 | 
| HbA1c Change at Week 91 |  | Baseline and week 91 | 
| HbA1c Change at Week 104 | The Full Analysis Set (FAS) included all treated and randomized patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last observation carried forward (LOCF) was used as imputation rule. | Baseline and week 104 | 
| Change in Baseline Lipid Parameter Cholesterol at Week 104 |  | Baseline and week 104 | 
| Change in Baseline Lipid Parameter HDL at Week 104 |  | Baseline and week 104 | 
| Change in Baseline Lipid Parameter Low Density Lipoprotein (LDL) at Week 104 |  | Baseline and week 104 | 
| Change in Baseline Lipid Parameter Triglyceride at Week 104 |  | Baseline and week 104 |