Safety and Efficacy of Linagliptin (BI 1356) Plus Metformin in Type 2 Diabetes, Factorial Design

Study Overview
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Brief Summary
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The objective of the randomised part of the study is to investigate the efficacy and safety of BI 1356 plus metformin compared to BI 1356 or metformin alone given for 24 weeks to drug naive or previously treated (4 weeks wash-out, 2 weeks placebo run-in) type 2 diabetic patients with insufficient glycaemic control. For the open-label part of the study the objective is to estimate the efficacy and safety of BI 1356 and metformin in type 2 diabetic patients with very poor glycaemic control for 24 weeks

Official Title
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A Phase III Randomised, Double-blind, Placebo-controlled Parallel Group Study to Compare the Efficacy and Safety of Twice Daily Administration of the Free Combination of BI 1356 2.5 mg + Metformin 500 mg, or of BI 1356 2.5 mg + Metformin 1000 mg, With the Individual Components of Metformin (500 mg or 1000 mg Twice Daily), and BI 1356 (5.0 mg Once Daily) Over 24 Weeks in Drug Naive or Previously Treated (4 Weeks Wash-out and 2 Weeks Placebo run-in) Type 2 Diabetic Patients With Insufficient Glycaemic Control

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI 1356
* Drug: BI 1356 + metformin
* Drug: Bi 1356 + metformin
* Drug: Metformin
* Drug: metformin
* Drug: matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with type 2 diabetes (drug naive or pre-treated) with insufficient glycaemic control (HbA1c higher or equal than 7.5 to less than 11.0 %), with very poor glycaemic control (HbA1c higher or equal than 11.0 %) who are not eligible for randomisation to be included in the open-label arm Exclusion criteria: Myocardial infarction, stroke or transient ischemic attack (TIA), unstable or acute congestive heart failure, impaired hepatic function, treatment with rosiglitazone or pioglitazone, with a GLP1 analogue, with insulin, with anti-obesity drugs, with systemic steroids, renal failure or impairment, gastric bypass

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 + metformin<br>BI 1356 low dose + metformin 500 mg, twice daily | Drug: BI 1356 + metformin<br>* BI 1356 low dose tablet + Metformin 500 mg tablet, twice daily<br>|
| Placebo Comparator: matching placebo<br>matching placebo | Drug: matching placebo<br>* matching placebo<br>|
| Experimental: BI 1356+ Metformin<br>BI 1356 low dose + metformin 1000 mg, twice daily | Drug: Bi 1356 + metformin<br>* BI 1356 low dose tablet + Metformin 1000 mg tablet, twice daily<br>|
| Active Comparator: Metformin<br>Metformin 500 mg, twice daily | Drug: Metformin<br>* Metformin 500 mg tablet, twice daily<br>|
| Active Comparator: metformin<br>Metformin 1000 mg, twice daily | Drug: metformin<br>* metformin 1000 mg tablet, twice daily<br>|
| Experimental: BI 1356<br>BI 1356 high dose, once daily | Drug: BI 1356<br>* BI 1356 high dose tablet, once daily<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 24 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline at Week 6 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and week 6 | 
| HbA1c Change From Baseline at Week 12 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and week 12 | 
| HbA1c Change From Baseline at Week 18 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and week 18 | 
| FPG Change From Baseline at Week 24 | This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. | Baseline and week 24 | 
| FPG Change From Baseline at Week 2 | This change from baseline reflects the Week 2 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. | Baseline and week 2 | 
| FPG Change From Baseline at Week 6 | This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. | Baseline and week 6 | 
| FPG Change From Baseline at Week 12 | This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. | Baseline and week 12 | 
| FPG Change From Baseline at Week 18 | This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. | Baseline and week 18 | 
| Percentage of Patients With HbA1c <7.0% at Week 24 | The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. | Baseline and Week 24 | 
| Percentage of Patients With HbA1c<7.0 at Week 24 | The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. | Baseline and Week 24 | 
| Percentage of Patients With HbA1c <6.5% at Week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%. Only patients with baseline HbA1c =< 6.5% | Baseline and Week 24 | 
| Percentage of Patients With HbA1c < 6.5% at Week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5% | Baseline and Week 24 | 
| Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | The percentage of patients with an HbA1c reduction from baseline greater than 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%. | Baseline and week 24 | 
| Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline 2h PPG and previous anti-diabetic medication. | Baseline and week 24 | 
| HbA1c Change From Baseline at Week 24 for Open-label Patients | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percentage. Mean is unadjusted. | Baseline and week 24 | 
| FPG Change From Baseline at Week 24 for Open-label Patients | This change from baseline reflects the Week 24 FPG minus the baseline FPG. Mean is unadjusted. | Baseline and week 24 | 
| Use of Rescue Therapy | The use of rescue therapy (SUs, thiazolidinediones [TZDs], or insulin) was permitted only during the randomised treatment period of the trial (i.e. Visits 3 to 7), and was to be administered only if a patient had a 'confirmed' glucose level after an overnight fast. | 24 weeks |