BI 1356 (Linagliptin) in Combination With Metformin and a Sulphonylurea in 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 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in combination with a sulphonylurea in patients with type 2 diabetes mellitus with insufficient glycaemic control.

Official Title
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A Randomised, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 (5 mg) Administered Orally Once Daily Over 24 Weeks, With an Open-label Extension to One Year (Placebo Patients Switched to BI 1356), in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite a Therapy of Metformin in Combination With a Sulphonylurea

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: linagliptin
* Drug: placebo


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, currently treated only with a stable total daily dose of preferably* >/= 1500 mg metformin and a dose of a sulphonylurea drug that has been documented, by the Investigator, to be the individual maximum tolerated dose of that sulphonylurea drug. Both the dose and dosing regimen of metformin and the sulphonylurea must be stable (i.e. unchanged) for 10 weeks prior to informed consent, and must not be changed for the duration of the trial Glycosylated haemoglobin A1 (HbA1c) >/= 7.0 and </= 10.0% at the screening Visit 1a and at Visit 2 (start of placebo run-in phase) Age >/= 18 and </= 80 years at Visit 1a (screening) BMI (Body Mass Index) </= 40 kg/m2 at Visit 1a (screening) Signed and dated written informed consent, at the latest by the date of Visit 1a, in accordance with GCP and local legislation *Patients currently treated with a total daily dose of less than 1500 mg metformin can be included in the trial if the Investigator has documented that the dose is the maximum tolerated dose of metformin for that patient. Exclusion criteria: Myocardial infarction, stroke or TIA (transient ischaemic attack) within 6 months prior to the date of informed consent Impaired hepatic function, defined by serum levels of either alanine transaminase (ALT/SGPT), aspartase transaminase (AST/SGOT), or alkaline phosphatase (ALP) above 3 times the upper limit of normal (ULN), as determined at Visit 1a Renal failure or renal impairment (serum creatinine >/= 1.5 mg/dl) as determined at Visit 1a Treatment with rosiglitazone or pioglitazone within 3 months prior to the date of informed consent Treatment with GLP-1 analogues (e.g. exenatide) within 3 months prior to the date of informed consent Treatment with insulin within 3 months prior to the date of informed consent Treatment with anti-obesity drugs (e.g. sibutramine, rimonabant, orlistat) within 3 months prior to the date of informed consent Current treatment with systemic steroids (i.e. at the time of informed consent) or a change in the dosage of thyroid hormones within 6 weeks prior to the date of informed consent Pre-menopausal women (last menstruation </= 1 year prior to the date of informed consent) who: are nursing or pregnant or are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to periodic pregnancy testing during their participation in the trial. Acceptable methods of birth control include transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence and vasectomised partner. No exception will be made. Known hypersensitivity or allergy to the investigational product or its excipients or to the trial background therapy (i.e. metformin in combination with a sulphonylurea) or sulphonamides Dehydration (as confirmed by the Investigators clinical opinion) Current acute or chronic metabolic acidosis

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: linagliptin 5 mg<br>linagliptin 5 mg once daily | Drug: linagliptin<br>* active<br>|
| Placebo Comparator: placebo<br>placebo matching linagliptin 5 mg tablets | Drug: placebo<br>* placebo to linagliptin 5 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline to 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 to 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 to 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 to 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 to 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 to 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 to 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 to Week 18 | This change from baseline reflects the Week 18 FPG minus the Week 0 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%. Only patients with baseline HbA1c >= 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 Who Have a HbA1c Lowering by 0.5% at Week 24 | The percentage of patients with an HbA1c reduction greater than 0.5% at week 24 from baseline 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 |