Efficacy and Safety Study of Linagliptin (5 mg Administered Orally Once Daily) Over 24 Weeks in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite Metformin Therapy

Study Overview
=================
Brief Summary
-----------------
In this randomised, double-blind, parallel group trial, the safety and efficacy of 5 mg of Linagliptin administered orally once daily will be compared with a placebo after 24 weeks of treatment as add-on therapy to metformin in patients with type 2 diabetes and insufficient glycaemic control.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 Over 24 Weeks in T2D Patients With Insufficient Glycaemic Control Despite Metformin Therapy

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

Intervention / Treatment
-----------------
* Drug: Linagliptin
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Male and female patients with a diagnosis of type 2 diabetes mellitus and previously treated with metformin alone, or with metformin and not more than one other oral antidiabetic drug (antidiabetic therapy has to be unchanged for 6 weeks prior to informed consent and patients should receive standard diet and exercise counseling) A dose of >/=1500 mg/day metformin is required for inclusion into the trial. The dosage needs to be stable for at least 8 weeks before randomisation. Patients with a total daily dose of less than 1500 mg metformin will only be included; if the investigator has documented them to be on their maximum tolerated dose (also in this case the 8 week time interval will apply for a stable dose). Diagnosis of type 2 diabetes prior to informed consent Glycosylated haemoglobin A1 (HbA1c) at Visit 1a (Screening): For patients undergoing wash out of previous medication: HbA1c =7.0 to =9.5% For patients not undergoing wash-out of previous medication: HbA1c =7.0 to =10.0% Glycosylated haemoglobin A1 (HbA1c) =7.0 to =10.0% at Visit 2 (Start of Run-in) Age = 18 and < 80 years at Visit 1a (Screening) BMI (Body Mass Index) = 45 kg/m2 at Visit 1a (Screening) Signed and dated written informed consent by date of Visit 1a in accordance with GCP and local legislation Exclusion criteria: Myocardial infarction, stroke or TIA within 6 months prior to informed consent Impaired hepatic function, defined by serum levels of either Alanine transaminase,Aspartate transaminase, or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at Visit 1a Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during wash-out / placebo run-in and confirmed by a second measurement (not on the same day). Known hypersensitivity or allergy to the investigational product or its excipients or metformin or placebo Treatment with rosiglitazone or pioglitazone within 3 months prior to informed consent Treatment with an injectable Glucagon-like peptide- 1 (GLP-1) analogue (e.g. exenatide) , Dipeptidyl-Peptidase 4 (DPP-IV) inhibitor within 3 months prior to informed consent Treatment with insulin within 3 months prior to informed consent Treatment with anti-obesity drugs (e.g. sibutramine, orlistat, rimonabant) within 3 months prior to informed consent. Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or drug abuse Participation in another trial with an investigational drug within 2 months prior to informed consent Pre-menopausal women (last menstruation =1 year prior to 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 submit to periodic pregnancy testing during 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. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. Renal failure or renal impairment (serum creatinine =1.5 mg/dl as determined at Visit 1a) Dehydration by clinical judgement of the investigator Unstable or acute congestive heart failure Acute or chronic metabolic acidosis (present in patient history) Hereditary galactose intolerance

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: Linagliptin<br>once a day | Drug: Linagliptin<br>* once a day<br>|
| Placebo Comparator: placebo<br>once a day | Drug: placebo<br>* once a day<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline at Week 24 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and at week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline at Week 6 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and at week 6 | 
| HbA1c Change From Baseline at Week 12 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and at week 12 | 
| HbA1c Change From Baseline at Week 18 | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and at week 18 | 
| HbA1c Change From Baseline at Week 24(Chinese Only) | Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. | Baseline and at 24 weeks | 
| FPG Change From Baseline at Week 24 | Means are treatment adjusted for baseline fasting plasma glucose (FPG) and previous anti-diabetic medication. | Baseline and at week 24 | 
| FPG Change From Baseline at Week 6 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. | Baseline and at week 6 | 
| FPG Change From Baseline at Week 12 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. | Baseline and at week 12 | 
| FPG Change From Baseline at Week 18 | Means are treatment adjusted for baseline FPG and previous anti-diabetic medication. | Baseline and at week 18 | 
| Number of Patients With HbA1c < 7.0% | Number of patients with HbA1c < 7.0% at week 24 | baseline and at week 24 | 
| Number of Patients With HbA1c < 7.0% at Week 24 With Baseline HbA1c >= 7.0%. | Number of patients with HbA1c < 7.0% at week 24 with baseline HbA1c >= 7.0%. | baseline and at week 24 | 
| Number of Patients With HbA1c < 6.5% | Number of patients with HbA1c < 6.5% at week 24 | baseline and at week 24 | 
| Number of Patients With HbA1c < 6.5% at Week 24 With Baseline HbA1c >= 6.5%. | Number of patients with HbA1c < 6.5% at week 24 with baseline HbA1c >= 6.5%. | baseline and at week 24 | 
| Number With HbA1c at Least Lowering 0.5% | Number with HbA1c at least 0.5% lowering from baseline at week 24 | baseline and at week 24 |