Linagliptin 2.5 mg Twice Daily Versus 5 mg Once Daily as add-on Therapy to Twice Daily Metformin in Type 2 Diabetes

Study Overview
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Brief Summary
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The objective of the study is to investigate the efficacy and safety of linagliptin 2.5 mg twice daily compared to 5 mg once daily compared to placebo given orally for 12 weeks as add-on therapy to metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control. It is planned to show non-inferiority of linagliptin 2.5 mg twice daily compared to 5 mg once daily and each treatment's superiority over placebo.

Official Title
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12 Week Randomised Double-blind BI 1356 2.5 mg Bid vs 5 mg qd add-on to Metformin

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: linagliptin low dose
* Drug: placebo
* Drug: linagliptin medium dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Diagnosis of type 2 diabetes mellitus. Current treatment with metformin alone (>/= 1500 mg or maximally tolerated dose) or metformin plus 1 other antidiabetic drug. Metformin must be administered in twice daily dosing regimen. Patients taking metformin three times daily can be included if posology is switched to twice daily and total daily dose is maintained. Glycosylated haemoglobin (HbA1c) is between 7.0% - 10.0%. Body Mass Index (BMI) </=45 kg/m2. Exclusion criteria Treatment with extended release metformin. Uncontrolled hyperglycaemia (fasting plasma glucose > 240 mg/dL or 13.3 mmol/L). Myocardial infarction (MI), stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent. Impaired hepatic or renal function, or gastric bypass surgery. Treatment with glitazones, glucagon like peptide-1 (GLP-1) analogues/mimetics, antiobesity agents, or insulin within 3 months of informed consent. Current treatment with systemic steroids or change in dosage of thyroid hormones. Alcohol or drug abuse within 3 months of informed consent. Participation in another trial with investigational drug within 2 months prior to informed consent. Pre-menopausal women who are nursing, pregnant or not practicing an acceptable method of birth control.

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 low dose<br>linagliptin low dose twice daily | Drug: linagliptin low dose<br>* patient to receive tablets containing low dose linagliptin twice daily<br>|
| Placebo Comparator: placebo<br>placebo matching linagliptin | Drug: placebo<br>* patient to receive placebo tablet(s) matching linagliptin<br>|
| Experimental: linagliptin medium dose<br>linagliptin medium dose once daily | Drug: linagliptin medium dose<br>* patient to receive a tablet containing medium dose linagliptin 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 12 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Treatment means are adjusted for baseline HbA1c and use of prior oral antidiabetics (OADs) in addition to background metformin. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. | Baseline and week 6 | 
| HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. | Baseline and week 12 | 
| FPG Change From Baseline at Week 12 | Change from baseline reflects the Week 12 FPG minus the baseline FPG. Treatment means are adjusted for baseline HbA1c, baseline fasting plasma glucose and use of prior oral antidiabetics (OADs) in addition to background metformin. | Baseline and week 12 | 
| FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. | Baseline and week 6 | 
| FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. | Baseline and week 12 | 
| Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12 | Percentage of patients with HbA1c lowering by at least 0.5% after 12 weeks. The analysis was performed on the full analysis set (FAS) using NCF. | Week 12 | 
| Percentage of Patients With Rescue Therapy | Percentage of patients with rescue therapy at Week 12. The analysis was performed on the full analysis set (FAS) using OC. | 12 weeks | 
| The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment | Percentage of those patients with baseline HbA1c >= 7.0% who had HbA1c < 7% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF. | 12 weeks | 
| The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment | Percentage of those patients with baseline HbA1c >= 6.5% who had HbA1c < 6.5% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF. | 12 weeks |