Safety and Efficacy of Linagliptin in Type-2-diabetes Mellitus Patients With Moderate to Severe Renal Impairment

Study Overview
=================
Brief Summary
-----------------
The objective of the current study is to investigate the efficacy, safety and tolerability of linagliptin (5 mg / once daily) compared to placebo given over 12 weeks in drug naive or previously treated type 2 diabetic patients with moderate to severe renal impairment and insufficient glycaemic control. In addition safety in this patient population with longer term (40 week) treatment in comparison to sulfonylurea drug (glimepiride).

Official Title
-----------------
A Phase III, Randomised, Double-blind, Placebo-controlled Parallel Group Safety and Efficacy Study of Linagliptin (5 mg Administered Orally Once Daily) Over 12 Weeks Followed by a 40 Week Double-blind Extension Period (Placebo Patients Switched to Glimepiride) in Drug Naive or Previously Treated Type 2 Diabetic Patients With Moderate to Severe Renal Impairment and Insufficient Glycaemic Control

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

Intervention / Treatment
-----------------
* Drug: Glimepiride
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Linagliptin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Type 2 diabetes mellitus GFR<60 ml/min HbA1c >=7.0% to <= 10% Age >= 18 years BMI <=45 kg/m2 Signed and dated written informed consent Exclusion criteria: Myocardial infarction, stroke or TIA within 3 months prior to informed consent Renal impairment requiring dialysis Bariatric surgery Impaired hepatic function Treatment with glitazones, GLP-1 analogues, DPP-4 inhibitors Treatment with anti-obesity drugs Treatment with SU, glinides and metformin 8 weeks prior to informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 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>52 weeks treatment | Drug: Placebo<br>* Placebo maching Glimepiride 1-4 mg after 12 weeks of treatment<br>Drug: Linagliptin<br>* 5 mg once daily<br>|
| Placebo Comparator: Placebo<br>First 12 weeks of treatment | Drug: Placebo<br>* Placebo mach to 5 mg linagliptin first 12 weeks of treatment once daily<br>|
| Active Comparator: Glimepiride<br>Placebo patients switch to glimepiride after 12 weeks (40 weeks treatment) | Drug: Glimepiride<br>* 1-4 mg daily after 12 weeks<br>Drug: Placebo<br>* Placebo mach to 5 mg linagliptin once daily after 12 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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, renal function impairment and prior use of antidiabetic agents. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline Over Time | HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent over time minus the baseline HbA1c percent. This outcome measure only provides descriptive statistics without any modelling. | Baseline, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 34, week 40, week 46, week 52 | 
| Fasting Plasma Glucose (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 prior use of insulin, week repeated within patient and week by treatment interaction. | Baseline and week 12 | 
| Fasting Plasma Glucose (FPG) Change From Baseline Over Time | This change from baseline reflects the FPG over time minus the baseline FPG. This outcome measure only provides descriptive statistics without any modelling. | Baseline, week 4, week 8, week 12, week 20, week 24, week 28, week 34, week 40, week 46, week 52 | 
| Percentage of Patients With HbA1c <7.0% | The percentage of patients with an HbA1c value below 7% at week 12 and week 52 were calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively, they were considered a failure, so HbA1c above 7%. | Baseline, week 12 and week 52 | 
| Percentage of Patients With HbA1c <6.5% | The percentage of patients with an HbA1c value below 6.5% at week 12 and week 52 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c above 6.5%. | Baseline, week 12 and week 52 | 
| Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | The percentage of patients with an HbA1c reduction of ≥0.5% at week 12 and week 52 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c reduction less than 0.5%. | Baseline, week 12 and week 52 | 
| Plasma Concentration of Linagliptin at Trough | Trough levels of concentration of Linagliptin in plasma. | Week 12, 24 and 52 |