30 Week Parallel Group Comparison Study of Linagliptin + Pioglitazone (5+15, 5+30 and 5+45 mg) qd Versus Respective Monotherapies, Followed by a Comparison of 5mg+30mg and 5mg+45mg Versus Respective Monotherapies in Type 2 Diabetes for up to 54 Weeks

Study Overview
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Brief Summary
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The primary objective is to demonstrate superior glycaemic control (HbA1c reduction) after 30 weeks of linagliptin/pioglitazone (5/15, 5/30 and 5/45 mg) versus the respective individual monotherapies of pioglitazone (15 mg, 30 mg, or 45 mg, administered orally once daily), and linagliptin (5 mg, administered orally once daily). In addition, durability of treatment effect and safety under chronic treatment conditions will be investigated.

Official Title
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A Randomised, Double-blind Parallel Group Study to Compare the Efficacy and Safety of Initial Combination Therapy With Linagliptin 5 mg + Pioglitazone 15 mg, 30 mg, or 45 mg, vs. Monotherapy With Pioglitazone (15 mg, 30 mg, or 45 mg) or Linagliptin 5 mg Once Daily for 30 Weeks, Followed by a Blinded Trial Period on Linagliptin 5 mg + Pioglitazone 30 or 45 mg Versus Pioglitazone Monotherapy 30 or 45 mg or Linagliptin 5 mg for up to 54 Weeks in Type 2 Diabetic Patients With Insufficient Glycaemic Control on Diet and Exercise

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Pioglitazone 15 mg
* Drug: Pioglitazone 45 mg
* Drug: Pioglitazone 30 mg
* Drug: Linagliptin 5mg / Pioglitazone 45 mg FDC
* Drug: Linagliptin 5mg / Pioglitazone 30 mg FDC
* Drug: Linagliptin 5mg
* Drug: Linagliptin 5mg / Pioglitazone 15 mg FDC


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of type 2 diabetes mellitus prior to informed consent Male and female patients with insufficient glycaemic control (HbA1c >= 7.0 to <= 10.5% at Visit 2) on diet and exercise alone, without oral antidiabetic drug therapy within 10 weeks prior to start of the run-in period (date of Visit 2) Age >= 18 and <= 80 years at start date of Visit 1 (Screening) BMI <= 45 kg/m2 (Body Mass Index) at start date of Visit 1 (Screening) Signed and dated written informed consent by start date of Visit 1 in accordance with GCP and local legislation Exclusion criteria: Uncontrolled hyperglycaemia with a confirmed glucose level > 240 mg/dl (> 13.3 mmol/l) after an overnight fast during screening or placebo run-in period (cf. Section 3.3.4.1) Myocardial infarction within 6 months, stroke or TIA within 3 months prior to informed consent Clinical evidence of active liver disease (e.g. jaundice) or the ALT level > 2.5 times the upper limit of normal (according to pioglitazone label) Bariatric surgery, performed within the past 2 years prior to informed consent or planned at the time of informed consent Gastrointestinal surgeries prior to informed consent that induce chronic malabsorption Known hypersensitivity or allergy to the investigational products (linagliptin and/or pioglitazone) or their excipients (including matching placebos) Contraindications to pioglitazone as defined in the local prescribing information (SPC), particularly : Diagnose of heart failure or history of heart failure Haemodialysis patients, due to limited experience with pioglitazone Treatment with gemfibrozil, montelukast, trimethoprim, or rifampicin - according to pioglitazone label and respective restrictions in Section 4.2.2 Treatment with rosiglitazone, pioglitazone, GLP-1 analogues, or insulin within 3 months prior to informed consent Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent Alcohol or drug abuse within the 3 months prior to informed consent or history of alcoholism Current treatment with systemic corticosteroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent Participation in another trial with an investigational drug within 30 days prior to informed consent Any other clinical condition as judged by the investigator that would not allow the safe completion of the protocol, e.g. inability of patients to comply with study procedures Pre-menopausal women (last menstruation <= 1 year prior to informed consent) who: are nursing or pregnant or are of child-bearing potential (i.e. not permanently sterilised) and are not practicing a highly effective 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. A highly effective method of birth control is defined - according to the Note for Guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) - as those which result in a low failure rate (i. e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal intrauterine devices/systems (IUDs/IUSs), sexual abstinence or vasectomised partner Symptomatic gallbladder disease in the last six months Medical history of pancreatitis. Patients with urinary bladder cancer or a history of urinary bladder cancer or uninvestigated macroscopic haematuria Any other contraindication or restriction for use of pioglitazone in accordance with the local prescribing information for pioglitazone.

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 |
| --- | --- |
| Active Comparator: Pioglitazone 15 mg<br>Pioglitazone Capsules 15 mg once daily | Drug: Pioglitazone 15 mg<br>* Pioglitazone Capsules 15 mg once daily for 30 weeks followed by Pioglitazone Capsules 30 mg once daily for up to 54 weeks<br>|
| Active Comparator: Pioglitazone 30 mg<br>Pioglitazone Capsules 30 mg once daily | Drug: Pioglitazone 30 mg<br>* Pioglitazone Capsules 30 mg once daily for up to 84 weeks<br>|
| Active Comparator: Pioglitazone 45 mg<br>Pioglitazone Capsules 45 mg once daily | Drug: Pioglitazone 45 mg<br>* Pioglitazone Capsules 30 mg once daily for 6 weeks followed by Pioglitazone Capsules 45 mg once daily for up to 78 weeks<br>|
| Active Comparator: Linagliptin 5mg<br>Linagliptin 5mg Tablets once daily | Drug: Linagliptin 5mg<br>* Linagliptin 5mg Tablets low dose once daily for 30 weeks followed by Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 54 weeks<br>|
| Experimental: Linagliptin 5mg / Pioglitazone 15 mg<br>Linagliptin 5mg / Pioglitazone 15 mg Tablets once daily | Drug: Linagliptin 5mg / Pioglitazone 15 mg FDC<br>* Linagliptin 5mg low dose / Pioglitazone 15 mg FDC Tablets once daily for 30 weeks followed by Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 54 weeks<br>|
| Experimental: Linagliptin 5mg / Pioglitazone 30 mg<br>Linagliptin 5mg / Pioglitazone 30 mg Tablets once daily | Drug: Linagliptin 5mg / Pioglitazone 30 mg FDC<br>* Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 84 weeks<br>|
| Experimental: Linagliptin 5mg / Pioglitazone 45 mg<br>Linagliptin 5mg / Pioglitazone 45 mg Tablets once daily | Drug: Linagliptin 5mg / Pioglitazone 45 mg FDC<br>* Linagliptin 5mg low dose / Pioglitazone 30 mg Tablets once daily for 6 weeks followed by Linagliptin 5mg low dose / Pioglitazone 45 mg FDC Tablets once daily for up to 78 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c After 30 Weeks of Treatment. | HbA1c is measured as a percentage. The change from baseline is the Week 30 HbA1c minus the baseline HbA1c. | Baseline and 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. | Baseline and 30 weeks | 
| Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. | Baseline and 30 weeks | 
| Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment) | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin. | Baseline and 30 weeks | 
| HbA1c Change From Baseline by Visit Over Time | HbA1c is measured as a percentage. The change from baseline is the HbA1c over time minus the baseline HbA1c. The model includes fixed effects for treatment, continuous baseline HbA1c, prior andi-diabetic medication, country, visit and treatment. by visit interaction. | Baseline, week 6, week 12, week 18, week 24, week 30 | 
| Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment | The change from baseline is the FPG after 30 weeks minus the baseline FPG. | Baseline and 30 weeks | 
| Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time | The change from baseline is the FPG over time minus the baseline FPG. Model includes fixed effects for treatment, continuous baseline FPG, continuous baseline HbA1c, prior anti-diabetic medication, country, visit and treatment by visit interaction | Baseline, week 6, week 12, week 18, week 24, week 30 | 
| Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT) | The change from baseline is the 2hPPG after 30 weeks minus the baseline 2hPPG. | Baseline and 30 weeks | 
| Time to First Use of Rescue Therapy | Proportion of patients at 30 weeks with rescue therapy using Kaplan-Meier analysis. | 30 weeks | 
| Incidence of Rescue Therapy During the First 30 Weeks of Treatment | Rescue therapy was defined to include any new antidiabetic medication taken for hyperglycemia and introduced on or after the start date of study treatment and before the end date of study treatment. | 30 weeks |