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
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Pioglitazone 15 mg; Pioglitazone 45 mg; Pioglitazone 30 mg; Linagliptin 5mg / Pioglitazone 45 mg FDC; Linagliptin 5mg / Pioglitazone 30 mg FDC; Linagliptin 5mg; Linagliptin 5mg / Pioglitazone 15 mg FDC
Intervention description: Pioglitazone Capsules 15 mg once daily for 30 weeks followed by Pioglitazone Capsules 30 mg once daily for up to 54 weeks; Pioglitazone Capsules 30 mg once daily for 6 weeks followed by Pioglitazone Capsules 45 mg once daily for up to 78 weeks; Pioglitazone Capsules 30 mg once daily for up to 84 weeks; 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; Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 84 weeks; 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; 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
Intervention MeSH terms: Pioglitazone; Linagliptin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 936.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion criteria:

          1. Diagnosis of type 2 diabetes mellitus prior to informed consent

          2. 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)

          3. Age >= 18 and <= 80 years at start date of Visit 1 (Screening)

          4. BMI <= 45 kg/m2 (Body Mass Index) at start date of Visit 1 (Screening)

          5. Signed and dated written informed consent by start date of Visit 1 in accordance with
             GCP and local legislation

        Exclusion criteria:

          1. 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)

          2. Myocardial infarction within 6 months, stroke or TIA within 3 months prior to informed
             consent

          3. 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)

          4. Bariatric surgery, performed within the past 2 years prior to informed consent or
             planned at the time of informed consent

          5. Gastrointestinal surgeries prior to informed consent that induce chronic malabsorption

          6. Known hypersensitivity or allergy to the investigational products (linagliptin and/or
             pioglitazone) or their excipients (including matching placebos)

          7. 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

          8. Treatment with gemfibrozil, montelukast, trimethoprim, or rifampicin - according to
             pioglitazone label and respective restrictions in Section 4.2.2

          9. Treatment with rosiglitazone, pioglitazone, GLP-1 analogues, or insulin within 3
             months prior to informed consent

         10. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to
             informed consent

         11. Alcohol or drug abuse within the 3 months prior to informed consent or history of
             alcoholism

         12. Current treatment with systemic corticosteroids at time of informed consent or change
             in dosage of thyroid hormones within 6 weeks prior to informed consent

         13. Participation in another trial with an investigational drug within 30 days prior to
             informed consent

         14. 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

         15. 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

         16. Symptomatic gallbladder disease in the last six months

         17. Medical history of pancreatitis.

         18. Patients with urinary bladder cancer or a history of urinary bladder cancer or
             uninvestigated macroscopic haematuria

         19. Any other contraindication or restriction for use of pioglitazone in accordance with
             the local prescribing information for pioglitazone.