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

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.