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

Boehringer Ingelheim

Status and phase: Completed; Phase 3

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Pioglitazone 30 mg; Drug: Linagliptin 5mg; Drug: Linagliptin 5mg / Pioglitazone 30 mg FDC; Drug: Linagliptin 5mg / Pioglitazone 15 mg FDC; Drug: Pioglitazone 15 mg; Drug: Linagliptin 5mg / Pioglitazone 45 mg FDC; Drug: Pioglitazone 45 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT01183013

2008-008127-15 (EudraCT Number)

1264.3

Details and patient eligibility

About

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.

Enrollment: 936 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

936 participants in 7 patient groups

Pioglitazone 15 mg

Active Comparator group

Description:

Pioglitazone Capsules 15 mg once daily

Treatment:

Drug: Pioglitazone 15 mg

Pioglitazone 30 mg

Active Comparator group

Description:

Pioglitazone Capsules 30 mg once daily

Treatment:

Drug: Pioglitazone 30 mg

Pioglitazone 45 mg

Active Comparator group

Description:

Pioglitazone Capsules 45 mg once daily

Treatment:

Drug: Pioglitazone 45 mg

Linagliptin 5mg

Active Comparator group

Description:

Linagliptin 5mg Tablets once daily

Treatment:

Drug: Linagliptin 5mg

Linagliptin 5mg / Pioglitazone 15 mg

Experimental group

Description:

Linagliptin 5mg / Pioglitazone 15 mg Tablets once daily

Treatment:

Drug: Linagliptin 5mg / Pioglitazone 15 mg FDC

Linagliptin 5mg / Pioglitazone 30 mg

Experimental group

Description:

Linagliptin 5mg / Pioglitazone 30 mg Tablets once daily

Treatment:

Drug: Linagliptin 5mg / Pioglitazone 30 mg FDC

Linagliptin 5mg / Pioglitazone 45 mg

Experimental group

Description:

Linagliptin 5mg / Pioglitazone 45 mg Tablets once daily

Treatment:

Drug: Linagliptin 5mg / Pioglitazone 45 mg FDC