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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01183013
• Other study ID #: 1264.3
• Secondary ID: 2008-008127-15
• Status: Completed
• Phase: Phase 3
• First received: August 16, 2010
• Last updated: October 9, 2014
• Start date: August 2010
• Est. completion date: February 2013

Study information

• Verified date: October 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Estonia: The State Agency of MedicineGermany: Federal Institute for Drugs and Medical DevicesLatvia: State Agency of MedicinesSpain: Spanish Agency of MedicinesUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 936
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• Pioglitazone 15 mg
Pioglitazone Capsules 15 mg once daily for 30 weeks followed by Pioglitazone Capsules 30 mg once daily for up to 54 weeks
• Pioglitazone 45 mg
Pioglitazone Capsules 30 mg once daily for 6 weeks followed by Pioglitazone Capsules 45 mg once daily for up to 78 weeks
• Pioglitazone 30 mg
Pioglitazone Capsules 30 mg once daily for up to 84 weeks
• Linagliptin 5mg / Pioglitazone 45 mg FDC
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 / Pioglitazone 30 mg FDC
Linagliptin 5mg low dose / Pioglitazone 30 mg FDC Tablets once daily for up to 84 weeks
• Linagliptin 5mg
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 / Pioglitazone 15 mg FDC
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

Locations

Country	Name	City	State
Estonia	1264.3.37207 Boehringer Ingelheim Investigational Site	Harju
Estonia	1264.3.37209 Boehringer Ingelheim Investigational Site	Pärnu
Estonia	1264.3.37203 Boehringer Ingelheim Investigational Site	Tallin
Estonia	1264.3.37204 Boehringer Ingelheim Investigational Site	Tallin
Estonia	1264.3.37205 Boehringer Ingelheim Investigational Site	Tallin
Estonia	1264.3.37201 Boehringer Ingelheim Investigational Site	Tallinn
Estonia	1264.3.37202 Boehringer Ingelheim Investigational Site	Tallinn
Estonia	1264.3.37208 Boehringer Ingelheim Investigational Site	Tallinn
Estonia	1264.3.37206 Boehringer Ingelheim Investigational Site	Tartu
Estonia	1264.3.37210 Boehringer Ingelheim Investigational Site	Viljandi County
Germany	1264.3.49001 Boehringer Ingelheim Investigational Site	Bad Lauterberg / Harz
Germany	1264.3.49007 Boehringer Ingelheim Investigational Site	Dietzenbach
Germany	1264.3.49002 Boehringer Ingelheim Investigational Site	Dortmund
Germany	1264.3.49009 Boehringer Ingelheim Investigational Site	Essen
Germany	1264.3.49003 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1264.3.49012 Boehringer Ingelheim Investigational Site	Ingelheim
Germany	1264.3.49008 Boehringer Ingelheim Investigational Site	Leipzig
Germany	1264.3.49005 Boehringer Ingelheim Investigational Site	Mainz
Germany	1264.3.49010 Boehringer Ingelheim Investigational Site	Offenbach
Germany	1264.3.49004 Boehringer Ingelheim Investigational Site	Stuhr
Latvia	1264.3.37105 Boehringer Ingelheim Investigational Site	Daugavpils
Latvia	1264.3.37112 Boehringer Ingelheim Investigational Site	Daugavpils
Latvia	1264.3.37113 Boehringer Ingelheim Investigational Site	Daugavpils
Latvia	1264.3.37110 Boehringer Ingelheim Investigational Site	Jelgava
Latvia	1264.3.37101 Boehringer Ingelheim Investigational Site	Liepaja
Latvia	1264.3.37106 Boehringer Ingelheim Investigational Site	Ogre
Latvia	1264.3.37104 Boehringer Ingelheim Investigational Site	Riga
Latvia	1264.3.37108 Boehringer Ingelheim Investigational Site	Riga
Latvia	1264.3.37109 Boehringer Ingelheim Investigational Site	Riga
Latvia	1264.3.37111 Boehringer Ingelheim Investigational Site	Riga
Latvia	1264.3.37107 Boehringer Ingelheim Investigational Site	Talsi
Latvia	1264.3.37102 Boehringer Ingelheim Investigational Site	Tukums
Latvia	1264.3.37103 Boehringer Ingelheim Investigational Site	Valmiera
Spain	1264.3.34013 Boehringer Ingelheim Investigational Site	Badía del Vallès - Barcelona
Spain	1264.3.34001 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1264.3.34008 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1264.3.34005 Boehringer Ingelheim Investigational Site	Borges del Camp- Tarragona
Spain	1264.3.34006 Boehringer Ingelheim Investigational Site	Canet de Mar - Barcelona
Spain	1264.3.34010 Boehringer Ingelheim Investigational Site	Centelles - Barcelona
Spain	1264.3.34009 Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat
Spain	1264.3.34004 Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat - Barcelona
Spain	1264.3.34002 Boehringer Ingelheim Investigational Site	Sant Adrià del Besós- Barcelona
Spain	1264.3.34007 Boehringer Ingelheim Investigational Site	Tarrega - Lleida
Spain	1264.3.34012 Boehringer Ingelheim Investigational Site	Valencia
Spain	1264.3.34011 Boehringer Ingelheim Investigational Site	Vic - Barcelona
United Kingdom	1264.3.44032 Boehringer Ingelheim Investigational Site	Annan
United Kingdom	1264.3.44028 Boehringer Ingelheim Investigational Site	Ash Vale, Aldershot
United Kingdom	1264.3.44029 Boehringer Ingelheim Investigational Site	Baillieston, Glasgow
United Kingdom	1264.3.44008 Boehringer Ingelheim Investigational Site	Balham
United Kingdom	1264.3.44021 Boehringer Ingelheim Investigational Site	Bradford on Avon
United Kingdom	1264.3.44019 Boehringer Ingelheim Investigational Site	Burbage
United Kingdom	1264.3.44012 Boehringer Ingelheim Investigational Site	Chesterfield
United Kingdom	1264.3.44027 Boehringer Ingelheim Investigational Site	Chestfield, Whitstable
United Kingdom	1264.3.44011 Boehringer Ingelheim Investigational Site	Chippenham
United Kingdom	1264.3.44033 Boehringer Ingelheim Investigational Site	Johnstone
United Kingdom	1264.3.44007 Boehringer Ingelheim Investigational Site	Midsomer Norton
United Kingdom	1264.3.44034 Boehringer Ingelheim Investigational Site	Paisley
United Kingdom	1264.3.44031 Boehringer Ingelheim Investigational Site	Warminster
United States	1264.3.01008 Boehringer Ingelheim Investigational Site	Atlanta	Georgia
United States	1264.3.01055 Boehringer Ingelheim Investigational Site	Atlanta	Georgia
United States	1264.3.01061 Boehringer Ingelheim Investigational Site	Atlanta	Georgia
United States	1264.3.01026 Boehringer Ingelheim Investigational Site	Birmingham	Alabama
United States	1264.3.01074 Boehringer Ingelheim Investigational Site	Blue Ridge	Georgia
United States	1264.3.01035 Boehringer Ingelheim Investigational Site	Boca Raton	Florida
United States	1264.3.01052 Boehringer Ingelheim Investigational Site	Brownsburg	Indiana
United States	1264.3.01045 Boehringer Ingelheim Investigational Site	Burlington	North Carolina
United States	1264.3.01049 Boehringer Ingelheim Investigational Site	Carmichael	California
United States	1264.3.01084 Boehringer Ingelheim Investigational Site	Cartersville	Georgia
United States	1264.3.01062 Boehringer Ingelheim Investigational Site	Chandler	Arizona
United States	1264.3.01044 Boehringer Ingelheim Investigational Site	Charlotte	North Carolina
United States	1264.3.01077 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1264.3.01078 Boehringer Ingelheim Investigational Site	Chino	California
United States	1264.3.01015 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1264.3.01081 Boehringer Ingelheim Investigational Site	Columbia	South Carolina
United States	1264.3.01031 Boehringer Ingelheim Investigational Site	Concord	California
United States	1264.3.01017 Boehringer Ingelheim Investigational Site	Corpus Christi	Texas
United States	1264.3.01067 Boehringer Ingelheim Investigational Site	Dallas	Texas
United States	1264.3.01027 Boehringer Ingelheim Investigational Site	Denver	Colorado
United States	1264.3.01075 Boehringer Ingelheim Investigational Site	Evansville	Indiana
United States	1264.3.01076 Boehringer Ingelheim Investigational Site	Evansville	Indiana
United States	1264.3.01051 Boehringer Ingelheim Investigational Site	Fleetwood	Pennsylvania
United States	1264.3.01073 Boehringer Ingelheim Investigational Site	Franklin	Indiana
United States	1264.3.01057 Boehringer Ingelheim Investigational Site	Great Falls	Montana
United States	1264.3.01003 Boehringer Ingelheim Investigational Site	Greer	South Carolina
United States	1264.3.01082 Boehringer Ingelheim Investigational Site	Hialeah	Florida
United States	1264.3.01004 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1264.3.01039 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1264.3.01041 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1264.3.01047 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1264.3.01070 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1264.3.01069 Boehringer Ingelheim Investigational Site	Hyattsville	Maryland
United States	1264.3.01036 Boehringer Ingelheim Investigational Site	Jacksonville	Florida
United States	1264.3.01040 Boehringer Ingelheim Investigational Site	Killeen	Texas
United States	1264.3.01011 Boehringer Ingelheim Investigational Site	Kingsport	Tennessee
United States	1264.3.01037 Boehringer Ingelheim Investigational Site	Lakewood	California
United States	1264.3.01010 Boehringer Ingelheim Investigational Site	Lexington	Kentucky
United States	1264.3.01013 Boehringer Ingelheim Investigational Site	Longwood	Florida
United States	1264.3.01065 Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	1264.3.01064 Boehringer Ingelheim Investigational Site	Mesa	Arizona
United States	1264.3.01038 Boehringer Ingelheim Investigational Site	Miami	Florida
United States	1264.3.01042 Boehringer Ingelheim Investigational Site	Miami	Florida
United States	1264.3.01079 Boehringer Ingelheim Investigational Site	Miami	Florida
United States	1264.3.01048 Boehringer Ingelheim Investigational Site	Midland	Texas
United States	1264.3.01021 Boehringer Ingelheim Investigational Site	Montgomery	Alabama
United States	1264.3.01020 Boehringer Ingelheim Investigational Site	Muscle Shoals	Alabama
United States	1264.3.01030 Boehringer Ingelheim Investigational Site	New Braunfels	Texas
United States	1264.3.01028 Boehringer Ingelheim Investigational Site	New Orleans	Louisiana
United States	1264.3.01056 Boehringer Ingelheim Investigational Site	Norfolk	Virginia
United States	1264.3.01071 Boehringer Ingelheim Investigational Site	North Richland Hills	Texas
United States	1264.3.01006 Boehringer Ingelheim Investigational Site	Norwalk	California
United States	1264.3.01033 Boehringer Ingelheim Investigational Site	Norwalk	Connecticut
United States	1264.3.01032 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	1264.3.01060 Boehringer Ingelheim Investigational Site	Perry	Georgia
United States	1264.3.01025 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania
United States	1264.3.01085 Boehringer Ingelheim Investigational Site	Plano	Texas
United States	1264.3.01019 Boehringer Ingelheim Investigational Site	Port Orange	Florida
United States	1264.3.01001 Boehringer Ingelheim Investigational Site	Rancho Cucamonga	California
United States	1264.3.01046 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	1264.3.01059 Boehringer Ingelheim Investigational Site	San Diego	California
United States	1264.3.01050 Boehringer Ingelheim Investigational Site	Savannah	Georgia
United States	1264.3.01066 Boehringer Ingelheim Investigational Site	Southfield	Michigan
United States	1264.3.01018 Boehringer Ingelheim Investigational Site	St. Cloud	Florida
United States	1264.3.01029 Boehringer Ingelheim Investigational Site	Sunset	Louisiana
United States	1264.3.01009 Boehringer Ingelheim Investigational Site	Tampa	Florida
United States	1264.3.01012 Boehringer Ingelheim Investigational Site	Tampa	Florida
United States	1264.3.01023 Boehringer Ingelheim Investigational Site	Tarzana	California
United States	1264.3.01016 Boehringer Ingelheim Investigational Site	Tustin	California
United States	1264.3.01058 Boehringer Ingelheim Investigational Site	Valencia	California
United States	1264.3.01083 Boehringer Ingelheim Investigational Site	Westlake Village	California
United States	1264.3.01002 Boehringer Ingelheim Investigational Site	Wichita	Kansas
United States	1264.3.01007 Boehringer Ingelheim Investigational Site	Wichita	Kansas
United States	1264.3.01022 Boehringer Ingelheim Investigational Site	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Estonia,  Germany,  Latvia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Time to First Use of Rescue Therapy	Proportion of patients at 30 weeks with rescue therapy using Kaplan-Meier analysis.	30 weeks	No
Secondary	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	No