Clinical trial NCT01183013: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2010-08-17
Enrollment: 936
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Change From Baseline in HbA1c After 30 Weeks of Treatment.
timeFrame: Baseline and 30 weeks
Secondary outcomes:
measure: Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 7.0% After 30 Weeks of Treatment
timeFrame: Baseline and 30 weeks
measure: Occurrence of Cumulative Treat to Target Efficacy Response, of HbA1c Under Treatment of < 6.5% After 30 Weeks of Treatment
timeFrame: Baseline and 30 weeks
measure: Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 30 Weeks of Treatment)
timeFrame: Baseline and 30 weeks
measure: HbA1c Change From Baseline by Visit Over Time
timeFrame: Baseline, week 6, week 12, week 18, week 24, week 30
measure: Fasting Plasma Glucose (FPG) Change From Baseline After 30 Weeks of Treatment
timeFrame: Baseline and 30 weeks
measure: Fasting Plasma Glucose (FPG) Change From Baseline by Visit Over Time
timeFrame: Baseline, week 6, week 12, week 18, week 24, week 30
measure: Two-hour Postprandial Glucose (2hPPG) Change From Baseline at Week 30 by Meal Tolerance Test (MTT)
timeFrame: Baseline and 30 weeks
measure: Time to First Use of Rescue Therapy
timeFrame: 30 weeks
measure: Incidence of Rescue Therapy During the First 30 Weeks of Treatment
timeFrame: 30 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 1264.3.01026 Boehringer Ingelheim Investigational Site
state: Alabama
city: Montgomery
country: United States
facility: 1264.3.01021 Boehringer Ingelheim Investigational Site
state: Alabama
city: Muscle Shoals
country: United States
facility: 1264.3.01020 Boehringer Ingelheim Investigational Site
state: Alabama
city: Chandler
country: United States
facility: 1264.3.01062 Boehringer Ingelheim Investigational Site
state: Arizona
city: Mesa
country: United States
facility: 1264.3.01064 Boehringer Ingelheim Investigational Site
state: Arizona
city: Carmichael
country: United States
facility: 1264.3.01049 Boehringer Ingelheim Investigational Site
state: California
city: Chino
country: United States
facility: 1264.3.01078 Boehringer Ingelheim Investigational Site
state: California
city: Concord
country: United States
facility: 1264.3.01031 Boehringer Ingelheim Investigational Site
state: California
city: Lakewood
country: United States
facility: 1264.3.01037 Boehringer Ingelheim Investigational Site
state: California
city: Los Angeles
country: United States
facility: 1264.3.01065 Boehringer Ingelheim Investigational Site
state: California
city: Norwalk
country: United States
facility: 1264.3.01006 Boehringer Ingelheim Investigational Site
state: California
city: Rancho Cucamonga
country: United States
facility: 1264.3.01001 Boehringer Ingelheim Investigational Site
state: California
city: San Diego
country: United States
facility: 1264.3.01059 Boehringer Ingelheim Investigational Site
state: California
city: Tarzana
country: United States
facility: 1264.3.01023 Boehringer Ingelheim Investigational Site
state: California
city: Tustin
country: United States
facility: 1264.3.01016 Boehringer Ingelheim Investigational Site
state: California
city: Valencia
country: United States
facility: 1264.3.01058 Boehringer Ingelheim Investigational Site
state: California
city: Westlake Village
country: United States
facility: 1264.3.01083 Boehringer Ingelheim Investigational Site
state: California
city: Denver
country: United States
facility: 1264.3.01027 Boehringer Ingelheim Investigational Site
state: Colorado
city: Norwalk
country: United States
facility: 1264.3.01033 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Boca Raton
country: United States
facility: 1264.3.01035 Boehringer Ingelheim Investigational Site
state: Florida
city: Clearwater
country: United States
facility: 1264.3.01015 Boehringer Ingelheim Investigational Site
state: Florida
city: Hialeah
country: United States
facility: 1264.3.01082 Boehringer Ingelheim Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: 1264.3.01036 Boehringer Ingelheim Investigational Site
state: Florida
city: Longwood
country: United States
facility: 1264.3.01013 Boehringer Ingelheim Investigational Site
state: Florida
city: Miami
country: United States
facility: 1264.3.01038 Boehringer Ingelheim Investigational Site
state: Florida
city: Miami
country: United States
facility: 1264.3.01042 Boehringer Ingelheim Investigational Site
state: Florida
city: Miami
country: United States
facility: 1264.3.01079 Boehringer Ingelheim Investigational Site
state: Florida
city: Port Orange
country: United States
facility: 1264.3.01019 Boehringer Ingelheim Investigational Site
state: Florida
city: St. Cloud
country: United States
facility: 1264.3.01018 Boehringer Ingelheim Investigational Site
state: Florida
city: Tampa
country: United States
facility: 1264.3.01009 Boehringer Ingelheim Investigational Site
state: Florida
city: Tampa
country: United States
facility: 1264.3.01012 Boehringer Ingelheim Investigational Site
state: Florida
city: Atlanta
country: United States
facility: 1264.3.01008 Boehringer Ingelheim Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: 1264.3.01055 Boehringer Ingelheim Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: 1264.3.01061 Boehringer Ingelheim Investigational Site
state: Georgia
city: Blue Ridge
country: United States
facility: 1264.3.01074 Boehringer Ingelheim Investigational Site
state: Georgia
city: Cartersville
country: United States
facility: 1264.3.01084 Boehringer Ingelheim Investigational Site
state: Georgia
city: Perry
country: United States
facility: 1264.3.01060 Boehringer Ingelheim Investigational Site
state: Georgia
city: Savannah
country: United States
facility: 1264.3.01050 Boehringer Ingelheim Investigational Site
state: Georgia
city: Chicago
country: United States
facility: 1264.3.01077 Boehringer Ingelheim Investigational Site
state: Illinois
city: Brownsburg
country: United States
facility: 1264.3.01052 Boehringer Ingelheim Investigational Site
state: Indiana
city: Evansville
country: United States
facility: 1264.3.01075 Boehringer Ingelheim Investigational Site
state: Indiana
city: Evansville
country: United States
facility: 1264.3.01076 Boehringer Ingelheim Investigational Site
state: Indiana
city: Franklin
country: United States
facility: 1264.3.01073 Boehringer Ingelheim Investigational Site
state: Indiana
city: Wichita
country: United States
facility: 1264.3.01002 Boehringer Ingelheim Investigational Site
state: Kansas
city: Wichita
country: United States
facility: 1264.3.01007 Boehringer Ingelheim Investigational Site
state: Kansas
city: Lexington
country: United States
facility: 1264.3.01010 Boehringer Ingelheim Investigational Site
state: Kentucky
city: New Orleans
country: United States
facility: 1264.3.01028 Boehringer Ingelheim Investigational Site
state: Louisiana
city: Sunset
country: United States
facility: 1264.3.01029 Boehringer Ingelheim Investigational Site
state: Louisiana
city: Hyattsville
country: United States
facility: 1264.3.01069 Boehringer Ingelheim Investigational Site
state: Maryland
city: Southfield
country: United States
facility: 1264.3.01066 Boehringer Ingelheim Investigational Site
state: Michigan
city: Great Falls
country: United States
facility: 1264.3.01057 Boehringer Ingelheim Investigational Site
state: Montana
city: Burlington
country: United States
facility: 1264.3.01045 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: 1264.3.01044 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Zanesville
country: United States
facility: 1264.3.01022 Boehringer Ingelheim Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: 1264.3.01032 Boehringer Ingelheim Investigational Site
state: Oklahoma
city: Fleetwood
country: United States
facility: 1264.3.01051 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: 1264.3.01025 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Columbia
country: United States
facility: 1264.3.01081 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Greer
country: United States
facility: 1264.3.01003 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Kingsport
country: United States
facility: 1264.3.01011 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Corpus Christi
country: United States
facility: 1264.3.01017 Boehringer Ingelheim Investigational Site
state: Texas
city: Dallas
country: United States
facility: 1264.3.01067 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1264.3.01004 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1264.3.01039 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1264.3.01041 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1264.3.01047 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1264.3.01070 Boehringer Ingelheim Investigational Site
state: Texas
city: Killeen
country: United States
facility: 1264.3.01040 Boehringer Ingelheim Investigational Site
state: Texas
city: Midland
country: United States
facility: 1264.3.01048 Boehringer Ingelheim Investigational Site
state: Texas
city: New Braunfels
country: United States
facility: 1264.3.01030 Boehringer Ingelheim Investigational Site
state: Texas
city: North Richland Hills
country: United States
facility: 1264.3.01071 Boehringer Ingelheim Investigational Site
state: Texas
city: Plano
country: United States
facility: 1264.3.01085 Boehringer Ingelheim Investigational Site
state: Texas
city: San Antonio
country: United States
facility: 1264.3.01046 Boehringer Ingelheim Investigational Site
state: Texas
city: Norfolk
country: United States
facility: 1264.3.01056 Boehringer Ingelheim Investigational Site
state: Virginia
city: Harju
country: Estonia
facility: 1264.3.37207 Boehringer Ingelheim Investigational Site
city: Pärnu
country: Estonia
facility: 1264.3.37209 Boehringer Ingelheim Investigational Site
city: Tallinn
country: Estonia
facility: 1264.3.37201 Boehringer Ingelheim Investigational Site
city: Tallinn
country: Estonia
facility: 1264.3.37202 Boehringer Ingelheim Investigational Site
city: Tallinn
country: Estonia
facility: 1264.3.37208 Boehringer Ingelheim Investigational Site
city: Tallin
country: Estonia
facility: 1264.3.37203 Boehringer Ingelheim Investigational Site
city: Tallin
country: Estonia
facility: 1264.3.37204 Boehringer Ingelheim Investigational Site
city: Tallin
country: Estonia
facility: 1264.3.37205 Boehringer Ingelheim Investigational Site
city: Tartu
country: Estonia
facility: 1264.3.37206 Boehringer Ingelheim Investigational Site
city: Viljandi County
country: Estonia
facility: 1264.3.37210 Boehringer Ingelheim Investigational Site
city: Bad Lauterberg / Harz
country: Germany
facility: 1264.3.49001 Boehringer Ingelheim Investigational Site
city: Dietzenbach
country: Germany
facility: 1264.3.49007 Boehringer Ingelheim Investigational Site
city: Dortmund
country: Germany
facility: 1264.3.49002 Boehringer Ingelheim Investigational Site
city: Essen
country: Germany
facility: 1264.3.49009 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1264.3.49003 Boehringer Ingelheim Investigational Site
city: Ingelheim
country: Germany
facility: 1264.3.49012 Boehringer Ingelheim Investigational Site
city: Leipzig
country: Germany
facility: 1264.3.49008 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1264.3.49005 Boehringer Ingelheim Investigational Site
city: Offenbach
country: Germany
facility: 1264.3.49010 Boehringer Ingelheim Investigational Site
city: Stuhr
country: Germany
facility: 1264.3.49004 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 1264.3.37105 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 1264.3.37112 Boehringer Ingelheim Investigational Site
city: Daugavpils
country: Latvia
facility: 1264.3.37113 Boehringer Ingelheim Investigational Site
city: Jelgava
country: Latvia
facility: 1264.3.37110 Boehringer Ingelheim Investigational Site
city: Liepaja
country: Latvia
facility: 1264.3.37101 Boehringer Ingelheim Investigational Site
city: Ogre
country: Latvia
facility: 1264.3.37106 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 1264.3.37104 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 1264.3.37108 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 1264.3.37109 Boehringer Ingelheim Investigational Site
city: Riga
country: Latvia
facility: 1264.3.37111 Boehringer Ingelheim Investigational Site
city: Talsi
country: Latvia
facility: 1264.3.37107 Boehringer Ingelheim Investigational Site
city: Tukums
country: Latvia
facility: 1264.3.37102 Boehringer Ingelheim Investigational Site
city: Valmiera
country: Latvia
facility: 1264.3.37103 Boehringer Ingelheim Investigational Site
city: Badía del Vallès - Barcelona
country: Spain
facility: 1264.3.34013 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1264.3.34001 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1264.3.34008 Boehringer Ingelheim Investigational Site
city: Borges del Camp- Tarragona
country: Spain
facility: 1264.3.34005 Boehringer Ingelheim Investigational Site
city: Canet de Mar - Barcelona
country: Spain
facility: 1264.3.34006 Boehringer Ingelheim Investigational Site
city: Centelles - Barcelona
country: Spain
facility: 1264.3.34010 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat - Barcelona
country: Spain
facility: 1264.3.34004 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: 1264.3.34009 Boehringer Ingelheim Investigational Site
city: Sant Adrià del Besós- Barcelona
country: Spain
facility: 1264.3.34002 Boehringer Ingelheim Investigational Site
city: Tarrega - Lleida
country: Spain
facility: 1264.3.34007 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1264.3.34012 Boehringer Ingelheim Investigational Site
city: Vic - Barcelona
country: Spain
facility: 1264.3.34011 Boehringer Ingelheim Investigational Site
city: Annan
country: United Kingdom
facility: 1264.3.44032 Boehringer Ingelheim Investigational Site
city: Ash Vale, Aldershot
country: United Kingdom
facility: 1264.3.44028 Boehringer Ingelheim Investigational Site
city: Baillieston, Glasgow
country: United Kingdom
facility: 1264.3.44029 Boehringer Ingelheim Investigational Site
city: Balham
country: United Kingdom
facility: 1264.3.44008 Boehringer Ingelheim Investigational Site
city: Bradford on Avon
country: United Kingdom
facility: 1264.3.44021 Boehringer Ingelheim Investigational Site
city: Burbage
country: United Kingdom
facility: 1264.3.44019 Boehringer Ingelheim Investigational Site
city: Chesterfield
country: United Kingdom
facility: 1264.3.44012 Boehringer Ingelheim Investigational Site
city: Chestfield, Whitstable
country: United Kingdom
facility: 1264.3.44027 Boehringer Ingelheim Investigational Site
city: Chippenham
country: United Kingdom
facility: 1264.3.44011 Boehringer Ingelheim Investigational Site
city: Johnstone
country: United Kingdom
facility: 1264.3.44033 Boehringer Ingelheim Investigational Site
city: Midsomer Norton
country: United Kingdom
facility: 1264.3.44007 Boehringer Ingelheim Investigational Site
city: Paisley
country: United Kingdom
facility: 1264.3.44034 Boehringer Ingelheim Investigational Site
city: Warminster
country: United Kingdom
facility: 1264.3.44031 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: