Efficacy vs Placebo as Initial Combination Therapy With Pioglitazone

A Randomised, Double-blind, Placebo Controlled, Parallel Group 24 Week Study to Assess the Efficacy and Safety of BI 1356 (5 mg) in Combination With 30 mg Pioglitazone (Both Administered Orally Once Daily), Compared to 30 mg Pioglitazone Plus Placebo in Drug Naive or Previously Treated Type 2 Diabetic Patients With Insufficient Glycaemic Control.

The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (Linagliptin) (5 mg / once daily) compared to placebo given for 24 weeks as initial combination therapy with pioglitazone 30 mg in patients with type 2 diabetes mellitus with insufficient glycaemic control.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Linagliptin + pioglitazone (30 mg); Drug: placebo + pioglitazone (30 mg)

• Study Type: Interventional
• Enrollment (Actual): 389
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Feldkirch, Austria
    • 1218.15.43004 Boehringer Ingelheim Investigational Site
  • Graz, Austria
    • 1218.15.43001 Boehringer Ingelheim Investigational Site
  • Wien, Austria
    • 1218.15.43003 Boehringer Ingelheim Investigational Site
  • Wien, Austria
    • 1218.15.43005 Boehringer Ingelheim Investigational Site
• Greece
  • Athens, Greece
    • 1218.15.30004 Boehringer Ingelheim Investigational Site
  • Athens, Greece
    • 1218.15.30007 Boehringer Ingelheim Investigational Site
  • Ioannina, Greece
    • 1218.15.30017 Boehringer Ingelheim Investigational Site
  • Melissia-Athens, Greece
    • 1218.15.30002 Boehringer Ingelheim Investigational Site
  • Nikaia, Greece
    • 1218.15.30003 Boehringer Ingelheim Investigational Site
  • Thessaloniki, Greece
    • 1218.15.30006 Boehringer Ingelheim Investigational Site
  • Thessaloniki, Greece
    • 1218.15.30014 Boehringer Ingelheim Investigational Site
  • Thessaloniki, Greece
    • 1218.15.30016 Boehringer Ingelheim Investigational Site
• Hungary
  • Budapest, Hungary
    • 1218.15.36003 Boehringer Ingelheim Investigational Site
  • Budapest, Hungary
    • 1218.15.36004 Boehringer Ingelheim Investigational Site
  • Budapest, Hungary
    • 1218.15.36006 Boehringer Ingelheim Investigational Site
  • Debrecen, Hungary
    • 1218.15.36008 Boehringer Ingelheim Investigational Site
  • Györ, Hungary
    • 1218.15.36005 Boehringer Ingelheim Investigational Site
  • Szombathely, Hungary
    • 1218.15.36002 Boehringer Ingelheim Investigational Site
• Japan
  • Amagasaki, Hyogo, Japan
    • 1218.15.81001 Boehringer Ingelheim Investigational Site
  • Koganei, Tokyo, Japan
    • 1218.15.81005 Boehringer Ingelheim Investigational Site
  • Osaka, Osaka, Japan
    • 1218.15.81002 Boehringer Ingelheim Investigational Site
  • Shinjyuku-ku,Tokyo, Japan
    • 1218.15.81004 Boehringer Ingelheim Investigational Site
  • Suita, Osaka,, Japan
    • 1218.15.81003 Boehringer Ingelheim Investigational Site
• Portugal
  • Aveiro, Portugal
    • 1218.15.35007 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 1218.15.35001 Boehringer Ingelheim Investigational Site
• Romania
  • Alba Iulia, Romania
    • 1218.15.40504 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1218.15.40501 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1218.15.40502 Boehringer Ingelheim Investigational Site
  • Sibiu, Romania
    • 1218.15.40503 Boehringer Ingelheim Investigational Site
  • Targu-Mures, Romania
    • 1218.15.40505 Boehringer Ingelheim Investigational Site
• Spain
  • Badalona, Spain
    • 1218.15.34002 Boehringer Ingelheim Investigational Site
  • Badia del Vallés, Spain
    • 1218.15.34011 Boehringer Ingelheim Investigational Site
  • Bercelona, Spain
    • 1218.15.34001 Boehringer Ingelheim Investigational Site
  • Borges del Camp, Spain
    • 1218.15.34012 Boehringer Ingelheim Investigational Site
  • Centelles, Spain
    • 1218.15.34013 Boehringer Ingelheim Investigational Site
  • Granada, Spain
    • 1218.15.34007 Boehringer Ingelheim Investigational Site
  • L'Hospitalet de Llobregat (Barcelona), Spain
    • 1218.15.34008 Boehringer Ingelheim Investigational Site
  • L'Hospitalet de Llobregat (Barcelona), Spain
    • 1218.15.34009 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1218.15.34004 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1218.15.34006 Boehringer Ingelheim Investigational Site
  • Sant Adrià del Besós (Barcelona), Spain
    • 1218.15.34010 Boehringer Ingelheim Investigational Site
  • Sevilla, Spain
    • 1218.15.34005 Boehringer Ingelheim Investigational Site
  • Vic (Barcelona), Spain
    • 1218.15.34014 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Signed and dated written Informed Consent (IC) by date of Visit 1a in accordance with Good Clinical Practice (GCP) and local legislation
2. Patients with a diagnosis of type 2 diabetes mellitus and treatment naive or previously treated with any oral hypoglycaemic agent; antidiabetic therapy has to be unchanged for ten weeks prior to informed consent.
3. Glycosylated haemoglobin A1 (HbA1c) 7.5-11% at Visit 2 (Start of Run-in).
4. Male and female patients aged > or = 18 and < or = to 80 years at Visit 1a (Screening).
5. Body Mass Index (BMI) < or = 40 kg/m2 at Visit 1a (Screening)
6. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation.

Exclusion criteria:

1. Myocardial infarction, stroke or Transient Isquemic Atack (TIA) within 6 months prior to Inform Consent (IC)
2. Impaired hepatic function, defined by serum levels of either Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) determined at Visit 1a.
3. Known hypersensitivity or allergy to the investigational product or its excipients and/or to hydrochloride of pioglitazone or its excipients
4. Treatment with Glucagon-like peptide-1 (GLP-1) analogue / agonist within 3 months prior to IC.
5. Treatment with insulin within 3 months prior to IC
6. Treatment with anti-obesity drugs 3 months prior to IC.
7. Alcohol abuse within the 3 months prior to IC that would interfere with trial participation or drug abuse.
8. Participation in another trial with an investigational drug within 2 months prior to IC.
9. Fasting blood glucose > 240 mg/dl (=13.3 mmol/L) at screening (Visit 1).

10. Pre-menopausal women (last menstruation < or =1 year prior to signing IC) who:

    • are nursing or pregnant,
    • or are of child-bearing potential and are not practicing an acceptable 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. Acceptable methods of birth control include transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence and vasectomised partner. No exception will be made.
11. Treatment with systemic steroids or change in the dosage of thyroid hormone within six weeks prior to IC
12. Heart failure New York Heart Asociation (NYHA) class I-IV, or history of heart failure.
13. Diabetic ketoacidosis within 6 months prior to IC.
14. Hemodialyzed patients due to limited experience with Thiazolidinediones (TZDs)
15. Any other clinical condition wich, in the opinion of the investigator, would not alow safe completion of the protocol and safe administration of BI1356 and pioglitazone.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 1356 (5 mg); BI 1356 5mg in initial combination therapy with pioglitazone 30 mg	Drug: Linagliptin + pioglitazone (30 mg); 5 mg tablet + overcapsulated 30 mg tablet, once daily
Placebo Comparator: Placebo matching BI 1356 5 mg; Placebo in initial combination therapy with pioglitazone 30 mg	Drug: placebo + pioglitazone (30 mg); placebo + overcapsulated 30 mg tablet, once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1c Change From Baseline to Week 24	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With HbA1c<7.0 at Week 24	The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%.	Baseline and Week 24
HbA1c Change From Baseline to Week 6	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 6
HbA1c Change From Baseline to Week 12	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 12
HbA1c Change From Baseline to Week 18	HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.	Baseline and week 18
FPG Change From Baseline to Week 12	This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.	Baseline and week 12
Percentage of Patients With HbA1c<6.5% at Week 24	The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%	Baseline and week 24
FPG Change From Baseline to Week 24	This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.	Baseline and week 24
FPG Change From Baseline to Week 6	This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.	Baseline and week 6
FPG Change From Baseline to Week 18	This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetes medication.	Baseline and week 18
Percentage of Patients With HbA1c <7.0% at Week 24	The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. Only patients with baseline HbA1c >= 7%	Baseline and Week 24
Percentage of Patients With HbA1c <6.5% at Week 24	The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%. Only patients with baseline HbA1c >= 6.5%	Baseline and Week 24
Percentage of Patients Who Have an HbA1c Lowering by 0.5% at Week 24	The percentage of patients with an HbA1c reduction from baseline greater than 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%.	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012 Jan 10;11:3. doi: 10.1186/1475-2840-11-3.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: February 29, 2008
• First Submitted That Met QC Criteria: March 20, 2008
• First Posted (Estimate): March 21, 2008

Study Record Updates

• Last Update Posted (Estimate): February 17, 2014
• Last Update Submitted That Met QC Criteria: January 22, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Pioglitazone; Linagliptin
• Other Study ID Numbers: 1218.15; 2007-002456-41 (EudraCT Number: EudraCT)