BI 1356 (Linagliptin) in Combination With Metformin and a Sulphonylurea in Type 2 Diabetes

A Randomised, Double-blind, Placebo-controlled Parallel Group Efficacy and Safety Study of BI 1356 (5 mg) Administered Orally Once Daily Over 24 Weeks, With an Open-label Extension to One Year (Placebo Patients Switched to BI 1356), in Type 2 Diabetic Patients With Insufficient Glycaemic Control Despite a Therapy of Metformin in Combination With a Sulphonylurea

The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in combination with a sulphonylurea in patients with type 2 diabetes mellitus with insufficient glycaemic control.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: linagliptin; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 1058
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina
    • 1218.18.54001 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 1218.18.54002 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 1218.18.54004 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 1218.18.54005 Boehringer Ingelheim Investigational Site
  • Capital Federal, Argentina
    • 1218.18.54010 Boehringer Ingelheim Investigational Site
  • Corrientes, Argentina
    • 1218.18.54014 Boehringer Ingelheim Investigational Site
  • Córdoba, Argentina
    • 1218.18.54009 Boehringer Ingelheim Investigational Site
  • Córdoba, Argentina
    • 1218.18.54013 Boehringer Ingelheim Investigational Site
  • Mar del Plata, Argentina
    • 1218.18.54003 Boehringer Ingelheim Investigational Site
  • Mar del Plata, Argentina
    • 1218.18.54012 Boehringer Ingelheim Investigational Site
  • Mendoza, Argentina
    • 1218.18.54011 Boehringer Ingelheim Investigational Site
  • Parque Velez Sarfield, Argentina
    • 1218.18.54015 Boehringer Ingelheim Investigational Site
  • Rosario, Argentina
    • 1218.18.54006 Boehringer Ingelheim Investigational Site
  • Salta, Argentina
    • 1218.18.54007 Boehringer Ingelheim Investigational Site
• Belgium
  • Brugge, Belgium
    • 1218.18.32005 Boehringer Ingelheim Investigational Site
  • Brussel, Belgium
    • 1218.18.32007 Boehringer Ingelheim Investigational Site
  • Edegem, Belgium
    • 1218.18.32006 Boehringer Ingelheim Investigational Site
  • Genk, Belgium
    • 1218.18.32004 Boehringer Ingelheim Investigational Site
  • Gent, Belgium
    • 1218.18.32003 Boehringer Ingelheim Investigational Site
  • Huy, Belgium
    • 1218.18.32002 Boehringer Ingelheim Investigational Site
  • Liège, Belgium
    • 1218.18.32001 Boehringer Ingelheim Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • 1218.18.01005 Boehringer Ingelheim Investigational Site
    • Calgary, Alberta, Canada
      • 1218.18.01010 Boehringer Ingelheim Investigational Site
  • British Columbia
    • Vancouver, British Columbia, Canada
      • 1218.18.01003 Boehringer Ingelheim Investigational Site
    • Vancouver, British Columbia, Canada
      • 1218.18.01011 Boehringer Ingelheim Investigational Site
  • Ontario
    • Etobicoke, Ontario, Canada
      • 1218.18.01006 Boehringer Ingelheim Investigational Site
    • Hamilton, Ontario, Canada
      • 1218.18.01009 Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada
      • 1218.18.01002 Boehringer Ingelheim Investigational Site
    • Oakville, Ontario, Canada
      • 1218.18.01012 Boehringer Ingelheim Investigational Site
    • Sarnia, Ontario, Canada
      • 1218.18.01008 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1218.18.01001 Boehringer Ingelheim Investigational Site
  • Prince Edward Island
    • Montague, Prince Edward Island, Canada
      • 1218.18.01004 Boehringer Ingelheim Investigational Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • 1218.18.01007 Boehringer Ingelheim Investigational Site
• China
  • Beijing, China
    • 1218.18.86001 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1218.18.86002 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1218.18.86004 Boehringer Ingelheim Investigational Site
  • Chengdu, Sichuan Province, China
    • 1218.18.86013 Boehringer Ingelheim Investigational Site
  • Dalian, China
    • 1218.18.86009 Boehringer Ingelheim Investigational Site
  • Guangzhou, China
    • 1218.18.86011 Boehringer Ingelheim Investigational Site
  • Haerbin, China
    • 1218.18.86014 Boehringer Ingelheim Investigational Site
  • Nanjing, Jiangsu Province, China
    • 1218.18.86005 Boehringer Ingelheim Investigational Site
  • Qingdao, China
    • 1218.18.86008 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 1218.18.86015 Boehringer Ingelheim Investigational Site
  • Shen Yang, China
    • 1218.18.86010 Boehringer Ingelheim Investigational Site
  • Weizikeng, China
    • 1218.18.86003 Boehringer Ingelheim Investigational Site
  • Wuhan, China
    • 1218.18.86007 Boehringer Ingelheim Investigational Site
  • Wuhan, Hubei Province, China
    • 1218.18.86012 Boehringer Ingelheim Investigational Site
  • Xian, Shanxi Province, China
    • 1218.18.86006 Boehringer Ingelheim Investigational Site
• Germany
  • Aschaffenburg, Germany
    • 1218.18.49004 Boehringer Ingelheim Investigational Site
  • Bad Mergentheim, Germany
    • 1218.18.49028 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1218.18.49022 Boehringer Ingelheim Investigational Site
  • Bosenheim, Germany
    • 1218.18.49024 Boehringer Ingelheim Investigational Site
  • Dresden, Germany
    • 1218.18.49020 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 1218.18.49101 Boehringer Ingelheim Investigational Site
  • Neuwied, Germany
    • 1218.18.49003 Boehringer Ingelheim Investigational Site
  • Nürnberg, Germany
    • 1218.18.49007 Boehringer Ingelheim Investigational Site
  • Saarbrücken, Germany
    • 1218.18.49014 Boehringer Ingelheim Investigational Site
• Korea, Republic of
  • Busan, Korea, Republic of
    • 1218.18.82004 Boehringer Ingelheim Investigational Site
  • Daegu, Korea, Republic of
    • 1218.18.82011 Boehringer Ingelheim Investigational Site
  • Incheon, Korea, Republic of
    • 1218.18.82008 Boehringer Ingelheim Investigational Site
  • Jeonju, Korea, Republic of
    • 1218.18.82010 Boehringer Ingelheim Investigational Site
  • Pusan, Korea, Republic of
    • 1218.18.82002 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 1218.18.82001 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 1218.18.82005 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 1218.18.82006 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 1218.18.82007 Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • 1218.18.82009 Boehringer Ingelheim Investigational Site
  • Suwon, Korea, Republic of
    • 1218.18.82003 Boehringer Ingelheim Investigational Site
• Philippines
  • Manila, Philippines
    • 1218.18.63005 Boehringer Ingelheim Investigational Site
  • Marikina, Philippines
    • 1218.18.63002 Boehringer Ingelheim Investigational Site
  • Pasig, Philippines
    • 1218.18.63001 Boehringer Ingelheim Investigational Site
  • Quezon City, Philippines
    • 1218.18.63004 Boehringer Ingelheim Investigational Site
  • San Juan, Philippines
    • 1218.18.63003 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Arkhangelsk, Russian Federation
    • 1218.18.70014 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 1218.18.70012 Boehringer Ingelheim Investigational Site
  • Rostov-on-Don, Russian Federation
    • 1218.18.70013 Boehringer Ingelheim Investigational Site
  • Samara, Russian Federation
    • 1218.18.70016 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1218.18.70015 Boehringer Ingelheim Investigational Site
• Taiwan
  • Changhua, Taiwan
    • 1218.18.88605 Boehringer Ingelheim Investigational Site
  • Taichung, Taiwan
    • 1218.18.88604 Boehringer Ingelheim Investigational Site
  • Tainan, Taiwan
    • 1218.18.88606 Boehringer Ingelheim Investigational Site
  • Taipei, Taiwan
    • 1218.18.88601 Boehringer Ingelheim Investigational Site
  • Taipei, Taiwan
    • 1218.18.88602 Boehringer Ingelheim Investigational Site
  • Taipei, Taiwan
    • 1218.18.88603 Boehringer Ingelheim Investigational Site
  • Taipei, Taiwan
    • 1218.18.88607 Boehringer Ingelheim Investigational Site
  • Taoyuan, Taiwan
    • 1218.18.88608 Boehringer Ingelheim Investigational Site
• Turkey
  • Erzurum, Turkey
    • 1218.18.90003 Boehringer Ingelheim Investigational Site
  • Istanbul, Turkey
    • 1218.18.90005 Boehringer Ingelheim Investigational Site
  • Izmir, Turkey
    • 1218.18.90001 Boehringer Ingelheim Investigational Site
  • Konya, Turkey
    • 1218.18.90004 Boehringer Ingelheim Investigational Site
• United Kingdom
  • Ashford, United Kingdom
    • 1218.18.44005 Boehringer Ingelheim Investigational Site
  • Baillieston, Glasgow, United Kingdom
    • 1218.18.44004 Boehringer Ingelheim Investigational Site
  • Bath, United Kingdom
    • 1218.18.44001 Boehringer Ingelheim Investigational Site
  • Burbage, United Kingdom
    • 1218.18.44003 Boehringer Ingelheim Investigational Site
  • Bury St Edmonds, United Kingdom
    • 1218.18.44010 Boehringer Ingelheim Investigational Site
  • Cardiff, United Kingdom
    • 1218.18.44009 Boehringer Ingelheim Investigational Site
  • Glasgow, United Kingdom
    • 1218.18.44008 Boehringer Ingelheim Investigational Site
  • Penarth, United Kingdom
    • 1218.18.44002 Boehringer Ingelheim Investigational Site
  • Reading, United Kingdom
    • 1218.18.44006 Boehringer Ingelheim Investigational Site
  • Waterloo, Liverpool, United Kingdom
    • 1218.18.44007 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. Male and female patients with a diagnosis of type 2 diabetes mellitus, currently treated only with a stable total daily dose of preferably* >/= 1500 mg metformin and a dose of a sulphonylurea drug that has been documented, by the Investigator, to be the individual maximum tolerated dose of that sulphonylurea drug. Both the dose and dosing regimen of metformin and the sulphonylurea must be stable (i.e. unchanged) for 10 weeks prior to informed consent, and must not be changed for the duration of the trial
2. Glycosylated haemoglobin A1 (HbA1c) >/= 7.0 and </= 10.0% at the screening Visit 1a and at Visit 2 (start of placebo run-in phase)
3. Age >/= 18 and </= 80 years at Visit 1a (screening)
4. BMI (Body Mass Index) </= 40 kg/m2 at Visit 1a (screening)
5. Signed and dated written informed consent, at the latest by the date of Visit 1a, in accordance with GCP and local legislation *Patients currently treated with a total daily dose of less than 1500 mg metformin can be included in the trial if the Investigator has documented that the dose is the maximum tolerated dose of metformin for that patient.

Exclusion criteria:

1. Myocardial infarction, stroke or TIA (transient ischaemic attack) within 6 months prior to the date of informed consent
2. Impaired hepatic function, defined by serum levels of either alanine transaminase (ALT/SGPT), aspartase transaminase (AST/SGOT), or alkaline phosphatase (ALP) above 3 times the upper limit of normal (ULN), as determined at Visit 1a
3. Renal failure or renal impairment (serum creatinine >/= 1.5 mg/dl) as determined at Visit 1a
4. Treatment with rosiglitazone or pioglitazone within 3 months prior to the date of informed consent
5. Treatment with GLP-1 analogues (e.g. exenatide) within 3 months prior to the date of informed consent
6. Treatment with insulin within 3 months prior to the date of informed consent
7. Treatment with anti-obesity drugs (e.g. sibutramine, rimonabant, orlistat) within 3 months prior to the date of informed consent
8. Current treatment with systemic steroids (i.e. at the time of informed consent) or a change in the dosage of thyroid hormones within 6 weeks prior to the date of informed consent

9. Pre-menopausal women (last menstruation </= 1 year prior to the date of informed consent) 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 periodic pregnancy testing during their 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.
10. Known hypersensitivity or allergy to the investigational product or its excipients or to the trial background therapy (i.e. metformin in combination with a sulphonylurea) or sulphonamides
11. Dehydration (as confirmed by the Investigators clinical opinion)
12. Current acute or chronic metabolic acidosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: linagliptin 5 mg; linagliptin 5 mg once daily	Drug: linagliptin; active
PLACEBO_COMPARATOR: placebo; placebo matching linagliptin 5 mg tablets	Drug: placebo; placebo to linagliptin 5 mg

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%. Only patients with baseline HbA1c >= 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 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 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
FPG Change From Baseline to Week 18	This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic 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%.	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 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
Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24	The percentage of patients with an HbA1c reduction greater than 0.5% at week 24 from baseline 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

• Del Prato S, Patel S, Crowe S, von Eynatten M. Efficacy and safety of linagliptin according to patient baseline characteristics: A pooled analysis of three phase 3 trials. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):886-92. doi: 10.1016/j.numecd.2016.06.015. Epub 2016 Jul 1.
• 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.
• Zeng Z, Yang JK, Tong N, Yan S, Zhang X, Gong Y, Woerle HJ. Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial. Curr Med Res Opin. 2013 Aug;29(8):921-9. doi: 10.1185/03007995.2013.805123. Epub 2013 Jun 4.
• Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011 Nov;28(11):1352-61. doi: 10.1111/j.1464-5491.2011.03387.x. Erratum In: Diabet Med. 2012 Jan;29(1):158.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (ACTUAL): May 1, 2009

Study Registration Dates

• First Submitted: January 15, 2008
• First Submitted That Met QC Criteria: January 25, 2008
• First Posted (ESTIMATE): January 28, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): March 28, 2014
• Last Update Submitted That Met QC Criteria: February 27, 2014
• Last Verified: February 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; Linagliptin
• Other Study ID Numbers: 1218.18; 2007-002450-28 (EUDRACT_NUMBER: EudraCT)