Linagliptin in Combination With Metformin in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

A Randomised, Double-blind, Double-dummy, Active-comparator Controlled Study Investigating the Efficacy and Safety of Linagliptin Co-administered With Metformin QD at Evening Time Versus Metformin BID Over 14 Weeks in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

The aim of this study is to investigate the impact of the combination therapy of linagliptin and metformin at submaximal doses in reduction of Glycosylated haemoglobin (HbA1c) and metformin pre-specified gastro-intestinal (GI) side effects in treatment naive patients of with type 2 diabetes mellitus.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 689
• Phase: Phase 4

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • 1218.60.90001 Boehringer Ingelheim Investigational Site
  • Dhaka, Bangladesh
    • 1218.60.90002 Boehringer Ingelheim Investigational Site
  • Dhaka, Bangladesh
    • 1218.60.90003 Boehringer Ingelheim Investigational Site
• Belgium
  • Genk, Belgium
    • 1218.60.32001 Boehringer Ingelheim Investigational Site
  • Ham, Belgium
    • 1218.60.32005 Boehringer Ingelheim Investigational Site
  • Hasselt, Belgium
    • 1218.60.32002 Boehringer Ingelheim Investigational Site
  • Natoye, Belgium
    • 1218.60.32004 Boehringer Ingelheim Investigational Site
  • Tremelo, Belgium
    • 1218.60.32003 Boehringer Ingelheim Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • 1218.60.20009 Boehringer Ingelheim Investigational Site
  • British Columbia
    • Burnaby, British Columbia, Canada
      • 1218.60.20003 Boehringer Ingelheim Investigational Site
    • Coquitlam, British Columbia, Canada
      • 1218.60.20014 Boehringer Ingelheim Investigational Site
    • Surrey, British Columbia, Canada
      • 1218.60.20010 Boehringer Ingelheim Investigational Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • 1218.60.20004 Boehringer Ingelheim Investigational Site
  • Ontario
    • Corunna, Ontario, Canada
      • 1218.60.20012 Boehringer Ingelheim Investigational Site
    • Hamilton, Ontario, Canada
      • 1218.60.20015 Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada
      • 1218.60.20006 Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada
      • 1218.60.20013 Boehringer Ingelheim Investigational Site
    • Sarnia, Ontario, Canada
      • 1218.60.20002 Boehringer Ingelheim Investigational Site
    • Sarnia, Ontario, Canada
      • 1218.60.20011 Boehringer Ingelheim Investigational Site
    • Strathroy, Ontario, Canada
      • 1218.60.20005 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1218.60.20007 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1218.60.20016 Boehringer Ingelheim Investigational Site
  • Quebec
    • St-Romuald, Quebec, Canada
      • 1218.60.20001 Boehringer Ingelheim Investigational Site
• China
  • Beijing, China
    • 1218.60.86001 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1218.60.86003 Boehringer Ingelheim Investigational Site
  • Changsha, China
    • 1218.60.86011 Boehringer Ingelheim Investigational Site
  • Chengdu, China
    • 1218.60.86012 Boehringer Ingelheim Investigational Site
  • Chongqing, China
    • 1218.60.86010 Boehringer Ingelheim Investigational Site
  • Hubei, China
    • 1218.60.86013 Boehringer Ingelheim Investigational Site
  • Hubei, China
    • 1218.60.86014 Boehringer Ingelheim Investigational Site
  • Nanjing, China
    • 1218.60.86006 Boehringer Ingelheim Investigational Site
  • Nanjing, China
    • 1218.60.86007 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 1218.60.86005 Boehringer Ingelheim Investigational Site
  • Shenyang, China
    • 1218.60.86009 Boehringer Ingelheim Investigational Site
  • Wuxi, China
    • 1218.60.86008 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 1218.60.49007 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1218.60.49008 Boehringer Ingelheim Investigational Site
  • Dresden, Germany
    • 1218.60.49005 Boehringer Ingelheim Investigational Site
  • Erfurt, Germany
    • 1218.60.49004 Boehringer Ingelheim Investigational Site
  • Frankfurt, Germany
    • 1218.60.49006 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1218.60.49003 Boehringer Ingelheim Investigational Site
  • Neuwied, Germany
    • 1218.60.49002 Boehringer Ingelheim Investigational Site
  • Unterschneidheim, Germany
    • 1218.60.49001 Boehringer Ingelheim Investigational Site
• Guatemala
  • Guatemala, Guatemala
    • 1218.60.50001 Boehringer Ingelheim Investigational Site
  • Guatemala, Guatemala
    • 1218.60.50002 Boehringer Ingelheim Investigational Site
  • Guatemala, Guatemala
    • 1218.60.50003 Boehringer Ingelheim Investigational Site
• Hong Kong
  • Hong Kong, Hong Kong
    • 1218.60.85001 Boehringer Ingelheim Investigational Site
  • Hong Kong, Hong Kong
    • 1218.60.85002 Boehringer Ingelheim Investigational Site
• India
  • Aurangabad, India
    • 1218.60.91004 Boehringer Ingelheim Investigational Site
  • Bangalore, India
    • 1218.60.91010 Boehringer Ingelheim Investigational Site
  • Coimbatore, India
    • 1218.60.91005 Boehringer Ingelheim Investigational Site
  • Kolkata, India
    • 1218.60.91008 Boehringer Ingelheim Investigational Site
  • Nagpur, India
    • 1218.60.91001 Boehringer Ingelheim Investigational Site
  • Nagpur, India
    • 1218.60.91007 Boehringer Ingelheim Investigational Site
  • Pune, India
    • 1218.60.91003 Boehringer Ingelheim Investigational Site
  • Pune, India
    • 1218.60.91006 Boehringer Ingelheim Investigational Site
• Lebanon
  • Beirut, Lebanon
    • 1218.60.96001 Boehringer Ingelheim Investigational Site
  • Beirut, Lebanon
    • 1218.60.96002 Boehringer Ingelheim Investigational Site
  • Byblos, Lebanon
    • 1218.60.96004 Boehringer Ingelheim Investigational Site
  • Hazmieh, Lebanon
    • 1218.60.96003 Boehringer Ingelheim Investigational Site
  • Saida, Lebanon
    • 1218.60.96005 Boehringer Ingelheim Investigational Site
• Mexico
  • Aguascalientes, Mexico
    • 1218.60.52005 Boehringer Ingelheim Investigational Site
  • Cuernavaca, Mexico
    • 1218.60.52003 Boehringer Ingelheim Investigational Site
  • Durango, Mexico
    • 1218.60.52001 Boehringer Ingelheim Investigational Site
  • Durango, Mexico
    • 1218.60.52002 Boehringer Ingelheim Investigational Site
  • Monterrey, Mexico
    • 1218.60.52004 Boehringer Ingelheim Investigational Site
• Peru
  • Lima, Peru
    • 1218.60.51001 Boehringer Ingelheim Investigational Site
  • Lima, Peru
    • 1218.60.51002 Boehringer Ingelheim Investigational Site
  • Piura, Peru
    • 1218.60.51004 Boehringer Ingelheim Investigational Site
• Philippines
  • Cebu City, Philippines, Philippines
    • 1218.60.63001 Boehringer Ingelheim Investigational Site
  • Iloilo City, Philippines, Philippines
    • 1218.60.63004 Boehringer Ingelheim Investigational Site
  • Manila, Philippines
    • 1218.60.63003 Boehringer Ingelheim Investigational Site
  • Marikina City, Philippines, Philippines
    • 1218.60.63002 Boehringer Ingelheim Investigational Site
  • Quezon City, Philippines
    • 1218.60.63005 Boehringer Ingelheim Investigational Site
• Spain
  • Barcelona, Spain
    • 1218.60.34001 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1218.60.34002 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1218.60.34003 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1218.60.34004 Boehringer Ingelheim Investigational Site
  • Borges del Camp- Tarragona, Spain
    • 1218.60.34006 Boehringer Ingelheim Investigational Site
  • Centelles, Spain
    • 1218.60.34005 Boehringer Ingelheim Investigational Site
  • Granada, Spain
    • 1218.60.34009 Boehringer Ingelheim Investigational Site
  • L'Hospitalet de Llobregat, Spain
    • 1218.60.34008 Boehringer Ingelheim Investigational Site
  • Mataró, Spain
    • 1218.60.34007 Boehringer Ingelheim Investigational Site
  • Valencia, Spain
    • 1218.60.34010 Boehringer Ingelheim Investigational Site
• Taiwan
  • Chiayi County, Taiwan
    • 1218.60.88006 Boehringer Ingelheim Investigational Site
  • Kaohsiung,, Taiwan
    • 1218.60.88003 Boehringer Ingelheim Investigational Site
  • Taichung, Taiwan
    • 1218.60.88001 Boehringer Ingelheim Investigational Site
  • Taichung, Taiwan
    • 1218.60.88007 Boehringer Ingelheim Investigational Site
  • Tainan,, Taiwan
    • 1218.60.88002 Boehringer Ingelheim Investigational Site
  • Taipei County, Taiwan
    • 1218.60.88004 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. Diagnosis of Type 2 diabetes mellitus (T2DM) prior to informed consent;
2. Male and female patients on diet and exercise regimen who are drug naive, defined as absence of any oral antidiabetic therapy or insulin for 12 weeks prior to randomization
3. Glycosylated haemoglobin A1c (HbA1c) >/= 7.0% (53 mmol/mol) to </= 10.0% (86 mmol/mol) at visit 1 (screening);
4. Age>/=18 and </=80 years at visit 1(screening);
5. Body Mass Index (BMI)</= 45kg/m2 at visit 1 (screening);
6. Signed and dated written informed consent by date of visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

1. Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (13.3mmol/L) after an overnight fast during screening/placebo run-in and confirmed by a second measurement (Not on the same day);
2. Treatment with any oral antidiabetic drug or insulin within 12 weeks prior to randomization
3. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris),stroke or Transient ischemia attack (TIA) within 3 months prior to informed consent;
4. Indication of liver disease/Impaired hepatic function, defined by serum levels of either Aspartate aminotransferase (ALT or SGPT), alanine aminotransferase (AST or SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1 and/or run-in phase,
5. Impaired renal function, defined as eGFR< 60ml/min (moderate or severe renal impairment, modification of diet in renal disease (MDRD) formula) as determined during screening or at run-in phase
6. Bariatric surgery within the past two years and other gastrointestinal surgeries that induced chronic malabsorption
7. Medical history of Cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
8. Blood dyscrasia or any other disorders causing haemolysis or unstable Red Blood Cell (eg. malaria, babesiosis, haemolytic anemia)
9. Known history of pancreatitis and chronic pancreatitis
10. Contraindications to metformin according to the local label
11. Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen etc) leading to unstable body weight
12. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM

13. Pre-menopausal women (last menstruation less than 1 year prior to informed consent) who:

    1. are nursing or pregnant or
    2. 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 or who do not agree to continue contraception for at least 30 days after the last dose of study drug. Acceptable methods of birth control include tubal ligation, transdermal patch, intra-uterine devices/systems(IUDs/IUSs), oral, implantable, or injectable contraceptives, complete sexual abstinence (if acceptable by local authorities), double barrier method and vasectomized partner.
14. Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
15. Participation in another trial with application of any investigational drug within 30 days prior to informed consent
16. Any other clinical condition that would jeopardize patients safety while participating in this trial

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 + metformin; patients to receive linagliptin +metformin QD	Drug: metformin; metformin tablets 500mg; Drug: metformin; metformin tablets 500 mg; Drug: linagliptin; linagliptin tablets 5mg
ACTIVE_COMPARATOR: metformin; patients to receive metformin BID	Drug: metformin; metformin tablets 500mg; Drug: metformin; metformin tablets 500 mg; Drug: metformin placebo; metformin placebo tablets 500mg; Drug: linagliptin placebo; linagliptin placebo tablets 5mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment	Adjusted mean change in HbA1c from baseline at Week 14 was analysed using an ANCOVA model. The Model included treatment and continuous baseline HbA1c.	Baseline and 14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <7.0% After 14 Weeks of Treatment, on no Occurrence of Moderate or Severe Gastrointestinal (GI) Side Effects During 14 Weeks of Treatment	The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 7.0% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe gastrointestinal (GI) side effects of metformin, as assessed by the investigators during 14 weeks of treatment)	14 weeks
Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment	Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks	14 weeks
Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment	Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose.	Baseline and 14 weeks
Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment	Patients could experience multiple events, therefore, multiple answers were possible for each patient.	14 weeks
Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment	The intensity of the GI side effects was also assessed by the patients using VAS scaled from 0 to 10; higher scores indicate more severe events. Means are adjusted by treatment and continuous baseline HbA1c.	14 weeks
Composite Endpoint of Occurrence of Treat to Target Efficacy Response, That is an HbA1c Under Treatment of <6.5% After 14 Weeks of Treatment, and no Occurrence of Moderate or Severe Metformin Pre-specified GI Side Effects Assessed by Investigators	The proportion of patients who achieved all the targets in a composite endpoint (HbA1c below 6.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).	14 weeks
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment)	The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment).	14 weeks
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment)	The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment).	14 weeks
Composite Endpoint of Occurence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) and no Occurence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by the Investigators During 14 Weeks	The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.5% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).	14 weeks
Change From Baseline in Body Weight by Visit at Week 14	Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight	Baseline and 14 weeks
Composite Endpoint of Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) and no Occurrence of Moderate and Severe Metformin Pre-specified GI Side Effects Assessed by Investigators During 14 Weeks	The proportion of patients who achieved all the targets in a composite endpoint (HbA1c lowered by at least 0.8% after 14 weeks of treatment; no occurrence of pre-specified moderate or severe GI side effects of metformin, as assessed by the investigators during 14 weeks of treatment).	14 weeks
Change From Baseline in HbA1c Over Time	Means are adjusted by treatment and continuous baseline HbA1c	Baseline, 2 weeks and 8 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Eli Lilly and Company

Publications and helpful links

General Publications

• Ji L, Zinman B, Patel S, Ji J, Bailes Z, Thiemann S, Seck T. Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naive patients with type 2 diabetes: a double-blind randomized trial. Adv Ther. 2015 Mar;32(3):201-15. doi: 10.1007/s12325-015-0195-3. Epub 2015 Mar 25.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: September 21, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (ESTIMATE): September 22, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): November 25, 2014
• Last Update Submitted That Met QC Criteria: November 13, 2014
• Last Verified: November 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; Metformin; Linagliptin
• Other Study ID Numbers: 1218.60; 2011-002276-16 (EUDRACT_NUMBER: EudraCT)