Linagliptin and Metformin Versus Linagliptin in Newly Diagnosed, Untreated Type 2 Diabetes

A 24-week, Randomized, Double-blind, Active-controlled, Parallel Group Trial to Assess the Superiority of Oral Linagliptin and Metformin Compared to Linagliptin Monotherapy in Newly Diagnosed, Treatment-naïve, Uncontrolled Type 2 Diabetes Mellitus Patients

The purpose of this trial is to determine whether a initial combination of linagliptin and metformin compared to linagliptin alone for 24 weeks is effective in newly diagnosed, treatment-naïve patients with Type 2 Diabetes.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 316
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • 1218.83.12011 Boehringer Ingelheim Investigational Site
    • Edmonton, Alberta, Canada
      • 1218.83.12007 Boehringer Ingelheim Investigational Site
    • Red Deer, Alberta, Canada
      • 1218.83.12001 Boehringer Ingelheim Investigational Site
  • Newfoundland and Labrador
    • Paradise, Newfoundland and Labrador, Canada
      • 1218.83.12002 Boehringer Ingelheim Investigational Site
    • St. John's, Newfoundland and Labrador, Canada
      • 1218.83.12009 Boehringer Ingelheim Investigational Site
  • Ontario
    • Kitchener, Ontario, Canada
      • 1218.83.12005 Boehringer Ingelheim Investigational Site
    • London, Ontario, Canada
      • 1218.83.12006 Boehringer Ingelheim Investigational Site
    • Smiths Falls, Ontario, Canada
      • 1218.83.12003 Boehringer Ingelheim Investigational Site
    • Sudbury, Ontario, Canada
      • 1218.83.12010 Boehringer Ingelheim Investigational Site
    • Winnipeg, Ontario, Canada
      • 1218.83.12012 Boehringer Ingelheim Investigational Site
• India
  • Bangalore, India
    • 1218.83.91003 Boehringer Ingelheim Investigational Site
  • Chennai, India
    • 1218.83.91005 Boehringer Ingelheim Investigational Site
  • Mumbai, India
    • 1218.83.91001 Boehringer Ingelheim Investigational Site
• Israel
  • Haifa, Israel
    • 1218.83.97004 Boehringer Ingelheim Investigational Site
  • Haifa, Israel
    • 1218.83.97005 Boehringer Ingelheim Investigational Site
  • Holon, Israel
    • 1218.83.97007 Boehringer Ingelheim Investigational Site
• Malaysia
  • Kelantan, Malaysia
    • 1218.83.60001 Boehringer Ingelheim Investigational Site
  • Perak, Malaysia
    • 1218.83.60002 Boehringer Ingelheim Investigational Site
  • Selangor, Malaysia, Malaysia
    • 1218.83.60003 Boehringer Ingelheim Investigational Site
• Mexico
  • Cuautla, Mexico
    • 1218.83.52004 Boehringer Ingelheim Investigational Site
  • Guadalajara, Mexico
    • 1218.83.52001 Boehringer Ingelheim Investigational Site
  • Guadalajara, Mexico
    • 1218.83.52002 Boehringer Ingelheim Investigational Site
  • Merida, Mexico
    • 1218.83.52005 Boehringer Ingelheim Investigational Site
  • Tampico, Mexico
    • 1218.83.52003 Boehringer Ingelheim Investigational Site
• Philippines
  • Cebu, Philippines
    • 1218.83.63001 Boehringer Ingelheim Investigational Site
  • Cebu City, Philippines
    • 1218.83.63007 Boehringer Ingelheim Investigational Site
  • Iloilo, Philippines
    • 1218.83.63003 Boehringer Ingelheim Investigational Site
  • Iloilo City, Philippines
    • 1218.83.63008 Boehringer Ingelheim Investigational Site
  • Marikina City, Philippines
    • 1218.83.63002 Boehringer Ingelheim Investigational Site
  • Marikina City, Philippines
    • 1218.83.63006 Boehringer Ingelheim Investigational Site
  • Quezon, Philippines
    • 1218.83.63004 Boehringer Ingelheim Investigational Site
• Puerto Rico
  • San Juan, Puerto Rico
    • 1218.83.11037 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Kazan, Russian Federation
    • 1218.83.07001 Boehringer Ingelheim Investigational Site
  • Petrozavodsk, Russian Federation
    • 1218.83.07002 Boehringer Ingelheim Investigational Site
  • Samara, Russian Federation
    • 1218.83.07004 Boehringer Ingelheim Investigational Site
  • Smolensk, Russian Federation
    • 1218.83.07006 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1218.83.07003 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1218.83.07007 Boehringer Ingelheim Investigational Site
  • Yaroslavl, Russian Federation
    • 1218.83.07005 Boehringer Ingelheim Investigational Site
• Sri Lanka
  • Dehiwela, Sri Lanka
    • 1218.83.94004 Boehringer Ingelheim Investigational Site
  • Galle, Sri Lanka, Sri Lanka
    • 1218.83.94002 Boehringer Ingelheim Investigational Site
  • Kandy, Sri Lanka
    • 1218.83.94003 Boehringer Ingelheim Investigational Site
  • Ragama, Sri Lanka
    • 1218.83.94001 Boehringer Ingelheim Investigational Site
• Thailand
  • Bangkok, Thailand
    • 1218.83.66002 Boehringer Ingelheim Investigational Site
  • Bangkok, Thailand
    • 1218.83.66003 Boehringer Ingelheim Investigational Site
  • Muang, Khonkaen, Thailand
    • 1218.83.66001 Boehringer Ingelheim Investigational Site
• Ukraine
  • Dnepropetrovsk, Ukraine
    • 1218.83.38007 Boehringer Ingelheim Investigational Site
  • Ivano-Frankivsk, Ukraine
    • 1218.83.38001 Boehringer Ingelheim Investigational Site
  • Kharkiv, Ukraine
    • 1218.83.38006 Boehringer Ingelheim Investigational Site
  • Odessa, Ukraine
    • 1218.83.38004 Boehringer Ingelheim Investigational Site
  • Vinnitsa, Ukraine
    • 1218.83.38008 Boehringer Ingelheim Investigational Site
  • Vinnytsya, Ukraine
    • 1218.83.38003 Boehringer Ingelheim Investigational Site
  • Vinnytsya, Ukraine
    • 1218.83.38005 Boehringer Ingelheim Investigational Site
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • 1218.83.11002 Boehringer Ingelheim Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States
      • 1218.83.11036 Boehringer Ingelheim Investigational Site
  • California
    • Chino, California, United States
      • 1218.83.11011 Boehringer Ingelheim Investigational Site
    • Huntington Beach, California, United States
      • 1218.83.11001 Boehringer Ingelheim Investigational Site
    • Huntington Park, California, United States
      • 1218.83.11019 Boehringer Ingelheim Investigational Site
    • Lomita, California, United States
      • 1218.83.11015 Boehringer Ingelheim Investigational Site
    • Norwalk, California, United States
      • 1218.83.11023 Boehringer Ingelheim Investigational Site
    • Roseville, California, United States
      • 1218.83.11014 Boehringer Ingelheim Investigational Site
    • San Diego, California, United States
      • 1218.83.11031 Boehringer Ingelheim Investigational Site
  • Florida
    • Fort Lauderdale, Florida, United States
      • 1218.83.11022 Boehringer Ingelheim Investigational Site
    • Orlando, Florida, United States
      • 1218.83.11025 Boehringer Ingelheim Investigational Site
    • Sanford, Florida, United States
      • 1218.83.11033 Boehringer Ingelheim Investigational Site
  • Georgia
    • Oakwood, Georgia, United States
      • 1218.83.11029 Boehringer Ingelheim Investigational Site
  • Kentucky
    • Owensboro, Kentucky, United States
      • 1218.83.11026 Boehringer Ingelheim Investigational Site
  • Maryland
    • Elkton, Maryland, United States
      • 1218.83.11008 Boehringer Ingelheim Investigational Site
  • Nebraska
    • Freemont, Nebraska, United States
      • 1218.83.11027 Boehringer Ingelheim Investigational Site
  • New Jersey
    • Edison, New Jersey, United States
      • 1218.83.11005 Boehringer Ingelheim Investigational Site
  • North Carolina
    • Jacksonville, North Carolina, United States
      • 1218.83.11013 Boehringer Ingelheim Investigational Site
    • Salisbury, North Carolina, United States
      • 1218.83.11028 Boehringer Ingelheim Investigational Site
    • Shelby, North Carolina, United States
      • 1218.83.11009 Boehringer Ingelheim Investigational Site
  • Ohio
    • Franklin, Ohio, United States
      • 1218.83.11003 Boehringer Ingelheim Investigational Site
    • Gallipolis, Ohio, United States
      • 1218.83.11024 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Columbia, South Carolina, United States
      • 1218.83.11018 Boehringer Ingelheim Investigational Site
  • Tennessee
    • Bristol, Tennessee, United States
      • 1218.83.11004 Boehringer Ingelheim Investigational Site
    • Chattanooga, Tennessee, United States
      • 1218.83.11017 Boehringer Ingelheim Investigational Site
  • Texas
    • Grand Prairie, Texas, United States
      • 1218.83.11032 Boehringer Ingelheim Investigational Site
    • Houston, Texas, United States
      • 1218.83.11030 Boehringer Ingelheim Investigational Site
    • San Antonio, Texas, United States
      • 1218.83.11034 Boehringer Ingelheim Investigational Site
    • Tomball, Texas, United States
      • 1218.83.11021 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

1. Patients must sign and date an Informed Consent consistent with International Conference on Harmonisation / Good Clinical Practice guidelines and local regulations prior to any evaluation and participation in the trial.
2. Male and female patients, 18 years of age or older at Visit 1 (Screen), with newly diagnosed (less than 12 months prior to Screen) Type 2 Diabetes Mellitus.
3. Patients who are treatment-naïve, defined as absence of any oral antidiabetic therapy, injectable glucagon-like peptide-1 agonist/analogue, or insulin, and uncontrolled for the 12 weeks prior to randomisation.
4. Patients must have an glycated (or glycosylated) haemoglobin (HbA1c) between 8.5% [69 millimoles per mole (mmol/mol)] and 12.0% (108 mmol/mol) at Visit 1 (Screen).
5. Patients must have a Body Mass Index (BMI) of 45 kg/m2 or less at Visit 1 (Screen).
6. In the investigators opinion, patients must be reliable, honest, compliant, and agree to cooperate with all planned future trial evaluations as explained in detail during the informed consent process and to be able to perform them.

Exclusion criteria:

Patients with, who are, who have, or who have had:

1. Acute coronary syndrome (non-ST Elevation Myocardial Infarction (STEMI), STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 3 months prior to informed consent.
2. Indication of liver disease determined during Screen and/or Run-In Period, defined by a serum level above 3 times the upper limit of normal (ULN) in any of the following: alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase. Gilbert-Meulengracht syndrome (also known as conjugated hyperbilirubinemia, constitutional hepatic dysfunction, or familial nonhemolytic jaundice) will be permitted.
3. Impaired renal function, defined as calculated creatinine clearance of less than 60 milliliters per minute (< 60 mL/min), by the Cockcroft-Gault Equation, as determined during Screen and/or Run-In Period.
4. Bariatric, gastric bypass, and other gastrointestinal surgeries (including all types of gastric banding and/or LapBand) within the past two years.
5. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.
6. Medical history of pancreatitis.
7. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (e.g., malaria, babesiosis, haemolytic anaemia).
8. Any contraindication to metformin and/or linagliptin therapies, according to local labels.
9. Treatment with anti-obesity drugs, including over-the-counter drugs such as Alli (orlistat), 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.
10. 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 Type 2 Diabetes Mellitus.

11. Pre-menopausal women (last menstruation of 1 year or less prior to informed consent) who are nursing or pregnant, 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 trial and do not agree to submit to periodic pregnancy testing during participation in the trial.

    Note: Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems, oral, implantable, intra-vaginal, or injectable contraceptives, Essure micro-inserts placed more than six months prior to Screen Visit, complete sexual abstinence (if acceptable by local authorities), double barrier method (e.g., diaphragm or condom and spermicide), and vasectomised partner.

12. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance to trial procedures or study medication intake in the opinion of the investigator.
13. Participation in another trial with an investigational drug within 2 months prior to informed consent.
14. Any other clinical condition that would jeopardize patient safety while participating in this clinical trial in the opinion of the Investigator.
15. Inability to commit to regular overnight fasting of at least 10 hours duration and attendance to study site visits between 07:00 and 11:00 ante meridiem (a.m.).

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: linagliptin; patients receive linagliptin tablet once daily	Drug: linagliptin; 5 mg daily; Drug: metformin placebo; 0 to 2 tablets daily; Drug: metformin placebo; 4 tablets daily
Experimental: linagliptin plus metformin; patients receive linagliptin tablet once daily and metformin tablets twice daily	Drug: linagliptin; 5 mg daily; Drug: metformin placebo; 0 to 2 tablets daily; Drug: metformin placebo; 4 tablets daily; Drug: metformin; 1000 mg to 2000 mg per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c After 24 Weeks	HbA1c is measured as a percentage. The change from baseline is the Week 24 HbA1c minus the baseline HbA1c. Means are adjusted for treatment and continuous baseline HbA1c	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment	The change from baseline is the FPG after 24 weeks minus the baseline FPG. Means are adjusted for treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose.	Baseline and 24 weeks
Change From Baseline in HbA1c 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 treatment, continuous baseline HbA1c in addition to week repeated within patient, week by baseline HbA1c interaction and week by treatment interaction.	Baseline, 6, 12, 18 and 24 weeks
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment)	The proportion of patients who achieved HbA1c lowering by at least 0.5% after 24 weeks of treatment.The model includes treatment, and continuous baseline HbA1c.	Baseline and 24 weeks
Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 1.0% After 24 Weeks of Treatment)	The proportion of patients who achieved HbA1c lowering by at least 1.0% after 24 weeks of treatment. The model includes treatment, and continuous baseline HbA1c.	Baseline and 24 weeks
Occurrence of Treat to Target Efficacy Response (HbA1c <7.0%) After 24 Weeks of Treatment	The proportion of patients who achieved HbA1c below 7.0% after 24 weeks of treatment. The model includes treatment, and continuous baseline HbA1c.	Baseline and 24 weeks
Change From Baseline in FPG by Visit Over Time	The change from baseline is the FPG over time minus the baseline FPG. Means are adjusted for treatment, continuous baseline HbA1c, continuous baseline FPG in addition to week repeated within patient, week by baseline FPG interaction and week by treatment interaction.	Baseline, 6, 12, 18 and 24 weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Ross SA, Caballero AE, Del Prato S, Gallwitz B, Lewis-D'Agostino D, Bailes Z, Thiemann S, Patel S, Woerle HJ, von Eynatten M. Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia. Postgrad Med. 2016 Nov;128(8):747-754. doi: 10.1080/00325481.2016.1238280. Epub 2016 Sep 29.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 16, 2012
• First Posted (Estimate): January 20, 2012

Study Record Updates

• Last Update Posted (Estimate): May 20, 2014
• Last Update Submitted That Met QC Criteria: May 12, 2014
• Last Verified: May 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: 1218.83; 2011-004158-24 (EudraCT Number: EudraCT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No