Study to Compare the Efficacy and Safety of Administration of the Fix Dose Combination of Linagliptin Plus Metformin in Drug naïve Type 2 Patients

A Phase III Randomised, Double-blind, Double-dummy, Parallel Group Study to Compare the Efficacy and Safety of Twice Daily Administration of the Fix Dose Combination of Linagliptin 2.5 mg + Metformin 500 mg, or of Linagliptin 2.5 mg + Metformin 1000 mg, With the Individual Components of Metformin (500 mg or 1000 mg, Twice Daily), and Linagliptin (5.0 mg, Once Daily) Over 24 Weeks in Treatment naïve Type 2 Diabetic Patients With Insufficient Glycaemic Control

Reduced factorial design study with 24 week randomized treatment of initial combination therapy with linagliptin and metformin in T2DM patients

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: linagliptin 5mg; Drug: Metformin 500mg; Drug: Metformin 1000mg; Drug: linagliptin2.5mg/metformin500mg; Drug: linagliptin2.5mg/metformin1000mg

• Study Type: Interventional
• Enrollment (Actual): 876
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • 1288.18.86001 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1288.18.86002 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1288.18.86003 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1288.18.86004 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 1288.18.86046 Boehringer Ingelheim Investigational Site
  • Changchun, China
    • 1288.18.86019 Boehringer Ingelheim Investigational Site
  • Changchun, China
    • 1288.18.86020 Boehringer Ingelheim Investigational Site
  • Changsha, China
    • 1288.18.86028 Boehringer Ingelheim Investigational Site
  • Changsha, China
    • 1288.18.86029 Boehringer Ingelheim Investigational Site
  • Changsha, China
    • 1288.18.86050 Boehringer Ingelheim Investigational Site
  • Chengdu, China
    • 1288.18.86045 Boehringer Ingelheim Investigational Site
  • Chongqing, China
    • 1288.18.86042 Boehringer Ingelheim Investigational Site
  • Dalian, China
    • 1288.18.86023 Boehringer Ingelheim Investigational Site
  • Guangzhou, China
    • 1288.18.86009 Boehringer Ingelheim Investigational Site
  • Guangzhou, China
    • 1288.18.86010 Boehringer Ingelheim Investigational Site
  • Guangzhou, China
    • 1288.18.86012 Boehringer Ingelheim Investigational Site
  • Haerbin, China
    • 1288.18.86047 Boehringer Ingelheim Investigational Site
  • Hefei, China
    • 1288.18.86032 Boehringer Ingelheim Investigational Site
  • Hengshui, China
    • 1288.18.86016 Boehringer Ingelheim Investigational Site
  • Jinan, China
    • 1288.18.86017 Boehringer Ingelheim Investigational Site
  • Lanzhou, China
    • 1288.18.86026 Boehringer Ingelheim Investigational Site
  • Nan Ning, China
    • 1288.18.86034 Boehringer Ingelheim Investigational Site
  • Nanchang, China
    • 1288.18.86039 Boehringer Ingelheim Investigational Site
  • Nanjing, China
    • 1288.18.86035 Boehringer Ingelheim Investigational Site
  • Nanjing, China
    • 1288.18.86036 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 1288.18.86006 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 1288.18.86007 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 1288.18.86008 Boehringer Ingelheim Investigational Site
  • Shantou, China
    • 1288.18.86013 Boehringer Ingelheim Investigational Site
  • Shenyang, China
    • 1288.18.86022 Boehringer Ingelheim Investigational Site
  • Shijiazhuang, China
    • 1288.18.86014 Boehringer Ingelheim Investigational Site
  • Shijiazhuang, China
    • 1288.18.86015 Boehringer Ingelheim Investigational Site
  • Suzhou, China
    • 1288.18.86038 Boehringer Ingelheim Investigational Site
  • Wuhan, China
    • 1288.18.86049 Boehringer Ingelheim Investigational Site
  • Wuhu, China
    • 1288.18.86033 Boehringer Ingelheim Investigational Site
  • Xi'An, China
    • 1288.18.86024 Boehringer Ingelheim Investigational Site
  • Xi'An, China
    • 1288.18.86025 Boehringer Ingelheim Investigational Site
  • Yueyang, China
    • 1288.18.86030 Boehringer Ingelheim Investigational Site
• Malaysia
  • Kelantan, Malaysia
    • 1288.18.60004 Boehringer Ingelheim Investigational Site
  • Melaka, Malaysia
    • 1288.18.60002 Boehringer Ingelheim Investigational Site
  • Negeri Sembilan, Malaysia
    • 1288.18.60005 Boehringer Ingelheim Investigational Site
  • Negeri Sembilan, Malaysia
    • 1288.18.60007 Boehringer Ingelheim Investigational Site
  • Perak, Malaysia
    • 1288.18.60001 Boehringer Ingelheim Investigational Site
  • Perak, Malaysia
    • 1288.18.60006 Boehringer Ingelheim Investigational Site
  • Putrajaya, Malaysia
    • 1288.18.60008 Boehringer Ingelheim Investigational Site
  • Selangor, Malaysia
    • 1288.18.60003 Boehringer Ingelheim Investigational Site
• Philippines
  • Cebu, Philippines
    • 1288.18.63007 Boehringer Ingelheim Investigational Site
  • Cebu City, Philippines
    • 1288.18.63003 Boehringer Ingelheim Investigational Site
  • Makati City, Philippines
    • 1288.18.63002 Boehringer Ingelheim Investigational Site
  • Manila, Philippines
    • 1288.18.63001 Boehringer Ingelheim Investigational Site
  • Quezon City, Philippines
    • 1288.18.63008 Boehringer Ingelheim Investigational Site
  • Surigao, Philippines
    • 1288.18.63006 Boehringer Ingelheim Investigational Site
  • Tagum City, Philippines
    • 1288.18.63005 Boehringer Ingelheim Investigational Site
• Vietnam
  • Hanoi, Vietnam
    • 1288.18.84003 Boehringer Ingelheim Investigational Site
  • Ho Chi Minh City, Vietnam
    • 1288.18.84001 Boehringer Ingelheim Investigational Site
  • Ho Chi Minh City, Vietnam
    • 1288.18.84002 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 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-naïve
3. Glycosylated haemoglobin A1c (HbA1c) at V1a >/=7.5 %<11% for main group and HbA1c >/= 11.0 % for the additional parallel group
4. Age >/= 18 and </= 80 years at Visit 1a (Screening)
5. Body Mass Index(BMI)</ = 40 kg/m2 at Visit 1a (Screening)
6. Signed and dated written informed consent by date of Visit 1a in accordance with good clinical practice(GCP) and local legislation

Exclusion criteria:

1. Uncontrolled hyperglycaemia required for rescue medication during placebo run-in phase
2. In main group, the patients with investigational medicinal product(IMP) compliance < 80 % or >120 % during 2 weeks placebo run in period
3. Acute coronary syndrome stroke or Transient ischaemic attack (TIA) within 3 months prior to randomisation
4. Impaired hepatic function, defined by serum levels of either Alanine aminotransferase(ALT) ,Aspartate aminotransferase(AST), or alkaline phosphatase (AP) above 3 x upper limit of normal (ULN) ,or total bilirubin above 1.5 x ULN as determined at Visit 1a
5. Known hypersensitivity or allergy to linagliptin or its excipients or metformin or placebo
6. Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening
7. Alcohol or drug abuse within the 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 in the opinion of the investigator.
8. Concurrent participation in another clinical trial or any investigational therapy within thirty days prior to signing the consent form or during the trial.
9. Pre-menopausal women (last menstruation </= 1 year prior to 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
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.
11. Renal failure or renal impairment at Visit 1a (screening) with an Estimated Glomerular Filtration Rate(eGFR) < 60 ml/min
12. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
13. Dehydration by clinical judgement of the investigator
14. Clinical detected unstable or acute congestive heart failure
15. Acute or chronic metabolic acidosis (present in patient history)
16. Hereditary galactose intolerance
17. Known history of pancreatitis and chronic pancreatitis
18. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within last 5 years.
19. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial at the discretion of investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: linagliptin2.5mg / metformin500mg BID; patient to receive a tablet containing linagliptin 2.5mg and metformin 500mg BID	Drug: linagliptin 5mg; linagliptin 5mg once daily; Drug: Metformin 500mg; Metformin 500mg BID
Experimental: linagliptin2.5mg / metformin1000mg BID; patient to receive a tablet containing linagliptin 2.5mg and metformin 1000mg BID	Drug: linagliptin 5mg; linagliptin 5mg once daily; Drug: Metformin 1000mg; Metformin 1000mg BID
Active Comparator: metformin 500mg BID; patient to receive a tablet containing metformin 500mg BID	Drug: linagliptin2.5mg/metformin500mg; linagliptin2.5mg/metformin500mg BID
Active Comparator: metformin 1000mg BID; patient to receive a tablet containing metformin 1000mg BID	Drug: linagliptin2.5mg/metformin1000mg; linagliptin2.5mg/metformin1000mg BID
Active Comparator: linagliptin 5 mg QD; patient to receive a tablet containing linagliptin 5mg once daily	Drug: linagliptin2.5mg/metformin500mg; linagliptin2.5mg/metformin500mg BID; Drug: linagliptin2.5mg/metformin1000mg; linagliptin2.5mg/metformin1000mg BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group	The change from baseline in HbA1c after 24 weeks of treatment in main group. The mean was adjusted by baseline HbA1c and treatment group.	Baseline and week 24
The Change From Baseline in HbA1c After 24 Weeks of Treatment in Main Group - FAS (OC)	The change from baseline in HbA1c after 24 weeks of treatment in main group. Only subjects from the FAS with measured HbA1c values (observed cases [OC]) were considered. The mean was adjusted by treatment, baseline HbA1c, week and treatment*week. The sensitivity analysis was added as the primary analysis failed with borderline results.	Baseline and week 24
The Change From Baseline in HbA1c After 12 Weeks of Treatment in APG	The change from baseline in HbA1c after 12 weeks of treatment in additional parallel group (APG) The mean was adjusted by baseline HbA1c and treatment group.	Baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 24 Weeks of Treatment in Main Group	The occurrence of treat to target efficacy response in terms of HbA1c < 7.0 % after 24 weeks of treatment in main group.	Week 24 (after first drug administration)
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 7.0 % After 12 Weeks of Treatment in APG	The occurrence of treat to target efficacy response in terms of HbA1c < 7.0 % after 12 weeks of treatment in APG.	Week 12 (after first drug administration)
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 24 Weeks of Treatment in Main Group	The occurrence of treat to target efficacy response in terms of HbA1c < 6.5% after 24 weeks of treatment in main group.	Week 24 (after first drug administration)
The Occurrence of Treat to Target Efficacy Response in Terms of HbA1c < 6.5% After 12 Weeks of Treatment in APG	The occurrence of treat to target efficacy response in terms of HbA1c < 6.5% after 12 weeks of treatment in APG.	Week 12 (after first drug administration)
The Occurrence of Relative Efficacy Response in Main Group	The occurrence of relative efficacy response (HbA1c lowering by at least 0.5% after 24 weeks of treatment) in main group	From baseline until week 24
The Occurrence of Relative Efficacy Response in APG	The Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 12 Weeks of Treatment) in APG	From baseline until week 12
The Change in Fasting Plasma Glucose (FPG) From Baseline After 24 Weeks of Treatment in Main Group	The change in fasting plasma glucose (FPG) from baseline after 24 weeks of treatment in main group. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.	Baseline and week 24
The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG	The Change in Fasting Plasma Glucose (FPG) From Baseline After 12 Weeks of Treatment in APG. Adjusted mean: The model includes continuous baseline HbA1c, continuous baseline FPG and treatment group.	Baseline and week 12
The Frequency of Patients With Use of Rescue Therapy During 24 Week Treatment Period in Main Group	The frequency of patients with use of rescue therapy during 24 week treatment period in main group. For this analysis the main group contrast 'Metformin 1000mg BID, Linagliptin 2.5mg / Metformin 1000mg BID' could not be analysed due to lack of events in the Metformin 1000mg BID group.	From baseline until week 24
The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG	The Frequency of Patients With Use of Rescue Therapy During 12 Week Treatment Period in APG.	From baseline until week 12

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Lv Q, Shen J, Miao L, Ye B, Schepers C, Plat A, Shi Y. Early Combination Therapy with Linagliptin and Metformin in People with Type 2 Diabetes Improves Glycemic Control to HbA1c </= 6.5% without Increasing Hypoglycemia: Pooled Analysis of Two Randomized Clinical Trials. Diabetes Ther. 2020 Jun;11(6):1317-1330. doi: 10.1007/s13300-020-00819-9. Epub 2020 Apr 23.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: October 16, 2012
• First Submitted That Met QC Criteria: October 16, 2012
• First Posted (Estimate): October 17, 2012

Study Record Updates

• Last Update Posted (Estimate): April 24, 2015
• Last Update Submitted That Met QC Criteria: April 8, 2015
• Last Verified: April 1, 2015

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: 1288.18