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

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: metformin placebo; Drug: linagliptin placebo; Drug: metformin; Drug: linagliptin	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	689 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	November 2011
Actual Primary Completion Date :	March 2013
Actual Study Completion Date :	March 2013

Arms and Interventions

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Arm	Intervention/treatment
Experimental: linagliptin + metformin; patients to receive linagliptin +metformin QD	Drug: metformin; metformin tablets 500 mg Drug: linagliptin; linagliptin tablets 5mg
Active Comparator: metformin; patients to receive metformin BID	Drug: metformin placebo; metformin placebo tablets 500mg Drug: linagliptin placebo; linagliptin placebo tablets 5mg Drug: metformin; metformin tablets 500mg

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

1. 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 [ Time Frame: 14 weeks ]
   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)
2. Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment [ Time Frame: 14 weeks ]
   Proportion of patients who experienced at least one metformin pre-specified moderate or severe GI side effect during 14 weeks
3. Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment [ Time Frame: Baseline and 14 weeks ]
   Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose.
4. Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment [ Time Frame: 14 weeks ]
   Patients could experience multiple events, therefore, multiple answers were possible for each patient.
5. Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment [ Time Frame: 14 weeks ]
   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.
6. 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 [ Time Frame: 14 weeks ]
   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).
7. Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment) [ Time Frame: 14 weeks ]
   The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.5% after 14 weeks of treatment).
8. Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment) [ Time Frame: 14 weeks ]
   The proportion of patients who achieved a relative efficacy response (HbA1c lowering by at least 0.8% after 14 weeks of treatment).
9. 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 [ Time Frame: 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).
10. Change From Baseline in Body Weight by Visit at Week 14 [ Time Frame: Baseline and 14 weeks ]
    Means are adjusted by treatment, continuous baseline HbA1c and continuous baseline weight
11. 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 [ Time Frame: 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).
12. Change From Baseline in HbA1c Over Time [ Time Frame: Baseline, 2 weeks and 8 weeks ]
    Means are adjusted by treatment and continuous baseline HbA1c

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

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
Dhaka, Bangladesh
Belgium
1218.60.32001 Boehringer Ingelheim Investigational Site
Genk, Belgium
1218.60.32005 Boehringer Ingelheim Investigational Site
Ham, Belgium
1218.60.32002 Boehringer Ingelheim Investigational Site
Hasselt, Belgium
1218.60.32004 Boehringer Ingelheim Investigational Site
Natoye, Belgium
1218.60.32003 Boehringer Ingelheim Investigational Site
Tremelo, Belgium
Canada, Alberta
1218.60.20009 Boehringer Ingelheim Investigational Site
Calgary, Alberta, Canada
Canada, British Columbia
1218.60.20003 Boehringer Ingelheim Investigational Site
Burnaby, British Columbia, Canada
1218.60.20014 Boehringer Ingelheim Investigational Site
Coquitlam, British Columbia, Canada
1218.60.20010 Boehringer Ingelheim Investigational Site
Surrey, British Columbia, Canada
Canada, Nova Scotia
1218.60.20004 Boehringer Ingelheim Investigational Site
Halifax, Nova Scotia, Canada
Canada, Ontario
1218.60.20012 Boehringer Ingelheim Investigational Site
Corunna, Ontario, Canada
1218.60.20015 Boehringer Ingelheim Investigational Site
Hamilton, Ontario, Canada
1218.60.20006 Boehringer Ingelheim Investigational Site
London, Ontario, Canada
1218.60.20013 Boehringer Ingelheim Investigational Site
London, Ontario, Canada
1218.60.20002 Boehringer Ingelheim Investigational Site
Sarnia, Ontario, Canada
1218.60.20011 Boehringer Ingelheim Investigational Site
Sarnia, Ontario, Canada
1218.60.20005 Boehringer Ingelheim Investigational Site
Strathroy, Ontario, Canada
1218.60.20007 Boehringer Ingelheim Investigational Site
Toronto, Ontario, Canada
1218.60.20016 Boehringer Ingelheim Investigational Site
Toronto, Ontario, Canada
Canada, Quebec
1218.60.20001 Boehringer Ingelheim Investigational Site
St-Romuald, Quebec, Canada
China
1218.60.86001 Boehringer Ingelheim Investigational Site
Beijing, China
1218.60.86003 Boehringer Ingelheim Investigational Site
Beijing, China
1218.60.86011 Boehringer Ingelheim Investigational Site
Changsha, China
1218.60.86012 Boehringer Ingelheim Investigational Site
Chengdu, China
1218.60.86010 Boehringer Ingelheim Investigational Site
Chongqing, China
1218.60.86013 Boehringer Ingelheim Investigational Site
Hubei, China
1218.60.86014 Boehringer Ingelheim Investigational Site
Hubei, China
1218.60.86006 Boehringer Ingelheim Investigational Site
Nanjing, China
1218.60.86007 Boehringer Ingelheim Investigational Site
Nanjing, China
1218.60.86005 Boehringer Ingelheim Investigational Site
Shanghai, China
1218.60.86009 Boehringer Ingelheim Investigational Site
Shenyang, China
1218.60.86008 Boehringer Ingelheim Investigational Site
Wuxi, China
Germany
1218.60.49007 Boehringer Ingelheim Investigational Site
Berlin, Germany
1218.60.49008 Boehringer Ingelheim Investigational Site
Berlin, Germany
1218.60.49005 Boehringer Ingelheim Investigational Site
Dresden, Germany
1218.60.49004 Boehringer Ingelheim Investigational Site
Erfurt, Germany
1218.60.49006 Boehringer Ingelheim Investigational Site
Frankfurt, Germany
1218.60.49003 Boehringer Ingelheim Investigational Site
Hamburg, Germany
1218.60.49002 Boehringer Ingelheim Investigational Site
Neuwied, Germany
1218.60.49001 Boehringer Ingelheim Investigational Site
Unterschneidheim, Germany
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
Guatemala, Guatemala
Hong Kong
1218.60.85001 Boehringer Ingelheim Investigational Site
Hong Kong, Hong Kong
1218.60.85002 Boehringer Ingelheim Investigational Site
Hong Kong, Hong Kong
India
1218.60.91004 Boehringer Ingelheim Investigational Site
Aurangabad, India
1218.60.91010 Boehringer Ingelheim Investigational Site
Bangalore, India
1218.60.91005 Boehringer Ingelheim Investigational Site
Coimbatore, India
1218.60.91008 Boehringer Ingelheim Investigational Site
Kolkata, India
1218.60.91001 Boehringer Ingelheim Investigational Site
Nagpur, India
1218.60.91007 Boehringer Ingelheim Investigational Site
Nagpur, India
1218.60.91003 Boehringer Ingelheim Investigational Site
Pune, India
1218.60.91006 Boehringer Ingelheim Investigational Site
Pune, India
Lebanon
1218.60.96001 Boehringer Ingelheim Investigational Site
Beirut, Lebanon
1218.60.96002 Boehringer Ingelheim Investigational Site
Beirut, Lebanon
1218.60.96004 Boehringer Ingelheim Investigational Site
Byblos, Lebanon
1218.60.96003 Boehringer Ingelheim Investigational Site
Hazmieh, Lebanon
1218.60.96005 Boehringer Ingelheim Investigational Site
Saida, Lebanon
Mexico
1218.60.52005 Boehringer Ingelheim Investigational Site
Aguascalientes, Mexico
1218.60.52003 Boehringer Ingelheim Investigational Site
Cuernavaca, Mexico
1218.60.52001 Boehringer Ingelheim Investigational Site
Durango, Mexico
1218.60.52002 Boehringer Ingelheim Investigational Site
Durango, Mexico
1218.60.52004 Boehringer Ingelheim Investigational Site
Monterrey, Mexico
Peru
1218.60.51001 Boehringer Ingelheim Investigational Site
Lima, Peru
1218.60.51002 Boehringer Ingelheim Investigational Site
Lima, Peru
1218.60.51004 Boehringer Ingelheim Investigational Site
Piura, Peru
Philippines
1218.60.63001 Boehringer Ingelheim Investigational Site
Cebu City, Philippines, Philippines
1218.60.63004 Boehringer Ingelheim Investigational Site
Iloilo City, Philippines, Philippines
1218.60.63003 Boehringer Ingelheim Investigational Site
Manila, Philippines
1218.60.63002 Boehringer Ingelheim Investigational Site
Marikina City, Philippines, Philippines
1218.60.63005 Boehringer Ingelheim Investigational Site
Quezon City, Philippines
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
Barcelona, Spain
1218.60.34006 Boehringer Ingelheim Investigational Site
Borges del Camp- Tarragona, Spain
1218.60.34005 Boehringer Ingelheim Investigational Site
Centelles, Spain
1218.60.34009 Boehringer Ingelheim Investigational Site
Granada, Spain
1218.60.34008 Boehringer Ingelheim Investigational Site
L'Hospitalet de Llobregat, Spain
1218.60.34007 Boehringer Ingelheim Investigational Site
Mataró, Spain
1218.60.34010 Boehringer Ingelheim Investigational Site
Valencia, Spain
Taiwan
1218.60.88006 Boehringer Ingelheim Investigational Site
Chiayi County, Taiwan
1218.60.88003 Boehringer Ingelheim Investigational Site
Kaohsiung,, Taiwan
1218.60.88001 Boehringer Ingelheim Investigational Site
Taichung, Taiwan
1218.60.88007 Boehringer Ingelheim Investigational Site
Taichung, Taiwan
1218.60.88002 Boehringer Ingelheim Investigational Site
Tainan,, Taiwan
1218.60.88004 Boehringer Ingelheim Investigational Site
Taipei County, Taiwan

Sponsors and Collaborators

Boehringer Ingelheim

Eli Lilly and Company

Investigators

Study Chair:	Boehringer Ingelheim	Boehringer Ingelheim

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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-naïve 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.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01438814 History of Changes
Other Study ID Numbers:	1218.60; 2011-002276-16 ( EudraCT Number: EudraCT )
First Posted:	September 22, 2011
Results First Posted:	June 3, 2014
Last Update Posted:	November 25, 2014
Last Verified:	November 2014

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Metformin; Linagliptin; Hypoglycemic Agents	Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action