Clinical trial NCT01438814: Linagliptin in Combination With Metformin in Treatment Naive Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2011-09-22
Enrollment: 689
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) After 14 Weeks Treatment
timeFrame: Baseline and 14 weeks
Secondary outcomes:
measure: 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
timeFrame: 14 weeks
measure: Occurence of Metformin Pre-specified Moderate to Severe GI Side Effects Assessed by Investigators During 14 Weeks of Treatment
timeFrame: 14 weeks
measure: Change From Baseline in Fasting Plasma Glucose (FPG) After 14 Weeks of Treatment
timeFrame: Baseline and 14 weeks
measure: Metformin Pre-specified GI Symptom Intensity Score Assessed by Investigators During 14 Weeks of Treatment
timeFrame: 14 weeks
measure: Metformin Pre-specified GI Symptom Intensity Score Assessed by Patients During 14 Weeks of Treatment
timeFrame: 14 weeks
measure: 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
timeFrame: 14 weeks
measure: Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 14 Weeks of Treatment)
timeFrame: 14 weeks
measure: Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.8% After 14 Weeks of Treatment)
timeFrame: 14 weeks
measure: 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
timeFrame: 14 weeks
measure: Change From Baseline in Body Weight by Visit at Week 14
timeFrame: Baseline and 14 weeks
measure: 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
timeFrame: 14 weeks
measure: Change From Baseline in HbA1c Over Time
timeFrame: Baseline, 2 weeks and 8 weeks
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: 1218.60.90001 Boehringer Ingelheim Investigational Site
city: Dhaka
country: Bangladesh
facility: 1218.60.90002 Boehringer Ingelheim Investigational Site
city: Dhaka
country: Bangladesh
facility: 1218.60.90003 Boehringer Ingelheim Investigational Site
city: Genk
country: Belgium
facility: 1218.60.32001 Boehringer Ingelheim Investigational Site
city: Ham
country: Belgium
facility: 1218.60.32005 Boehringer Ingelheim Investigational Site
city: Hasselt
country: Belgium
facility: 1218.60.32002 Boehringer Ingelheim Investigational Site
city: Natoye
country: Belgium
facility: 1218.60.32004 Boehringer Ingelheim Investigational Site
city: Tremelo
country: Belgium
facility: 1218.60.32003 Boehringer Ingelheim Investigational Site
city: Calgary
country: Canada
facility: 1218.60.20009 Boehringer Ingelheim Investigational Site
state: Alberta
city: Burnaby
country: Canada
facility: 1218.60.20003 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Coquitlam
country: Canada
facility: 1218.60.20014 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Surrey
country: Canada
facility: 1218.60.20010 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Halifax
country: Canada
facility: 1218.60.20004 Boehringer Ingelheim Investigational Site
state: Nova Scotia
city: Corunna
country: Canada
facility: 1218.60.20012 Boehringer Ingelheim Investigational Site
state: Ontario
city: Hamilton
country: Canada
facility: 1218.60.20015 Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: 1218.60.20006 Boehringer Ingelheim Investigational Site
state: Ontario
city: London
country: Canada
facility: 1218.60.20013 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1218.60.20002 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1218.60.20011 Boehringer Ingelheim Investigational Site
state: Ontario
city: Strathroy
country: Canada
facility: 1218.60.20005 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1218.60.20007 Boehringer Ingelheim Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: 1218.60.20016 Boehringer Ingelheim Investigational Site
state: Ontario
city: St-Romuald
country: Canada
facility: 1218.60.20001 Boehringer Ingelheim Investigational Site
state: Quebec
city: Beijing
country: China
facility: 1218.60.86001 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1218.60.86003 Boehringer Ingelheim Investigational Site
city: Changsha
country: China
facility: 1218.60.86011 Boehringer Ingelheim Investigational Site
city: Chengdu
country: China
facility: 1218.60.86012 Boehringer Ingelheim Investigational Site
city: Chongqing
country: China
facility: 1218.60.86010 Boehringer Ingelheim Investigational Site
city: Hubei
country: China
facility: 1218.60.86013 Boehringer Ingelheim Investigational Site
city: Hubei
country: China
facility: 1218.60.86014 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 1218.60.86006 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 1218.60.86007 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 1218.60.86005 Boehringer Ingelheim Investigational Site
city: Shenyang
country: China
facility: 1218.60.86009 Boehringer Ingelheim Investigational Site
city: Wuxi
country: China
facility: 1218.60.86008 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1218.60.49007 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1218.60.49008 Boehringer Ingelheim Investigational Site
city: Dresden
country: Germany
facility: 1218.60.49005 Boehringer Ingelheim Investigational Site
city: Erfurt
country: Germany
facility: 1218.60.49004 Boehringer Ingelheim Investigational Site
city: Frankfurt
country: Germany
facility: 1218.60.49006 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1218.60.49003 Boehringer Ingelheim Investigational Site
city: Neuwied
country: Germany
facility: 1218.60.49002 Boehringer Ingelheim Investigational Site
city: Unterschneidheim
country: Germany
facility: 1218.60.49001 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1218.60.50001 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1218.60.50002 Boehringer Ingelheim Investigational Site
city: Guatemala
country: Guatemala
facility: 1218.60.50003 Boehringer Ingelheim Investigational Site
city: Hong Kong
country: Hong Kong
facility: 1218.60.85001 Boehringer Ingelheim Investigational Site
city: Hong Kong
country: Hong Kong
facility: 1218.60.85002 Boehringer Ingelheim Investigational Site
city: Aurangabad
country: India
facility: 1218.60.91004 Boehringer Ingelheim Investigational Site
city: Bangalore
country: India
facility: 1218.60.91010 Boehringer Ingelheim Investigational Site
city: Coimbatore
country: India
facility: 1218.60.91005 Boehringer Ingelheim Investigational Site
city: Kolkata
country: India
facility: 1218.60.91008 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 1218.60.91001 Boehringer Ingelheim Investigational Site
city: Nagpur
country: India
facility: 1218.60.91007 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 1218.60.91003 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 1218.60.91006 Boehringer Ingelheim Investigational Site
city: Beirut
country: Lebanon
facility: 1218.60.96001 Boehringer Ingelheim Investigational Site
city: Beirut
country: Lebanon
facility: 1218.60.96002 Boehringer Ingelheim Investigational Site
city: Byblos
country: Lebanon
facility: 1218.60.96004 Boehringer Ingelheim Investigational Site
city: Hazmieh
country: Lebanon
facility: 1218.60.96003 Boehringer Ingelheim Investigational Site
city: Saida
country: Lebanon
facility: 1218.60.96005 Boehringer Ingelheim Investigational Site
city: Aguascalientes
country: Mexico
facility: 1218.60.52005 Boehringer Ingelheim Investigational Site
city: Cuernavaca
country: Mexico
facility: 1218.60.52003 Boehringer Ingelheim Investigational Site
city: Durango
country: Mexico
facility: 1218.60.52001 Boehringer Ingelheim Investigational Site
city: Durango
country: Mexico
facility: 1218.60.52002 Boehringer Ingelheim Investigational Site
city: Monterrey
country: Mexico
facility: 1218.60.52004 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1218.60.51001 Boehringer Ingelheim Investigational Site
city: Lima
country: Peru
facility: 1218.60.51002 Boehringer Ingelheim Investigational Site
city: Piura
country: Peru
facility: 1218.60.51004 Boehringer Ingelheim Investigational Site
city: Cebu City, Philippines
country: Philippines
facility: 1218.60.63001 Boehringer Ingelheim Investigational Site
city: Iloilo City, Philippines
country: Philippines
facility: 1218.60.63004 Boehringer Ingelheim Investigational Site
city: Manila
country: Philippines
facility: 1218.60.63003 Boehringer Ingelheim Investigational Site
city: Marikina City, Philippines
country: Philippines
facility: 1218.60.63002 Boehringer Ingelheim Investigational Site
city: Quezon City
country: Philippines
facility: 1218.60.63005 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1218.60.34001 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1218.60.34002 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1218.60.34003 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1218.60.34004 Boehringer Ingelheim Investigational Site
city: Borges del Camp- Tarragona
country: Spain
facility: 1218.60.34006 Boehringer Ingelheim Investigational Site
city: Centelles
country: Spain
facility: 1218.60.34005 Boehringer Ingelheim Investigational Site
city: Granada
country: Spain
facility: 1218.60.34009 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: 1218.60.34008 Boehringer Ingelheim Investigational Site
city: Mataró
country: Spain
facility: 1218.60.34007 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1218.60.34010 Boehringer Ingelheim Investigational Site
city: Chiayi County
country: Taiwan
facility: 1218.60.88006 Boehringer Ingelheim Investigational Site
city: Kaohsiung,
country: Taiwan
facility: 1218.60.88003 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1218.60.88001 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1218.60.88007 Boehringer Ingelheim Investigational Site
city: Tainan,
country: Taiwan
facility: 1218.60.88002 Boehringer Ingelheim Investigational Site
city: Taipei County
country: Taiwan
facility: 1218.60.88004 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.