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

Diabetes Mellitus, Type 2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01438814
• Other study ID #: 1218.60
• Secondary ID: 2011-002276-16
• Status: Completed
• Phase: Phase 4
• First received: September 21, 2011
• Last updated: November 13, 2014
• Start date: November 2011
• Est. completion date: March 2013

Study information

• Verified date: November 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Bangladesh: Directorate of Drug AdministrationBelgium: Federal Agency for Medicinal and Health ProductsCanada: Health CanadaChina: Food and Drug AdministrationGermany: Federal Institute for Drugs and Medical DevicesGuatemala: Ministry of Public Health and Social AssistanceHong Kong: Department of HealthIndia: Drugs Controller General of IndiaLebanon: Ministry of Public HealthMexico: Federal Commission for Protection Against Health RisksPeru: General Directorate of Pharmaceuticals, Devices, and DrugsPhilippines: Bureau of Food and DrugsSpain: Spanish Agency of MedicinesTaiwan : Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 689
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• metformin placebo
metformin placebo tablets 500mg
• linagliptin placebo
linagliptin placebo tablets 5mg
• metformin
metformin tablets 500mg
• metformin
metformin tablets 500 mg
• linagliptin
linagliptin tablets 5mg

Locations

Country	Name	City	State
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
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
Canada	1218.60.20003 Boehringer Ingelheim Investigational Site	Burnaby	British Columbia
Canada	1218.60.20009 Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	1218.60.20014 Boehringer Ingelheim Investigational Site	Coquitlam	British Columbia
Canada	1218.60.20012 Boehringer Ingelheim Investigational Site	Corunna	Ontario
Canada	1218.60.20004 Boehringer Ingelheim Investigational Site	Halifax	Nova Scotia
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	1218.60.20001 Boehringer Ingelheim Investigational Site	St-Romuald	Quebec
Canada	1218.60.20005 Boehringer Ingelheim Investigational Site	Strathroy	Ontario
Canada	1218.60.20010 Boehringer Ingelheim Investigational Site	Surrey	British Columbia
Canada	1218.60.20007 Boehringer Ingelheim Investigational Site	Toronto	Ontario
Canada	1218.60.20016 Boehringer Ingelheim Investigational Site	Toronto	Ontario
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
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
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
Hong Kong	1218.60.85001 Boehringer Ingelheim Investigational Site	Hong Kong
Hong Kong	1218.60.85002 Boehringer Ingelheim Investigational Site	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
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
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
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
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
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
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

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Countries where clinical trial is conducted

Bangladesh,  Belgium,  Canada,  China,  Germany,  Guatemala,  Hong Kong,  India,  Lebanon,  Mexico,  Peru,  Philippines,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Change From Baseline in HbA1c Over Time	Means are adjusted by treatment and continuous baseline HbA1c	Baseline, 2 weeks and 8 weeks	No

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