Patients with documented diagnosis of T2DM with insufficient glycaemic control and at high risk of CV events prior to informed consent can be enrolled in the study. MedDRA version: 20.0 Level: LLT Classification code 10045242 Term: Type II diabetes mellitus System Organ Class: 100000072461
Conditions
Sponsors
SCS Boehringer Ingelheim Comm.V
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Documented diagnosis of T2DM and concurrently 1) insufficient glycaemic control and 2) a high risk of CV events prior to informed consent 1) Insufficient glycaemic control (at Visit 1a) defined as: a) HbA1c 6.5 - 8.5% (48 - 69 mmol/mol) while patient is treatment naïve or treated with (if intolerant or contra-indicated to first line antidiabetic treatment): - metformin monotherapy, or - alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or - metformin + alpha-glucosidase inhibitor or b) HbA1c 6.5 - 7.5% (48 - 58 mmol/mol) while patient is treated with - sulphonylurea (SU) monotherapy, or - glinide monotherapy (e.g. repaglinide, nateglinide), or - metformin + sulphonylurea (combination maximal up to 5 years), or - metformin + glinide (combination maximal up to 5 years), or - alpha-glucosidase inhibitor + SU (combination maximal up to 5 years) - alpha-glucosidase inhibitor + glinide (combination maximal up to 5 years) 2) High risk of CV events defined as any one (or more) of A), B), C) or D): A) Previous Vascular Disease: - Myocardial infarction (> 6 weeks prior to informed consent) - Documented coronary artery disease (=50% luminal diameter narrowing of left main coronary artery or in at least two major coronary arteries in angiogram) - Percutaneous Coronary Intervention (PCI) > 6 weeks prior informed consent - Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed consent or with recurrent angina following surgery - Ischemic or hemorrhagic stroke (> 3 months prior to informed consent) - Peripheral occlusive arterial disease (previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or foot amputation due to circulatory insufficiency, angiographic or ultrasound detected significant vessel stenosis (>50%) of major limb arteries (common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), history of intermittent claudication, with an ankle: arm blood pressure ratio 10 years at Visit 1a. - Systolic blood pressure (SBP) > 140 mmHg (or on at least one blood pressure lowering treatment at Visit 1a) - Current daily cigarette smoking - LDL cholesterol = 135 mg/dL (3.5 mmol/l) (or specific current treatment for this lipid abnormality) at Visit 1a 3) Body Mass Index (BMI) = 45 kg/m2 at Visit 1a 4) Age = 40 and = 85 years at Visit 1a 5) Signed and dated written informed consent at the latest by the date of Visit 1a, in accordance with GCP and local legislation Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 4000 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2000
Exclusion criteria
Exclusion criteria: • Type 1 diabetes mellitus • Any history and/or current treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, GLP-1 analogue/agonists, DPP-IV inhibitors or any insulin) prior to informed consent. Note 1: This also includes clinical trials where these antidiabetic drugs have been provided to the patient. Note 2: Previous short term use of insulin (up to two consecutive weeks) is allowed (e.g. during hospitalisation) if taken at least 8 weeks prior informed consent • Treatment with anti-obesity drugs within 3 months prior to informed consent • Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day) • Any previous (or planned within next 12 months) bariatric surgery (open or laparascopic) or intervention (gastric sleeve) • Current treatment with systemic corticosteroids at time of informed consent or pre-planned initiation of such therapy. Note: inhaled use of steroids (e.g. for asthma/COPD) is no exclusion criterion, as this does not cause systemic steroid action • Change in dose of thyroid hormones within 6 weeks prior informed consent • Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1a • Pre-planned coronary artery re-vascularisation (PCI, CABG) within next 6 months after V1a or any previous PCI and/or CABG = 6 weeks prior informed consent • Known hypersensitivity or allergy to the investigational product or its excipients, or glimepiride (or the SU class) • Inappropriateness of glimepiride treatment for renal safety issues or other issues (e.g. allergy) according to local prescribing information • Congestive heart failure of NYHA class III or IV • Acute or chronic metabolic acidosis (present condition in patient history) • Hereditary galactose intolerance • Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation • Participation in another trial with an investigational drug given within 2 months prior to informed consent 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 (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. • Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than 5 years for non-CV causes, or has cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study • Acute coronary syndrome = 6 weeks prior to informed consent • Stroke or TIA = 3 months prior to informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to demonstrate non-inferiority (by means of comparing the upper limit of a two-sided 95% confidence interval with the non-inferiority margin of 1.3) of treatment with linagliptin in comparison to glimepiride (as monotherapy or as add-on therapy) with respect to time to first occurrence of any of the adjudicated components of the primary composite endpoint (i.e. cardiovascular [CV] death, nonfatal stroke or non-fatal myocardial infarction [MI] (excluding silent MI) in patients with type 2 diabetes mellitus [T2DM]. If the non-inferiority hypothesis with margin 1.3 has revealed a significant result, then secondly, the primary composite endpoint will be tested hierarchically with a superiority hypothesis.;Secondary Objective: If the superiority test has revealed a significant result, then thirdly the first key secondary endpoint will be tested hierarchically. If the test of the first key secondary hypothesis has revealed a significant result, then fourthly the second key secondary endpoint will be tested hierarchically. If the test of the second key secondary hypothesis has revealed a significant result, then fifthly the third key secondary endpoint will be tested hierarchically.;Primary end point(s): Primary endpoint: time to first occurrence of any of the following adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke or non-fatal MI (excluding silent MI).;Timepoint(s) of evaluation of this end point: The number of confirmed adjudicated primary endpoint events will be continuously monitored during the trial. Based on the available number of events the projected number of expected future events will be calculated. As soon as the projection reliably suggests that the total number of patients with a by adjudication confirmed primary endpoint event will reach 631 within the next 4 months, the trial team will perform respective actions to stop the trial. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Every 16 weeks the secondary endpoints will be evaluated (up to an estimated 432 weeks).;Secondary end point(s): First key secondary endpoint: time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI) or hospitalization for unstalble angina pectoris. Second First key secondary endpoint: composite endpoint of (treatment sustainability defined as the proportion of patients that are on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c = 7.0%) without need for rescue medication (between end of titration [Visit 6] and Final Visit) and patients without any moderate/severe hypoglycaemic episodes (between Visit 6 and Final Visit) and without > 2% weight gain at Final Visit (between Visit 6 and Final Visit)). Third Second key secondary endpoint: composite endpoint of (treatment sustainability defined as the proportion of patients that are on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c = 7.0%) without need for rescue medication (between Visit 6 and Final Visit) and patients without > 2% weight gain at Final Visit (between Visit 6 and Final Visit)) | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Czech Republic, Finland, France, Georgia, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Portugal, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Tunisia, Ukraine, United Kingdom, United States
Contacts
Public ContactQRPE PSC CT Information Disclosure
Boehringer Ingelheim Pharma GmbH & Co. KG
Outcome results
None listed