CAROLINA: cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients With Type 2 Diabetes

INTERVENTION: Product Name: linagliptin Product Code: BI1356 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: linagliptin CAS Number: 668270‐12‐0 Current Sponsor code: BI 1356 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5.0‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Trade Name: Amaryl Product Name: Amaryl Pharmaceutical Form: Tablet INN or Proposed INN: GLIMEPIRIDE CAS Number: 93479971 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Trade Name: Amaryl Product Name: Amaryl Pharmaceutical Form: Tablet INN or Proposed INN: GLIMEPIRIDE CAS Number: 93479971 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Trade Name: Amaryl Product Name: Amaryl Pharmaceutical Form: Tablet INN or Proposed INN: GLIMEPIRIDE CAS Number: 93479971 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 3‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use Trade Name: Amaryl Product Name: Amaryl Pharmaceutical Form: Tablet INN or Proposed INN: GLIMEPIRIDE CAS Number: 93479971 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 4‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: 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 Therapeutic area: Body processes [G] ‐ Metabolic Phenomena [G03] SECONDARY OUTCOME: 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 unstable 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 INCLUSION CRITERIA: 1) Documented diagnosis of T2DM and concurrently 1) insufficient glycaemic control and 2) a high risk of CV events prior to informed consent 2) Insufficient glycaemic control (at Visit 1a) defined as: a) HbA1c 6.5 ‐ 8.5% (48 ‐ 69 mmol/mol) while patient is treatment naïve (if intolerant or contra‐indicated to first line antidiabetic treatment) or treated with: ‐ metformin monotherapy, or ‐ alpha‐glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or ‐ metformin + alpha‐glucosidase inhibitor or PRIMARY OUTCOME: Main Objective: The primary objective is to demonstrate non‐inferiority (by means of comparing the upper limit of a two‐sided (1‐2*alpha)*100% 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, non‐fatal stroke or non‐fatal myocardial infarction [MI] (excluding silent MI)and hospitalisation for unstable angina pectoris [UAP]) 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 with a superiority hypothesis.; 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) and; hospitalisation for unstable angina pectoris. Secondary Objective: If the superiority test has revealed a significant result, then thirdly the first key secondary endpoint will be tested hierarchically with a superiority hypothesis. 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. 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. ; > 2% weight gain at Final Visit (between Visit 6 and Final Visit)) Timepoint(s) of evaluation of this end point: Every 16 weeks the secondary endpoints will be evaluated (up to max 400 weeks). 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 inh