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

Phase 1

• Conditions: 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: 19.1Level: LLTClassification code 10045242Term: Type II diabetes mellitusSystem Organ Class: 100000004861; Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

• Registration Number: EUCTR2009-013157-15-IE
• Lead Sponsor: Boehringer Ingelheim Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2010-10-06
• Last Update Posted: 22 October 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 6000

Inclusion Criteria

1) Documented diagnosis of T2DM and concurrently 2) insufficient glycaemic control and a high risk of CV events 3) 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 anti-diabetic treatment) or treated with:
- metformin monotherapy, or
- alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or
- metformin + alpha-glucosidase inhibitor (e.g. acarbose, voglibose), 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
- SU + alpha-glucosidase inhibitor (combination maximal up to five years), or
- glinide + alpha-glucosidase inhibitor (combination maximal up to five years)

3) 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 =50% 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, stenting 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 < 0.90 on at least one side).

B) Evidence of vascular related end-organ damage:
- Moderately impaired renal function (as defined by modified diet of renal disease (MDRD) formula) with estimated glomerular filtration rate [eGFRF]) 30-59 mL/min/1.73 m2
- Random spot urinary albumin:creatinine ratio = 30 µg/mg (= 3.4 mg/mmol) in two of three unrelated specimens in previous 12 months prior Visit 1a
- Proliferative retinopathy defined as retinal neovascularisation or previous retinal laser coagulation therapy.

C) Age = 70 years (at Visit 1a)

D) At least two of the following CV risk factors:
- Type 2 diabetes mellitus duration > 10 years at Visit 1a.
- Current* Systolic blood pressure (SBP) > 140 mmHg (or on at least one blood pressure lowering treatment at Visit 1a)
- Current daily cigarette smoking
- Current* LDL cholesterol = 135 mg/dL (3.5 mmol/l) (or specific current treatment for this lipid abnormality) at Visit 1a

* Current = measurement < 6 months prior V1a.

4) Body Mass Index (BMI) = 45 kg/m2 at Visit 1b

5) Age = 40 and = 85 years at Visit 1a

6) Signed and dated written informed consent at the latest by the date of Visit 1a, in accordance with GCP and local legislation

7) Stable anti-diabetic background medication (unchanged daily dose) for at least 8 weeks prior V1a and without short term use of insulin. Background medication should be stab

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: previous short term use of any 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 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 steriods (e.g. for asthma/COPD) is no exclusion criterion, as this does not cause systemic steriod 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-vascularization (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 glimepriride (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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified