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

Study Description

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Brief Summary:

The aim of the study is to investigate the longterm impact on cardiovascular morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: linagliptin; Drug: glimepiride; Drug: linagliptin placebo; Drug: glimepride placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	6072 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	A Multicentre, International, Randomised, Parallel Group, Double Blind Study to Evaluate Cardiovascular Safety of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.
Actual Study Start Date :	October 26, 2010
Estimated Primary Completion Date :	February 1, 2019
Estimated Study Completion Date :	March 1, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: linagliptin; patient to receive linagliptin or glimepiride placebo overencapsulated tablet QD	Drug: linagliptin; linagliptin tablets 5mg QD Drug: glimepride placebo; glimepiride placebo
Active Comparator: glimepiride 1-4 mg QD; patient to receive glimepiride 1-4 mg or linagliptin placebo tablet QD	Drug: glimepiride; glimepiride over-encapsulated tablet 1-4 mg QD Drug: linagliptin placebo; linagliptin placebo

Outcome Measures

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Primary Outcome Measures :

1. 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 MI (excluding silent MI) or non-fatal stroke [ Time Frame: 432 weeks ]

Secondary Outcome Measures :

1. Time to first occurrence of any of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke or hospitalisation for unstable angina pectoris [ Time Frame: 432 weeks ]
2. Proportion of patients on study treatment at study end, that at Final Visit maintain glycemic control (HbA1c <= 7.0%) without need for rescue medication, without any moderate/severe hypoglycaemic episodes and without > 2% weight gain (from V6 on) [ Time Frame: 432 weeks ]
3. Occurence of any of the adjudicated components of the composite primary and composite first key secondary endpoint. [ Time Frame: 432 weeks ]
4. Transitions in albuminuria classes between baseline and Final visit. [ Time Frame: 432 weeks ]
5. Proportion of patients on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c <= 7.0%) without need for rescue medication and without > 2% weight gain (from V6 on) [ Time Frame: 432 weeks ]
6. Occurence of and time to composite endpoint of all CEC confirmed adjudicated events [ Time Frame: 432 weeks ]
7. Change from baseline to Final Visit in diabetes related laboratory parameters: HbA1c, fasting plasma glucose, Total cholesterol, LDL cholesterol, HDL cholesterol, Triglycerides, Creatinine, eGFR (MDRD formula), Urinary Albumin [ Time Frame: 432 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	40 Years to 85 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

1. Type 2 diabetes
2. Elevated glycosylated haemoglobin (HbA1c): 6.5 - 8.5%, inclusive, if treatment naïve or mono-/dual therapy with metformin and/or an alpha-glucosidase inhibitor; 6.5 - 7.5%, inclusive, if treatment with sulphonylurea/glinide in mono- or dual (with metformin OR an alpha-glucosidase inhibitor) therapy)
3. Pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age => 70 years OR two or more specified cardiovascular risk factor
4. BMI =< 45kg/m²
5. age between >= 40 and =< 85 years
6. signed and dated written ICF
7. stable anti-diabetic background for at least 8 wks before study start

Exclusion criteria:

1. Type 1 diabetes
2. Treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, Glucagon-like peptide 1 (GLP-1) analogue/agonists, Dipeptidyl-peptidase IV (DPP-IV) inhibitors or any insulin) prior to informed consent (previous short term use of insulin (up to two weeks) is allowed if taken at least 8 weeks prior informed consent)
3. treatment with any anti-obesity drug less than 3 months before ICF
4. uncontrolled hyperglycemia
5. previous or planned bariatric surgery or intervention
6. current or planned system corticoid treatment
7. change in thyroid hormones treatment
8. acute liver disease or impaired hepatic function
9. pre-planned coronary artery revascularization within 6 months of ICF
10. known hypersensitivity to any of the components
11. Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information
12. congestive heart failure class III or IV
13. acute or chronic metabolic acidosis
14. hereditary galactose intolerance
15. alcohol or drug abuse
16. participation in another trail with IMP given 2 months before IMP start
17. pre-menopausal women who are nursing or pregnant or of child-bearing potential and not willing to use acceptable method of birth control
18. patients considered reliable by the investigator
19. acute coronary syndrome =< 6 wks before ICF
20. stroke or TIA =< 3 months prior to ICF

Contacts and Locations

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  Show 615 Study Locations

Sponsors and Collaborators

Boehringer Ingelheim

Eli Lilly and Company

Investigators

Study Chair:	Boehringer Ingelheim	Boehringer Ingelheim

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Biessels GJ, Janssen J, van den Berg E, Zinman B, Espeland MA, Mattheus M, Johansen OE; CAROLINA® investigators. Rationale and design of the CAROLINA® - cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus. BMC Neurol. 2018 Jan 15;18(1):7. doi: 10.1186/s12883-018-1014-7.

Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen OE, Woerle HJ. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015 May;12(3):164-74. doi: 10.1177/1479164115570301. Epub 2015 Mar 15.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01243424 History of Changes
Other Study ID Numbers:	1218.74; 2009-013157-15 ( EudraCT Number: EudraCT )
First Posted:	November 18, 2010
Last Update Posted:	April 13, 2018
Last Verified:	April 2018

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Glimepiride; Linagliptin; Anti-Arrhythmia Agents; Hypoglycemic Agents; Physiological Effects of Drugs	Immunosuppressive Agents; Immunologic Factors; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action