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

Tracking Information
First Submitted Date ICMJE	November 17, 2010
First Posted Date ICMJE	November 18, 2010
Last Update Posted Date	May 21, 2018
Actual Study Start Date ICMJE	October 26, 2010
Estimated Primary Completion Date	February 1, 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 19, 2017)	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 ]
Original Primary Outcome Measures ICMJE; (submitted: November 17, 2010)	Time to first occurence of any of the following components of the primary composite endpoint: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for unstable angina pectoris
Change History	Complete list of historical versions of study NCT01243424 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: May 17, 2018)	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 ]; 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 ]; Occurence of any of the adjudicated components of the composite primary and composite first key secondary endpoint. [ Time Frame: 432 weeks ]; Transitions in albuminuria classes between baseline and Final visit. [ Time Frame: 432 weeks ]; 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 ]; Occurence of and time to composite endpoint of all CEC confirmed adjudicated events [ Time Frame: 432 weeks ]; 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 ]; Beta-cell function sub-study: The model-calculated insulin secretion rate at a fixed glucose concentration at 4 years as derived from a 3-hour meal tolerance test [ Time Frame: 208 weeks ]; Continuous glucose monitoring sub-study: The glucose variability determined by the change from baseline in the inter-quartile range of diurnal glucose variability to end of study [ Time Frame: 432 weeks ]; Cognition sub-study: Occurrence of accelerated cognitive decline at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) [ Time Frame: 432 weeks ]
Original Secondary Outcome Measures ICMJE; (submitted: November 17, 2010)	Composite endpoint of (proportion of patients on study treatment at study end, maintain glycemic control (HbA1c =< 7%) without need of rescue medication and without moderate/severe hypoglycemic episodes and without => 2% weight gain at final visit; Composite endpoint of (proportion of patients on study treatment at study end, maintain glycemic control (HbA1c =< 7%) without need of rescue medication and without => 2% weight gain at final visit
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes
Official Title ICMJE	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.
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.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition ICMJE	Diabetes Mellitus, Type 2
Intervention ICMJE	Drug: linagliptin linagliptin tablets 5mg QD; Drug: glimepiride glimepiride over-encapsulated tablet 1-4 mg QD; Drug: linagliptin placebo linagliptin placebo; Drug: glimepride placebo glimepiride placebo
Study Arms	Experimental: linagliptin patient to receive linagliptin or glimepiride placebo overencapsulated tablet QD Interventions: Drug: linagliptin Drug: glimepride placebo; Active Comparator: glimepiride 1-4 mg QD patient to receive glimepiride 1-4 mg or linagliptin placebo tablet QD Interventions: Drug: glimepiride Drug: linagliptin placebo
Publications *	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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: March 3, 2017)	6072
Original Estimated Enrollment ICMJE; (submitted: November 17, 2010)	6000
Estimated Study Completion Date	March 1, 2019
Estimated Primary Completion Date	February 1, 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion criteria: Type 2 diabetes; 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); Pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age => 70 years OR two or more specified cardiovascular risk factor; BMI =< 45kg/m²; age between >= 40 and =< 85 years; signed and dated written ICF; stable anti-diabetic background for at least 8 wks before study start Exclusion criteria: Type 1 diabetes; 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); treatment with any anti-obesity drug less than 3 months before ICF; uncontrolled hyperglycemia; previous or planned bariatric surgery or intervention; current or planned system corticoid treatment; change in thyroid hormones treatment; acute liver disease or impaired hepatic function; pre-planned coronary artery revascularization within 6 months of ICF; known hypersensitivity to any of the components; Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information; congestive heart failure class III or IV; acute or chronic metabolic acidosis; hereditary galactose intolerance; alcohol or drug abuse; participation in another trail with IMP given 2 months before IMP start; pre-menopausal women who are nursing or pregnant or of child-bearing potential and not willing to use acceptable method of birth control; patients considered reliable by the investigator; acute coronary syndrome =< 6 wks before ICF; stroke or TIA =< 3 months prior to ICF
Sex/Gender	Sexes Eligible for Study: All
Ages	40 Years to 85 Years (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, 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
Removed Location Countries	Czech Republic
Administrative Information
NCT Number ICMJE	NCT01243424
Other Study ID Numbers ICMJE	1218.74; 2009-013157-15 ( EudraCT Number: EudraCT )
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Boehringer Ingelheim
Study Sponsor ICMJE	Boehringer Ingelheim
Collaborators ICMJE	Eli Lilly and Company
Investigators ICMJE	Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account	Boehringer Ingelheim
Verification Date	May 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP