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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01243424




Registration number
NCT01243424
Ethics application status
Date submitted
17/11/2010
Date registered
18/11/2010
Date last updated
7/01/2020

Titles & IDs
Public title
CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes
Scientific 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.
Secondary ID [1] 0 0
2009-013157-15
Secondary ID [2] 0 0
1218.74
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus, Type 2 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - linagliptin
Treatment: Drugs - glimepiride
Treatment: Drugs - linagliptin placebo
Treatment: Drugs - glimepiride placebo

Experimental: linagliptin - patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD)

Active comparator: glimepiride 1-4 mg QD - patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (QD)


Treatment: Drugs: linagliptin
linagliptin tablets 5mg QD

Treatment: Drugs: glimepiride
glimepiride over-encapsulated tablet 1-4 mg QD

Treatment: Drugs: linagliptin placebo
linagliptin placebo

Treatment: Drugs: glimepiride placebo
glimepiride placebo
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
The First 3-point Major Adverse Cardiovascular Events (3P-MACE)
Timepoint [1] 0 0
From randomization until individual day of trial completion, up to 432 weeks
Secondary outcome [1] 0 0
The First 4-point (4P)- MACE
Timepoint [1] 0 0
From randomization until individual day of trial completion, up to 432 weeks
Secondary outcome [2] 0 0
Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c =7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase
Timepoint [2] 0 0
From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Secondary outcome [3] 0 0
Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c =7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase
Timepoint [3] 0 0
From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Secondary outcome [4] 0 0
Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE
Timepoint [4] 0 0
From randomization until individual day of trial completion, up to 432 weeks
Secondary outcome [5] 0 0
Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE
Timepoint [5] 0 0
From randomization until individual day of trial completion, up to 432 weeks
Secondary outcome [6] 0 0
Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Timepoint [6] 0 0
From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Secondary outcome [7] 0 0
Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Timepoint [7] 0 0
From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Secondary outcome [8] 0 0
Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c)
Timepoint [8] 0 0
Baseline and week 432
Secondary outcome [9] 0 0
Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG)
Timepoint [9] 0 0
Baseline and week 432
Secondary outcome [10] 0 0
Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol
Timepoint [10] 0 0
Baseline and week 432
Secondary outcome [11] 0 0
Change From Baseline to Final Visit in Triglycerides
Timepoint [11] 0 0
Baseline and week 432
Secondary outcome [12] 0 0
Change From Baseline to Final Visit in Creatinine
Timepoint [12] 0 0
Baseline and week 432
Secondary outcome [13] 0 0
Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR)
Timepoint [13] 0 0
Baseline and week 432
Secondary outcome [14] 0 0
Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR)
Timepoint [14] 0 0
Baseline and week 432
Secondary outcome [15] 0 0
Percentage of Participants With Transition in Albuminuria Classes
Timepoint [15] 0 0
Baseline and week 432
Secondary outcome [16] 0 0
Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks
Timepoint [16] 0 0
Baseline and week 208
Secondary outcome [17] 0 0
Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up
Timepoint [17] 0 0
433 weeks
Secondary outcome [18] 0 0
Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study
Timepoint [18] 0 0
Baseline
Secondary outcome [19] 0 0
CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study
Timepoint [19] 0 0
Baseline

Eligibility
Key inclusion 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 International Conference of Harmonisation( ICF)
7. stable anti-diabetic background for at least 8 wks before study start
Minimum age
40 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 Investigational Medicinal/Medical Product (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 Transient Ischemic Attack (TIA) =< 3 months prior to ICF

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
11/11/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/08/2018
Sample size
Target
Accrual to date
Final
6103
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 0 0
Royal Brisbane & Women's Hospital-Endocrinology - Herston
Recruitment hospital [2] 0 0
Logan Hospital - Meadowbrook
Recruitment hospital [3] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 0 0
Eastern Clinical Research Unit - East Ringwood
Recruitment hospital [5] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
4029 - Herston
Recruitment postcode(s) [2] 0 0
4131 - Meadowbrook
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3135 - East Ringwood
Recruitment postcode(s) [5] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
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Alaska
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United States of America
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Arizona
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Arkansas
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Colorado
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Truro

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Boehringer Ingelheim
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Eli Lilly and Company
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01243424
Trial related presentations / publications
Verhagen C, Janssen J, Minderhoud CA, van den Berg E, Wanner C, Passera A, Johansen OE, Biessels GJ. Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk. J Diabetes Complications. 2022 Oct;36(10):108303. doi: 10.1016/j.jdiacomp.2022.108303. Epub 2022 Aug 31.
Verhagen C, Janssen J, Biessels GJ, Johansen OE, Exalto LG. Females with type 2 diabetes are at higher risk for accelerated cognitive decline than males: CAROLINA-COGNITION study. Nutr Metab Cardiovasc Dis. 2022 Feb;32(2):355-364. doi: 10.1016/j.numecd.2021.10.013. Epub 2021 Oct 27.
Biessels GJ, Verhagen C, Janssen J, van den Berg E, Wallenstein G, Zinman B, Espeland MA, Johansen OE. Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study. Diabetologia. 2021 Jun;64(6):1235-1245. doi: 10.1007/s00125-021-05393-8. Epub 2021 Feb 9.
Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK, Marx N; CAROLINA Investigators. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019 Sep 24;322(12):1155-1166. doi: 10.1001/jama.2019.13772. Erratum In: JAMA. 2019 Dec 3;322(21):2138. doi: 10.1001/jama.2019.19012.
Janssen J, van den Berg E, Zinman B, Espeland MA, Geijselaers SLC, Mattheus M, Johansen OE, Biessels GJ. HbA1c, Insulin Resistance, and beta-Cell Function in Relation to Cognitive Function in Type 2 Diabetes: The CAROLINA Cognition Substudy. Diabetes Care. 2019 Jan;42(1):e1-e3. doi: 10.2337/DC18-0914. No abstract available.
Biessels GJ, Janssen J, van den Berg E, Zinman B, Espeland MA, Mattheus M, Johansen OE; CAROLINA(R) investigators. Rationale and design of the CAROLINA(R) - 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(R)). Diab Vasc Dis Res. 2015 May;12(3):164-74. doi: 10.1177/1479164115570301. Epub 2015 Mar 15.
Chilton R. Linagliptin versus glimepiride add-on for the long-term treatment of Type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2013 Jul;8(4):345-349. doi: 10.1586/17446651.2013.811849.
Public notes

Contacts
Principal investigator
Name 0 0
Boehringer Ingelheim
Address 0 0
Boehringer Ingelheim
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01243424