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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01243424
Recruitment Status : Completed
First Posted : November 18, 2010
Results First Posted : January 7, 2020
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE November 17, 2010
First Posted Date  ICMJE November 18, 2010
Results First Submitted Date  ICMJE August 21, 2019
Results First Posted Date  ICMJE January 7, 2020
Last Update Posted Date January 7, 2020
Actual Study Start Date  ICMJE November 11, 2010
Actual Primary Completion Date August 21, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
The First 3-point Major Adverse Cardiovascular Events (3P-MACE) [ Time Frame: From randomization until individual day of trial completion, up to 432 weeks ]
The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented.
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
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • The First 4-point (4P)- MACE [ Time Frame: From randomization until individual day of trial completion, up to 432 weeks ]
    The first key secondary endpoint was 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 hospitalisation for unstable angina pectoris.
  • 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 [ Time Frame: From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase) ]
    The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients 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.
  • 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 [ Time Frame: From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase) ]
    The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients 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.
  • Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE [ Time Frame: From randomization until individual day of trial completion, up to 432 weeks ]
    Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.
  • Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE [ Time Frame: From randomization until individual day of trial completion, up to 432 weeks ]
    Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.
  • Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events [ Time Frame: From start of the treatment until 7 days after the end of treatment, up to 433 weeks ]
    Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of:
    • CV death (including fatal stroke and fatal MI)
    • non-fatal MI
    • non-fatal stroke
    • hospitalisation for unstable angina pectoris
    • TIA
    • hospitalisation for heart failure
    • hospitalisation for coronary revascularisation procedures (CABG, PCI)
  • Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events [ Time Frame: From start of the treatment until 7 days after the end of treatment, up to 433 weeks ]
    Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of:
    • CV death (including fatal stroke and fatal MI)
    • non-fatal MI
    • non-fatal stroke
    • hospitalisation for unstable angina pectoris
    • Transient ischaemic attack (TIA)
    • hospitalisation for heart failure
    • hospitalisation for coronary revascularisation procedures (CABG, PCI)
  • Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit in Triglycerides [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit in Creatinine [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
  • Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) [ Time Frame: Baseline and week 432 ]
    Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment.
  • Percentage of Participants With Transition in Albuminuria Classes [ Time Frame: Baseline and week 432 ]
    Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.
  • Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks [ Time Frame: Baseline and week 208 ]
    The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint.
  • Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up [ Time Frame: 433 weeks ]
    Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint.
  • Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study [ Time Frame: Baseline ]
    Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
  • CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study [ Time Frame: Baseline ]
    Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
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 Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures 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  ICMJE 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: glimepiride placebo
    glimepiride placebo
Study Arms  ICMJE
  • Experimental: linagliptin
    patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD)
    Interventions:
    • Drug: linagliptin
    • Drug: glimepiride placebo
  • Active Comparator: glimepiride 1-4 mg QD
    patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (QD)
    Interventions:
    • Drug: glimepiride
    • Drug: linagliptin placebo
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: June 27, 2018)
6103
Original Estimated Enrollment  ICMJE
 (submitted: November 17, 2010)
6000
Actual Study Completion Date  ICMJE August 21, 2018
Actual Primary Completion Date August 21, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE 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 )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE 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 December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP