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

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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

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: glimepiride placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6103 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 : November 11, 2010
Actual Primary Completion Date : August 21, 2018
Actual Study Completion Date : August 21, 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: linagliptin
patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD)
 Drug: linagliptin
linagliptin tablets 5mg QD

Drug: glimepiride placebo
glimepiride placebo
Active Comparator: glimepiride 1-4 mg QD
patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (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. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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)

  7. 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)

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.


Eligibility Criteria
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Ages Eligible for Study:   40 Years to 85 Years   (Adult, Older Adult)
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 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01243424


Locations
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Sponsors and Collaborators
Boehringer Ingelheim
Eli Lilly and Company
Investigators
Layout table for investigator information
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] April 20, 2016
Statistical Analysis Plan  [PDF] March 16, 2018

More Information
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Additional Information:

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

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01243424    
Other Study ID Numbers: 1218.74
2009-013157-15 ( EudraCT Number )
First Posted: November 18, 2010    Key Record Dates
Results First Posted: January 7, 2020
Last Update Posted: January 7, 2020
Last Verified: December 2019
Additional relevant MeSH terms:
Layout table for 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