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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
Last Update Posted : July 18, 2019
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: glimepride 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

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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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]

Eligibility Criteria
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Layout table for eligibility information
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 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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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


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Sponsors and Collaborators
Boehringer Ingelheim
Eli Lilly and Company
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01243424     History of Changes
Other Study ID Numbers: 1218.74
2009-013157-15 ( EudraCT Number )
First Posted: November 18, 2010    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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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