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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: linagliptin
* Drug: glimepiride
* Drug: linagliptin placebo
* Drug: glimepiride placebo


Participation Criteria
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Eligibility Criteria
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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 International Conference of Harmonisation( 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 Investigational Medicinal/Medical Product (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 Transient Ischemic Attack (TIA) =< 3 months prior to ICF

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: linagliptin<br>patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD) | Drug: linagliptin<br>* linagliptin tablets 5mg QD<br>Drug: glimepiride placebo<br>* glimepiride placebo<br>|
| Active Comparator: glimepiride 1-4 mg QD<br>patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (QD) | Drug: glimepiride<br>* glimepiride over-encapsulated tablet 1-4 mg QD<br>Drug: linagliptin placebo<br>* linagliptin placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The First 3-point Major Adverse Cardiovascular Events (3P-MACE) | 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. | From randomization until individual day of trial completion, up to 432 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The First 4-point (4P)- MACE | 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. | From randomization until individual day of trial completion, up to 432 weeks | 
| 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 | 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. | From Visit 6 (Week 16) to Final visit (Week 432) (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 | 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. | From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase) | 
| Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE | 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. | From randomization until individual day of trial completion, up to 432 weeks | 
| Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE | 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. | From randomization until individual day of trial completion, up to 432 weeks | 
| Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | 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) | 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 Components of the Composite Endpoint of All Adjudication-confirmed Events | 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) | From start of the treatment until 7 days after the end of treatment, up to 433 weeks | 
| Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit in Triglycerides | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit in Creatinine | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) | 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. | Baseline and week 432 | 
| Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) | 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. | Baseline and week 432 | 
| Percentage of Participants With Transition in Albuminuria Classes | 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. | Baseline and week 432 | 
| Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks | 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. | Baseline and week 208 | 
| Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up | 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. | 433 weeks | 
| Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study | 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. | Baseline | 
| CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study | 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. | Baseline |