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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
6,103
linagliptin tablets 5mg QD
glimepiride over-encapsulated tablet 1-4 mg QD
linagliptin placebo
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.
Time frame: From randomization until individual day of trial completion, up to 432 weeks
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.
Time frame: 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.
Time frame: 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.
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glimepiride placebo
North Alabama Research Center, LLC
Athens, Alabama, United States
Alabama Internal Medicine, PC
Birmingham, Alabama, United States
Cahaba Research, Inc.
Birmingham, Alabama, United States
Internal Medicine Center, LLC
Mobile, Alabama, United States
Diagnostic and Medical Clinic
Mobile, Alabama, United States
Extended Arm Physicians, Inc.
Montgomery, Alabama, United States
Office of Dr. Terence T. Hart MD
Tuscumbia, Alabama, United States
Advanced Clinical Research
Pell City, Alaska, United States
Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC
Mesa, Arizona, United States
Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC
Mesa, Arizona, United States
...and 603 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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)
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 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)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline