MK-0616 (Oral PCSK9 Inhibitor) Cardiovascular Outcomes Study (MK-0616-015) CORALreef Outcomes

Study Overview
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Brief Summary
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This is a phase 3, randomized, placebo-controlled study of the efficacy and safety of MK-0616, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in participants with high cardiovascular risk. The primary objective is to evaluate the efficacy of MK-0616 compared with placebo in increasing the time to the first occurrence of major adverse cardiovascular events (MACE) including coronary heart disease (CHD) death, ischemic stroke, myocardial infarction (MI), acute limb ischemia or major amputation, or urgent arterial revascularization.

Official Title
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Phase 3 Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-0616 in Reducing Major Adverse Cardiovascular Events in Participants at High Cardiovascular Risk

Conditions
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Arteriosclerosis, Hypercholesterolaemia

Intervention / Treatment
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* Drug: MK-0616
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets one of the following: Age ≥18 years with a history of a major atherosclerotic cardiovascular disease (ASCVD) event defined as at least 1 of the following: ≥30 days post MI (presumed Type 1 due to plaque rupture or erosion); ≥30 days post ischemic stroke (presumed due to atherosclerosis); or ≥30 days post successful peripheral (carotid or lower extremity) arterial revascularization (surgical or endovascular) or major (ankle or above) amputation due to atherosclerosis; or High risk for first major ASCVD event defined as at least 1 of the following: Age ≥50 years with evidence of coronary artery disease; Age ≥50 years with evidence of atherosclerotic cerebrovascular disease; Age ≥50 years with evidence of peripheral arterial disease; or Age ≥60 years with diabetes mellitus and at least one of the following: microvascular disease or urine albumin-creatinine ratio ≥30 mg/mmol within 6 months before Visit 1, daily insulin use, or diabetes for ≥10 years Has fasted lipid values (evaluated by the Central Laboratory) at Visit 1 (Screening) as follows: History of major ASCVD Event: LDL-C ≥70 mg/dL (1.81 mmol/L) OR non-HDL-C ≥100 mg/dL (2.59 mmol/L) High risk for first major ASCVD Event: LDL-C ≥90 mg/dL (2.33 mmol/L) OR non-HDL-C ≥120 mg/dL (3.11 mmol/L) Is treated with moderate- or high-intensity statin (± nonstatin lipid-lowering therapy [LLT]) at Visit 1 Is on a stable dose of all background LLTs (including statin and nonstatin agents) for at least 30 days before Visit 1 (Screening) with no medication or dose changes planned during the participation in the study Exclusion Criteria: Has a history of homozygous familial hypercholesterolemia (FH) based on genetic or clinical criteria, compound heterozygous FH, or double heterozygous FH Has New York Heart Association Class IV heart failure, last known Left Ventricular Ejection Fraction ≤25% by any imaging method, or had a Heart Failure hospitalization within 3 months before Visit 1 (Screening) Has recurrent ventricular tachycardia within 3 months prior to randomization Has a planned arterial revascularization procedure Is undergoing or previously underwent an LDL-C apheresis program within 3 months before Visit 1 (Screening) or plans to initiate an LDL-C apheresis program Was previously treated/is being treated with certain other cholesterol lowering medications, including protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors without adequate washout. Has a fasting triglyceride value ≥400 mg/dL (≥4.52 mmol/L) at Visit 1 (Screening) Has history of severe renal insufficiency defined as estimated glomerular filtration rate <30 mL/min/1.73 m2 at Visit 1 (Screening) or has end-stage renal disease on dialysis.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-0616<br>Participants receive MK-0616 20 mg once daily. | Drug: MK-0616<br>* MK-0616 20 mg tablet taken by mouth.<br>|
| Placebo Comparator: Placebo<br>Participants receive placebo once daily. | Drug: Placebo<br>* Placebo tablet matched to MK-0616 taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of Coronary Heart Disease (CHD) Death-Based Major Adverse Cardiovascular Events (MACE)-Plus | Time to the first occurrence of CHD death-based MACE-plus, which is defined as any of the following: coronary heart disease death, myocardial infarction (MI), ischemic stroke (fatal and nonfatal), acute limb ischemia or major amputation, or urgent arterial revascularization (coronary, cerebrovascular, or peripheral). | From date of randomization until the date of first occurrence of CHD death-based MACE-plus, assessed up to approximately 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of 3-point MACE | Time to the first occurrence of 3-point MACE (defined as cardiovascular death, MI, or ischemic stroke). | From date of randomization until the date of first occurrence of 3-point MACE, assessed up to approximately 6 years | 
| Time to First Occurrence of Cardiovascular (CV) Death-Based MACE Plus | Time to the first occurrence of CV death-based MACE plus, defined as any of the following: cardiovascular death, MI, ischemic stroke, acute limb ischemia or major amputation, or urgent arterial revascularization (coronary, cerebrovascular, or peripheral). | From date of randomization until the date of first occurrence of CV death-based MACE plus, assessed up to approximately 6 years | 
| Time to First Occurrence of CHD Death or MI | Time to the first occurrence of CHD death or MI. | From date of randomization until the date of first occurrence of CHD death or MI, assessed up to approximately 6 years | 
| Time to CV Death | Time to cardiovascular death. | From date of randomization until the date of CV death, assessed up to approximately 6 years | 
| Time to All-Cause Death | Time to all-cause death. | From date of randomization until the date of death, assessed up to approximately 6 years | 
| Time to CHD Death | Time to CHD death. | From date of randomization until the date of CHD death, assessed up to approximately 6 years | 
| Time to First Event of MI | Time to the first occurrence of MI. | From date of randomization until the date of MI, assessed up to approximately 6 years | 
| Time to First Event of Ischemic Stroke | Time to the first occurrence of ischemic stroke. | From date of randomization until the date of first occurrence of ischemic stroke, assessed up to approximately 6 years | 
| Time to First Event of Acute Limb Ischemia or Major Amputation | Time to the first occurrence of acute limb ischemia or major amputation. | From date of randomization until the date of first occurrence of acute limb ischemia or major amputation, assessed up to approximately 6 years | 
| Time to First Event of Urgent Arterial Revascularization | Time to the first occurrence of urgent arterial revascularization (coronary, cerebrovascular, or peripheral). | From date of randomization until the date of urgent arterial revascularization, assessed up to approximately 6 years | 
| Percent Change from Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | The percent change from baseline in LDL-C. | Baseline and Week 52 | 
| Percent Change from Baseline in Apolipoprotein B | The percent change from baseline in apolipoprotein B. | Baseline and Week 52 | 
| Percent Change from Baseline in Non-High-Density Lipoprotein Cholesterol (non-HDL-C) cholesterol | The percent change from baseline in Non-HDL-C. | Baseline and Week 52 | 
| Percent Change from Baseline in Lipoprotein (a) | The percent change from baseline in lipoprotein (a). | Baseline and Week 52 | 
| Number of Participants with an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with AE(s) in each arm will be reported. | Up to  6 years | 
| Number of Participants Discontinuing from Study Therapy Due to AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants discontinuing due to AE(s) in each arm will be reported. | Up to  6 years |