Impact of LDL-cholesterol Lowering on Platelet Activation

Phase 4

Terminated

• Conditions: Familial Hypercholesterolemia
• Interventions: Drug: Evolocumab

• Registration Number: NCT03331666
• Lead Sponsor: Columbia University

Brief Summary

The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol.

The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.

Detailed Description

Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.

Study Timeline

• Study First Submitted: 2017-10-20
• Study First Submitted QC: 2017-10-31
• Study First Posted: 2017-11-06
• Study Start: 2018-11-16
• Primary Completion: 2020-02-04
• Study Completion: 2020-02-04
• Results First Submitted: 2021-01-22
• Status Verified: 2021-03
• Results First Submitted QC: 2021-03-05
• Last Update Submitted: 2021-03-05
• Results First Posted: 2021-04-01
• Last Update Posted: 2021-04-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 4

Inclusion Criteria

• Subjects who have a clinical diagnosis of familial hypercholesterolemia (FH)
• Subjects who are referred to Dr. Ginsberg's Lipid Practice for treatment with PCSK9 inhibitor
• Subjects with LDL cholesterol levels >100 mg/dl on baseline treatment with statins and/or ezetimibe

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Exclusion Criteria

• Children under 18 years of age

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Evolocumab	Evolocumab	Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196.
Placebo	Evolocumab	Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196.

Primary Outcome Measures

Name	Time	Method
Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU))	Day 7, Day 14, Day 21, Day 28, Day 84	ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU
Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU))	Day 7, Day 14, Day 21, Day 28, Day 84	ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU)

Trial Locations

Locations (1)

Columbia University Medical Center; 🇺🇸 New York, New York, United States