Impact of Evolocumab on the Effects of Clopidogrel in Patients With High On-Treatment Platelet Reactivity

NCT03096288 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: IIS AMG001
• Study Type: interventional
• Target: 259
• Locations: 1 country
• Sites: 1

Brief Summary

Clopidogrel is the most widely used P2Y12 receptor inhibitor and is the only agent of this class currently recommended in patients with stable coronary artery disease (CAD) undergoing PCI, and for the treatment of stroke or PAD. Pharmacodynamic (PD) studies have shown that approximately 30-40% of patients experience high on-treatment platelet reactivity (HPR) while receiving clopidogrel treatment. Importantly HPR status has been strongly associated with an increased risk of ischemic events. Multiple approaches have been advocated to reduce HPR rates. In a previous study treatment with high-dose atorvastatin in addition to double-dose clopidogrel reduced platelet reactivity significantly more than double-dose clopidogrel alone in statin-naïve patients with stable CAD and HPR. To date, the exact biological mechanisms involved in the statin modulation of platelet function are not fully understood, although likely attributed to both its lipid-lowering and non-lipid-related effects. Evolocumab is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). The use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced the incidence of cardiovascular events. Whether the reduction in cardiovascular events is simply due to LDL reduction or might be related to other mechanisms is currently subject of investigation. Although LDL reduction with statin therapies has been associated with reduction in platelet reactivity, to date the effects on platelet aggregation of adjunctive lipid lowering with evolocumab has not been explored. The aim of the present study is to investigate the effects of evolocumab in addition to statin therapy on HPR rates and platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) and HPR while on clopidogrel treatment.

Conditions

Atherosclerotic Cardiovascular Disease

Outcome Measures

Primary Outcomes (1)

• Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients

  The primary end point of our study is the comparison of P2Y12 reaction units (PRU) measured by VerifyNow between evolocumab and placebo at 30 days after randomization. PRU is a well-established measure of platelet reactivity and aggregation in response to antiplatelet medications. The higher is the PRU the lower is the effect of the antiplatelet medication. HPR is defined as PRU\>208 and NPR as PRU 85-208.

  30 days

Study Arms (2)

Evolocumab

EXPERIMENTAL

Evolocumab (Repatha) 420 mg s.c. single injection

Drug: Evolocumab

Placebo

PLACEBO COMPARATOR

0.9% sodium chloride s.c. single injection

Other: Placebo

Interventions

Evolocumab DRUG

Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).

Also known as: Repatha

Evolocumab

Placebo OTHER

Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with atherosclerotic cardiovascular disease (ASCVD), defined as prior ACS, history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or PAD presumed to be of atherosclerotic origin.
• On therapy with clopidogrel (75mg od), with or without low-dose aspirin (81mg od), as per standard-of-care for at least 30 days.
• HPR, defined as P2Y12 reaction units (PRU) \> 208 by VerifyNow P2Y12.
• Fasting LDL-cholesterol ≥70 mg/dL or a non-high-density lipoprotein cholesterol (HDL-C) of ≥100 mg/dL after ≥2 weeks of optimized stable lipid-lowering therapy with maximally tolerated dose of statin, which would ideally include a high-intensity statin, but must be at least moderate intensity statin (i.e. atorvastatin 20 mg or equivalent, with or without ezetimibe. Maximal tolerated dose will be defined based on patient clinical history (no statin re-challenge will be performed).
• Age ≥ 18 years old.

You may not qualify if:

• On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).
• On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days.
• Use of PCSK9 inhibitors in the past 90 days
• Creatinine clearance \<30 mL/minute.
• Known severe hepatic impairment.
• History of a serious hypersensitivity reaction to evolocumab
• Hemodynamic instability
• Pregnant and breastfeeding women \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].

Sponsors & Collaborators

• University of Florida: lead
• Amgen: collaborator

Study Sites (1)

University of Florida

Jacksonville, Florida, 32209, United States

Location

Related Publications (1)

• Franchi F, Ortega-Paz L, Rollini F, Been L, Rivas A, Maaliki N, Zhou X, Pineda AM, Suryadevara S, Soffer D, Zenni M, Angiolillo DJ. Impact of evolocumab on the pharmacodynamic profiles of clopidogrel in patients with atherosclerotic cardiovascular disease: a randomised, double-blind, placebo-controlled study. EuroIntervention. 2023 Mar 20;18(15):1254-1265. doi: 10.4244/EIJ-D-22-00719.

  PMID: 36602868 DERIVED

MeSH Terms

Conditions

Atherosclerosis

Interventions

evolocumab

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Dominick J. Angiolillo, MD, PhD
• Organization: University of Florida College of Medicine - Jacksonville

dominick.angiolillo@jax.ufl.edu

+1-904-244-3378

Study Officials

• Dominick Angiolillo, MD, PhD

  University of Florida College of Medicine-Jacksonville

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind, placebo-controlled
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: March 30, 2017
• Study Start: October 3, 2017
• Primary Completion: November 2, 2020
• Study Completion: November 2, 2020
• Last Updated: February 17, 2022
• Results First Posted: February 17, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)