Atherosclerotic Cardiovascular DiseasePhase 4NCT03096288
Impact of Evolocumab on the Effects of Clopidogrel in Patients With High On-Treatment Platelet Reactivity
A Phase 4 study testing Evolocumab in people with Atherosclerotic Cardiovascular Disease, run by University of Florida at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Atherosclerotic Cardiovascular Disease
- What is being tested?
- Evolocumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 259 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Oct 2017to 2 Nov 2020
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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].
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of Clopidogrel in Patients With Atherosclerotic Cardiovascular Disease and High On-Treatment Platelet Reactivity
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.
Read the detailed description
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. Although the efficacy of DAPT with aspirin and clopidogrel has been consistently shown in different clinical settings, rates of ischemic recurrences remain elevated despite this treatment regimen, especially in high risk patients. This has been in part attributed to the high interindividual variability in responses to clopidogrel. 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, in particular stent thrombosis, in patients with ACS and following PCI. This underscores the need for strategies aimed to reduce HPR rates in patients treated with clopidogrel. Multiple approaches have been advocated to reduce HPR rates. The pleiotropic effects associated with lipid lowering therapies, in particular statins, have been subject to extensive research. 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) that is administered subcutaneously (s.c.) at a dosage of 140 mg every 2 weeks or 420 mg once monthly. In clinical trials evolocumab was more effective than placebo and/or ezetimibe in reducing LDL cholesterol, including when added to statin therapy. 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
- Being tested
- Evolocumab, Placebo
- Medical subject headings
- Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EvolocumabDrug
Also called Repatha
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).
PlaceboOther
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).
| Study group | Role | What they receive |
|---|---|---|
| Evolocumab | Experimental | Evolocumab (Repatha) 420 mg s.c. single injection Receives: Drug: Evolocumab |
| Placebo | Placebo comparator | 0.9% sodium chloride s.c. single injection Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2017
- Study start3 Oct 2017
- Primary completion2 Nov 2020
- Study completion2 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Atherosclerotic Cardiovascular DiseaseStudies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 259 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- Amgen
- Responsible party
- Sponsor
- Investigators
- Dominick Angiolillo, MD, PhD, Principal investigator, University of Florida College of Medicine-Jacksonville
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03096288
- Sponsor's protocol ID
- IIS AMG001
- Status last verified
- Feb 2022
- First submitted
- 23 Mar 2017
- Last updated
- 17 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ortega-Paz L, Thomas CD, Laudani C, Giordano S, Franchi F, Tunehag KR, Rollini F, Durukan S, Rossi JS, Farahmandsadr M, Stouffer GA, Been L, Keeley EC, Duarte JD, Beitelshees AL, Lee CR, Cavallari LH, Angiolillo DJ. Impact of Race on Profiles of Platelet Reactivity and Clinical Outcomes in Clopidogrel-Treated Participants. Clin Pharmacol Ther. 2026 Jan;119(1):168-178. doi: 10.1002/cpt.70045. Epub 2025 Aug 28.
PubMed 40875095Franchi 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.
PubMed 36602868
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of Clopidogrel in Patients With Atherosclerotic Cardiovascular Disease and High On-Treatment Platelet Reactivity
- ClinicalTrials.gov ID
- NCT03096288
- Acronym / sponsor ID
- IIS AMG001
- Conditions
- Atherosclerotic Cardiovascular Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 259 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- Amgen
- Study start
- 3 Oct 2017 (actual)
- Primary completion
- 2 Nov 2020 (actual)
- Study completion
- 2 Nov 2020 (actual)
- First posted
- 30 Mar 2017 (actual)
- Results
- Posted 17 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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. Although the efficacy of DAPT with aspirin and clopidogrel has been consistently shown in different clinical settings, rates of ischemic recurrences remain elevated despite this treatment regimen, especially in high risk patients. This has been in part attributed to the high interindividual variability in responses to clopidogrel. 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, in particular stent thrombosis, in patients with ACS and following PCI. This underscores the need for strategies aimed to reduce HPR rates in patients treated with clopidogrel. Multiple approaches have been advocated to reduce HPR rates. The pleiotropic effects associated with lipid lowering therapies, in particular statins, have been subject to extensive research. 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) that is administered subcutaneously (s.c.) at a dosage of 140 mg every 2 weeks or 420 mg once monthly. In clinical trials evolocumab was more effective than placebo and/or ezetimibe in reducing LDL cholesterol, including when added to statin therapy. 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Evolocumab | Experimental | Drug: EvolocumabEvolocumab (Repatha) 420 mg s.c. single injection |
| Placebo | Placebo comparator | Other: Placebo0.9% sodium chloride s.c. single injection |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EvolocumabAlso: RepathaPatients 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). | Drug | Evolocumab |
| PlaceboPatients 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). | Other | Placebo |
Primary outcome
Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients
Time frame: 30 days
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40875095Ortega-Paz L, Thomas CD, Laudani C, Giordano S, Franchi F, Tunehag KR, Rollini F, Durukan S, Rossi JS, Farahmandsadr M, Stouffer GA, Been L, Keeley EC, Duarte JD, Beitelshees AL, Lee CR, Cavallari LH, Angiolillo DJ. Impact of Race on Profiles of Platelet Reactivity and Clinical Outcomes in Clopidogrel-Treated Participants. Clin Pharmacol Ther. 2026 Jan;119(1):168-178. doi: 10.1002/cpt.70045. Epub 2025 Aug 28.
- Derived from this study: PubMed 36602868Franchi 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dominick Angiolillo, MD, PhD principal investigator
University of Florida College of Medicine-Jacksonville
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Evolocumab in people with Atherosclerotic Cardiovascular Disease, run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03096288, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2022.