Conditions: Atherosclerotic Cardiovascular Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 259
Healthy volunteers: no

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.

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.

Arms:
arm 1: Evolocumab (Repatha) 420 mg s.c. single injection arm 2: 0.9% sodium chloride s.c. single injection

Interventions: intervention 1: Evolocumab intervention 2: Placebo
Intervention descriptions: intervention 1: 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). intervention 2: 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).

Protocol document:
Prot_SAP_000.pdf: 
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Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of 
Clopidogrel in Patients with Atherosclerotic Cardiovascular Disease and 
High or Normal On-Treatment Platelet Reactivity 
 
 
 
 
 
 
 
 
Dominick J. Angiolillo, MD, PhD 
University of Florida College of Medicine-Jacksonville 
655 West 8th Street 
Jacksonville, Florida, 32209 
Tel: +1-904-244-3933 
Fax: +1-904-244-3102 
E-mail: dominick.angiolillo@jax.ufl.edu    
 
 
 
 
 
 
 


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Background and Significance 
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the 
standard of care for the long-term secondary prevention of atherothrombotic events in patients with 
acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) [1]. 
Moreover antiplatelet therapy is commonly used in patients with other atherothrombotic disease 
manifestations, such as stroke and peripheral arterial disease (PAD). 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 
[2]. 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 [1,3]. This has been in part attributed to the high 
interindividual variability in responses to clopidogrel [3,4]. Clopidogrel is a pro-drug which 
requires a two-step metabolic transformation to exert its antiplatelet effect. Pharmacodynamic (PD) 
studies have shown that approximately 30-40% of patients experience high on-treatment platelet 
reactivity (HPR) while receiving clopidogrel treatment [3,4]. 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 [4]. This underscores the need for strategies aimed to reduce 
HPR rates in patients treated with clopidogrel. Several factors (clinical, cellular, and genetic) have 
been associated with HPR on clopidogrel [3,4]. Among these, genetic polymorphisms of the hepatic 
cytochrome P450 (CYP) 2C19 gene, the enzyme involved in both metabolic steps of transformation 
of clopidogrel pro-drug into its active metabolite, have shown to affect clopidogrel PD and 
pharmacokinetic and impact clinical outcomes [3,4]. In particular, the *2 and *3 loss-of-function 


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(LOF) allelic variants confer loss of enzyme function, which leads to attenuated clopidogrel 
bioactivation, lower platelet inhibition and worse outcomes [3,4]. 
Multiple approaches have been advocated to reduce HPR rates. Intuitively, the use of the 
more potent P2Y12 receptor inhibitors prasugrel and ticagrelor represent potential treatment options 
[1]. However, their increased costs and risk of bleeding complications compared with clopidogrel 
have limited their broad uptake in clinical practice [1]. The pleiotropic effects associated with lipid 
lowering therapies, in particular statins, have been subject to extensive research [5]. In a previous 
study we showed that 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 [6]. 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 [7,8]. In fact, there is increasing evidence that 
circulating lipoproteins affect platelet function. In particular, LDL, VLDL, and especially oxidized 
LDL are atherogenic lipoproteins and increase platelet activation [9]. Also, familial 
hypercholesterolaemia is associated with increased platelet activity, such as hyperaggregability, and 
the application of a lipid-lowering drug resulted in a reduction of platelet reactivity [10]. 
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 [11]. In clinical trials in patients with primary hypercholesterolemia or mixed 
dyslipidemia, evolocumab was more effective than placebo and/or ezetimibe in reducing LDL 
cholesterol, including when added to statin therapy [11-13]. Importantly, in an exploratory analysis, 
the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly 
reduced the incidence of cardiovascular events [13]. Whether the reduction in cardiovascular events 


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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. 
 
Study aims 
The primary aim of the present study is to investigate the effects of evolocumab in addition 
to statin therapy on platelet reactivity in patients with atherosclerotic cardiovascular disease 
(ASCVD) while on clopidogrel treatment. Secondary aims will include the effects on cholesterol 
levels. 
 
Research Plan 
Study Population 
Inclusion criteria: 
1. Patients with 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. 
2. On therapy with clopidogrel (75mg od), with or without low-dose aspirin (81mg od), as per 
standard-of-care for at least 30 days. 
3. HPR, defined as P2Y12 reaction units (PRU) > 208 by VerifyNow P2Y12, or normal platelet 
reactivity (NPR), defined as PRU between 85 and 208. 


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4. 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). 
5. Age ≥ 18 years old. 
 
Exclusion criteria: 
 
1. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, 
apixaban, edoxaban). 
2. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days. 
3. Use of PCSK9 inhibitors in the past 90 days 
4. Creatinine clearance <30 mL/minute. 
5. Known severe hepatic impairment. 
6. History of a serious hypersensitivity reaction to evolocumab 
7. Hemodynamic instability 
8. Pregnant and breastfeeding women [women of childbearing age must use reliable birth control 
(i.e. oral contraceptives) while participating in the study]. 
 
Research Design  


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The proposed investigation will be a prospective, randomized, parallel-design, double-blind, 
placebo-controlled, PD study conducted in patients with ASCVD and HPR (PRU>208) or NPR 
(PRU 85-208) on clopidogrel. Patients with low platelet reactivity (PRU<85) will be excluded given 
that their distribution profile of platelet reactivity would be unlikely to unravel a platelet inhibitory 
treatment effect of evolucomab. The study will be performed at the University of Florida Health 
Science Center at UF Health Jacksonville - Division of Cardiology. Patients will be recruited in the 
Cardiology Clinics of our institution and will be screened by Cardiology Research staff, who will 
verify that all candidates meet inclusion and exclusion criteria. Results from blood tests performed 
within the last 90 days will be considered valid for screening purposes. If these are not available, a 
blood sample will be collected for the screening phase. 
After providing written informed consent, patients meeting study entry criteria will be 
randomly assigned to receive either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. 
injection). Blood sampling for PD testing will be conducted at 3 time-points: baseline, and 14±2 
days and 30±2 days after randomized drug administration. At each time point, blood will be 
collected before the morning dose of clopidogrel, in order to measure trough levels of platelet 
inhibition. During study treatment major adverse cardiac events (death, MI, stroke, and urgent 
revascularization procedures) and serious adverse events (bleeding and other adverse events) will be 
collected. A flow diagram of the study design is illustrated below.  
 
 
 
 
 
ASCVD patients on therapy with 
Clopidogrel 75 mg/d 
HPR (PRU>208) or NPR (85-208) 
Background statin therapy  


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Laboratory testing 
PD testing 
Peripheral venous blood samples will be drawn through a short venous catheter inserted into 
a forearm vein and collected in citrate, EDTA, and serum tubes as appropriate for assessments. The 
first 2-4 mL of blood will be discarded to avoid spontaneous platelet activation. Blood sampling 
will be performed at 3 time points as indicated above in the study design section. Various PD assays 
will be performed as described below: 
 
1. 
VerifyNow P2Y12 
2. 
Light transmittance aggregometry (LTA)  
3. 
Thrombelastograph Coagulation Analyzer TEG 6s Series system (CORA® system) 
 
Description of laboratory assays 
 
1) VerifyNow (VN) P2Y12: The VerifyNow System is a turbidimetric based optical detection 
system which measures platelet induced aggregation as an increase in light transmittance 
(Accumetrics, San Diego, CA) and will be utilized according to manufacturer’s instructions, as 
previously described [14]. The assay is based on microbead agglutination and uses specific reagents 
for the pathways of interest. The VN-P2Y12 assay, by combining ADP+PGE1, measures changes in 


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platelet function specific to P2Y12 receptor inhibitors. The assay is based upon the ability of 
activated platelets to bind fibrinogen. Fibrinogen-coated microparticles aggregate in proportion to 
the number of GP IIb/IIIa receptors expressed. Microbead aggregation is more rapid and 
reproducible if platelets are activated; therefore the reagents are incorporated into the assay channel 
to induce platelet activation without fibrin formation. Light transmittance increases as activated 
platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in 
optical signal and reports results in P2Y12 Reaction Units (PRU). HPR will be defined as PRU>208 
and NPR as PRU 85-208 [4]. 
2) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.2%) tubes. LTA will be 
assessed using platelet rich plasma (PRP) by the turbidimetric method in a 2-channel aggregometer 
(Chrono-Log 490 Model, Chrono-Log Corp., Havertown) as previously described [14]. Platelet 
agonists will include arachidonic acid (AA, 1 mM), collagen (3µg/ml), ADP (5 and 20 µM), TRAP 
(15 μM). PRP will be obtained as a supernatant after centrifugation of citrated blood at 1000 rpm 
for 10 minutes. The isolated PRP will be kept at 37° C before use. Platelet poor plasma (PPP) will 
be obtained by a second centrifugation of the blood fraction at 2800 rpm for 10 minutes. Light 
transmission will be adjusted to 0% with the PRP and to 100% for the PPP for each measurement. 
Curves will be recorded for 6 minutes and platelet aggregation will be determined as the maximal 
percent change (MPA) in light transmittance from baseline using PPP as a reference. HPR will be 
defined as MPA with 20 µM ADP > 59% and MPA with 5 µM ADP > 46% [4]. 
3) TEG 6s Series system (CORA® system): the TEG 6s system (Haemonetics Corporation, 
Braintree, MA, USA) will be used according to manufacture instructions [15]. In brief, the CORA® 
system is a new generation portable thrombelastography technology able to evaluate all phases of 


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hemostasis, including time to clot formation, rate of clot formation, strength of clot and residual clot 
strength due to antiplatelet drugs, rate of clot lysis. Disposable assay cartridges contain all of the 
components necessary to allow the analyzer to prepare samples and perform hemostasis tests. The 
analyzer automatically draws the blood into the active area of the cartridge, meters the exact amount 
required for the test, and mixes it with the reagents spotted in the cartridge. The analyzer then 
monitors the harmonic motion of a pendant drop of blood in response to external vibration. As the 
sample transitions from a liquid state to a gel-like state during clotting, the modulus of elasticity and 
resonant frequency increase. The instrument measures these variations in resonant frequency during 
clotting and lysis. The results are displayed in a table and on a graphical tracing that reflects a 
hemostasis profile of clot formation. The resulting hemostasis profile is a measure of the time it 
takes for the first measurable clot to be formed, the kinetics of clot formation, the strength of the 
clot, and the breakdown of the clot, or fibrinolysis. In particular, the PlateletMapping Cartridge are 
used to assess platelet function in patients who have received platelet inhibiting drugs. The 
PlateletMapping assay consists of a set of agonists, ADP and AA platelet agonists together with 
ActivatorF, which can measure the inhibition of platelet function. This assay specifically determines 
the MA (Maximum Amplitude, a measure of clot strength) and the reduction in MA due to 
antiplatelet therapy and reports it as a percentage of reduction in clot strength. The assay uses AA 
and ADP agonists to generate test results that reflect the inhibiting effects of antiplatelet agents such 
as TxA2 Inhibitors (e.g., aspirin) and ADP P2Y12 inhibitors (e.g., clopidogrel). Since thrombin 
(present in blood samples) is the primary and most potent activator of platelets, its activity must be 
inhibited with heparin so that the platelet activating effects of ADP and AA can be measured. Since 
thrombin has been rendered inactive by heparin, activatorF is used to replace thrombin’s role in the 
conversion of fibrinogen to fibrin and Factor XIII to Factor XIIIa. Thus, with this cross-linked fibrin 


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network as the foundation, additional clot strength due to platelet-fibrin bonding related to ADP and 
AA platelet receptor activation can be measured. The HKH reagent, a combination of kaolin and 
heparinase, generates test data for the uninhibited MA resulting from thrombin activation of the 
blood sample, while the heparinase neutralizes the effects of heparin. The HKH test provides 
measures of R (Reaction time; the amount of time between the start of the test and the beginning of 
coagulation), K (the speed of formation of the clot from R time to a specific clot strength), Angle 
(the speed of clot strengthening), LY30 (Percent lysis 30 minutes after MA is finalized) and MA 
parameters; The activatorF test provides the contribution of fibrin to the overall strength of the clot.  
This test value is used in the calculation of aggregation/inhibition for MA ADP and MA AA. The 
AA and ADP test provide measures of MA, percent inhibition and percent aggregation. HPR will be 
defined as MA ADP > 47 mm [15]. 
 
Genetic testing 
 
Spartan RX rapid genotyping: Spartan RX (Spartan Bioscience Inc., Ontario, Canada) is the 
rapid genotyping system determining the CYP2C19 (*1,*2,*3,*17) allele status within 1 hour [16]. 
This test consists of four separate steps intended to be done in less than 8 minutes: acquisition of a 
buccal swab; insertion of the swab into the cartridge; insertion of the reaction solution into the 
device; and analysis of CYP2C19 genotype triggered by a button on the device. 
 
Lipid profile and PCSK9 levels 
Blood for the evaluation of the effects on lipids will be drawn at the same time points as 
described above for PD measurements. Cholesterol measures will include a standard lipid profile 
and lipoprotein(a) [Lp(a)], which will be measured by the central laboratory of our institution 


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according to standard protocols. At each time point, blood samples samples will also be stored for 
measurement of PCSK9 serum levels and for possible future analyses. PCSK9 levels will be 
measured by ELISA as previously described [17]. 
 
Study endpoints and sample size calculation 
The primary end point of our study is the reduction in platelet reactivity, as defined by PRU, 
between evolocumab and placebo at 30 days after randomization in each cohort. We hypothesize 
that evolocumab therapy will be associated with a reduction of 30 PRU in patients with HPR and 
NPR. The rationale for considering a reduction of 30 PRU is because this value approximates that 
observed with more intense lipid lower therapy using statin therapy [18]. Statistical assumptions 
were derived for each cohort of patients based on distribution of their PRU levels from a cohort of 
subjects on maintenance clopidogrel therapy (HPR: 247 ± 29; NPR: 150 ± 35). In patients with 
HPR, 17 patients per group (34 total) are needed to detect a 30 PRU difference with 80% power. In 
NPR patients, 23 patients per group (46 total) are needed to detect a 30 PRU difference with 80% 
power. Therefore, under the assumption of a 30 PRU reduction with evolocumab compared with 
placebo in each cohort, 80% power and α of 0.05, 80 total patients with a valid primary end point 
will be needed. Considering a possible dropout rate of 10%, up to 90 patients will need to be 
randomized. We anticipate that up to 500 patients will need to be screened to reach our sample size. 
Given the absence of preliminary studies exploring the effects of PCSK9 inhibitors on platelet 
aggregation the expected reduction in PRU was arbitrarily defined.  
Other endpoints will include the comparisons between evolocumab and placebo of all PD 
parameters measured by multiple assays, and of cholesterol levels at each time point. Exploratory 
analyses will assess the differential response to evolocumab treatment according to the presence of 


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LOF genetic polymorphisms as well as the levels of PCSK9. We will also investigate different 
response profiles in patients with and without aspirin. 
 
 
Statistical analysis plan  
Categorical variables will be expressed as frequencies and percentages. Continuous 
variables will be presented as mean ± SD or median [IQR]. An analysis of covariance (ANCOVA) 
method with a general linear model will be used to evaluate the primary end point as well as all 
between-groups comparisons of platelet reactivity, cholesterol levels and HS-CRP. The Fisher’s 
exact test or Pearson’s chi square test will be used to evaluate t comparisons of HPR and NPR rates 
between groups.  
A 2-tailed p value of < 0.05 will be considered to indicate a statistically significant 
difference for all the above analyses. Statistical analysis will be performed by our group using SPSS 
v22.0 software (SPSS Inc. Chicago, IL).  
 
Publication Strategy/Additional Information  
Study subjects will be identified first (months 1-24): we expect to enroll 3-4 subjects 
monthly and complete enrollment in 24 months (total: 90 subjects randomized). Month 25 will be 
implied for statistical analysis and months 26-27 for manuscript preparation. We intend to present 
data at a major scientific meeting at completion of the study. 
 
Possible Discomforts and Risk 


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In clinical trials, the most commonly reported adverse events with evolocumab included 
nasopharyngitis (4.0% of evolocumab recipients vs. 3.9% of controls), arthralgia (1.8% vs. 1.6%), 
myalgia (2.0% vs. 1.8%), upper respiratory tract infection (2.1% vs. 2.2%), back pain (2.3% vs. 
2.2%), and nausea (1.8% vs. 1.2 %). Injection-site reactions were reported in 3.3% of evolocumab 
recipients and 3.0% of controls. Allergic reactions occurred in 5.1% and 4.7% of evolocumab-
treated and placebo-treated patients, respectively. The most common allergic reactions were rash 
(1.0% vs. 0.5% for evolocumab and placebo, respectively), eczema (0.4% vs. 0.2%), erythema 
(0.4% vs. 0.2%), and urticaria (0.4% vs. 0.1%) [19]. 
All clinical events described above, if they were to occur, as well as death, myocardial 
infarction, stroke, and urgent revascularization procedure with PCI or coronary artery bypass 
grafting will be recorded. Clinical events will be evaluated by a local committee, comprised of 2 
faculty members (2 cardiologists), not directly involved in the research. In the event of a report of a 
serious adverse event, the local committee will meet and treatment management will be managed 
according to physician recommendation. 
 
Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the course 
of the clinical investigation whether or not it is considered to be therapy related.  This includes any 
newly occurring event or previous condition that has increased in severity or frequency since the 
initiation of study treatment.  Adverse events will be followed until resolution while the patient 
remains on-study.  Once the patient is removed from study, events thought to be related to the study 
therapy will be followed until resolution or until the patient starts a new treatment regimen. 


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Serious Adverse Events (SAE): An adverse event occurring while on study that results in 
any of the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth  
defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
All SAEs will be collected, recorded and reported, whether or not considered causally related to the 
study drug, or to the study procedure(s). Study related SAE is defined as SAE occurring while on 
study and considered  related (reasonable possibility that the study treatment caused the adverse 
experience) to the study treatment. 
The definition of serious adverse event also includes ‘important medical event’.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient and/or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
All suspected unexpected serious adverse reactions (SUSARs) related or possibly related to 
evolocumab and their follow-up reports will be reported to Amgen within 24 hours of submission to 
the regulatory agency, IRB or IEC. A copy of any safety report involving an Amgen drug (e.g. 
evolocumab) submitted to the regulatory agency, IRB or IEC, will be faxed to Amgen, within 24 


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hours of such submission. All pregnancies and pregnancies occurring in the partner of a patient 
participating in the study will be reported within 10 calendar days of Investigator’s awareness. 
 
Possible benefits 
The present investigation is aimed to evaluate the PD effects of evolocumab as an add-on 
therapy to standard antiplatelet treatment in patients with CAD. This study is not designed to 
evaluate differences in clinical benefit. However, differences in antiplatelet profiles may potentially 
prompt further investigations of the clinical implication of this difference by means of a larger scale 
clinical study.   
 
Potential Financial Risks or Benefits 
 
None 
 
Conflict of Interest 
None 


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Am Coll Cardiol. 2014;64:1005-14. 
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www.accessdata.fda.gov/cdrh_docs/pdf14/k140893.pdf Accessed on February 2016 
16. FDA Spartan RX CYP2C19 Test System label package: 
http://www.accessdata.fda.gov/cdrh_docs/reviews/k123891.pdf Accessed on July 6, 2016. 
17.  Navarese EP, Kolodziejczak M, Winter MP, et al. Association of PCSK9 with platelet 
reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: The 
PCSK9-REACT study. Int J Cardiol. 2017;227:644-649. 
18. Leoncini M, Toso A, Maioli M, et al. High-dose atorvastatin on the pharmacodynamic effects of 
double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The 


NCT03096288 
 
Version 10/17/2018 
18 
 
ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet 
activity) study. JACC Cardiovasc Interv. 2013;6:169-79. 
19. FDA evolocumab full prescribing information [online] 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125522s000lbl.pdf. Accessed on 
November 2016. 

ICF_001.pdf: 
 
IRB APPROVED 
 
AS MODIFIED 
 
Oct 30, 2018 
 
 
 
1
 
 
University of Florida – Jacksonville 
 
SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
Impact of the PCSK9 Inhibitor Evolocumab on the 
Pharmacodynamic Effects of Clopidogrel in Patients with 
Atherosclerotic Cardiovascular Disease and High or Normal On-
Treatment Platelet Reactivity 
 
PROTOCOL NO.: 
None 
 
WIRB® Protocol #20170222 
 
IIS AMG001 
 
NCT03096288 
 
SPONSOR: 
University of Florida 
 
INVESTIGATOR: 
Dominick J. Angiolillo, MD, PhD 
 
655 West 8th Street 
 
Jacksonville, Florida 32209 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Dominick J. Angiolillo, MD, PhD 
 
904-244-3933 
 
904-244-0411 (24 hours) 
 
 
Name of person seeking your consent:  ____________________________________________ 
 
 
Place of employment & position:  _________________________________________________ 
 
 
Name of Participant (“Study Subject”) ____________________________________________ 
 
This consent form may contain words that you do not understand. Please ask the study doctor or 
the study staff to explain any words or information that you do not clearly understand. 
 
WHAT WILL BE DONE AS PART OF YOUR NORMAL CLINICAL CARE (EVEN IF 
YOU DID NOT PARTICIPATE IN THIS RESEARCH STUDY)? 
If you choose not to participate in this study, you will be treated and followed by your primary 
care team per normal standard of care. 
 


 
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WHY IS THIS RESEARCH STUDY BEING DONE? 
You are being asked to participate in this study because you have atherosclerotic cardiovascular 
disease (a prior heart attack, or a stroke, mini stroke, peripheral arterial disease or a stent placed 
in one of the arteries of your body) and you are taking blood thinning medications including 
clopidogrel (commercially known as Plavix®). You must be informed so you can decide whether 
you want to participate. 
 
Platelets are parts of your blood that stick together to help form a clot. The stickier your platelets 
are, the greater your chances of having heart attacks, strokes, or clots in your stents. Platelets 
from patients with vascular disease tend to stick together more, increasing the risk of having 
further heart attacks or stroke. To prevent these, there are antiplatelet drugs (blood thinners) to 
keep your platelets from sticking together. Clopidogrel (Plavix®) is the most common antiplatelet 
drug used in the treatment of patients with vascular disease like yours. However, the effect of 
clopidogrel is extremely variable and it is not uncommon that patients who are on treatment with 
clopidogrel have insufficient effect. However, it has been shown that cholesterol lowering 
medications, such as statins, are able to improve clopidogrel effects. Different types of 
treatments are used to lower high LDL (bad cholesterol). Statins are the most commonly 
prescribed treatments. Recently, a new cholesterol lowering medication, called evolocumab 
(Repatha®), has been approved for use by the U.S. Food and Drug Administration (FDA). 
Repatha is an injectable medicine that is an antibody and helps the liver to clear LDL by limiting 
the actions of PCSK9, a protein involved on how much LDL is in your blood. Taken together, 
Repatha plus a statin is proven to dramatically lower LDL. However, the effects of adding 
Repatha on platelets of patients already taking a statin and clopidogrel is unknown. 
 
The purpose of this study is to evaluate the effects of Repatha injection in addition to statin 
therapy on the ability of clopidogrel to prevent platelets from sticking together in subjects with 
atherosclerotic cardiovascular disease who have reduced response (known as “poor responders”) 
or normal response to clopidogrel. You will not be asked to be part of the study if you have a 
strong response to clopidogrel as your platelets are not sticky enough to be able to observe an 
effect of Repatha. Subjects participating in this study will be randomized (like a flip of a coin) to 
receive either a single injection of either Repatha or placebo (a water injection) in addition to 
their therapy with a statin and clopidogrel. Afterwards you will receive your standard-of-care 
therapy. 
 
The dose in which Repatha is being used in this research has been approved by the FDA, and 
subjects taking part in this study have a clinical indication to be on Repatha. 
 
HOW MANY PEOPLE ARE EXPECTED TO TAKE PART IN THIS RESEARCH 
STUDY? 
Up to 90 people are expected to take part in this study and receive either Repatha or placebo. Up to 
500 people are expected to be screened. 
 
HOW LONG WILL YOU BE IN THIS RESEARCH STUDY? 
If you are eligible and agree to participate, you will be expected to take part in the research for up 
to 32 days. 
 


 
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WHO CAN PARTICIPATE IN THIS STUDY? 
Your study doctor will determine if you are able to participate in this research study. Please feel 
free to ask the study doctor about the study requirements for participation. 
 
WHAT WILL BE DONE ONLY BECAUSE YOU ARE IN THIS RESEARCH STUDY? 
Your study doctor will fully explain the study, other possible treatments, and any known or 
possible side effects of participating in this study. If you consent to participate in this study, your 
study doctor will collect data from your medical records. You will be evaluated to see if you 
meet criteria to enter into the research protocol. If you are a woman of childbearing potential, a 
pregnancy test will be done prior to taking any study medication. If you are found to be pregnant, 
you will not be randomized and your participation in this study will end. If you are breastfeeding 
you will not be randomized and your participation in this study will end. 
 
At the screening visit, if results from blood tests performed in the last 90 days are not available, 
blood will be collected for determination of complete blood count and kidney function. In any 
case, at the screening visit blood will be collected to evaluate the effects of clopidogrel and the 
levels of PCSK9, and a buccal swab will be performed to evaluate your genetic profile of 
response to clopidogrel. After undergoing screening, if you are shown to be a “poor responder” 
or normal responder to clopidogrel, you will be considered eligible to participate in the rest of 
the study. You will come for a total of 3 visits and a total of 1 blood draw per visit. 
Approximately 30 cc (or two tablespoons) of blood will be collected at each visit from you by 
inserting a needle directly into your vein or from a catheter in your vein. Baseline platelet 
function tests (while you are taking clopidogrel and statin) will be done to see how sticky your 
platelets are. After this, you will be randomized (chosen, like the flip of a coin) to one receive a 
single dose (3 injections) of either Repatha 420 mg or placebo. You will be asked to come to our 
clinical site after 14±2 days in the morning, 24±4 hours after the last dose of clopidogrel, to re-
assess how sticky your platelets are, your cholesterol levels, and your levels of PCSK9. After 
30±2 days from the day of the injections you will be asked to return to our clinical site in the 
morning, 24±4 hours after the last dose of clopidogrel, to perform the last blood draw (to assess 
how sticky your platelets are, your cholesterol levels, and your levels of PCSK9). After this 
blood draw, the study will be over and you will resume your standard of care therapy as 
instructed by your treating physician. 
 
WHAT ARE THE POSSIBLE DISCOMFORTS AND RISKS? 
Your study doctor will be responsible for reviewing and monitoring your well-being. 
 
The following are potential risks: 
i. 
Blood drawing. There is the discomfort of blood drawing and you may experience 
bruising, and/or bleeding where the needle is inserted.  Occasionally some people become 
dizzy or feel faint. 
ii. 
The most common side effects of Repatha are: runny nose, sore throat, symptoms of the 
common cold, flu or flu-like symptoms, back pain, and redness, pain, or bruising at the 
injection site.  
iii. 
Repatha may cause allergic reactions that may be life-threatening and require immediate 
health care treatment. An allergic reaction may include a severe rash, redness, severe 
itching, a swollen face or trouble breathing. 
iv. 
Loss of confidentiality. 
 


 
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To protect you from above concerns: 
i. 
The blood tests will be drawn by experienced personnel. 
ii. 
Research personnel will evaluate you and the need for treatment   
iii. 
The data will be stored as secured coded access.  
 
This study may include risks that are unknown at this time. 
 
Taking part in more than one research study or project may further increase the risks to you. If 
you are currently enrolled or have recently taken part in another research study, you must tell the 
person reviewing this consent form with you. 
 
Throughout the study, the researchers will notify you of new information that may become 
available and might affect your decision to remain in the study. 
 
If you wish to discuss the information above or any discomforts you may experience, you may 
ask questions now or call the Principal Investigator or contact person listed on the front page of 
this form. 
 
WHAT ARE THE POSSIBLE BENEFITS TO YOU? 
Participation in this study will not help to improve your condition. It is also possible that your 
condition may worsen. There is no guarantee that you will personally benefit by participating in 
this research study. 
 
HOW COULD OTHERS POSSIBLY BENEFIT FROM THIS RESEARCH STUDY? 
Your participation in this study may help the investigators to learn more about the effects of 
administering Repatha in addition to clopidogrel and a statin, and may help other people in the 
future. 
 
HOW COULD THE RESEARCHERS BENEFIT FROM THIS RESEARCH STUDY? 
The sponsor is paying the University of Florida for conducting this research study. In general, 
presenting research results helps the career of a scientist. Therefore, the study doctor may benefit 
if the results of this study are presented at scientific meetings or in scientific journals. 
 
CONFLICT OF INTEREST 
Dr. Angiolillo has received consulting fees from Amgen, the maker of Repatha, in the past 12 
months.  Please feel free to ask any further questions you might have about this matter. 
 
IF YOU CHOOSE TO TAKE PART IN THIS STUDY, WILL IT COST YOU 
ANYTHING? 
The study drug will be provided at no cost to you while you are participating in this study. The 
Sponsor will pay for the medical services that you receive as part of your participation in this 
study which are described in the section of the consent form headed by the question “What Will 
Be Done Only Because You Are in This Research Study”. This may include some medical 
services that you would have received if you were not in this study.  All other medical services 
will be billed to you or your insurance company.  You will be responsible for paying any 
deductible, co-insurance, or co-payments for those services, and for any non-covered or out-of-
network services. Some insurance companies may not cover costs associated with research 
studies.  Please contact your insurance company for additional information. 
 


 
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WILL YOU BE PAID FOR TAKING PART IN THIS RESEARCH STUDY? 
You will be paid $15.00 in Visa debit cards for each completed study visit to help cover time and 
travel. It may take up to 48 hours to process your debit card. If you do not complete all of your 
visits you will be paid for the visits that were completed. 
 
If you are paid more than $75 for taking part in this study, your name and social security number 
will be reported to the appropriate University employees for purposes of making and recording 
the payment as required by law. You are responsible for paying income taxes on any payments 
provided by the study. If the payments total $600 or more or you are a nonresident alien, 
payment will be processed through the University of Florida Accounts Payable department and 
the University must report the amount you received to the Internal Revenue Service (IRS). The 
IRS is not provided with the study name or its purpose. If you have questions about the 
collection and use of your Social Security Number, please visit: 
http://privacy.ufl.edu/SSNPrivacy.html.  
 
Your payment for participation in this research study is handled through the University of 
Florida’s Human Subject Payment (HSP) Program. Your information which will include your 
name, address, date of birth, and SSN (depending on amount of money you are paid) is 
protected.  Access to the (HSP) Program site is limited to certain staff with the assigned security 
role.  You will be randomly assigned a specific identification (ID) number to protect your 
identity. 
 
The study team will provide you with an informational form called the Prepaid Card Facts 
document. If you have any problems regarding your payment call the HSP Office at: 
(352) 392-9057. 
 
WHAT IF YOU ARE INJURED BECAUSE OF THE RESEARCH STUDY? 
If you are injured as a direct result of your participation in this study, only professional medical 
care that you receive at the University of Florida Health Science Center will be provided without 
charge. Hospital expenses will be billed to you or your insurance. You will be responsible for 
any deductible, co-insurance, or co-payments. Some insurance companies may not cover costs 
associated with research studies. Please contact your insurance company for additional 
information. 
 
No additional compensation is routinely offered. 
 
The Principal Investigator and others involved in this study may be University of Florida 
employees. As employees of the University, they are protected under state law, which limits 
financial recovery for negligence. 
 
Please contact Dominick Angiolillo, MD, PhD at 904-244-0411 if you experience an injury or 
have questions about any discomforts that you experience while participating in this study. 
 
WHAT OTHER CHOICES DO YOU HAVE IF YOU DO NOT WANT TO BE IN THIS 
RESEARCH STUDY? 
If you choose not to participate in this study, you will still continue receiving your medical care 
just as you normally do. 
 


 
IRB APPROVED 
 
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6
DO YOU HAVE TO BE IN THIS STUDY? 
Your participation in this study is voluntary. You may decide not to participate or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which 
you are entitled. 
 
If you leave this study for any reason, please contact Dominick J. Angiolillo, M.D., Ph.D. at  
904-244-3933 or 904-244-0411 (24 hours).  They will tell you how to stop your participation 
safely. 
 
CAN YOU BE WITHDRAWN FROM THIS RESEARCH STUDY? 
The FDA, your study doctor, your local institution, has the right to stop your participation in the 
study, or cancel the study, without your consent at any time. Your study doctor may take you off 
the study at any time for any of the following reasons: 
 if he/she decides it is in your best interest. 
 if you do not consent to continue in the study after being told of changes in the research 
that may affect you;  
 or for any reason. 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
If you agree to participate in this study, the study doctor will create, collect, and use private 
information about you and your health. This information is called protected health information or 
PHI. In order to do this, the study doctor needs your authorization. The following section 
describes what PHI will be collected, used and shared, how it will be collected, used, and shared, 
who will collect, use or share it, who will have access to it, how it will be secured, and what your 
rights are to revoke this authorization. 
 
Your protected health information may be collected, used, and shared with others to determine if 
you can participate in the study, and then as part of your participation in the study. This 
information can be gathered from you or your past, current or future health records, from 
procedures such as physical examinations, x-rays, blood or urine tests or from other procedures or 
tests. This information will be created by receiving study treatments or participating in study 
procedures, or from your study visits and telephone calls.  More specifically, the following 
information may be collected, used, and shared with others: 
 Complete past medical history to determine eligibility criteria  
 Records of physical exams 
 Laboratory, x-ray, MRI, and other test results 
 Records about study medications or drugs 
 
This information will be stored in locked filing cabinets or in computers with security passwords. 
 
Some of the information collected could be included in a "limited data set" to be used for other 
research purposes.  If so, the limited data set will include only information that does not directly 
identify you. For example, the limited data set cannot include your name, address, telephone 
number, social security number, or any other photographs, numbers, codes, or so forth that link 
you to the information in the limited data set.  If limited data sets are created and used, 
agreements between the parties creating and receiving the limited data set are required in order to 
protect your identity and confidentiality and privacy. 


 
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Your PHI may be collected, used, and shared with others to make sure you can participate in the 
research, throughout your participation in the research, and to evaluate the results of the research 
study.  More specifically, your PHI may be collected, used, and shared with others for the 
following study-related purpose(s): 
 to determine the effectiveness of the study drug in treating patients with atherosclerotic 
cardiovascular disease 
 to evaluate a possible new use for the study drug 
 to determine the causes or effects of the study condition: atherosclerotic cardiovascular 
disease 
 
Once this information is collected, it becomes part of the research record for this study. 
 
Only certain people have the legal right to collect, use and share your research records, and they 
will protect the privacy and security of these records to the extent the law allows. These people 
include: 
 the study doctor, and research staff associated with this project 
 other professionals at the University of Florida or Shands Hospital that provide study-
related treatment or procedures 
 The University of Florida Institutional Review Board 
 
Your PHI may be shared with: 
 The study sponsor Dominick J. Angiolillo, MD, PhD and Amgen. 
 United States and foreign governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health and Human 
Services, and the Office of Human Research Protections 
 Government agencies who are responsible for overseeing public health concerns such as 
the Centers for Disease Control and federal, state and local health departments 
 Western Institutional Review Board 
 Your insurance company for purposes of obtaining payment 
 
Every attempt will be made to protect your right to privacy within legal limits.  However, records 
associated with your participation in the study, including medical histories (case histories) which 
may identify you, and this informed consent signed by you, will be made available for inspection 
by the Western Institutional Review Board® (WIRB®), Amgen or designee (including any 
persons or companies which are contracted by Amgen to have access to the research information 
during and after the study, such as the monitor(s) and auditor(s)), the US Food and Drug 
Administration (FDA), and state and other local authorities.  Because of the need to release 
information to these parties, absolute confidentiality cannot be guaranteed.  In addition, the 
results of treatment and laboratory data may be published for scientific purposes, but your 
identity will not be disclosed. By signing a written informed consent form, you are authorizing 
such access. 
 
Otherwise, your research records will not be released without your permission unless required by 
law or a court order. It is possible that once this information is shared with authorized persons, it 
could be shared by the persons or agencies who receive it and it would no longer be protected by 
the federal medical privacy law. 
 


 
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Your PHI will be used and shared with others until the end of study. 
 
This information will be destroyed 2 years after research is conducted or longer per University of 
Florida and/or FDA requirements. 
 
You may not be allowed to see or copy certain information in your medical records collected in 
connection with your participation with this study while the research is in progress if the research 
includes treatment. When the research study is completed you will have access to inspect or copy 
your records with certain exceptions under applicable law. 
 
You are not required to sign this consent and authorization or allow researchers to collect, use 
and share your PHI. Your refusal to sign will not affect your treatment, payment, enrollment, or 
eligibility for any benefits outside this research study. However, you cannot participate in this 
research unless you allow the collection, use and sharing of your protected health information by 
signing this consent and authorization. 
 
You have the right to review and copy your protected health information. However, we can make 
this available only after the study is finished. 
 
You can revoke your authorization at any time before, during, or after your participation in this 
study.  If you revoke it, no new information will be collected about you. However, information 
that was already collected may still be used and shared with others if the researchers have relied 
on it to complete the research. You can revoke your authorization by giving a written request 
with your signature on it to the study doctor. 
 
Your withdrawal must be made in writing and sent to Dominick J. Angiolillo, M.D. Ph.D., 655 
West 8th Street, Jacksonville, Florida 32209. 
 
NEW INFORMATION ON THE STUDY DRUG 
You will be informed about any new information, such as adverse reactions (side effects) that 
could affect your decision to continue in this study. You may be asked to sign a new consent 
form if that should occur. 
 
WHAT IF I BECOME PREGNANT DURING THE STUDY? 
If you are pregnant or nursing before you enroll in the study, you may not participate in the 
study. 
 
WHERE CAN I FIND INFORMATION ABOUT THE STUDY? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 


 
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WHO WOULD YOU CALL IF YOU HAVE ANY QUESTIONS? 
If you have questions about the study, please ask us before signing this form. If you require 
further general information regarding the research study, if at any time you feel you have had 
a research-related injury or reaction to the study drug, or if you have questions, concerns or 
complaints about the research please contact: 
 
Dominick J. Angiolillo, M.D., Ph.D. at 904-244-3933 or 904-244-0411 (24 hours). 
 
If you have questions about your rights as a research subject or if you have questions, concerns or 
complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 
 
Or 
 
The University of Florida in Jacksonville at (904) 244-9478. 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 


 
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CONSENT TO PARTICIPATE IN THIS RESEARCH STUDY. 
I have been informed about this study’s purpose, procedures, possible benefits and risks. I have 
also been told alternatives to being in the study and how my protected health information will be 
collected, used, and shared with others. I have been given the opportunity to ask questions. My 
questions have all been answered satisfactorily. I agree to be in this research study. I have 
received a copy of this form. 
 
By signing this consent form, I have not given up any of my legal rights. 
 
I authorize the release of my medical records for research or regulatory purposes to those agencies 
listed under the Authorization section of this consent form. 
 
 
 
 
Name of Participant (Print) 
Date 
 
 
 
 
Signature of Participant 
 
As an investigator or the investigator’s representative, I have explained to the participant the 
purpose, the procedures, the possible benefits, and the risks of this research study, the alternative 
to being in the study; and how the subject’s protected health information will be collected, used, 
and shared with others: 
 
 
 
 
 
 
Printed Name of Person Conducting Informed Consent Discussion 
 
Position 
 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion  
 
Date