Clinical trial NCT03258281
Conditions: Diabetes Mellitus, Type 2 Dyslipidemia Associated With Type II Diabetes Mellitus Percutaneous Coronary Intervention
Sponsor: Inova Health Care Services
Start date: 2018-05-01; Completion date: 2019-10-01
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prospective, single center, double-blind, randomized pharmacodynamic experimental study. The study will enroll 150 subjects with ASCVD on optimal statin therapy as per physician and Diabetes Mellitus (DM) undergoing elective Percutaneous Coronary Intervention (PCI). Eligible patients will be randomized for 30 day treatment to either 1) evolocumab 420 mg ; or 2) placebo.

Detailed description:
This is a double-blind randomized clinical trial of evolocumab versus placebo in patients with ASCVD and DM on clopidogrel and aspirin undergoing PCI. The study is aimed to assess

1. the effect of evolocumab therapy on platelet activation and reactivity;
2. the effect of evolocumab on biomarkers of platelet activation and inflammation.

Eligible patients will be randomized prior to start the PCI equally to either:

1. 420 mg evolocumab ; or
2. placebo. The randomized treatment will be administered in subcutaneous injections.

The laboratory assessments will be performed before (baseline), and 16-24 hours and 30-days after randomization.

Subject participation will be 30 days from the randomization.

Arms: arm 1: 75 subjects on optimal statin therapy undergoing elective PCI will receive evolocumab 420mg. arm 2: 75 subjects on optimal statin therapy undergoing elective PCI will receive placebo
Interventions: intervention 1: Evolocumab intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive evolocumab 420 mg administered subcutaneously intervention 2: Patients will receive placebo administered subcutaneously

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
  
Effects of Evolocumab on Platelet Reactivity in Patients with Diabetes Mellitus after  
Elective Percutaneous Coronary Intervention:  
The HI-REACT-SIRIO study 
 
 
Principal Investigators:  
Paul. A. Gurbel, M.D., F.A.C.C 
Co-Investigators: Eliano P. Navarese, M.D., Ph.D., FESC; Kevin Bliden, B.S., M.B.A., Udaya 
Tantry, PhD  
Inova Center for Thrombosis Research and Drug Development 
 
Drug Name: Evolocumab 
 
 
 
Sponsor: Inova Heart and Vascular Institute at Inova Fairfax Hospital,  
Falls Church, VA 
 
 
 
Site of Investigation: Inova Heart and Vascular Institute at Inova Fairfax Hospital,  
Falls Church, VA 
 
 
 
Date of Protocol:  04-24-2018 
 
 
 
Contact Information:  
Paul A. Gurbel, M.D. 
Inova Center for Thrombosis Research and Drug Development,  
Inova Heart and Vascular Institute 
3300 Gallows Road, Falls Church, VA 22042 
Phone: 410-367-2590, Fax: 410-367-2596 
Email: paul.gurbel@inova.org 


2 
 
PROTOCOL SYNOPSIS 
Title: Effects of Evolocumab on platelet reactivity in patients with Diabetes Mellitus after 
Elective Percutaneous Coronary Intervention: The HI-REACT-SIRIO study 
 
Short Title:  HI-REACT  
 
Rationale: Diabetes mellitus is associated with accelerated atherothrombosis; a 2-to 4-fold 
greater CV risk of coronary artery disease is observed in subjects with DM in comparison to non-
DM patients translating into a higher risk of recurrent cardiovascular complications despite 
optimal statin and antiplatelet treatment1-3. A prothrombotic state associated with increased 
platelet reactivity is well demonstrated in DM individuals, placing them at higher risk for 
atherothrombotic events4. High platelet reactivity determined in type 2 DM patients with 
coronary artery disease while on chronic dual antiplatelet therapy is associated with a 
prominently higher risk of adverse cardiovascular events despite optimal statin and 
antithrombotic therapy4; there are therefore unmet needs for drug regimens that can reduce 
platelet activation in these high-risk patients. Recently available evidence corroborates the role 
of PCSK9 in influencing platelet reactivity that in turn may impact patient’s risk. A relationship 
among dyslipidemia, high oxLDL levels, elevated plasma fibrinogen levels, and platelet 
activation has been demonstrated in patients with cardiovascular disease5,6. Oxidized LDL can 
activate platelets via several mechanisms that include interaction with scavenger receptor A and 
CD367,8. The relation between oxLDL, platelet reactivity and thrombotic risk may be more 
pronounced in patients with DM and treatment with PCSK9 antibodies may be associated with a 
significant reduction in platelet reactivity. 
Objectives 
 
Primary  Objective: To compare the effects of the clopidogrel plus evolocumab therapy versus 
clopidogrel plus placebo therapy on platelet reactivity measured by adenosine diphosphate 
(ADP)-stimulated p-selectin by flow cytometry at 30 day post- dose in patients with 
atherosclerotic vascular disease (ASCVD) on optimal statin therapy as per physician and 
diabetes mellitus (DM) undergoing elective percutaneous coronary intervention (ePCI) and 
clopidogrel administration. 
 
Secondary Objectives: To compare the effects of clopidogrel plus evolocumab therapy versus 
clopidogrel plus placebo therapy on platelet activation and aggregation, oxidation, inflammation, 
and lipids by determining the following: 
1) Unstimulated and ADP-stimulated (except 30 day times point, primary endpoint) p-selectin  
     and GPIIb/IIIa receptor expression and unstimulated CD36, and LOX-1 by flow cytometry. 
 2) ADP-, collagen-, and TRAP-induced platelet aggregation by light transmittance  
     aggregometry. 
 3) Plasma hs-CRP, atherox, oxLDL, p-selectin, hs-troponin, and fibrinogen.  
 4) Lipid profile including LDL-C. 
 5) Platelet reactivity measured by VerifyNow P2Y12 assay and the prevalence of high  
    on-clopidogrel platelet reactivity (HPR) (>208 PRU). 
 


3 
 
Study Type: Pospective, single center, double-blind, randomised pharmacodynamic 
experimental study.  
 
Study Design: This is a randomized study that will be conducted at Inova Heart and Vascular 
Institute at Fairfax  in 150 subjects with ASCVD on optimal statin therapy as per physician and 
DM undergoing elective PCI. Eligible patients will be randomized for 30 day treatment to  either  
1) evolocumab 420 mg ; or 2) placebo.   
    
The randomized treatment will be administered in subcutaneous injections at the investigational 
site. The laboratory assessments will be performed before (baseline), 16-24 hours  and 30±5days 
after randomization. 
 
Study Methodology: This is a double-blind randomized clinical trial of evolocumab versus 
placebo in patients with ASCVD and DM on clopidogrel and aspirin undergoing ePCI. The study 
is aimed to assess  
1) the effect of evolocumab therapy on platelet activation and reactivity;  
2) the effect of evolocumab on biomarkers of platelet activation and inflammation.   
 
The randomization process will start before PCI.  
 
Eligible patients will be randomized equally to either:  
1) 420 mg evolocumab; or  
2) placebo.  
The randomized treatment will be administered in subcutaneous injections. 
 
Patients: This investigation will be conducted in subjects >18 years of age with ASCVD on 
optimal statin therapy as per physician and DM undergoing ePCI and treated with clopidogrel 
and aspirin.  
 
Statistical Methodology: The enrollment of 150 patients (75 per group) would give the study a 
statistical power of 85% (two-sided alpha=0.05) to detect a significant difference in platelet 
reactivity between the treatment group and placebo group. Categorical variables will be 
compared using 2 test or the Fisher exact test whereas continuous variables will be assessed 
with independent-samples t-test or the Mann-Whitney U test in case of non parametric 
distribution of data; normality of data will be checked with the Kolmogorov Smirnov test. 
Analyses will be performed with SPSS software (SPSS, Inc., Chicago, IL) and p<0.05 will be 
considered significant. 


4 
 
1. INTRODUCTION 
1.1 Specific Aims 
To measure  platelet activation and aggregation, oxidation, inflammation, and lipids at baseline 
(before randomization), and 16-24 hours and 30-day after randomization by determining the 
following:  
 Platelet activation markers: 
Unstimulated and ADP-stimulated P-selectin, activated GPIIb/IIIa, CD36, LOX-1, 
and oxLDL expressions on  platelets by flow cytometry. 
 Platelet Aggregation:  
ADP-, collagen and TRAP-induced  platelet aggregation by light transmittance 
aggregometry. 
 Lipid profile and soluble markers:  
Lipid profile including LDL-C by conventional laboratory methods  
Soluble markers (oxLDL, hsCRP, p-selectin, atherox and fibrinogen) in plasma by 
enzyme linked immunoassay. 
 Prevalence of high on-clopidogrel platelet reactivity by the VerifyNow P2Y12 assay. 
 
1.2 Hypothesis 
Treatment with evolocumab will be associated with an increased reduction in platelet 
activation and aggregation and biomarkers associated with platelet activation, oxidative 
stress, and inflammation as compared to placebo. 
 
1.3 Background and Significance 
               Diabetes mellitus (DM) is a major public health problem which currently affects 
millions of people worldwide. The incidence is expected to double over next 10 years, almost 
exclusively due to an increase in the prevalence of type-2 DM. Approximately 25 to 30% of all 
percutaneous coronary interventions (PCIs) are performed in DM patients1. The disease is 
associated with accelerated atherothrombosis; a 2-to 4-fold greater CV risk of coronary artery 
disease is observed in subjects with DM in comparison to non-DM patients translating into a 
higher risk of recurrent cardiovascular complications despite optimal statin and antiplatelet 
treatment2, 3. A prothrombotic state associated with increased platelet reactivity is well 
demonstrated in DM individuals, placing them at higher risk for atherothrombotic events4. This 
status of increased cardiovascular risk persists despite optimal control of traditional risk factors 
and glycaemia, indicating that the heightened platelet reactivity plays a prominent prognostic 
role in these patients. Of concern, high platelet reactivity following dual antiplatelet therapy is 
more frequent in diabetic compared to non-diabetic subjects9. This figure stems from the 
unsolved issue of inadequate responsiveness or ‘resistance’ to antiplatelet agents, which has a 
greater prevalence among diabetic patients10,11. Numerous sources have demonstrated a direct 
relationship between low response to clopidogrel or clopidogrel resistance and atherothrombotic 
events in high-risk DM patients treated with elective PCI and stent implantation11. High platelet 
reactivity determined in type 2 DM patients with coronary artery disease while on chronic dual 


5 
 
antiplatelet therapy is associated with a prominently higher risk of adverse cardiovascular events 
despite optimal statin and antithrombotic therapy11; there are therefore unmet needs for drug 
regimens that can reduce platelet activation in these high-risk patients.  
 
Human monoclonal antibodies against PCSK9 enzyme have been identified as an innovative 
lipid-lowering strategy. Recently available evidence corroborates the role of PCSK9 in 
influencing platelet reactivity that in turn may impact patient’s risk. A relationship among 
dyslipidemia, high oxLDL levels, elevated plasma fibrinogen levels, and platelet activation has 
been demonstrated in patients with cardiovascular disease5,6. Oxidized LDL can activate platelets 
via several mechanisms that include interaction with scavenger receptor A and CD367,8. By 
enhancing LDL cholesterol clearance from the circulation, PCSK9 antibodies can decrease 
platelet activation and aggregation induced by native LDL and oxLDL (Figure 2). 
 
Figure 1. Navarese et al. Ann Intern Med. 2016;164:600-7. 
                                               
 
Recent data already show a stepwise increase of platelet reactivity related to the increased levels 
of PCSK9 in acute coronary syndrome patients treated with more potent antiplatelet therapies 
such as ticagrelor and prasugrel (Figure 2). This result is expected to be amplified in elective 
patients with DM treated with PCI and clopidogrel, that is a less potent antiplatelet agent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


6 
 
Figure 2. Navarese et al. Int J Cardiol 2016;227:644-649 
 
 
2. STUDY DESIGN AND SUBJECT SELECTION 
    2.1 Study Type  
Prospective, single center, double-blind, randomised (1:1) pharmacodynamic study that will 
be conducted in subjects with ASCVD on optimal statin therapy as per physician and DM 
undergoing elective PCI. The randomization  
process will start before PCI. Eligible patients will be randomized to either   
   1) evolocumab 420 mg; or  
   2) placebo.   
   The randomized treatment will be administered in subcutaneous injections. The laboratory   
   assessments will be performed before (baseline), and 16-24 hours  and 30±5days after  
   randomization (see Figure 1). 
 


7 
 
  Figure 1 Design of the HI-REACT-SIRIO study. 
    
2.2 Setting 
The study will be done at Inova Fairfax Hospital in an inpatient setting. Screening will take    
place at the emergency room (ER), coronary angiography preparation room, or coronary  
angiography suite. Study procedures after obtaining consent will occur at the emergency room 
and IHVI (coronary angiography suite, coronary angiography recovery room, intensive care 
coronary care unit, and coronary care step-down units). 
2.3 
Duration of Study 
Subject participation will be 30±5 days from the randomization.  
 
2.4. 
Number of Subjects  
One hundered fifty  patients with ASCVD on optimal statin therapy as per physician and DM 
undergoing ePCI and clopidogrel administration will be randomized to evolocumab or placebo 
therapy. 
 
2.5. 
Study Population 
 
2.5.1. Gender of subjects 
The study’s intended population is inclusive of both genders (males and females). 
  
2.5.2. Age of Subjects 
Subject enrollment will be comprised of subjects >18 years of age.  
 
2.5.3  Racial and Ethnic Origin 
The study’s intended population is inclusive of all racial and ethnic groups and subgroups.   
 


8 
 
2.5.4 Vulnerable Population 
Children, pregnant women, institutionalized persons, and persons with decisional incapacity will 
be not be enrolled in this study. Participants whose primary language is Spanish will have access 
to translation/interpreter services as provided by the Inova Health System. An IRB approved 
translated consent form will be provided for the consenting process. 
 
2.6. 
Recruitment 
Recruitment will occur at the Inova Fairfax Hospital. The expected length of the recruitment 
period is 12 months. If the study conduct (e.g. recruitment rate; drop-out rate; data quality; 
protocol compliance) does not suggest a proper completion of the trial within the reasonable time 
frame as agreed upon, the recruitment period may be extended to reach the desired sample size. 
 
2.7 Inclusion criteria: Subjects will qualify for trial participation if ALL criteria below are met: 
o Male or female, >18 years of age 
o Patients with ASCVD on optimal statin therapy as per physician indication 
o Hemodynamically stable patients undergoing elective PCI for coronary artery 
disease 
o Patients with DM will be defined as:  
Patients with Type 1 or type II DM receiving treatment with oral  
            medications or insulin  
 
2.8 Exclusion criteria: Subjects will be excluded from entry if ANY of the criteria listed below 
are met: 
o Patients undergoing emergent PCI for coronary artery disease 
o Patients on any PCSK9 inhibition treatment. 
o Patients with a history of a serious hypersensitivity reaction to Repatha.   
o Patients on any oral thrombin inhibitors 
o Patients on factor Xa inhibitors 
o Use of  cangrelor or Cilostazol,  therapy during PCI 
o Use of any GPI’s during PCI 
o Use of any parenteral direct thrombin inhibitors during PCI 
o Patients with recent ACS (≤1 month) 
 Patients on Clopidogrel therapy with baseline platelet reactivity <43% ADP-
induced aggregation as measured by light transmittance aggregometry using 5 µM 
ADP)  
o Patients on dual antiplatelet treatment (DAPT) with ticagrelor or prasugrel 
o Patients undergoing urgent/emergent PCI for stent thrombosis 
o Participation in any investigational study within the last 60 days. 
o Severe renal dysfunction, defined as an eGFR <20 mL/min/1.73 m2 at screening 
o Active liver disease or hepatic dysfunction, defined as AST or ALT >3 x  ULN as 
determined by central laboratory analysis at screening 


9 
 
o Recipient of any major organ transplant (e.g., lung, liver, heart, bone marrow, 
renal) 
o Known major active infection or major hematologic, renal, metabolic, 
gastrointestinal, or endocrine dysfunction in the judgment of the investigator 
o Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 
years 
o Subject has received drugs via a systemic route that have known major 
interactions with background statin therapy within 1 month before randomization 
or is likely to require such treatment during the study period (e.g. cyclosporine, 
clarithromycin, HIV protease inhibitors, gemfibrozil) 
o Female subject who is unwilling to use at least 2 effective birth control methods* 
for at least 1 month before screening and 15 weeks after the end of treatment with 
investigational products, unless the subject is sterilized or postmenopausal. 
o Subject is pregnant or breast feeding, or planning to become pregnant or to 
breastfeed during receipt of investigational products and within 15 weeks after the 
end of study treatment 
o Known previous hypersensitivity reaction/s to the investigational products’ active 
components and excipients.  
o Subject likely to not be available to complete all protocol-required study visits or 
procedures, to the best of the subject's and investigator's knowledge 
o History or evidence of any other clinically significant disorder, condition, or 
disease other than those outlined above that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed consent, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion. 
 
*Acceptable methods of contraception (birth control) while taking part in this study are: 
• Total Abstinence (no sexual intercourse), absence of menstrual periods in women for more than 
one year after menopause (change of life), sterilization surgery, including tubal ligation (tubes 
tied) or hysterectomy (removal of the uterus or womb) in women or a vasectomy in men. 
• Oral contraceptives (birth control pills), intrauterine device (IUD), implantable or injectable 
contraceptives (Norplant or Depo-Provera), contraceptive patch, vaginal ring or use of condom 
with spermicide.  These methods must be used exactly as directed. 
 
3. STUDY METHODS AND PROCEDURES 
3.1 Allowed treatments 
Subjects enrolled may be receiving a range of antithrombotic therapies during PCI as 
recommended by evidence-based guidelines. The investigator or qualified designee is 
responsible for verifying compliance in source documentation and ensuring that any other 
treatments delivered are according to the local standard of care. Standard of care 
treatments/parameters that are allowed in the context of this study include: 
1. Aspirin: 325 mg loading dose followed by 81 mg qd. 
2. Clopidogrel: 600 mg loading dose for clopidogrel naïve patients administered in the 
catheterization laboratorybefore the start of the ePCI or just following the ePCI, followed by 
75 mg per day maintenance dose. 
3. Unfractionated heparin (UFH): as needed (e.g., 2,000 to 5,000 U) to achieve an ACT of 
200 to 250 s. 


10 
 
 
Subjects who receive other P2Y12 receptor blockers aside from clopidogrel (ticlodipine, 
cangrelor, ticagrelor, and prasugrel), cilostazol, GP IIb/IIIa inhibitors, direct thrombin 
inhibitors, factor Xa inhibitors, and warfarin will be excluded from the study.  
 
3.2 Consent 
Eligible subjects may only be included in the study after providing written, IRB-approved 
informed consent,  The investigator or qualified designee will explain the study and answer 
all questions to the prospective subject. If the subject is capable of doing so, he/she should 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form.  Informed consent must be obtained before conducting any study-
specific procedures (i.e., all of the procedures described in the protocol). In this trial, consent 
can be obtained upon admission to ER, inpatient setting, pre-procedural or procedural area. 
The process of obtaining informed consent should be documented in the subject source 
documents and a copy of the informed consent given to the subject. 
 
3.3 Control group 
The control group consists of subjects receiving placebo trteatment. 
 
3.4  Randomization 
Patients will be randomized to receive 1:1 evolocumab or placebo. Allocation of study 
treatment will be performed via a web-based interactive randomization system, based on a 
computer-generated random sequence with a random block size. This study has a double-
blind design with evolocumab and matching placebo. The subjects, study site research 
personnel, academic research center staff, and treating physicians involved in the treatment 
and/or clinical evaluation of the subjects will not be aware of treatments received. 
 
3.5 Timing of Study Treatment Administration 
     Qualified subjects will receive the study drug after randomization, within two  hours after PCI  
      start  time (wire crosses lesion).   
     
3.6 Study Treatment Administration 
The study treatments are evolocumab and its matching placebo. The total evolocumab dose to 
be administered is 420mg. The dosage form and strength of evolocumab supplied for this trial 
is 140mg/mL solution in a single-useprefilled SureClick autoinjector. To administer 420 mg 
of evolocumab/placebo, three separate subcutaneous injections, given consecutively within 
30 minutes will be administered to randomized subjects. Evolocumab/placebo will be 
administered by a qualified member of the study staff following successful randomization. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


11 
 
Figure 3: Guide to parts 
Before use 
After use 
 
 


12 
 
Important: Needle is inside 
 
Matching placebos will be identical in appearance except that they contain no active 
substance. Study treatment will be maintained, stored, and distributed by the research 
pharmacy. Once the study drug is available for administration from the pharmacy, follow the 
following steps: 
 
 
Step 1: Prepare 
Step 1A: Prepare 3 prefilled autoinjectors for administration. Wait 30 minutes for the 
autoinjectors to reach room temperature before injecting. Do not heat autoinjectors.  
Step 1B; Inspect all SureClick autoinjectors. Check the expiration dates.  
Step 1C: Gather all materials needed for the injection and wash hands well with soap and 
water. 
Step 1D: Prepare and clean an injection site. Body areas that can be used include: thigh; 
abdomen, except for 2-inch area around the navel; and outer area of upper arm. For the 
second and third injections, use a different spot than the last injection. Do not inject into 
areas where the skin is tender, bruised, red, or hard. 
Step 2: Get ready 
Step 2A: Pull the orange cap off only when ready to inject. Do not leave the orange cap 
off for more than five minutes, this can dry out the study drug. 
Step 2B: Stretch or pinch the injection site to create a firm surface. 
Step 3: Inject 
Step 3A: Hold the stretched or pinched skin. With the orange cap off, place the yellow 
end of the autoinjector on the skin at 90 degrees. Do not touch the gray start button yet. 
Step 3B: Firmly push down the autoinjector onto the skin until it stops moving. You must 
push all the way down but do not touch the gray start button until ready to inject. 
Step 3C: When ready to inject, press the gray start button. You will hear a click. 
Step 3D: Keep pushing the autoinjector down on the skin. Then lift thumb while still 
holding the autoinjector on skin. Each injection could take about 15 seconds. The 
medicine window will turn from clear to yellow when the injection is done. You may 
hear a second click. 
Step 4: Finish 
Step 4A: When the injection is done, throw away the used autoinjector and orange needle 
cap. 
Step 4B: Check the injection site. If there is blood, press a cotton ball or gauze pad on the 
injection site. Apply adhesive bandage if needed. Do not rub the injection site. 
 
 
Repeat steps 1B to 4B for the second and third injections. Total dose administered should 
be 420 mg. Use a different injection site for each injection. Administer injections 
consecutively within 30 minutes. 
 
 
 


13 
 
3.7 Study Treatment Storage 
The prefilled autoinjectors are stored in the original carton and are kept in refrigerated 
storage. Allowed temperature excursions while in storage is 36°F to 46°F (2°C to 8°C). Once 
removed from the refrigerator, the autoinjectors should be kept at room temperature at 68°F 
to 77°F (20°C to 25°C) in the original carton and must be used within 30 days. The prefilled 
autoinjectors cannot be frozen. Do not use a prefilled autoinjector that has been frozen. 
 
3.8 Endpoints/Outcomes Measurements 
3.8.1 Primary endpoints 
      Absolute difference in ADP-stimulated P-selectin expression 30 days post-dose in 
between  patients treated with clopidogrel plus evolocumab therapy and clopidogrel 
plus placebo therapy for 30±5days. First absolute difference in p-selectin expression 
between baseline and 30±5 days post-dose will be calculated in each group followed 
by estimation of absolute difference between the two groups. 
3.8.2 
Secondary endpoints 
 Absolute differences in unstimulated and ADP-stimulated (except 30 day 
times point, primary endpoint) p-selectin and GPIIb/IIIa receptor 
expression and unstimulated CD36, and LOX-1 measured at baseline and 
16-24 hours and 30±5day post-randomization in patients treated with 
clopidogrel plus evolocumab therapy and clopidogrel plus placebo therapy.   
 Absolute differences in lipid profile including LDL-C, oxLDL, fibrinogen, 
hsCRP, p-selectin, atherox (soluble markers) measured at baseline and 16-
24 hours and 30±5day post-randomization in patients treated with 
clopidogrel plus evolocumab therapy and clopidogrel plus placebo therapy. 
 Prevalence of high on-clopidogrel platelet reactivity by the VerifyNow 
P2Y12 assay measured at baseline, and 16-24 hours and 30±5day post 
randomization. 
 
 
3.8.3 Clinical endpoints – None 
3.8.4 Exploratory analysis  
An exploratory analysis of the effect of evolocumab on platelet reactivity in the following 
subset  of patients will be addressed: 
i) patients ≥65 years,  
ii) previous myocardial infarction (>one year),  
iii) glomerular filtration rate (GFR) < 60/min/1.73 m2,  
iv) complex coronary artery disease (left main and/or bifurcation and/or multivessel disease). 
3.8.5 Blood sampling 
Phlebotomy sites will be carefully chosen to minimize risk and platelet activation. After 
discarding the first 2-3mL of free flowing blood, the blood collection tubes will be filled 
to capacity and gently inverted 3 to 5 times to ensure complete mixing of the 
anticoagulant. Tubes containing 3.2% trisodium citrate will be used for flow cytometry, 
light transmittance aggregometry and biomarker analysis.  
 


14 
 
 Platelet activation markers: 
Unstimulated and ADP-stimulated P-selectin, activated GPIIb/IIIa, CD36, LOX-1, 
and oxLDL on  platelets by flow cytometry. 
 Platelet Aggregation:  
Adenosine diphosphate (ADP)-, collagen and TRAP-induced  platelet aggregation by 
light transmittance aggregometry. 
 Lipid profile and soluble markers:  
Lipid profile including LDL-C by conventional laboratory methods  
Soluble markers such as oxLDL, hsCRP, p-selectin, Atherox in plasma by enzyme 
linked immunoassay. 
 Prevalence of high on-clopidogrel platelet reactivity by the VerifyNow P2Y12 assay. 
 
4. 
STATISTICAL CONSIDERATIONS/DATA ANALYSIS  
4.1 Sample Size Calculation  
Sample Size Calculation: In our previous study in patients loaded with clopidogrel for 
elective PCI, baseline stimulated P-selectin expression was 45±16% and 23±10% inhibition 
of P-selectin expression was occurred at 30 days. The absolute change in percent positivity 
was ~22%12. We hypothesize that evolocumab therapy will result in a further 6% absolute 
reduction in platelet activation (~ 14% percent change from baseline). To detect a 6 percent 
in absolute reduction of platelet aggregation with evolocumab, assuming a standard 
deviation of 11, α of 0.05, two-tailed, 85% power, a final sample size of approximately 122 
patients (61per group) will be required. To account for drop outs as well as incomplete data 
assessment at all time points, a final sample size of 150 patients (75 per group) will be 
recruited. 
 
     4.2     Method of Data Analysis  
Categorical variables will be compared using 2 test or the Fisher exact test whereas 
continuous variables will be assessed with independent-samples t-test or the Mann-Whitney 
U test in case of non parametric distribution of data; normality of data will be checked with 
the Kolmogorov Smirnov test. Analyses will be performed with SPSS software (SPSS, Inc., 
Chicago, IL) and p<0.05 will be considered a significant difference between clopidogrel plus 
evolocumab therapy versus clopidogrel plus placebo therapy. 
4 DATA MANAGEMENT 
4.1 Data collection 
Designated study site staff will record data required by the protocol into the case report forms 
(CRFs) and enter it into the electronic database. Authorized research staff will review the 
CRFs for completeness and accuracy and make any necessary corrections to the data entered 
into the electronic database.  
4.2 Confidentiality, data storage, and retention 
Information about study subjects will be kept confidential and managed according to the 


15 
 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Each subject screened and enrolled will be assigned a subject identification number (ID) and 
a list of subjects with their corresponding subject ID will be maintained separately from 
collected data. 
Physical CRFs will be stored in the research site in a locked office and electronic subject data 
will be locked in a password protected file on a secure internet server, accessed only by 
authorized research staff. All data records will be stored on site until 2 years after the 
investigation is formally discontinued. Paper records will be shredded and recycled. 
 
5 VISIT SCHEDULE AND ASSESSMENTS 
 
Informed consent will be obtained from subjects meeting the inclusion criteria and none of 
the exclusion criteria before the initiation of any study-specific procedures. Subjects will 
receive 1 dose of the study drug after randomization at the investigational unit. Data 
analysis is summed up by timepoints: Baseline/pre-PCI, and 16-24 hours, and 30±5 days 
post-randomization. Required assessments for each study visit are listed in Table 1. Subjects 
should be seen for all visits on the designated day or according to the allowed window 
period (see Table 1).  
 
Table 1 
Schedule of Events 
 
V1 
V2 
V2 
EOS 
 
Screening/
Baseline 
Randomization 
 
16-24 Hours 
Post-First 
Dose of 
Evolocumab/ 
Placebo1 
 
30 Days (+/-
5days) Post Dose 
of Evolocumab/ 
Placebo 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
Medical History 
X 
 
 
X 
Review 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
Safety labs (CMP and 
CK) 
X2 
 
 
X 
Urine Pregnancy Test3 
X 
 
 
X 
Physical Examination4 
X 
 
 
 
Vital signs (BP and HR) 
X 
X 
X 
X 
Laboratory 
Measurements  
X 
 
X 
X 
Administer Study Drug 
(Evolocumab or Placebo) 
 
X 
 
 
Adverse Events 
 
X 
X 
X 
1Discharge day may coincide with the 16-24 hours post- dose of study drug time point. 


16 
 
2 CMP laboratory results within 3 months of visit 1 are acceptable. If not available, a CMP needs to be obtained 
and results reviewed during screening, prior to randomization. 
3Urine specimen for pregnancy test will be collected on women of childbearing potential at screening and EOS 
visit. 
4 May be conducted as a nursing assessment if a physical was performed as standard of care ≤1 month prior to 
screening if no AE/SAE’s have occured. 
5.1 Timing of Assessments 
5.1.1 Baseline/Pre-study drug administration 
Subjects will be pre-screened to ensure that the subject is eligible for the study. During 
the baseline visit, the following will be completed and documented in the Case Report 
Forms (CRF): 
 Obtain written informed consent 
 Complete inclusion/exclusion criteria 
 Obtain demographic information (i.e. date of birth, gender, and race) 
 Record medical history (including medical, surgical, and smoking history) 
 Record concomitant medications  
 Obtain height and weight 
 Obtain and record pre-PCI vital signs  
 Perform complete physical examination to evaluate the general status of the subject 
and to further elucidate patient symptoms, risk factors, or concerns that may increase 
the subject’s risk for adverse reactions to the study treatment 
 Obtain safety laboratory results (comprehensive metabolic panel) to check for renal 
and hepatic function (see exclusion criteria) 
 For women of childbearing potential, a urine pregnancy test will be performed 
 Obtain blood specimen for platelet activation, aggregation, and biomarkers prior to 
ePCI. Laboratory specimen should be obtained prior to clopidogrel loading dose 
 Adverse events collection once informed consent obtained 
 
5.1.2 Randomization 
When a subject qualifies for enrollment/randomization, the clinical site staff will access 
the web-based interactive randomization system and allocate the patients for particular 
treatment. The randomization system is based on a computer-generated random sequence 
with a random block size. The subject will be randomized to receive either  1) 420 mg 
evolocumab or 2) placebo.   
 
5.1.3 Administration of study drug 
The subject will receive the study drug after randomization, once PCI commences. PCI 
will be perfomed as according to institutional guidelines and standards of care including 
parenteral anticoagulant and oral anti-platelet if indicated. The 420 mg of evolocumab or 
placebo will be administered, subcutaneously, within two hours after PCI start time (wire 
crosses lesion)(see section 3 for study treatment administration). 
 
If a randomized subject received any of the exclusionary medications specified in section 
2.8 or does not undergo PCI, the subject will not receive the study drug and will be exited 


17 
 
from the study. The reason for non-intervention must be documented in the subject’s 
medical records. 
 
5.1.4 16-24 hours post-study drug administration 
Subjects are expected to be seen as an inpatient during this timepoint or may coincide 
with the subject’s discharge. During this time point, the following study procedures will 
be completed: 
 Obtain laboratory specimens for platelet activation, aggregation, and biomarkers. 
 Record any changes in the subject’s medical condition, concomitant medications. 
 Review and record adverse events. 
 Assess for continued subject eligibility. 
Provide patient education about study drug (see section 5.3). 
 Provide subject with wallet medication card. 
 Set up an appointment for an outpatient visit at the investigational site 30 days  
(+/-5 days) post- dose of study drug. 
 
 
5.1.5 End of study visit/ 30±5 days post-dose of study drug 
Subjects will return as an outpatient to the research site 30 days (+/- 5 days) post- dose of 
evolocumab/matching placebo to obtain laboratory measurements for platelet activation, 
aggregation, and biomarkers, and to review and record changes in concomitant 
medications, safety lab, pregnancy and adverse events.  
 
 
5.2 Safety Assessments 
Safety assessments will consist of monitoring and recording of adverse events and serious 
adverse events (see section 6). The occurrence of adverse events should be sought by non-
directive questioning of the subject at each visit during the study. AEs may also be detected 
when these are volunteered by the subject during or between visits or through physical 
examination, laboratory test, or other assessments. Medical conditions/diseases present 
before starting the study drug are considered AEs only if they worsen after starting the study 
drug. Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. Abnormal values 
that constitute a SAE or lead to discontinuation of administration of study drug must be 
reported and recorded as an AE. Adverse event collection will commence when informed 
consent is obtained. 
 
Additional assessments required to ensure safety of subjects should be administered as 
deemed necessary by the investigator on a case by case basis.  
 
Patients experiencing adverse events should be followed clinically until their health has 
returned to baseline status or until all parameters have returned to normal or have otherwise 
been explained. It is expected that the investigator will provide or arrange appropriate care 
for the patient if necessary. The principal investigators are responsible for ensuring that all 
staff involved in the study are familiar with the content of this section. This information 
should be captured in the source document at each visit. 


18 
 
5.3 Patient Education 
All subjects will be counseled and given instructions in regards to study treatments. Subject 
education will include study treatment action, side effects, benefits and risks, dosage, food-
drug/drug-drug interactions, pregnancy/lactation warning, and when to call 
investigator/physician. Subjects will be instructed to inform physicians and dentists of study 
treatment intake and to list all prescription medications, over-the-counter medications, or 
dietary supplements they are taking or plan to take so study personnel knows about other 
treatments that may affect adverse event risk.  
5.4 Study Drug Administration 
Only trained research personnel will administer study drug to qualified subjects. The study 
drug will be administered via subcutaneous injection using outer area of upper arm, thigh or 
stomach (abdomen) area (except for two inch area around the belly button. Study drugs will 
be stored and administered as according to manufacturer’s instructions. 
 
6 ADVERSE EVENTS 
6.1 Adverse Event (AE) Definitions   
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product which does not necessarily have to have a 
causal relationship with this treatment. An adverse event can be any unfavorable and 
unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, without any judgment about causality (i.e., 
whether or not it is considered to be drug-related). This includes any newly occurring event 
or previous condition that has increased in severity or frequency since the administration of 
the study treatment/intervention. 
A suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. A suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug. 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. An adverse event or suspected adverse reaction is considered “unexpected” 
if it is not specifically mentioned as occurring with the particular drug under investigation. 
Information about common side effects already known about the study drug/s drug can be 
found in the study drug/s package inserts. This information will be included in the subject’s 
informed consent and should be discussed with the subject during the study as needed. 
 
6.2 Serious Adverse Event (SAE) Definition 
An SAE is defined as an event that: 
 is fatal or life-threatening;  
 results in persistent or significant  disability/incapacity; 
 constitutes a congenital anomaly/birth defect; 


19 
 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the 
subject’s general condition 
 is medically significant, i.e., defined as an event that jeopardizes the subject or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
 
6.3 AE Grading Scale 
The descriptions and grading scales found in NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be used for AE reporting. Each AE term is 
associated with a 5-point severity scale.  
 
6.4 AE Collection and Reporting 
All SAEs and AEs which are not serious but which lead to permanent discontinuation of 
study medication will be captured in the CRF. Non-serious AEs which do not lead to 
discontinuation of study medication will not be collected. AE collection will commence once 
informed consent is obtained. A detected SAE or an AE deemed related to study drug that led 
to permanent study drug discontinuation should be followed until its resolution or until the 
subject completes the study. 
 
6.5 Procedures for Recording and Reporting of Adverse Events 
All AEs, as specified in section 6.4, will be reported to the principal investigator. For both 
serious and non-serious AEs, the investigator has the primary responsibility for AE. 
identification, documentation, grading, and assignment of attribution to the study 
treatment/intervention. The sponsor will consider the investigator’s view when assessing the 
safety of the drug and determining whether to report expeditiously to the FDA, local 
institutional review board (IRB), and other regulatory agencies.  
AEs, as specified in section 6.4, occurring once informed consent is obtained through the last 
day of study participation must be recorded on the AE CRF with the following information:  
 The intensity grade (grade 1, 2, 3, 4, 5; see CTCAE v4.03 grading) 
 The relationship to the study drug(s)  
 Attribution: An assessment of the relationship between the AE and the medical 
intervention (i.e., study drug administration). After naming and grading the 
event, the clinical investigator must assign an attribution to the AE using the 
following attribution categories: 


20 
 
 The duration (start and end dates or if continuing at final exam) 
 Occurrence (known risks for study drug/s, underlying illness or population) 
o Expected 
o Unexpected 
 Other contributing causes 
 Action taken with study drug 
 Any other actions in response to event 
 Outcome  
o Death related to AE 
o Recovered/resolved with sequelae 
o Not recovered/resolved 
o Recovered/resolved without sequelae 
o Recovering/resolving 
o Intervention for AE continues 
o Unknown 
 Whether it constitutes a serious adverse event (SAE) 
 
For serious adverse events not previously documented in study drug/s Package Insert (new 
occurrence) and are thought to be related to the study drug/s, the investigator may urgently 
require further information from the investigator for Health Authority reporting. Amgen or 
designee may need to issue an IND Safety Letter (Investigator Notification) to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
All suspected unexpected serious adverse reactions (SUSARs) related or possibly related to 
evolocumab and their follow-up reports must 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, must be 
faxed to Amgen, within 24 hours of such submission. 
 
6.6 Reporting of Pregnancies 
Pregnant, lactating women, or women planning to become pregnant or to breastfeed during 
receipt of investigational products and within 15 weeks after the end of study treatment are 
excluded from participating in this trial. Women of child-bearing potential recruited into the 
study must have a negative urine pregnancy test prior to initiation of evolocumab therapy 
(screening visit) and will undergo urine pregnancy testing at the end of study visit. Women of 
child-bearing potential must agree to use at least 2 forms of medically accepted method of 
contraception during the entire study duration. Male participants will be advised to use a 
medically accepted method of contraception during the study duration. If a female partner 
conceives and becomes pregnant while the male subject is participating in this study, the 
sponsor will be notified as per the procedures described above. The sponsor will report all 
pregnancies and pregnancies occurring in the partner of a patient participating in the study or 
potential infant exposure through lactation within 10 calendar days of sponsor’s awareness to 
Amgen.  
 


21 
 
6.7 Adverse Event Treatment  
All AEs should be treated appropriately and managed as according to standard of care, at the 
discretion of the investigator. The action taken to treat the AE should be recorded on the AE 
CRF. A detected AE deemed related to study drug/s that led to permanent study drug 
discontinuation should be followed until its resolution or until the subject completes the 
study. Assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, relationship to the study drug, the interventions required to treat it, and 
the outcome. 
 
7 SUBJECT COST AND FUNDING 
This is an investigator initiated study funded by Amgen Inc. Amgen, Inc will provide the 
investigational products.  
 
The subject or their insurance company will not be billed for this study. All study related 
tests and procedures will be paid for by the research site.  
 
8 SUBJECT COMPENSATION 
A total of $120 financial compensation will provided for study participation with the 
following breakdown each visit (Visit 1: $40 Visit 2: $40, and EOS:$40) to cover 
transportation, parking, and meal expenses. Compensation will only be paid for completed 
visits. Payment will be received by subjects after completion of each visit using 
reimbursement card of direct deposit as according to Inova Healthy System policy 
9 CONFLICTS OF INTEREST   
Dr. Gurbel reports personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Janssen 
Pharmaceuticals, Bayer, and Haemonetics; grants from Haemonetics, Merck, Duke Clinical 
Research Institute, Harvard Clinical Research Institute, National Institutes of Health,  
Coramed Technologies, MedImmune, and Sinnowa; a patent for platelet function testing. 
 
10 FACILITIES AND EQUIPMENT  
The research site is equipped with its own laboratory equipment, which includes state of the 
art technologies for platelet assays, centrifuges, refrigerators, and freezers for study specimen 
processing and storage. For outpatient visits, subjects will be seen in the site’s outpatient 
clinic room equipped with supplies and equipment for subject assessment. 
 
11 OUTSIDE CONSULTANTS/COLLABORATORS  
There are no outside consultants/collaborators participating. 
 
10  CONTRACTURAL AGREEMENTS     
There are no outside consultants/collaborators participating. 


22 
 
REFERENCES 
1. Aronson D, Edelman ER. Revascularization for coronary artery disease in diabetes 
mellitus: Angioplasty, stents and coronary artery bypass grafting. Rev. Endocr. Metab. 
Disord. 2010;11:75-86. 
2. Emerging Risk Factors C, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di 
Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, 
Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Diabetes 
mellitus, fasting blood glucose concentration, and risk of vascular disease: A 
collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-2222 
3. Clark CM, Jr., Perry RC. Type 2 diabetes and macrovascular disease: Epidemiology and 
etiology. Am. Heart J. 1999;138:S330-333. 
4. Morel O, Kessler L, Ohlmann P, Bareiss P. Diabetes and the platelet: Toward new 
therapeutic paradigms for diabetic atherothrombosis. Atherosclerosis. 2010;212:367-376 
5. Pawlowska Z, Swiatkowska M, Krzeslowska J, Pawlicki L, Cierniewski CS. Increased 
platelet-fibrinogen 
interaction 
in 
patients 
with 
hypercholesterolemia 
and 
hypertriglyceridemia. Atherosclerosis. 1993;103:13-20. 
6. Naseem KM, Goodall AH, Bruckdorfer KR. Differential effects of native and oxidatively 
modified low-density lipoproteins on platelet function. Platelets. 1997;8:163-173 
7. Korporaal SJ, Van Eck M, Adelmeijer J, Ijsseldijk M, Out R, Lisman T, Lenting PJ, Van 
Berkel TJ, Akkerman JW. Platelet activation by oxidized low density lipoprotein is 
mediated by cd36 and scavenger receptor-a. Arterioscler. Thromb. Vasc. Biol. 
2007;27:2476-2483. 
8. Akkerman JW. From low-density lipoprotein to platelet activation. Int. J. Biochem. Cell 
Biol. 2008;40:2374-2378. 
9. Colwell JA, Nesto RW. The platelet in diabetes: Focus on prevention of ischemic events. 
Diabetes care. 2003;26:2181-2188. 
10. Gurbel PA, Jeong YH, Navarese EP, Tantry US. Platelet-mediated thrombosis: From 
bench to bedside. Circ. Res. 2016;118:1380-1391. 
11. Jung JH, Tantry US, Gurbel PA, Jeong YH. Current antiplatelet treatment strategy in 
patients with diabetes mellitus. Diabetes & metabolism journal. 2015;39:95-113 
12. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: 
response variability, drug resistance, and the effect of pretreatment platelet reactivity. 
Circulation. 2003;107:2908-13. 
 

ICF_001.pdf: 
ClinicalTrials.gov ID: NCT03258281 
Unique Protocol ID:  17-2639 
Official Title: Effects of Evolocumab on Platelet Reactivity in Patients With 
Diabetes Mellitus (ISS-DMII) 
Brief Title: The HI-REACT-SIRIO study 
Document dates: 
Protocol: April 24 2018 
Informed consent: June 19, 2019 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
Reviewed by Inova IRB 
Date: August 18, 2017; File # 17-2639 
 
 
Version 2017 
 
Page 1 of 2 
Health Insurance Portability and Accountability Act (HIPAA) 
Authorization to Use/ Disclose Protected Health Information for Research 
 
This form will explain how health information about you will be used, protected, and disclosed (shared).  
In addition, you will receive a summary of Inova Health System’s “Notice of Privacy Practices”. If the 
study requires you to have follow-up visits in the investigators’ private practice office, you should ask for 
a copy of his/her “Notice of Privacy Practices” at the time of your visit. If you agree to participate in the 
research, and allow the use and disclosure of your medical information for research purposes, please sign 
this form.  If you choose not to allow the use and disclosure of your health information you may not 
participate in the research study. 
 
What protected health information about me will be used or disclosed as part of this research? 
You will be asked about your health information that is related to the study.  In addition, your non-
research medical records will be reviewed and researchers may need to discuss your health information 
with your treating doctor(s), if applicable.  Researchers will also collect new information about you as a 
result of the research tests, procedures, visits and/or questionnaires/interviews. This collected information 
constitutes and is called your “Research Record”.  
 
The following health information will be obtained from my medical record: 
 Your medical history including any medications you have been taking;  
 Specific tests and/or procedures and treatments you have had;  
 Personal information such as, your name, address, telephone number, and date of birth will be 
collected and placed in your research record.  
 
The following new information will be obtained about me as a result of the research: 
 Records about your lipid profile, platelet function, and biomarker testing; 
 Records about the study drug you received 
 Information on any side effects you may experience during your participation in the study and 
how these side effects have been treated;  
 Follow-up information about your health status collected in this study. 
 
Who will be allowed to use or share my protected health information? 
If you agree to participate in the study, you allow the investigators and research study staff to use and 
share your protected health information contained in your Research Record. In addition, Inova offices that 
manage research oversight, billing or quality assurance will be able to use and release your protected 
health information. 
 
To whom will the protected health information be shared? 
Your protected health information will be shared with the following: 
 The sponsor of the study Amgen, Inc. or others that are assisting the sponsor to collect data at 
Inova Heart and Vascular Institute. 
 
Your information may be given to:  
 Inova Institutional Review Board, the hospital committee that oversees the research. 
 Federal and state agencies that have authority over the study, Inova Health System, or patients. 
Government agencies may include the U.S. Food and Drug Administration (FDA), and the U.S. 
Department of Health and Human Services (DHHS).  


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
Reviewed by Inova IRB 
Date: August 18, 2017; File # 17-2639 
 
 
Version 2017 
 
Page 2 of 2 
 To your health insurer or payer, if necessary, in order to secure their payment for any covered 
treatment not paid for through the research. 
 
All reasonable efforts will be used to protect the privacy of your protected health information. Once your 
health information is shared with the sponsor, federal agencies and others as described above, they may 
share your information without your permission. 
 
Why is it necessary to share my protected health information with others? 
The reason is to conduct the research as described in the consent form for the research study. 
 
How long does my authorization remain in effect? 
This authorization expires when the study is complete, or if you take it back. 
 
How can I take back my authorization? 
You may take back your authorization at any time by sending a written request to Dr. Paul Gurbel at 
Inova Heart and Vascular Institute, 3300 Gallows Road, Falls church, VA, 22042.  If you take back your 
authorization, your participation in the study will end and no further private health information will be 
collected.  The research study staff may keep or share information obtained before you took back your 
authorization in order to preserve the scientific reliability of the study.   
 
If you choose not to authorize the use and release of your information or withdraw from the study, you 
will continue to have access to medical care at Inova Heart and Vascular Institute.  
 
Will I have access to the information in my Research Record? 
While the study is in progress, your access to your Research Record will be temporarily limited to ensure 
proper evaluation of the research study results. You will continue to have access to your non-research 
medical record during the study. You will be able to see your Research Record when the research is 
completed. You have the right to see and copy the medical information that is collected from you during 
the study and kept by the Inova Health System. You will have that right for so long as that information is 
maintained by the research staff and the other entities that are subject to federal privacy regulations. This 
does not include information about the study itself, such as study documents which may otherwise be 
confidential, and do not relate to an individual subject. 
 
I have been told that I will be given a signed copy of this authorization form. 
 
 
____________________________________ 
 
 
__________________ 
Signature of Research Participant 
 
 
 
 
Date 
 
 
 
____________________________________ 
 
 
___________________ 
Witness Signature 
 
 
 
 
 
 
Date 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 1 of 9 
 
Informed Consent for a Research Study 
 
 
Study Title:                  Effects of Evolocumab on Platelet Reactivity in Patients with Diabetes    
 
 
 
   Mellitus after Elective Percutaneous Coronary Intervention: 
  The HI-REACT-SIRIO study 
 
Funding Source:           Amgen, Inc. 
 
Principal Investigator: Paul A. Gurbel, M.D. 
 
Sub-Investigators:        Alexander Truesdell, MD; Behnam Tehrani, MD; Hamid Taheri, MD; 
 
 
                Kelly Epps, MD; Marjaneh Akbari, MD; Nadim Geloo, MD;    
 
 
 
    Matthew Sherwood, MD; Shahram Yazdani, MD 
 
Site of Investigation:    Inova Fairfax Hospital, Falls Church, VA 
 
Study Related Contact  
Information:                  (703) 776-3330 (During Office Hours) 
                                        (410) 202-0960 (After Office Hours, ask to have Dr. Gurbel 
                                        or the doctor covering for Dr. Gurbel paged) 
 
Introduction 
You may be eligible to take part in a research study because you have diabetes, heart disease, and 
you will be undergoing a procedure, called percutaneous coronary intervention (PCI). This 
research consent form gives you important information about the study.  It explains why this 
research study is being done, what is involved in participating in the research study, the possible 
risk and benefits of participation, choices for participation and your rights as a research 
participant.  
 
Please take your time to review this information carefully. You may also wish to talk to others 
(for example, your family, friends, or other doctors) about your participation. The decision to 
participate is yours. You may leave the study at any time without losing any benefits you would 
have normally received. If you decide to take part in the study, you will be asked to sign and date 
at the end of this form.  We will give you a copy of the form so that you can refer to it while you 
are involved in this research study.  We encourage you to ask questions now and at any time in 
the future. 
 
You should know that Inova Heart and Vascular Institute and Dr. Paul Gurbel as the principal 
investigator are being paid by Amgen Inc. to conduct this research study.  
 
What if I am already participating in another study? 
Are you already participating in any other research studies?  Yes  
No  
If yes, please state which study (ies) _______________________________________________ 
 
While participating in this study, you may not take part in any other research study without 
approval from the principal investigator.  


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 2 of 9 
 
Why is this study being done? 
Over time, diabetes can lead to serious long-term health complications. When you have diabetes, 
your body does not produce enough insulin or cannot use it properly; therefore, cannot control its 
blood sugar level. High blood sugar can damage and speed up the hardening of the arteries 
(blood vessels), called atherosclerosis. Atherosclerosis is a disease, in which plaque builds up 
inside the arteries that carry oxygen-rich blood to the heart and other parts of the body. 
Atherosclerosis can lead to a heart attack, stroke or peripheral artery disease. 
 
Plaque is made up of fat, cholesterol, and other substances in the blood. When plaque builds up, 
it narrows the coronary arteries and reduces blood flow to the heart, which may cause chest pain, 
shortness of breath, or other heart problems. If plaque breaks or ruptures, it causes injury to the 
inside wall of the affected artery. As a response to the injury, platelets (blood cell fragments that 
help blood clotting) become sticky and clump at the site to form a blood clot within the artery 
causing a blockage. A complete blockage can cause a heart attack.  
 
In addition people with diabetes are more likely to have certain risk factors that increase the 
chances of having heart disease or stroke, such as high cholesterol.  There are two types of 
cholesterol: LDL (low-density lipoprotein), known as the “bad’ cholesterol and HDL (high-
density lipoprotein), known as the "good" cholesterol. Having high levels of LDL stimulates 
plaque buildup in the arteries, causes platelets to become sticky, and thus increases the risk of 
heart attack and stroke. Cholesterol and triglycerides (another type of fat in the blood) are 
important to our life, however in excess they may do harm to our body. 
 
Evolocumab (Repatha®) is an injectable medication developed by Amgen Inc., a for-profit 
biopharmaceutical company to help lower the LDL cholesterol in the blood. Evolocumab is 
approved by the U.S. Food and Drug Administration for use in addition to diet and optimal statin 
therapy in people with atherosclerotic disease. In clinical trials, evolocumab has shown to 
dramatically lower the levels of “bad” cholesterol and, in the same time, to reduce the 
occurrences of cardiovascular events such as, heart attack, stroke, hospitalization for worsening 
chest pain, coronary angioplasty, or bypass surgery. We have reason to believe that evolocumab 
will favorably affect platelet function (making platelets less sticky) in patient with diabetes and, 
therefore, lower the risks of cardiovascular events. 
 
This research is being done to evaluate the effects of evolocumab on platelet function and 
biomarkers (substances in the blood that can indicate the presence of certain diseases) in patients 
with diabetes undergoing a PCI procedure.  
 
How many people will take part in this study? 
Approximately 150 people, 18 years of age or older will be enrolled at Inova Heart and Vascular 
Institute. 
 
What other choices do I have if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
 You may choose to have the usual standard therapy for your condition as prescribed by 
your doctor.  
 You may choose to take part in a different study, if one is available. 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 3 of 9 
 
 You could decide not to be treated. 
This study is designed for research purposes only and is not intended to treat a medical 
condition.  
 
How long will I be in this study? 
If you decide to participate, you will be in this study for about 30 days.  
 
What will happen if I take part in this research study? 
Most of the exams, tests and procedures you will have during your participation in the study are 
part of the usual approach for your coronary artery disease and may be done even if you do not 
join the study.  However, there are some extra exams, tests or procedures that you will need to 
have if you take part in the study. 
 
If you qualify to participate and agree to take part, you will be asked to sign this consent form 
before any study related tests and procedures are performed. 
 
If you agree to take part in the study, you will be “randomized” to receive either evolocumab or 
placebo (a substance that has no therapeutic effect). Randomization means that you will be 
assigned to receive either evolocumab or placebo by chance, like flipping a coin. Neither you, 
nor your doctor will choose what you will receive.  You will have an equal chance to receive the 
study drug or matching placebo.  
 
This is a double-blinded study, which means that neither you nor the study doctor will know 
which study group you have been assigned to. However, in a medical emergency, the study 
doctor will be able to find out your group.  
 
The effect of evolocumab/placebo on platelet function and biomarkers will be measured at 3 time 
points during the study: 
 Before PCI procedure to determine your ‘usual clotting level’ prior to drug 
administration;  
 At 16-24 hours after administration of evolocumab/placebo; and 
 At 30 days (+/- 5 days) after administration of evolocumab/placebo. 
 
For the purpose of this study, evolocumab and placebo are called “study drug”. 
 
Visit 1 - Prior to PCI procedure:  
 Provide informed consent and demographic information (sex, date of birth, race, 
ethnicity); 
 Provide your complete medical and surgical history ( including any allergies, tobacco 
use, contraceptive method/s use); 
 Provide your current medications (including vitamins, over-the-counter drugs and herbal 
supplements);  
 Have a physical exam and your vital signs checked (blood pressure and heart rate) 
 Have your height and weight measured; 
 If you are a woman of childbearing potential, provide urine specimen for pregnancy test; 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 4 of 9 
 
 Provide blood samples (approximately 5 teaspoons) for: 
o safety laboratory tests;  
o platelet function and biomarker testing; 
o lipid profile (cholesterol and triglycerides).  
 
Visit 2 - During and After your PCI procedure 
Your doctor will use the current standard of care guidelines, your medical condition, and the 
local practices at the Inova Heart and Vascular Institute to perform your PCI procedure. You 
have already received information about the procedure including the possible risks and benefits, 
and have provided consent separately with your study doctor as part of your routine medical 
care. As part of the study you will: 
 Be randomized to receive either 420 mg of evolocumab or placebo; 
 Receive either 420 mg of evolocumab or placebo subcutaneously.  You will receive the 
study drug/placebo as three separate subcutaneous injections, given consecutively within 
30 minutes.  
 
After your PCI procedure, while you are still in the hospital, about 16-24 hours after the 
administration of the study drug, you will be required to:  
 Report if you have any changes in you medical history and medications you are taking; 
 Report if you have experienced any side (bad) effects since your last study visit; 
 Have your vital signs checked (blood pressure and heart rate); 
 Provide blood sample (about 4 teaspoons) platelet function, biomarkers, and lipid profile. 
 
Visit 3/End of Study - 30 Days (+/-5days) after your study drug administration 
You will be asked to come to the study center 30 days of the study drug administration. You will 
be required to: 
 Report if you have any changes in you medical history and medications you are taking; 
 Report if you have experienced any side (bad) effects since your last study visit; 
 Have your vital signs checked (blood pressure and heart rate); 
 Provide blood sample (about 5 teaspoons) for: 
o safety laboratory tests;  
o platelet function and biomarker testing; 
o lipid profile (cholesterol and triglycerides).  
 
What side effects or risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that you may:   
 Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
 Be asked sensitive or private questions which you normally do not discuss 
 The most important non-medical risk is the disclosure of your protected health 
information (PHI). PHI is any health information that is collected about you, including 
your history and new information collected during this study. You will have an 
opportunity to review the ways in which your PHI may be used and disclosed in the 
HIPAA Authorization for Research form may also have access to these records. 
 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 5 of 9 
 
There is also a risk that you could have side effects. Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 The study doctor may be able to treat some side effects. 
 
The table below shows the most common and the most serious side effects that researchers know 
about.  There might be other side effects that researchers do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Risks and side effects related to administering evolocumab include those which are:  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving evolocumab,  between 1 and 10 may have: 
 Runny nose (nasopharyngitis) 
 Nose and throat infection (upper respiratory tract infection) 
 Back pain 
 Feeling sick to the stomach (nausea) 
 Flu (influenza) 
 Joint pain (arthralgia) 
 Injection site reactions (redness, pain, and bruising) 
 Rash 
 
 
UNCOMMON, SOME MAY BE SERIOUS 
In 1000 people receiving evolocumab, between 1 and 10 may have: 
 Hives (urticaria) 
 
Other potential side effects with evolocumab: 
 Low Levels of Cholesterol 
It is possible that evolocumab could decrease your cholesterol to very low levels in your 
blood. In clinical studies with evolocumab there was no difference in side effects in 
patients who achieved very low cholesterol compared with those patients who did not. 
The long-term effects of very low levels of cholesterol are unknown.  
 Allergic Reactions 
Allergic reactions to evolocumab have been reported, including rash and hives. In 
addition, you may experience other symptoms of an allergic reaction including headache, 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 6 of 9 
 
itching, flushing, swelling, shortness of breath, nausea and sometimes vomiting. Severe 
allergic reactions can cause dizziness, severe skin reactions, difficulty breathing or 
swallowing, a decrease in blood pressure, and could be life threatening. 
 Antibodies 
After you start taking evolocumab, it is possible that your body may make antibodies 
(proteins that may stop evolocumab from working or cause side effects). In clinical 
studies with evolocumab to date, no patients have made antibodies that caused 
evolocumab not to work or that caused side effects. 
 
Evolocumab may cause all, some, or none of the side effects listed above. These side effects can 
be mild but could also be serious and life-threatening. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  
 
Are there reproductive risks while on this study? 
You should not get pregnant, breastfeed, or father a baby while on this study because we cannot 
predict the effects on an unborn baby.  
 
A pregnancy test will be performed on all women who may be pregnant before taking part in this 
study.  This includes all women except those whose menstrual periods have not occurred for 
more than one year after menopause (change of life) or those who have had sterilization surgery 
(tubes tied) or a hysterectomy (removal of the uterus or womb).  Pregnant women may not take 
part in this research study. 
 
If you decide to take part in this study, you must agree to protect yourself or your partner from 
becoming pregnant. You must protect yourself or your partner before, during the study and for 
15 weeks after the last dose of the study drug.  If you or your partner becomes pregnant when 
either parent is taking the drug, birth defects may occur.  If you are a female and think that you 
might be pregnant, you must immediately tell your study doctor. It may be harmful for a child to 
breastfeed from a woman taking a study drug. Because of this, female participants must not 
breastfeed during the study and for 15 weeks after the study ends. 
 
If you become pregnant while taking study drug, you will agree to release your health records 
while pregnant. You will also agree to release your child’s health records for the first year of 
his/her life.  
 
Acceptable methods of contraception (birth control) while taking part in this study are: 
1. Total Abstinence (no sexual intercourse), absence of menstrual periods in women for 
more than one year after menopause (change of life), sterilization surgery, including tubal 
ligation (tubes tied) or hysterectomy (removal of the uterus or womb) in women or a 
vasectomy in men. 
2. Oral contraceptives (birth control pills), intrauterine device (IUD), implantable or 
injectable contraceptives (Norplant or Depo-Provera), contraceptive patch, vaginal ring 
or use of condom with spermicide.  These methods must be used exactly as directed. 
 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 7 of 9 
 
The following methods of contraception are not acceptable to prevent pregnancy during 
study participation: diaphragm, cervical cap, vaginal sponge, and “female condom”. 
 
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better.  We hope the information 
learned from this study will benefit others in the future. 
 
Can I stop being in the study? 
Yes. You can choose not to be in the study. You can decide to stop at any time. It is important to 
tell the study doctor if you are thinking about stopping a study drug or leaving the study so any 
risks from the evolocumab can be evaluated by your doctor. You may want to discuss what 
follow-up care and testing could be most helpful for you.  
 
Your participation can also be stopped without your approval by any of the following: 
 the study doctor;  
 the Institutional Review Board (IRB – hospital committee that reviews and approves 
research). 
 
The study doctor may decide to take you off this study for any of the following reasons: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study rules 
 If the study is stopped by the sponsor 
 
What are the costs of taking part in this study? 
You will not be responsible for the cost of the following procedures and tests that are a part of 
the study: 
 Lipid profile, platelet and function and biomarkers testing; 
 The study drug will be provided to you for free. 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating coronary artery disease in this study. Check with your health plan or insurance company 
to find out the total costs to you for treatment while on this study. You may be responsible for 
any co-payments and deductibles that are standard for your insurance charges  
 
Will I be paid for taking part in this study? 
You will be compensated for your time in the study. You may receive a total of $120 for your 
participation (Visit 1 - $40, Visit 2 - $40, and Visit 3 - $40). If you do not finish the study, you 
will be paid only for the visits you have completed.  
 
What if I am injured because I took part in this study? 
In the event that you believe you have been injured because of taking part in this study, it is 
important that you call your study doctor.  You can call Dr. Paul Gurbel, the principal 
investigator, at (703) 776-3330 during business hours or (410) 202-0960 after business hours, 
and he will review the matter with you.  Inova Health System and the study doctor do not 
provide funds or free medical treatment for injuries that result from taking part in this study.  
Medical treatment is available to you if you are injured as a result of taking part in this study. 
 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 8 of 9 
 
You and/or your health plan will be billed for the cost of this care. If your insurance does not pay 
for your care, or pays only a portion of the cost of such care, you may be billed for any unpaid 
amounts. 
 
You should not expect anyone to pay you for pain, worry, lost income, or non-medical care costs 
that occur from taking part in this research study.  No funds have been set aside, by Inova Health 
System and Inova Heart and Vascular Institute to repay you in case of injury.  
 
You are not waiving any legal claims or rights because of your participation in this study.  
 
Will my medical information be kept private? 
We will keep your records private to the amount allowed by law.  Research records are stored 
and kept according to legal requirements. You will not be identified in any reports or 
publications about this study.  However, certain people and groups will have access to your 
research and medical records.  The sponsor of the study will look at your research and medical 
records.  The Inova Health System Institutional Review Board (IRB) and federal and state 
agencies that have authority over the study may look at your research records.  Members of the 
study staff will also have access to your research records.  Additional groups, explained in the 
HIPAA Authorization for Research form may also have access to these records. 
 
You will be assigned a unique study number by which you will be identified for the study.  
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. A member of your research team will tell you about new information or changes in the 
study that may affect your health or your willingness to continue in the study. 
 
If you would like more information about your rights as a participant in a research study, contact: 
Inova Health System Institutional Review Board (IRB) at (571) 472-3458. The Inova Health 
System IRB may contact you by mail or telephone to find out if you were satisfied with your 
study participation. 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study. 
Contact your study doctor, Dr. Paul Gurbel, at (703) 776-3330 during business hours or (410) 
202-0960 after business hours. 
 
Where can I get more information? 
A description of this clinical trial will be available on 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. 


Short Title: 17-2639 Evolocumab DM 
Principal Investigator: Paul Gurbel, MD 
RESEARCH CONSENT  
Date Approved:  June 19, 2019 
Inova IRB: Joanne Muratori, IRB Coordinator 
IRB File # 17-2639 
 
 
Protocol date: 04/24/2018 
Consent version # 4/ Date: June 2019 
 
Page 9 of 9 
 
 
SIGNATURE 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to participate in a research 
study.  I have had the opportunity to ask questions and have had the questions answered to my satisfaction.  I 
voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
 
 
____________________________________________ 
____________________________ 
 
Signature of Subject 
Printed Name of Subject  
 
____________________________ 
 
Date  
 
 
 
 
 
 
 
 
Investigator/Research Staff 
 
I have explained the purpose, the procedures, the benefits and risks that are involved in this research study before 
requesting the signature(s) above.  Any questions that have been raised have been answered to the individual’s 
satisfaction.  A copy of this form has been given to the participant or his/her representative. 
 
_______________________________________ 
______________________________ 
Signature of Person Obtaining Consent   
Printed Name of Person Obtaining Consent 
 
______________________________ 
 
Date  
 
The following witness lines may be left blank, unless an impartial witness is required.  
 
An impartial witness, who is a witness to the informed consent process that is not involved in 
the conduct of the research, is required when utilizing a legally authorized representative or 
when an oral interpreter and short form is used. 
 
________________________________________ 
______________________________ 
Signature of Impartial Witness 
Printed Name of Impartial Witness 
 
______________________________ 
 
Date