Clinical trial NCT03829046
Conditions: Atherosclerotic Vascular Disease Type2 Diabetes Microvascular Dysfunction
Keywords: PCSK9 inhibition Evolocumab Inflammatory Signals Circulating monocyte subsets
Sponsor: Robert Rosenson
Start date: 2019-06-03; Completion date: 2021-11-15
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Experimental models have linked lipid lowering therapies with systemic inflammation; however, relatively little is known about this network in clinical populations and specifically how it changes with PCSK9 inhibition. The eligible subjects will have 6 visits in 13 to 16 weeks and will have Repatha/placebo 140mg subcutaneous every 4 weeks for 3 times since randomization visit, blood tests will be done in each visit to evaluate the effects of evolocumab upon biocellular markers potentially altered by PCSK9 inhibition in a population of type 2 diabetes patients with microvascular dysfunction.

Primary Aims:

Determine the ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular markers of inflammation, immune mediated thrombosis and rheology. The data from this trial will be used to support a clinical trial to assess the role of PCSK9 inhibition in type 2 diabetes patients with cardiac microvascular dysfunction.

Secondary Aims:

1. To define the association between PCSK 9 concentrations and immune-related phenotype.
2. To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL), ApoB, biocellular markers of inflammation, tissue factor and immunothrombosis.

Detailed description:
Multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The population will include 40 participants with documented Atherosclerotic Vascular Disease (CAD, Stroke, PAD) and type 2 diabetes who receive treatment with maximal tolerated statin therapy and stable doses of anti-hyperglycemic therapy.

Subjects will be followed for 12 weeks during the treatment phase, maintaining the double-blind throughout. Assessments of ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular markers of endothelial function will be measured at baseline, Week 2, and Week 12. Safety assessments will be undertaken at each study visit.

Arms: arm 1: Placebo SC QM arm 2: Evolocumab SC 420mg/dL QM
Interventions: intervention 1: Placebo intervention 2: Evolocumab
Intervention descriptions: intervention 1: 12 weeks of treatment intervention 2: 12 weeks of treatment

Protocol documents:
Prot_SAP_000.pdf: 
The Effects of Evolocumab on Endothelial and Inflammatory Biocellular 
Markers in Patients With Diabetes and Atherosclerotic Vascular Disease 
(METCHNIKOFF) 
PI: Robert Rosenson, MD
NCT03829046
Document Date: July 9, 2021


Page 1 of 19 
THE EFFECTS OF EVOLOCUMAB ON ENDOTHELIAL AND INFLAMMATORY BIOCELLULAR MARKERS
IN PATIENTS WITH DIABETES AND ATHEROSCLEROTIC VASCULAR DISEASE (METCHNIKOFF) 
Amgen Reference Number 20167719 
Date: 
Original Protocol Date: 11 Sep 2016 
Superceding Protocol Date: 05 Dec 2016 
Superceding Protocol Date: 13 Dec 2016 
Superceding Protocol Date: 27 Nov, 2018 Amendment 1.0 
Superceding Protocol Date: 28 May, 2019 Amendment 1.1 
Superceding Protocol Date: 10 Mar, 2020 Amendment 1.2 
Superceding Protocol Date: 09 Jul, 2021 Amendment 1.3 
PRIMARY INVESTIGATORS: 
Robert S. Rosenson, MD, FACC, FACP, FAHA, FESC, FNLA 
Director, Cardiometabolics Unit, Mount Sinai Hospital 
Professor of Medicine (Cardiology), Icahn School of Medicine at Mount Sinai 
The Mount Sinai Health System 
One Gustave L. Levy Place, Box 1030 
New York, NY, USA 10029 
Sascha N. Goonewardena, MD 
Assistant Professor of Medicine (Cardiology) 
Michigan Nanotechnology Institute for Medicine and Biological Sciences 
University of Michigan 
Ann Arbor, MI 48109 


Page 2 of 19 
1.
RATIONALE:
Atherosclerosis is a chronic inflammatory disease of the arterial wall that involves endothelial cell (EC) 
dysfunction; monocyte recruitment, retention and activation; and vascular smooth muscle cell (SMC) 
proliferation.1 ECs can be activated by diverse physiologic stimuli including cytokines, catecholamines, and 
shear stress.2, 3 Persistent activation of EC can lead to vascular dysfunction and systemic inflammation, 
both of which are known to drive vascular events including stroke.4, 5 In aortic endothelial cells and 
vascular SMC, NADPH oxidase dependent reactive oxygen species (ROS) increases PCSK9 expression via 
lectin LDLR-1 (LOX-1).6 Atherosclerosis is site specific with increased expression of PCSK9 as in low wall 
shear stress regions of murine aorta.7  
Although we appreciate that inflammation is a driver of acute coronary syndromes (ACS) and strokes, 
profiling circulating inflammatory mediators (e.g. CRP, cytokines, lipoproteins) has not greatly added to 
traditional management strategies.  One possible explanation for this gap is that circulating inflammatory 
markers capture the systemic inflammatory state of the patient and not local inflammation in specific 
arterial beds. In animal models, the innate immune system responds to local plaque rupture, leading to the 
recruitment of circulating monocytes.  In human observational studies, elevated levels of monocytes 
correlate with infarct and stroke size.8 Although it is clear that circulating monocytes are elevated in 
patients with atherosclerotic diseases, their molecular profiles and how they relate to clinical 
atherosclerotic cardiovascular disease remain largely unknown.  Furthermore, even though it is known 
that circulating monocytes can change with acute and chronic inflammatory stresses, it remains unclear 
how PCSK9 inhibition and subacute reductions in lipoproteins impact circulating monocyte subsets and 
their functional responses.  As sentinels of innate immune system, the circulating monocytes may provide 
a snapshot into local plaque microenvironment providing a functional “biocellular-marker” that integrates 
both the systemic and local inflammatory state of patients with atherosclerotic disease.9 
Although experimental models have linked lipoproteins and EC dysfunction with systemic inflammation, 
relatively little is known about this network in clinical populations and specifically how it changes with 
PCSK9 inhibition. Because of PCSK9 effects on the LDL receptor, PCSK9 inhibition is likely to inhibit pro-
inflammatory changes in circulating monocyte subsets and functions.  In circulating monocytes, toll-like 
receptors (TLR) sense inflammatory molecules.  TLR responses are mediated through MyD88 and TRIF, 
which leads to activation of signaling pathways including Jak-STAT, Akt, AMPK, mTOR, PKA, NFkB, and 
MAPK, which mediate inflammatory transcriptional programs.  The participation of PCSK9 in vascular 
inflammation is supported by preclinical studies using PCSK9 siRNA in macrophages. These studies have 
demonstrated that PCSK9 inhibition in macrophages reduces NF-kB inflammatory responses.10  
Furthermore, oscillatory shear stress increases the activation of pro-inflammatory signaling pathways and 
reduces activation of anti-inflammatory pathways. As an exploratory aim, we will measure low shear blood 
viscosity to examine the associations between baseline and on-trial change in low shear blood viscosity 
with inflammatory mediators. The data on blood viscosity will also be used to support our larger aim 
concerning the putative role of PCSK9 inhibition on cardiac microvascular dysfunction, as blood flow in the 
microcirculation is highly dependent on changes in blood viscosity. 
Our aim is to define how PCSK9 inhibition alters the circulating monocyte populations and to 
systematically profile the transcriptional and proteomic responses to TLRS and how these responses are 
modulated by PCSK9 inhibition in the peripheral blood mononuclear cells (PBMC) clinical samples and 
relate these molecular signatures to clinical and imaging variables. The overall rationale for the work 
proposed is to understand the molecular mechanisms through which PCSK9 and circulating lipoproteins 
orchestrate TLR response in circulating monocytes.  The outcome measures for this aim include PBMC 
subset analysis and transcriptional and proteomic analysis of inflammatory signaling pathways in 


Page 3 of 19 
response to TLR stimulation.  After the proposed studies for this aim have been completed, it is our 
expectation that we will have defined the molecular pathways through which PCSK9 modulates inflammatory 
responses in circulating monocytes and how these molecular signatures relate to clinical variables known to 
be important in CVD risk stratification.   
Microfluidic technology has recently been applied to molecular biology and to clinical diagnostics.  Because 
of its small sample requirements and exquisite spatial control, microfluidics is an exciting complement to 
existing diagnostic technologies. We recently engineered microfluidic-proteomic device that allows for the 
rapid profiling of immune cell activation (Figure 1). Studies have suggested that understanding the 
molecular signatures associated immune cell stress responses can be more informative than static 
measures of inflammation.  Profiling the activation patterns of circulating monocytes from clinical patients 
has been difficult because of the amount and processing of clinical samples required for traditional 
molecular assays.  This microfluidic profiling device will overcome many of these obstacles, allowing us to 
profile the molecular activation patterns of circulating blood monocytes in parallel with markers of 
systemic inflammation, lipoproteins, and other clinical variables with the requisite throughput and fidelity. 
This technology will allow us to link the biological effects of PCSK9 inhibition with immune cell function, 
providing mechanistic insight into the relationship between lipoprotein metabolism, microvascular 
dysfunction, and inflammation, ultimately resulting in novel surrogate markers that could result in 
identification of “at-risk” populations that would benefit from more aggressive LDL cholesterol reduction.    
Monocytes are key innate immune system mediators of inflammatory responses and have been implicated 
as drivers of CVD.  Monocyte subsets can be characterized using flow cytometry for surface expression of 
FcγIII receptor CD16 and the lipopolysaccharide receptor CD14.  We will profile monocytes in patients 
using flow cytometry.  Briefly, blood will be collected in Cell Preparation Tubes (CPT) with sodium citrate 
(BD, New Jersey).  Cells will be resuspended in FACS buffer and stained with fluorescently labeled 
antibodies.  Monocyte subsets will be defined using CD14 and CD16.  The Nomenclature Committee of the 
International Union of Immunological Societies defines three monocyte subsets by this method: 
CD14++CD16- (classical), CD14++CD16+ (intermediate), and CD14+CD16++ (non-classical).  Flow 
cytometric analysis will be performed on a BD Accuri C6 flow cytometer and the data analyzed using FlowJo 
software (Tree Star, Inc).  Monocyte subsets will be defined using CD14 and CD16.  Because cholesterol 
metabolism has been associated with monocyte egress from the bone marrow, we anticipate that PCSK9 
inhibition will alter monocyte subsets compared with patients not on therapy.      
We will systematically define functional relationships between clinical data, cell-surface markers, and 
molecular activation of signaling pathways using our microfluidic proteomic platform and PCR arrays. 
Briefly, circulating monocytes will be isolated and processed as described above.  To understand how 
PCSK9 inhibition modulates transcriptional and signaling responses to inflammatory stimuli, monocytes 
will be stimulated with TLR ligands and RNA and protein will be isolated at 2 time points (30 min and 2 
hours).  Inflammatory transcriptional programs will be profiled using PCR arrays (SA Biosciences, 
Maryland).  Activation of inflammatory signaling pathways (MAPK, NFkB, Akt, AMPK, mTOR, Jak-STAT, 
PKA) will be profiled using our novel microfluidic immunoblotting platform.  We anticipate that PCSK9 
inhibition will significantly alter TLR activation of signaling pathways and inflammatory transcriptional 
programs in monocytes.  The dynamic responses characteristic of circulating monocytes cannot be 
captured with typical profiling experiments; we anticipate that by using circulating monocytes as a 
“biocellular” marker of inflammatory risk, tremendous insight will be gained into how PCSK9 modulates 
inflammatory responses and these dynamic molecular signatures have the potential to identify patients 
most at risk of CVD disease and those who would benefit from more aggressive LDL cholesterol reduction.  
Circulating biomarkers that interface with inflammation and endothelial function will be measured. These 
include soluble VCAM-1, ICAM-1, LOX-1, MCP-1 and MIP-1α.  Due to the critical role of low wall shear stress 


Page 4 of 19 
in endothelial dysfunction, inflammation and site-specificity of atherosclerosis, we will measure blood 
viscosity profiles. Lipoprotein subclasses will be measured by NMR spectroscopy (LabCorp). The choice of 
NMR is based on a recent study that showed an inverse association between large HDL particle 
concentration and myocardial perfusion reserve index.11 
1.1. 
Aims: 
We therefore propose to evaluate the effects of evolocumab upon biocellular markers potentially altered by 
PCSK9 inhibition in a population of type 2 diabetes patients with cardiac microvascular dysfunction.   
1.1.1. 
Primary Objective 
Determine the ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular 
markers of inflammation, immune mediated thrombosis and rheology. The data from this trial will be 
used to support a clinical trial to assess the role of PCSK9 inhibition in type 2 diabetes patients with 
microvascular dysfunction. 
1.1.2. 
Secondary Objective: 
a) To define the association between PCSK 9 concentrations and immune-related phenotype.
b) To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL), ApoB,
biocellular markers of inflammation, tissue factor and immunothrombosis.


Page 5 of 19 
2.
SUBJECT ELIGIBILITY
This study can only fulfill its objectives if appropriate subjects are enrolled.  In addition to the eligibility 
criteria listed below, all relevant medical and non-medical considerations will be taken into account when 
deciding whether an individual subject will be suitable to enter this particular study. 
2.1. 
Inclusion Criteria 
a) Subjects ≥ 18 years of age at signing of informed consent
b) A history of clinical ASCVD, which is defined as: acute coronary syndrome, or a history of MI, stable
or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack
(TIA), or peripheral arterial disease presumed to be of atherosclerotic origin.12
c) Clinical diagnosis of type 2 diabetes according to ADA/CDA guidelines
d) Subject on stable dose of maximally-tolerated statin therapy for ≥4 weeks prior to screening and
LDL-C ≥ 70mg/dL.  For subjects whose maximally tolerated dose of statin is no type or dose (i.e.
determined to be statin intolerant by primary investigator), background lipid-lowering therapy is
not required.
e) Fasting triglycerides ≤ 400 mg/dL (4.52 mmol/L) be central laboratory at screening
f)
Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial
procedures
g) Abnormal urinary Albumin Creatinine Ratio (ACR) as defined by an ACR >2.
2.2. 
Exclusion Criteria 
a) Personal or family history of hereditary muscular disorders
b) NYHA III or IV heart failure, or last know left ventricular ejection fraction (LVEF) < 30%
c) Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular
tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that
are not controlled by medications, in the past 6 weeks prior to randomization
d) Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI) within 6 weeks,
coronary artery graft (CABG) or stroke within 3 months prior to randomization
e) Planned cardiac surgery or revascularization
f)
Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <
30 mL/min/1.73m2 at screening.
g) Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c > 10%), newly diagnosed type 2 diabetes
(within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting
serum glucose ≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%) without prior diagnoses of diabetes
h) Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic
BP (DBP) > 100 mmHg
i)
Subject who has taken a cholesterol ester transfer protein (CETP) inhibitor in the last 12 months
prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib


Page 6 of 19 
j)
Treatment in the last 3 months prior to LDL-C screening with any of the following drugs:
immunosuppresives like cyclosporine, systemic steroids (e.g., IV, intramuscular [IM], or PO) (Note:
hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the
treatment of dermatologic conditions (e.g., Accutane); (Note: vitamin A in a multivitamin
preparation is permitted).  Topical retinol prescription and non-prescription derivatives or creams
are permitted.
k) Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) 
< 1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening. Potential
subjects with TSH < 1.0 time the lower limit of normal due to thyroid replacement therapy is not
considered an exclusion
l)
Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at screening
m) Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine
dysfunction in the judgment of the investigator
n) Diagnosis of deep vein thrombosis or pulmonary embolism or major surgical procedures within 3
months prior to randomization
o) Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the
subject (e.g. alcohol or other drug abuse)
p) Currently enrolled in another investigational device or drug study, or less than 30 days since ending
another investigational device or drug study(s), or receiving other investigational agent(s)
q) Female subject who has either (1) not used at least 1 highly effective method of contraception for
at least 1 month prior to screening or (2) is not willing to use such a method during treatment and
for an additional 15 weeks after the end of treatment, unless the subject is sterilized or
postmenopausal;
a.
Menopause is defined as: 12 months of spontaneous and continuous amenorrhea in a female ≥
55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-
stimulating hormone (FSH) level > 40 IU/L (or according to the definition of "postmenopausal
range" for the laboratory involved) in a female < 55 years old unless the subject has undergone
bilateral oophorectomy
b. Highly effective methods of birth control include: not having intercourse or using birth control
methods that work at least 99% of the time when used correctly and include: birth control pills,
shots, implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity
with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or
cervical/vault caps) used with spermicide
r) Subject who is pregnant or breast feeding, or planning to become pregnant during treatment and/or
within 15 weeks after the end of treatment
s) Use of a PCSK9 inhibitor within 10 weeks from screening visit
t) Subject who has any kind of disorder that, in the opinion of the investigator, may compromise the
ability of the subject to give written informed consent and/or to comply with all required study
procedures
u) Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within
the last 5 years


Page 7 of 19 
v) Subject who has known sensitivity to any of the products or components to be administered during
dosing
w) Subject who is likely to not be available to complete all protocol-required study visits or procedures,
and/or to comply with all required study procedures to the best of the subject and investigator’s
knowledge
x) History or evidence of any other clinically significant disorder, condition or disease (with the
exception of those outlined above) that, in the opinion of the principal investigator would pose a
risk to subject safety or interfere with the study evaluation, procedures or completion
y) Blood donation 4 weeks prior to screening, or stated intention to donate blood or blood products
during the period of the study or within one month following completion of the study
z) Subjects who have participated in other studies within 30 days prior to screening, or have five times
the plasma half-life (if known) of the investigational drug, whichever is longer.
aa) BMI >40 kg/m2 


Page 8 of 19 
 
3. 
STUDY DESIGN 
3.1. 
Study Overview 
This is a double-blind, randomized, placebo-controlled, parallel group Phase IV study with two treatment 
arms:  evolocumab SC 420 mg/dL QM or matching placebo. The population will include men and women 
of non-child-bearing potential with documented CAD and type 2 diabetes.  
Approximately 100 subjects will be screened in order to keep 40 subjects to complete the study. Subjects 
will be followed for 12 weeks during the treatment phase, maintaining the double-blind throughout.  
Assessments of ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular 
markers of endothelial function will be measured at baseline, Week 2, and Week 12. Safety assessments 
will be undertaken at each study visit.  Subjects whose maximally tolerated dose of statin is no type or dose 
(i.e. determined to be statin intolerant by primary investigator) must be randomized fairly between 2 
treatment arms to prevent selection bias. 
Subjects should continue on their stable dose of anti-hyperglycaemic therapies during the course of the 
study.  However, it is important that the haemoglobin A1c (HbA1c) does not rise above 10% and that the 
patient does not develop severe hypoglycaemia or frequent episodes of mild-moderate hypoglycaemia, as 
defined by the Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and 
Management of Diabetes.13 
3.2 
Randomization Procedure 
A randomization list will be produced using a validated system that automates the random assignment of 
treatment arms to randomization numbers in the specified ratio.  At Visit 2, eligible subjects will be given 
the lowest available randomization number. This number assigns the patient to one of the treatment arms.   
3.3 
Study Medication 
The blinded study medication will consist of: 
Evolocumab 420 mg SC QM   
Matching Placebo SC QM   
The study will utilize the SureClick® auto-injection formulation of evolocumab (formulated with and 
without the active ingredient). Three doses (140mg per dose) will be administered at each time point. 
3.4 
Blinding 
The identity of the treatments will be concealed by the use of matching placebo to the study drug that are 
identical in packaging, labeling, appearance and schedule of administration. 
3.5 
Premature Interruption or Withdrawal from the Study 
3.5.1 
Premature Interruption of Study Treatment 
Subjects have the right to discontinue study treatment for any reason.  However, unless they withdraw 
consent and are no longer willing to participate, they should be followed by telephone calls for the 
remainder of the trial and all serious events must be reported, regardless of whether or not the event 
is of cardiovascular origin or occurs under the care of another physician or institution. 


Page 9 of 19 
 
In case of a temporary interruption of study treatment, all efforts should be made to re-institute study 
treatment as soon as the clinical condition of the subject has stabilized based on the judgment of the 
Investigator. 
3.5.2 
Withdrawal of Consent 
Subjects may decide to fully or partially withdraw their consent to participate in the study.  At that 
point, it should be established, whether the withdrawal is related to study treatment, further 
assessments, or any further involvement in the study.  If the withdrawal is primarily related to study 
treatment or specific assessments, subjects should be encouraged to continue follow-up by telephone 
calls and to attend all other subsequent study assessments. Reports on serious events should be 
collected until completion of the study for all withdrawals, unless the subject objects to such follow-up. 
 
 


Page 10 of 19 
 
4 
SCHEDULE OF STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can only be performed 
after obtaining written informed consent. 
All on-study visits and dosing should be scheduled from Day 1 (first IP administration).  For example, the 
Week 2 visit is 2 calendar weeks after the study Day 1 visit, which corresponds to study Week 2.  When it 
is not possible to perform the study visit at the specified time point, the visit should be performed within 
the visit window specified in Table 1.  If a study visit is missed or late, including visits outside the visit 
window, subsequent visits should resume on the original visit schedule.  Missed assessments at prior visits 
should not be duplicated at subsequent visits.  With the exception of screening, all study procedures for a 
visit should be completed on the same day if possible. 
 
Visit 1: Screening 
- 
Written informed consent 
- 
Demographics 
- 
Medical history 
- 
Vital signs 
- 
12 lead ECG measument 
- 
Concomitant therapy 
- 
Dietary instruction; medication compliance reminder  
- 
Physical examination 
- 
Body height, waist circumference 
- 
Body weight 
- 
Seattle Angina Questionnaire 7 (SAQ7)  
- 
Laboratory assessments: TSH, hematology (CBC), blood chemistry (creatinine/eGFR and 
electrolytes), Liver Function Tests (ALT, AST),  creatinine/eGFR, HbA1C, , local lipid panel,  urine 
albumin to creatinine ratio (ACR), urine pregnancy test (if female of child bearing potential) 
 
Visit 2 (Randomization) 7-28 days after Screening 
- 
Review for AEs/SAEs/CV events 
- 
Concomitant therapy 
- 
Vital signs 
- 
Dietary instruction; medication compliance reminder 
- 
Randomization 
- 
Seattle Angina Questionnaire 7 (SAQ7) 
- 
Laboratory assessments:  fibrinogen, whole blood viscosity analysis, NMR lipoprotein subclass 
analysis, Apo B, lipoprotein (a), biocellular marker analysis, Oxidized lipid Analysis 
- 
DNA/mRAN test for lipoprotein and inflammatory polymorphisms that may influence the response 
to therapy (the specimens will be stocked at site and the tests will be performed later). 
- 
SC IP administration, QM (in-clinic) and 30 minute post-injections observation 
 
Visit 3 (Week 2) ±4 days 
- 
Review for AEs/SAEs/CV events 
- 
Concomitant therapy 
- 
Vital signs 


Page 11 of 19 
 
- 
Dietary instruction; medication compliance reminder 
- 
Seattle Angina Questionnaire 7 (SAQ7) 
- 
Laboratory assessments: hematology (CBC), blood chemistry (creatinine/eGFR, electrolytes), Liver 
Function Tests (ALT/AST), fibrinogen, whole blood viscosity analysis, NMR lipoprotein subclass 
analysis, Apo B, lipoprotein (a), biocellular marker analysis, Oxidized lipid Analysis 
 
Visit 4 (Week 4) ±7 days 
- 
Review for AEs/SAEs/CV events 
- 
Concomitant therapy 
- 
Vital signs 
- 
Dietary instruction; medication compliance reminder 
- 
Seattle Angina Questionnaire 7 (SAQ7) 
- 
SC IP administration, QM (in-clinic) and 30 minute post-injections observation 
 
Visit 5 (Week 8) ±7 days 
- 
Review for AEs/SAEs/CV events 
- 
Concomitant therapy 
- 
Vital signs 
- 
Dietary instruction; medication compliance reminder 
- 
Seattle Angina Questionnaire 7 (SAQ7) 
- 
SC IP administration, QM (in-clinic) and 30 minute post-injections observation 
 
Visit 6 (Week 12) ±7 days 
- 
Body height, waist circumference 
- 
Body weight 
- 
Review for AEs/SAEs/CV events 
- 
Concomitant therapy 
- 
Dietary instruction; medication compliance reminder 
- 
Seattle Angina Questionnaire 7 (SAQ7) 
- 
Laboratory assessments: hematology (CBC), blood chemistry (creatinine/eGFR, electrolytes), Liver 
Function Tests (ALT/AST),  fibrinogen, whole blood viscosity analysis, NMR lipoprotein subclass 
analysis, Apo B, lipoprotein (a), biocellular marker analysis, Oxidized lipid Analysis 
 


Page 12 of 19 
 
Table 1. Schedule of Assesments 
Schedule of Assessments 
Screening 
Baseline/ 
Randomization 
Week 2 
Week 4 
Week 8 
Week 
12 
Visit Number 
1 
2 
3 
4 
5 
6 
Visit Window 
  
± 7-28 Days 
± 4 Days 
± 7 Days 
± 7 Days ± 7 Days 
Informed consent 
X 
  
  
  
  
  
Demographics & Medical history 
X 
  
  
  
  
  
Vital signs (HR, BP)  
X 
X 
X 
X 
X 
X 
ECG 
X 
  
  
  
  
  
Review for AEs/SAEs/CV events 
  
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
Dietary instruction; medication compliance reminder 
X 
X 
X 
X 
X 
  
Physical examination 
X 
  
  
  
  
  
Body height, waist circumference 
X 
  
  
  
  
X 
Body weight 
X 
  
  
  
  
X 
Seattle Angina Questionnaire 7 (SAQ7) 
X 
X 
X 
X 
X 
X 
Placebo Injection 
X 
  
  
  
  
  
Laboratory Analyses: 
  
  
  
  
  
  
TSH 
X 
  
  
  
  
  
Hematology (CBC)  
X 
  
X 
  
  
X 
Chemistry (creatinine/eGFR, electrolytes) 
X 
  
X 
  
  
X 
Liver Function Tests (AST, ALT) 
X 
  
X 
  
  
X 
Urine albumin to creatinine ratio (ACR) 
X 
  
  
  
  
X 
HbA1c  
X 
  
  
  
  
  
Local Lipid Panel 
X 
  
  
  
  
  
Urine pregnancy (if applicable) 
X 
  
  
  
  
  
Fibrinogen 
  
X 
X 
  
  
X 
lipoprotein(a), Apo B 
  
X 
X 
  
  
X 
Whole Blood Viscosity Analysis 
  
X 
X 
  
  
X 
NMR Lipoprotein Subclass Analysis 
  
X 
X 
  
  
X 
Biocellular Marker Analysis 
  
X 
X 
  
  
X 
Oxidized lipid Analysis 
  
X 
X 
  
  
X 
DNA/mRNA test 
  
X 
  
  
  
  
Randomization 
  
X 
  
  
  
  
Investigational Product: SC IP Administration, QM 
  
X 
  
X 
X 
  


Page 13 of 19 
 
5 
CLINICAL PROCEDURES AND SAFETY EVALUATIONS 
5.1 
Informed Consent 
Once deemed appropriate candidates for the study, the subject will be informed of the possibility of study 
participation.  The benefits and risks of participating in the study will be explained to the subject, and the 
subject will be provided an opportunity to read the informed consent form and ask any questions he/she 
may have.  Prior to conducting any study-related procedures, the subject must provide consent to 
participate by signing the Institutional Review Board/Research Ethics Board (IRB/REB) approved consent 
form. 
5.2 
 Demography 
This includes age, sex and race. 
5.3 
 Medical History 
Data will be collected from subjects at baseline consisting of demographics, history, previous cardiac 
investigations, previous cardiac history, and current medication. 
5.4 
Physical Examination 
A routine physical examination is required at Visit 1. Any abnormality must be recorded. 
5.5 
 Vital Signs 
Vital signs including blood pressure and heart rate will be recorded at the intervals indicated on the 
schedule of study procedures in Table 1. 
5.6 
ECG 
A 12-lead ECG will be performed at screening visit. 
5.7 
 Body weight, Height, and Waist Circumference 
Body weight, height, and waist circumference will be recorded. 
5.8 
 Laboratory Tests 
5.8.1 
Local Laboratory Tests 
Local laboratory assessments include TSH, hematology, blood chemistry, liver function tests (LFTs), 
eGFR, HbA1C, fibrinogen and urine ACR, Apo B, lipoprotein(a). Please see Table 1 for the exact schedule 
of all laboratory tests. 
5.8.2 
Additional Laboratory Tests 
The following labs will be performed centrally: whole blood viscosity, lipoprotein subclass, and 
biocellular marker analyses.  In addition, blood samples will be retained and frozen for future analysis 
including mRNA and DNA analysis. 


Page 14 of 19 
 
5.8.3 
Biocellular Marker Assessments 
We will evaluate the impact on evolocumab on biomarkers of endothelial function.  We will assess 
biomarkers of oxidative stress (MDA), inflammation (MPO), cytokines (IL‐6, IL‐18 and TNF‐α) and 
vascular endothelial activation (PECAM, ICAM, VCAM and alpha5/beta 3 activations).  
5.9 
 Concomitant Therapy 
Medications are not altered for the purpose of this trial, however, any medication changes during the study 
must be recorded, as must those started before randomization and continued thereafter. During the 
hospital stay and at following study visits, changes in concomitant therapy must be recorded.  
5.10  Study Drug Accounting 
Double-blind study medication may only be dispensed and administered according to the study protocol 
by authorized personnel, as documented in the investigator’s trial staff list.  At each visit, compliance will 
be checked and recorded in the case report form. 
 
 


Page 15 of 19 
 
6 
MANAGEMENT OF ADVERSE EVENTS 
6.1  
Adverse Event (AE) Reporting 
An adverse event (AE, AEs) is defined as any untoward medical occurrence in a subject who has been 
administered a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. AEs include those reported spontaneously by the subject and those noted incidentally 
or as observed by the investigator or study staff. 
Study staff will assess all AEs that occur during the period from signing of consent until end of study 
participation and document these in the source documents.  Investigators will evaluate any changes in 
laboratory values and physical symptoms/signs and will determine if the change is clinically significant. If 
clinically significant and unexpected adverse experiences occur, they will be recorded in the case report 
form (CRF). 
6.2 
 Serious Adverse Events (SAEs) and Serious Adverse Drug Reactions (SADRs)  
A Serious Adverse Event is defined as any untoward medical occurrence that at any dose results in: 
1) Death 
2) A life-threatening situation (subject was at risk of death at the time of the event.  This does not refer 
to an event that might have caused death if it was of greater intensity.) 
3) New in-patient hospitalization or prolongation of an existing hospitalization 
4) Persistent or significant disability or incapacity 
5) Congenital anomaly or birth defect 
6) Important medical events that may not result in death, be life-threatening, or require 
hospitalization but may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the above outcomes (based upon appropriate medical judgment), e.g., allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether other conditions should also be 
considered serious, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above.  These should also be considered serious. Follow up information 
regarding SAEs will be pursued until the event has resolved (with or without sequelae), until death, or until 
30 days after the final study visit (whichever comes first.).  For any deaths where there is uncertainty about 
the cause of death, site investigators may request an autopsy if appropriate.  
6.3 
Reporting Serious Adverse Events (SAE) 
Any SAE, including death due to any cause, which occurs between enrolment and the final follow up visit 
whether or not related to the study drug, must be reported immediately (within 1 business day of the study 
site’s knowledge of the event).  The report will contain as much available information concerning the SAE 
to enable a report to be produced that satisfies regulatory reporting requirements.  
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 
or severe pain); the event itself, however, may be of relatively minor medical significance (such as severe 
headache).   By contrast, the term “serious” is used to describe an event based on an event outcome or 


Page 16 of 19 
 
actions usually associated with events that pose a threat to a subject’s life or functioning.   Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
For all collected SAE’s, the clinician who examines and evaluates the subject will determine the event’s 
causality based on temporal relationship and his/her clinical judgment.  The degree of certainty about 
causality will be graded using the categories below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.  
Probably Related: There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely.  
Possibly Related: There is some evidence to suggest a causal relationship.  However, the influence of other 
factors may have contributed to the event.  
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal relationship to 
drug administration makes a causal relationship improbable and in which other drugs or chemicals or 
underlying disease provides plausible explanations  
Not Related: The SAE is completely independent of study drug administration, and/or evidence exists that 
the event is definitely related to another etiology.  
Pre-existing conditions should be recorded upon patient enrolment (including start date of the condition, 
and severity - mild, moderate, severe).  After the patient signs the informed consent form, any worsening 
of these conditions would be recorded.   
Any new conditions would be recorded including date of onset, date of resolution, severity (mild, moderate, 
severe, or serious as defined above) and possible relationship to study drug or procedure.  As part of the 
source notes, follow up clinical assessments, laboratory tests, ECGs and diagnostic imaging related to 
adverse event should be documented. 
6.4 
Reporting of Serious Unexpected Adverse Drug Reactions (SUADRs) 
The PI (or an authorized representative) is responsible for submitting reports of SUADRs to the 
appropriate regulatory body within the required reporting period.  All investigators participating in 
ongoing clinical studies with the study drug will be notified by the Coordinating Center (or an authorized 
representative) of all SUADRs that require prompt submission to the REB/IRB. Investigators are 
responsible for notifying the REB/IRBs in writing of the SUADRs within the required reporting timelines.  
Copies of the notification will be maintained by the investigator in the study documentation files.  Sites will 
receive detailed reporting guidelines for the SAE reporting process. 
 
 


Page 17 of 19 
 
7 
STATISTICAL ANALYSIS AND SAMPLE SIZE CALCULATION: 
7.1 
Sample Size Estimation 
The goal of this study is to estimate biologically plausible effects as a result of PCSK9 inhibition in a 
population of patients with type 2 diabetes and microvascular dysfunction. As a result, this will be treated 
as a “signal” finding trial – and used as preliminary data to support a formal sample size estimation for a 
larger clinical trial. We anticipate that 40 subjects will be required to provide sufficient data to 
adequately identify robust changes in the large range of  biocellular markers being assessed. 
 
7.2 
Statistical Analysis 
 
As we seek to address both early and late changes in biocellular responses as a result of PCSK9i, we will 
compare changes between week 2 and week 12 with baseline. We will also compare week 2 with week 12 
to identify how the expected rheological changes may impact biocellular responses.  
7.3 
Primary efficacy analysis 
The primary efficacy comparison between groups will be by means of linear regression (ANCOVA model). 
The point estimate of the effect and 95% confidence interval will be obtained, after adjustment for the 
baseline values.The primary analysis will be ITT. These analyses are viewed as complementary or 
exploratory, so the interest will be on the estimated treatment effects more than actual hypothesis tests. 
Protein immunoblots will be analyzed using ImageJ software. Gene expression will be analyzed using 
comparative Ct method (∆∆Ct) and normalized to GAPDH.  
 
 
 


Page 18 of 19 
 
8 
DATA MANAGEMENT 
 
All study data will be stored in an electronic database system, eSOCDAT, which is created and managed by 
SOCAR Research SA. Study personnel needing access will have their own Login/Password. Access to clinical 
study information will be based on individuals' roles and responsibilities.  The application provides 
hierarchical user permission for data entry, viewing, and reporting options. 
 
 
 
 


Page 19 of 19 
 
9 
 REFERENCES: 
 
1. 
Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nature reviews 
Immunology 2015; 15(2): 104-16. 
2. 
Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear 
stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and 
vascular behavior. Journal of the American College of Cardiology 2007; 49(25): 2379-93. 
3. 
Dai G, Kaazempur-Mofrad MR, Natarajan S, et al. Distinct endothelial phenotypes evoked by 
arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human 
vasculature. Proceedings of the National Academy of Sciences of the United States of America 2004; 
101(41): 14871-6. 
4. 
Libby P. Inflammation in atherosclerosis. Nature 2002; 420(6917): 868-74. 
5. 
Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an 
atheroprotective force. Arteriosclerosis, thrombosis, and vascular biology 1998; 18(5): 677-85. 
6. 
Ding Z, Liu S, Wang X, et al. Hemodynamic shear stress via ROS modulates PCSK9 expression in 
human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxidants & redox 
signaling 2015; 22(9): 760-71. 
7. 
Giunzioni I, Tavori H, Covarrubias R, et al. Local effects of human PCSK9 on the atherosclerotic 
lesion. The Journal of pathology 2016; 238(1): 52-62. 
8. 
Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair 
after myocardial infarction. Circulation 2010; 121(22): 2437-45. 
9. 
Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by 
cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012; 220(2): 381-6. 
10. 
Chang HN, Leroueil PR, Selwa K, et al. Profiling inflammatory responses with microfluidic 
immunoblotting. PloS one 2013; 8(11): e81889. 
11. 
Narang A, Mor-Avi V, Bhave NM, et al. Large high-density lipoprotein particle number is 
independently associated with microvascular function in patients with well-controlled low-density 
lipoprotein concentration: A vasodilator stress magnetic resonance perfusion study. Journal of clinical 
lipidology 2016; 10(2): 314-22. 
12. 
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood 
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American 
College of Cardiology 2014; 63(25 Pt B): 2889-934. 
13. 
Bhattacharyya OK, Estey EA, Cheng AY, Canadian Diabetes A. Update on the Canadian Diabetes 
Association 2008 clinical practice guidelines. Canadian family physician Medecin de famille canadien 2009; 
55(1): 39-43. 
 

ICF_001.pdf: 
The Effects of Evolocumab on Endothelial and Inflammatory Biocellular 
Markers in Patients With Diabetes and Atherosclerotic Vascular Disease 
(METCHNIKOFF) 
PI: Robert Rosenson, MD
NCT03829046
Document Date: July 27, 2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 1 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
TITLE OF RESEARCH STUDY:
Title: THE EFFECTS OF EVOLOCUMAB ON ENDOTHELIAL AND INFLAMMATORY BIOCELLULAR 
MARKERS IN PATIENTS WITH MYOCARDIAL MICROVASCULAR DYSFUNCTION
PRINCIPAL INVESTIGATOR (HEAD RESEARCHER) NAME AND CONTACT INFORMATION:
Name: Robert S. Rosenson, MD
Physical Address: 1425 Madison Ave, MC Level, Freedom Trial Office, New York, NY 10029
Mailing Address: One Gustave L. Levy Place, Box 1030, New York, NY 10029
Phone: 212-241-9101
WHAT IS A RESEARCH STUDY?
A research study is when scientists try to answer a question about something that we don’t 
know enough about.  Participating may not help you or others.  
People volunteer to be in a research study.  The decision about whether or not to take part is 
totally up to you. You can also agree to take part now and later change your mind. Whatever 
you decide is okay.  It will not affect your ability to get medical care within the Mount Sinai 
Health System.  
Someone will explain this research study to you. Feel free to ask all the questions you want 
before you decide.  Any new information that develops during this research study that might 
make you change your mind about participating will be given to you promptly.
Basic information about this study will appear on the website http://www.ClinicalTrials.gov.  
There are a few reasons for this:  the National Institutes of Health (NIH) encourages all 
researchers to post their research; some medical journals only accept articles if the research 
was posted on the website; and, for research studies the U.S. Food and Drug Administration 
(FDA) calls "applicable clinical trials” a description of this clinical trial will be available on 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 2 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
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.
PURPOSE OF THIS RESEARCH STUDY:
The purpose of this study is to better understand how blocking one specific protein 
(proprotein convertase subtilisin kinexin 9 or PCSK9) lowers the risk of heart attack and 
stroke. In three large trials of patients with cardiovascular disease, it has been shown that 
blocking the effect of PCSK9 lowered the “bad cholesterol” or LDL cholesterol, and lowered 
the risk of heart attack and stroke. Heart attacks and strokes occur when there is interruption 
of blood flow to the arteries that supply the heart or brain.  Most often, the blood flow is 
interrupted when there is cholesterol buildup in an inflamed artery. Further research is 
needed to determine whether blocking PCSK9 has an effect on inflammation.
Inflammation in the arteries is caused when a certain type of white blood cell, the 
mononuclear cell, moves from the blood stream into the artery.  The movement of white cells 
is controlled by messages sent from the white blood cells to the artery wall. One of the most 
established pathways that direct this movement are the Toll like receptors.  In this study, we 
will examine how these Toll like receptor pathways are changed in people given a Food and 
Drug Administration approved inhibitor of PCSK9.
This study involves treatment of one group with evolocumab (Repatha) and one group with a 
matching placebo for 4 months.  This study has been supported by Amgen, the manufacturer 
of Repatha, through a research grant to the Icahn School of Medicine at Mount Sinai.
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE
Your participation in this research study is expected to last about 16 weeks from the day you 
are enrolled in the study.
The number of people expected to take part in this research study at Icahn School of 
Medicine at Mount Sinai is 100.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 3 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
During your participation, if the primary investigator (head researcher) decides to withdraw 
you from the research study because you experienced an event (such as major bleeding) and 
the event continues, the primary investigator and research study team will follow-up with you 
at least until the cause of the event is determined.  The length of this planned follow-up will 
be determined based on the type of event and other factors as determined by the primary 
investigator. The primary investigator will discuss the details, appropriate length of follow-up, 
and answer any questions that you may have to ensure your safety and understanding.
DESCRIPTION OF WHAT’S INVOLVED:
If you agree to participate in this research study, the following information describes what 
may be involved.
You need come to our site (the address mentioned above), sign this informed consent form.
After you sign the informed consent and pass the initial screening (first visit), the data such as 
your age, gender, medical history and medication use will be recorded. A physical exam, 
ECG, blood pressure measurement, and vital signs will be done. Additionally, blood samples 
will be collected for laboratory tests. Once we received the results of all the tests from the 
screening visit, we will decide your eligibility according to the inclusion and exclusion criteria 
and inform you by phone. The first visit will take about 2 hours, the remaining visits will take 
about one to one and half hour. Here is the detail information of the study visits:
Visit 1: Screening
- Written informed consent
- Demographics
- Medical history
- Vital signs, including heart rate, sitting and standing blood pressure using standardized 
techniques 
- 12-lead ECG – the electrocardiogram will only be done at visit 1.  The ECG  is a test 
that checks for problems with the electrical activity of your heart
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 4 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
- Physical exam – will be a general examination of the major organ systems of your 
body 
- Blood samples for the laboratory tests – about one tablespoon [20 ml] of blood will be 
drawn from your vein for testing complete blood count (CBC), TSH, chemistry, fasting 
lipid profile, and a comprehensive metabolic panel (the tests to make sure that you will 
be safe and eligible to participate in this clinical trial), urine sample will be collected for 
urinalysis and pregnancy test (if female of child bearing potential). Blood samples that 
are collected will be stored in tubes with a unique barcode that will not directly identify 
you.  Some of the blood samples will be analyzed at Mount Sinai while other samples 
will be analyzed at an outside laboratory.  Also, some of your blood samples will be 
stored in -70°C freezer for future analysis and genetic testing. The outside laboratory 
will not have access to any of your personal information, just the unique barcode on 
tube in which your blood was collected.  All laboratories will deliver your results using a 
unique ID number to Dr. Robert S. Rosenson and his research study team in a secure 
and private manner.
- Review for adverse events (AEs)/serious adverse events (SAEs)
- Concomitant therapy (any therapy during the period you participating this trial)
- Dietary instruction; medication compliance reminder 
- Body height, waist circumference
- Body weight
- Seattle Angina Questionnaire 
- Screening placebo injection and 30 minute post-injections observation
Visit 2 (Randomization) 7-28 days after Screening
- Review for AEs/SAEs/cardiovascular (CV) events
- Vital signs
- Concomitant therapy
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 5 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
- Dietary instruction; medication compliance reminder
- Randomization
- Seattle Angina Questionnaire 
- Laboratory assessments: about one tablespoon [20 ml] of blood will be drawn from 
your vein for testing of your blood in order to make sure again that you are safe to 
participate in this trial and to get the baseline of the test before you have the treatment 
of the study medication, including fibrinogen, whole blood viscosity analysis,  
lipoprotein subclass analysis, lipoprotein (a),  biocellular marker analysis.
- DNA/mRNA test for lipoprotein and inflammatory polymorphisms that may influence 
the response to therapy.
- Investigational product (IP, study medication) administration subcutaneously (SC), 
every month (QM) (in-clinic) and 30 minute post-injections observation
Visit 3 (Week 2) ±4 days
- Review for AEs/SAEs/CV events
- Concomitant therapy
- Vital signs
- Dietary instruction; medication compliance reminder
- Seattle Angina Questionnaire 
- Laboratory assessments: about one tablespoon [20 ml] of blood will be drawn from 
your vein for testing hematology, blood chemistry, Liver Function Tests (LFTs), 
fibrinogen, whole blood viscosity analysis, lipoprotein subclass analysis, lipoprotein 
(a), biocellular marker analysis.
Visit 4 (Week 4) ±7 days
- Review for AEs/SAEs/CV events
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 6 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
- Concomitant therapy
- Vital signs
- Dietary instruction; medication compliance reminder
- Seattle Angina Questionnaire 
- SC IP administration, QM (in-clinic) and 30 minute post-injections observation
Visit 5 (Week 8) ±7 days
- Review for AEs/SAEs/CV events
- Concomitant therapy
- Vital signs
- Dietary instruction; medication compliance reminder
- Seattle Angina Questionnaire 
- SC IP administration, QM (in-clinic) and 30 minute post-injections observation
Visit 6 (Week 12) ±7 days
- Body height, waist circumference
- Body weight
- Vital signs
- Review for AEs/SAEs/CV events
- Concomitant therapy
- Seattle Angina Questionnaire 
- Laboratory assessments: about one tablespoon [20 ml] of blood will be drawn from 
your vein for testing hematology, blood chemistry, Liver Function Tests (LFTs), 
fibrinogen, whole blood viscosity analysis, lipoprotein subclass analysis, lipoprotein 
(a), biocellular marker analysis, urine sample will be collected for urinalysis.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 7 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Fasting
You will be asked to fast for at least 9 hours before each of your visits to prepare for your 
blood tests. Fasting means that you have not eaten any food or had a drink (except water) 
before coming to the study site. If you have not been fasting, or if some of the procedures 
cannot be done during the visit for other reasons, you may be asked to return to the study 
site to complete these procedures. The research facility staff will provide you with a schedule 
for when you need to return to the research facility. 
Diet and Exercise
Your doctor will discuss with you how maintaining a “heart healthy” diet is beneficial for 
reducing cardiovascular risk.
Evolocumab Administration
As we mentioned previously, Evolocumab (Repatha) was approved by FDA in 2015 for 
reducing cholesterol by blocking PCSK9 as the PCSK 9 inhibitor. Evolocumab will be given 
by subcutaneous (that is, under the skin) injection. Study drug injections every 4 weeks will 
be with a prefilled 1.0 mL autoinjector/pen (AI/Pen) that will contain the study drug and can 
be used to administer the drug yourself after being trained at the beginning of the trail when 
study team member giving you the injection. Each administration will be 3 injections, using 3 
AI/Pens. 
To help you to remember your study visit appointments and when to take your study drug 
injections, the study site staff may contact you.
The table and schema below showed the information of this clinical trial.
The study treatment you get will be chosen by chance, like flipping a coin. Neither you nor the 
study doctor will choose what study treatment you get. You will have an equal chance of 
being given a placebo medication or a real treatment, placebo is the fake medication which is 
not distinguishable from real medication. Neither you nor the study doctor will know which 
study treatment you are getting. This information could be obtained in an emergency, 
however, you will not be told which study treatment you are getting; only your study doctor 
will know.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 8 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
These study procedures will be performed at each study visit. These procedures involve 
measurement of your weight, blood pressure and pulse rate; collection of blood and urine 
specimens, and investigational product injection.
No.
Description
Electrocardiogram
Lab samples
IP injection
Total Time
Visit 1
Screening
Yes
Yes
Yes (Placebo)
1.5-2 Hrs
Visit 2
Randomization
No
Yes
Yes
 1-1.5 Hr
Visit 3
Week 2
No
Yes
No
 1-1.5 Hr
Visit 4
Week 4
No
No
Yes
 1-1.5 Hr
Visit 5
Week 8
No
No
Yes
 1-1.5 Hr
Visit 6
Week 12
No
Yes
No
 1-1.5 Hr
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 9 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Other Medications
During your participation in this study, you are required to continue taking your cholesterol-
lowering medication (such as a statin), unless a change is clinically necessary. Depending on 
the statin you are taking, there may be restrictions on certain other medicines that you may 
be taking. A Patient Information Leaflet (PIL) with this information will be provided to you by 
the doctor who is prescribing or providing you with your statin (the cholesterol lowering 
medication, such as a statin, will be provided as the routine care by your cardiologist). Since 
statins or other cholesterol lowering medications are not the study medication, you should 
follow your doctor’s instruction of the cholesterol lowering medication (such as the restrictions 
on certain other medications). The only requirement for this study is that you should continue 
taking the cholesterol lowering medication since the study requires a stable treatment for 
cholesterol. 
It is very important that you notify the study doctor what medication you are currently 
receiving or have received in the past. It is also very important that you notify the study doctor 
or the study staff before you take any new medication during the study, including changes to 
your current medications. The dose of any prescription or over-the-counter drugs or 
preparations to lower your cholesterol should not be changed during the entire time that you 
are on the study. However, if your primary care physician prescribes any adjustment in the 
medications that you are taking, you must inform your study doctor.
Birth Control:
For Women:
Since you are participating in a study that involves drugs or investigational treatment with 
potential risks to a developing fetus, it is recommended, for your protection, that you not 
become pregnant for the duration of the study. Also, you should not participate if you are 
breastfeeding. Therefore, practicing effective contraception is important. No individual 
contraceptive is 100% effective. 
Recommended methods of birth control are:

The consistent use of an approved hormonal contraception (birth control pill/patches, 
rings), 

An intrauterine device (IUD), 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 10 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

Contraceptive injection (Depo-Provera), 

Double barrier methods (Diaphragm with spermicidal gel or condoms with 
contraceptive foam), 

Sexual abstinence (no sexual intercourse) or 

Sterilization.
If you have any questions about birth control, your study coordinator or study doctor will be 
able to answer your questions and give you advice.
Should you become pregnant, regardless of the outcome, the sponsor may ask for 
information on your pregnancy, even if you are withdrawn from the study. Your written 
consent will be obtained separately in the case that this happens.
For Men:
Since you are participating in a study that involves drugs or treatment with potential risks to a 
developing fetus, it is recommended that you use a condom and not father a child or donate 
sperm while you are taking the study drug. Also, it is recommended that you use a condom 
and not father a child and/or donate sperm for 90 days after you stop taking the study drug. 
This is because levels of the study drug may be present in the sperm and/or seminal fluid 
even after you stop taking the study drug. Continuing to use a condom and not donating 
sperm during this 90-day period may allow time for any study drug that is still present in 
sperm and/or seminal fluid to be eliminated from your body before you attempt to father a 
child or donate sperm. You are encouraged to tell your female partner(s) and/or their 
doctor(s) that you are participating in a clinical trial.
 Future research:
 
The researchers will not keep information collected about you during this study to use it in 
future research studies. However, the researchers would like to ask your permission to keep 
specimens (blood sample) collected from you during this study to use them in future research 
studies. They would also like to know your wishes about how they might use your specimens in 
future research studies. You should also know that it is possible that products may someday be 
developed with the help of your specimens, and there are no plans to share any profits from such 
products with you. 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 11 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
(1) Will you allow the researchers to store your specimens to use in future research studies? 
Yes_________ No__________
If no, please stop here. If yes, please continue to the next question.
 
(2) The researchers can keep your specimens stored in one of two different ways: one way will 
store your specimens in a way that it is linked to your identity (through the use of a code that can 
indicate the information came from you personally) and the other way will store your specimens 
anonymously (no one will know who the information is from). It will not be stored both ways, so 
you must choose one of these two options. Please note that if you choose to have your 
specimens stored anonymously, you will not be able to change your mind to ask for your 
specimens to be destroyed at a future date. 
How would you like your specimens stored? Please initial ONE choice: 
I would like my specimens stored with a link to my identity___________ 
I would like my specimens stored anonymously _____________ 
(3) Do you give the researchers permission to contact you in the future to collect additional 
information about you, discuss how your specimens might be used, or to discuss possible 
participation in another research project? Please initial your choice: 
Yes_________ No__________
(4) Do you give the researchers permission to keep the specimens indefinitely and use them for 
future studies that are directly related to the purpose of the current study? Please initial your 
choice: 
Yes_________ No__________ 
(5) Do you give the researchers permission to keep the specimens indefinitely and use them for 
future studies that are not related to the purpose of the current study (for example, a different 
area of research)? Please initial your choice: 
Yes_________ No__________ 
(a) If the future research in a different area can be done without having to know that the 
specimens came from you personally, that will be done. 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 12 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
(b) If the future research in a different area requires that it is known specifically who the 
specimens came from, then one of the following will be done: 
(i) If you allowed the researchers to contact you in the future, they will be able to contact you to 
explain why your specimen is needed and what will be done with it. Your permission will be asked 
to use your specimens in that research project. 
(ii) If you do not give permission to be contacted in the future, or if it is found that contacting you 
is not practical, for example, because you have moved, your specimens may still be used. Either 
all links to your identity will be removed from the specimens, or an Institutional Review Board will 
be asked for permission to use the specimens linked to your identity. The Institutional Review 
Board (IRB) is a committee of doctors and scientists and non-scientists and people not 
associated with this hospital or medical school whose job it is to protect people who participate in 
research. The IRB can give permission for researchers to use and share health information 
connected to specimens that are linked to people’s identities, but only if it determines that doing 
this will not be more than a minimal risk to people or their privacy. 
(6) Your specimens will not be given to other researchers at Mount Sinai or other institutions for 
any use in research that is either related or not related to the purpose of this study.
 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH:
If you decide to take part in this research study you will be responsible for the following 
things:
1. Attend the scheduled visits
2. Take study drugs
3. Take the study tests at Mount Sinai
4. Tell the study doctor and research study team about any other medicines that you are 
taking
5. Agree to complete research study surveys if you are asked
6. Agree to have the health diet and excise as the study team discussed with you.
7. Agree to participate in follow-up and data collection for the remainder of the study, 
including the study doctor collecting information regarding study related health 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 13 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
information from available sources such as medical records and outside hospitals and 
care providers
8. In the event, that you have a serious or emergency medical treatment, have concerns, 
and/or side-effects, you will tell the study doctor and/or research study team.
9. Agree to use birth control while participating in the study, and in the event that you 
learn that you or your partner is pregnant, you will stop using the study drug and 
contact the study doctor and/or research study team as soon as possible.
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION:
You will not be paid for participating in this research study. Being in this research study will 
not lead to extra costs to you.
Taking part in this research study will not lead to added costs to you. You will receive study 
medications and the medical testing needed for this study at no cost.  There are no costs to 
you or your insurance for study medications and study procedures. Lab tests and 
medications will all be provided at no cost to you.  However, if your study doctor arranges for 
you to have additional medical tests which are not part of the study but are needed for your 
regular healthcare or usual care, you may have to pay for these if they are not covered by 
your government’s health plan or your private insurance.  
If you agree to take part in this research study, we will pay you $75 per visit to cover travel 
expenses and for your time and effort. Reimbursement will be paid by check and the payment 
process will take approximately 4 to 6 weeks.  Checks require some time to be prepared and 
will be given to you as available. The total amount of the reimbursement will be $450 if you 
complete all the six study visits.
Tax law may require the Mount Sinai Finance Department to report the amount of payment 
you receive from Mount Sinai to the Internal Revenue Service (IRS) or other agencies, as 
applicable.  Generally, this reporting would take place if you receive payments that 
equal $600 or more from Mount Sinai in a calendar year.  You would be responsible for the 
payment of any tax that may be due.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 14 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
POSSIBLE BENEFITS:
No one knows if participation in this study will help you. Your condition may get better if you 
are signed in the treatment group since evolocumab was approved by FDA in 2015 as a lipid 
regulating medication. However, since you have the chance to be assigned to the placebo 
group, your condition could stay the same or even get worse. The information from this study 
might help in the development of additional treatments in the future for cardiovascular 
disease.
You may have possible benefit for LDL reduction if you are randomized into real treatment 
group.  
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS:
a. Are there any risks from taking part in this study?
There may be risks to being in this study, from the study drug (evolocumab), from the 
device(s) used to deliver evolocumab (1.0 mL prefilled autoinjector/pen [AI/Pen]), or from 
some of the procedures or tests done in this study. Also, your condition may get better but it 
could stay the same or even get worse.
If you participate in this study, you or your family members should tell the study doctor or the 
study staff immediately if you have any unusual health problems, injuries, or side effects, 
even if you do not think these problems are caused by the study, or evolocumab, or the 
device(s).
If there is any new important safety information or other information that could affect your 
willingness to participate in this study, the study doctor will let you know.
b. What are the likely risks with evolocumab?
Evolocumab may cause all, some, or none of the side effects listed below. These side effects 
can be mild but could also be serious, life threatening, or even result in death. You may also 
experience an allergic reaction that has not been seen before.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 15 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
As of July 2016, approximately 22,000 study participants have received evolocumab in 
research studies and, approximately 44,000 patients have been prescribed evolocumab by 
their doctors. Evolocumab (Repatha®) was approved for sale in July 2015.
Side effects that people have had in research studies that are thought to have been caused 
by evolocumab are:
Common side effects (which may affect between 1 and 10 people in every 100):
• 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 side effects (which may affect between 1 and 10 people in every 1000):
• Hives (urticaria)
Potential side effects with evolocumab reported from research studies:
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. There are people with a very rare 
inherited condition who lack the PCSK9 protein (the protein that evolocumab blocks) and 
have very low cholesterol levels in their blood. These people appear to be healthy.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 16 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
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, 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 or even result in death.
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.
Blood tests will be used to check for such anti-evolocumab antibodies during the study.
c. What are the risks of using evolocumab in combination with other drugs?
Tell the study doctor or the study staff about any drugs you are taking, have recently taken or 
are planning to take, including herbal remedies, supplements, experimental therapies, and 
drugs you take without a prescription. The side effects of using evolocumab in combination 
with other drugs are unknown at this time. Please discuss any concerns you may have with 
the study doctor.
d. What are the risks of taking the other drugs required by this study?
The following drugs are not being studied by Amgen, but you are required to take them as 
part of this study. These drugs are often used to treat your condition as standard of care. The 
study doctor will talk with you about the risks of taking these drugs.
Cholesterol-lowering medications
It is recommended that you continue taking the same cholesterol-lowering medication, such 
as a statin, for the duration of this study. Cholesterol-lowering medications, such as a statin, 
are not being studied by Amgen but are often used to treat your condition. The study doctor 
will talk with you about the risks of taking cholesterol-lowering medications (such as a statin).
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 17 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
e. What are the risks associated with procedures done in this study?
The known risks and side effects of study related tests or procedures (listed in Section 2) are 
noted here.
Fasting
You will need to be fasting (not eating or drinking anything except water) for at least 9 hours 
before each of your visits to prepare for your blood tests. Possible side effects of fasting are 
feeling weak, hungry, sweaty, nervous or restless.
Blood draws
You will have your blood drawn during the study. Possible side effects of having blood drawn 
are tenderness, pain, bruising, bleeding, and/or infection where the needle goes into the skin 
and blood vein. Having your blood drawn may also cause you to feel nauseated and/or 
lightheaded.
f. What are the risks associated with the prefilled AI/Pen used to give evolocumab into 
the tissue below your skin?
If you agree to participate in this study, a prefilled AI/Pen will be used to inject evolocumab 
into the soft tissue below your skin.
When using the prefilled AI/Pen, you may experience all, some, or none of the following 
every time after you having the IP administration:
• Pain or discomfort at the injection site during or after the injection
• Bleeding, bruising, redness, warmth, itching, swelling, or firmness of the skin near the 
injection site
• Infection at the injection site
When using the prefilled AI/pen, you may experience the following:
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 18 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
• An allergic reaction to the dry natural rubber in a specific part of the prefilled AI/pen. The 
needle cover contains dry natural rubber, (which is derived from latex). Tell your study doctor 
or the study staff if you are allergic to latex.
It is possible that the AI/pen will not work properly during the injection. If this occurs, it is 
possible that you could receive an incomplete dose or even no dose at all of evolocumab. 
Contact your study doctor immediately if you believe that your AI/pen used to administer 
evolocumab did not work properly during the injection.
g. What if you become pregnant, breastfeed, or father a child during the sudy?
Please notify the study doctor if you become pregnant, or breastfeed (nurse), or father a child 
while you are taking evolocumab because further information may be asked of you (the study 
doctor will discuss the details with you).
h. Could evolocumab be harmful to an unborn or breastfed baby?
It is not known if evolocumab is harmful to an unborn or breastfed baby.
If you become pregnant during this study and within 15 weeks after stopping evolocumab, 
potential risks could include complications such as a miscarriage (loss of the pregnancy) or 
birth defects.
Female Participants
Pregnant or breastfeeding (nursing) women, and women planning to become pregnant or 
breastfeed, should not participate in this study.
If you are unable to become pregnant for one of the following reasons, the use of birth control 
methods is not required during this study:
• Your healthcare provider has confirmed that you are postmenopausal
• You have had your uterus, or both ovaries, or both fallopian tubes removed
If you could become pregnant, you:
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 19 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
• Must agree to use an acceptable method of effective birth control during treatment and for 
an additional 15 weeks after the last dose of evolocumab
• Must discuss your pregnancy prevention method with the study doctor to ensure it is 
acceptable. You should be aware that true sexual abstinence is the only 100% effective 
method of birth control
Acceptable Methods of Effective Birth Control for Female Participants include:
o Hormonal methods of birth control (combined estrogen and progestogen or progestogen-
only): pills, shots/injections, implants (placed under the skin by a healthcare provider), vaginal 
rings, or skin patches
• Intrauterine device (IUD)
• Intrauterine hormonal-releasing system (IUS)
• Surgery to tie both fallopian tubes (bilateral tubal ligation/occlusion)
• Your male partner has had a vasectomy and testing shows there is no sperm in the semen
• Sexual abstinence (not having sex)
o Double barrier method: the male uses a condom and the female may choose either a 
cervical cap, diaphragm, or contraceptive sponge with spermicide (a female condom is not an 
option due to the risk of tearing when both partners use a condom).
Unacceptable methods of contraception include: 
Periodic abstinence (calendar), withdrawal, or spermicides only.
It is not known if evolocumab is transferred into breast milk. If you are breastfeeding (nursing) 
and wish to be in this study, you will be required to discontinue breastfeeding (nursing) during 
treatment with evolocumab and for an additional 15 weeks after the end of treatment with 
evolocumab.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 20 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Male Participants
Male participants are not required to use birth control during treatment with evolocumab. 
However, you should let your female partner know that you are in this study. Based on long-
term monkey data, evolocumab does not damage sperm. Based on human data with a 
different monoclonal antibody, the concentration of evolocumab in semen is expected to be 
so low it will not harm your partner or unborn baby.
Female and Male Participants
The pregnancy, breastfeeding (nursing), and birth control information in this document is 
specific to evolocumab. There may be additional risks to an unborn child or breastfed baby 
from other drugs, such as statins, that you may receive during the study. This may require 
that you change the type and/or length of time that you must use birth control or length of 
time that you must avoid breastfeeding (nursing). Please discuss this with the study doctor.
i. What if you become pregnant or breastfeed during the study?
If you decide to participate in this study, you must agree to not become pregnant or 
breastfeed (nurse).
If you think you are pregnant, or accidentally become pregnant or breastfeed (nurse) during 
treatment with evolocumab and for an additional 15 weeks after stopping evolocumab, you 
must tell the study doctor or the study staff right away. Treatment with evolocumab may be 
stopped. The study doctor will notify Amgen of the pregnancy or that you are breastfeeding 
(nursing). You will be asked to provide information on the pregnancy or breastfeeding 
(nursing) outcome for you and the baby.
j. What if your partner becomes pregnant during the study?
If your partner becomes pregnant during treatment with evolocumab and for an additional 15 
weeks after stopping evolocumab, you must tell the study doctor or the study staff as soon as 
possible.
The study doctor will notify Amgen of the pregnancy and ask to obtain information on the 
pregnancy outcome for both the mother and baby.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 21 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
There is a Federal law called the Genetic Information Nondiscrimination Act (GINA). In 
general, this law makes it illegal for health insurance companies, group health plans, and 
most employers of over 15 people to discriminate against you based on your genetic 
information. However, it does not protect you against discrimination by companies that sell 
life insurance, disability insurance, or long-term care insurance.
OTHER POSSIBLE OPTIONS TO CONSIDER:
You may decide not to take part in this research study without any penalty.  The choice is 
totally up to you.
If you decide not to participate, this will not affect your ability to receive medical care at Mount 
Sinai or to receive any benefits to which you are otherwise entitled. You still will get the 
standard care for coronary heart disease and lipid reduction.
Your primary doctor or study doctor can explain other treatments that are available.
Optimal medical therapy for the prevention of cardiovascular events in CAD patients includes 
treatment with aspirin and/or other lipid regulating medication, such as Statins. It also 
includes the procedures of re-vascularization or treatment with Evolocumab (Repatha®), a 
FDA approved drug in 2015 which is available even if you decide not to participate in this 
study. This is the same medication used in this study for reducing cholesterol by blocking 
PCSK9 as the PCSK 9 inhibitor. 
IN CASE OF INJURY DURING THIS RESEARCH STUDY:
If you believe that you have suffered an injury related to this research as a participant in this 
study, you should contact the Principal Investigator. 
If you are injured or made sick from taking part in this research study, medical care will be 
provided. The sponsor will reimburse your reasonable and necessary medical expenses for 
diagnosis and treatment of a research-related injury or illness.
This does not prevent you from seeking payment for injury related to malpractice or 
negligence. Contact the investigator for more information.
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 22 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
By agreeing to the above, you do not waive any of your legal rights which you otherwise 
would have as a research subject, nor do you release Amgen, study doctors, or the hospital 
from liability for negligence.
ENDING PARTICIPATION IN THE RESEARCH STUDY:
You may stop taking part in this research study at any time without any penalty. This will not 
affect your ability to receive medical care at any of the Mount Sinai Health System hospitals 
or to receive any benefits to which you are otherwise entitled.
If you decide to stop being in the research study, please contact the Principal Investigator or 
the research staff.  You should not stop taking the study medication without talking to the 
Principal Investigator first.  If you decide to stop being in the research study, you should be 
aware that people who stop taking the study medication may have a higher risk of getting a 
blood clot or having a heart attack.  The study doctor will instruct you as to what you should 
do.  
If you decide to stop being in the research study, already collected information may not be 
removed from the research study database and will continue to be used to complete the 
research analysis.  You may be asked whether the investigator can collect information from 
your routine medical care. If you agree, this data will be handled the same as research data. 
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page.
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page. Even if you withdraw your permission, the Principal Investigator for 
the research study may still use the information that was already collected if that information 
is necessary to complete the research study. Your health information may still be used or 
shared after you withdraw your authorization if you have an adverse event (a bad effect) from 
participating in the research study.
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop 
your involvement in this research study at any time without your consent. This may be 
because the research study is being stopped, the instructions of the study team have not 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 23 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
been followed, the investigator believes it is in your best interest, or for any other reason. If 
specimens or data have been stored as part of the research study, they too can be destroyed 
without your consent. The study doctor will make the decision and let you know if it is not 
possible for you to continue in the study. 
CONTACT PERSON(S):
If you have any questions, concerns, or complaints at any time about this research, or you 
think the research has hurt you, please contact the office of the research team and/or the 
Principal Investigator at phone number Dr. Robert S. Rosenson at telephone number 212-
241-9101. If you experience an emergency during your participation in this research, contact 
Dr. Robert S. Rosenson at telephone number 212-241-9101.  You may also call 911 or go to 
the emergency room.
This research has been reviewed and approved by an Institutional Review Board. You may 
reach a representative of the Program for Protection of Human Subjects at the Icahn School 
of Medicine at Mount Sinai at telephone number (212) 824-8200 during standard work hours 
for any of the reasons listed below. This office will direct your call to the right person within 
the Mount Sinai Health System:

Your questions, concerns, or complaints are not being answered by the research 
team.

You cannot reach the research team.

You are not comfortable talking to the research team.

You have questions about your rights as a research subject.

You want to get information or provide input about this research.
DISCLOSURE OF FINANCIAL INTERESTS:
Sometimes, physicians/researchers receive payments for consulting or similar work 
performed for industry.  Effective September 2014 Mount Sinai reviews only payments to an 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 24 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
individual totaling more than $5,000 a year per entity when determining potential conflicts of 
interest.  If you have questions regarding industry relationships, we encourage you to talk 
your physician/researcher or visit our website at http://icahn.mssm.edu/ where Mount Sinai 
publicly discloses the industry relationships of our faculty. 
The company sponsoring this research study manufactures the drug/device being tested and 
so has a financial interest that could be affected by the outcome of this research study.
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION:
As you take part in this research project it will be necessary for the research team and others 
to use and share some of your private protected health information. Consistent with the 
federal Health Insurance Portability and Accountability Act (HIPAA), we are asking your 
permission to receive, use and share that information.
What protected health information is collected and used in this study, and might also be 
disclosed (shared) with others?
As part of this research project, the research team at the hospital(s) involved in the research 
will collect your Name, Address and Telephone number.
The researchers will also get information from your medical record from Mount Sinai Medical 
Center and your referring physicians. 
During the study the researchers will gather information by:

taking a medical history (includes current and past medications or therapies, illnesses, 
conditions or symptoms, family medical history, allergies, etc.)

doing a physical examination that generally also includes blood pressure reading, 
heart rate, breathing rate and temperature

completing the tests, procedures, questionnaires and interviews explained in the 
description section of this consent.
Why is your protected health information being used?
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 25 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Your personal contact information is important to be able to contact you during the study. 
Your health information and the results of any tests and procedures being collected as part of 
this research study will be used for the purpose of this study as explained earlier in this 
consent form. The results of this study could be published or presented at scientific meetings, 
lectures, or other events, but would not include any information that would let others know 
who you are, unless you give separate permission to do so.
The Principal Investigator may also use and share the results of these tests and procedures 
to treat you in collaboration with others in the Mount Sinai Health System. 
The research team and other authorized members of The Mount Sinai Health System 
(“Mount Sinai”) workforce may use and share your information to ensure that the research 
meets legal, institutional or accreditation requirements. For example, the School’s Program 
for the Protection of Human Subjects is responsible for overseeing research on human 
subjects, and may need to see your information. If you receive any payments for taking part 
in this study, the Mount Sinai Finance Department may need your name, address, social 
security number, payment amount, and related information for tax reporting purposes.  If the 
research team uncovers abuse, neglect, or reportable diseases, this information may be 
disclosed to appropriate authorities. 
Who, outside Mount Sinai, might receive your protected health information?
As part of the study, the Principal Investigator, study team and others in the Mount Sinai 
workforce may disclose your protected health information, including the results of the 
research study tests and procedures, to the following people or organizations: (It is possible 
that there may be changes to the list during this research study; you may request an up-to-
date list at any time by contacting the Principal Investigator.)
-
Outside laboratory who will be performing laboratory analysis for all the research 
centers involved in this project: LabCorp and Rheovector, LLC 
-
The commercial sponsor and/or their representative (who will use the results for 
submissions to the Food and Drug Administration): Amgen, and its Affiliates, which are 
located around the world A Data Safety Monitoring Board or other committee that will 
monitor the study on an ongoing basis for safety.
-
The United States Food and Drug Administration
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 26 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
-
The United States Department of Health and Human Services and the Office of 
Human Research Protection.
In all disclosures outside of Mount Sinai, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier unless disclosure 
of the direct identifier is required by law. Some records and information disclosed may be 
identified with a unique code number. The Principal Investigator will ensure that the key to the 
code will be kept in a locked file, or will be securely stored electronically. The code will not be 
used to link the information back to you without your permission, unless the law requires it, or 
rarely if the Institutional Review Board allows it after determining that there would be minimal 
risk to your privacy. It is possible that a sponsor or their representatives, a data coordinating 
office, a contract research organization, may come to inspect your records. Even if those 
records are identifiable when inspected, the information leaving the institution will be stripped 
of direct identifiers.  Additionally, when applicable, the monitors, auditors, the IRB, the Office 
of Human Subjects Protection (OHRP) of the Department of Health and Human Services as 
well as the Food and Drug Administration (FDA) will be granted direct access to your medical 
records for verification of the research procedures and data. OHRP and FDA are authorized 
to remove information with identifiers if necessary to complete their task. By signing this 
document you are authorizing this access. We may publish the results of this research. 
However, we will keep your name and other identifying information confidential.
For how long will Mount Sinai be able to use or disclose your protected health information?
The sponsor may use and share your PHI for internal reference, for comparison with other 
data, to help design subsequent trials, and in papers submitted to United States and/or 
foreign regulatory agencies regarding later-developed products. Your authorization for use of 
your protected health information for this specific study does not expire.
Will you be able to access your records?
During your participation in this study, you will not be able to access your medical records. 
This will be done to prevent the knowledge of study results from affecting the reliability of the 
study. Your information will be available should an emergency arise that would require your 
treating physician to know this information to best treat you. You will have access to your 
medical record and any study information that is part of that record when the study is over or 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 27 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
earlier, if possible. The investigator is not required to release to you research information that 
is not part of your medical record.
Do you need to give us permission to obtain, use or share your health information?
NO! If you decide not to let us obtain, use or share your health information you should not 
sign this form, and you will not be allowed to volunteer in the research study. If you do not 
sign, it will not affect your treatment, payment or enrollment in any health plans or affect your 
eligibility for benefits.
Can you change your mind?
You may withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page. Even if you withdraw your permission, the Principal Investigator for 
the research study may still use your protected information that was already collected if that 
information is necessary to complete the study. Your health information may still be used or 
shared after you withdraw your authorization if you should have an adverse event (a bad 
effect) from being in the study. If you withdraw your permission to use your protected health 
information for research that means you will also be withdrawn from the research study, but 
standard medical care and any other benefits to which you are entitled will not be affected. 
You can also tell us you want to withdraw from the research study at any time without 
canceling the Authorization to use your data.
If you have not already received it, you will also be given The Hospital’s Notice of Privacy 
Practices that contains more information about how The Hospital uses and discloses your 
protected health information.
It is important for you to understand that once information is disclosed to others outside 
Mount Sinai, the information may be re-disclosed and will no longer be covered by the federal 
privacy protection regulations. However, even if your information will no longer be protected 
by federal regulations, where possible, Mount Sinai has entered into agreements with those 
who will receive your information to continue to protect your confidentiality.
If as part of this research project your medical records are being reviewed, or a medical 
history is being taken, it is possible that HIV-related information may be revealed to the 
researchers.  If that is the case, the following information concerns you.  If this research does 
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 28 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
not involve any review of medical records or questions about your medical history or 
conditions, then the following section may be ignored.  
_________________________________________________________________________________
Notice Concerning HIV-Related Information
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law.  You also have a right to request a list of people who may receive or 
use your HIV-related information without authorization.  If you experience discrimination because of the 
release or disclosure of HIV-related information, you may contact the New York State Division of Human 
Rights at (888) 392-3644 or the New York City Commission on Human Rights at (212) 306-5070.  These 
agencies are responsible for protecting your rights.
_____________________________________________________________________________________
Effective Date: 7/27/2021
End Date:7/26/2022


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai
Page 29 of 29
Study ID #: Study-18-00678
Form Version Date: 02 Jul 2021
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Signature Block for Capable Adult
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you.
Signature of subject
Date 
Printed name of subject
Time
 [required if used for FDA 
documentation purposes]
Person Explaining Study and Obtaining Consent 
Signature of person obtaining consent
Date 
Printed name of person obtaining consent
Time 
Witness Section: For use when a witness is required to observe the consent process, 
document below (for example, subject is illiterate or visually impaired, or this accompanies a 
short form consent):
My signature below documents that the information in the consent document and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that consent was freely given by the subject.
Signature of witness to consent process
Date 
Printed name of person witnessing consent process
Time 
Effective Date: 7/27/2021
End Date:7/26/2022