Evaluation of WSS and Neointimal Healing Following Percutaneous Coronary Intervention of Angulated Vessels With Resolute® Integrity Zotarolimus Eluting Coronary Stent Compared to XIENCE Xpedition® Everolimus Eluting Coronary Stent
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: Emory University

 
 
 
 
 
Evaluation of Wall Shear Stress and Neointimal Healing 
Following Percutaneous Coronary Intervention of 
Angulated Vessels with Resolute® Integrity Zotarolimus 
Eluting Coronary Stent Compared to XIENCE XPEDITION® 
Everolimus Eluting Coronary Stent 
(SHEAR-STENT Study) 
NCT02098876 
 
 
Date: September 4, 2020 
IRB number: 00066353 

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
1
Evaluation of Wall Shear Stress and Neointimal Healing 
Following Percutaneous Coronary Intervention of 
Angulated Vessels with Resolute® Integrity Zotarolimus 
Eluting Coronary Stent Compared to XIENCE XPEDITION® 
Everolimus Eluting Coronary Stent 
(SHEAR-STENT Study)
Protocol
CONFIDENTIAL
NOT FOR DISSEMINATION

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
2
Table of Contents
STUDY LOCATIONS........................................................................................................................................................3
INVESTIGATORS ............................................................................................................................................................3
RATIONALE ...................................................................................................................................................................6
SPECIFIC AIM: ........................................................................................................................................................................7
HYPOTHESES:.........................................................................................................................................................................7
DESIGN .........................................................................................................................................................................7
METHODOLOGY: ....................................................................................................................................................................9
1. Angiography and Percutaneous Coronary Intervention.............................................................................................9
2. Angiographic assessment of angulation....................................................................................................................9
3. Intravascular Imaging................................................................................................................................................9
4. Wall Shear Stress Calculations.................................................................................................................................10
PATIENT SELECTION ..............................................................................................................................................................11
STUDY ENDPOINTS................................................................................................................................................................12
STATISTICS...........................................................................................................................................................................13
DURATION OF STUDY.............................................................................................................................................................13
FOLLOW-UP.........................................................................................................................................................................13
DATA MANAGEMENT............................................................................................................................................................14
RECORDING DATA.................................................................................................................................................................14
Source Documents .......................................................................................................................................................15
Confidentiality of Data.................................................................................................................................................15
Data and Document Retention ....................................................................................................................................15
Amendment to Study Forms ........................................................................................................................................16
DEVIATIONS FROM CLINICAL STUDY PLAN.................................................................................................................................16
MONITORING AND REPORTING ...............................................................................................................................................16
EMERGENCY CONTACT...........................................................................................................................................................17
PUBLICATIONS......................................................................................................................................................................17
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL STUDY.............................................................................................17
RESUMING THE CLINICAL STUDY AFTER TEMPORARY SUSPENSION.................................................................................................18
REFERENCES................................................................................................................................................................19

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
3
Study Locations
Emory University Hospital (Atlanta, GA), Hospital Clinico San Carlos (Madrid, Spain), Seoul National University College of 
Medicine (Seoul, S. Korea), Keimyung University Dongsan Medical Center (Daegu, S. Korea), Ulsan University Hospital - 
University of Ulsan College of Medicine (Dong-gu, S. Korea), Wakayama Medical University (Wakayama, Japan), Kobe 
University (Kobe, Japan), Clinical Center of Serbia (Belgrade, Serbia), Nanjing Medical University (Nanjing, China), 
Samsung Medical Center (Seoul, S. Korea), Kyushu Medical Center (Fukuoka, Japan), Teikyo University (Tokyo, Japan), 
New Tokyo Hospital (Tokyo, Japan), University of Latvia, (Riga, Latvia)
Investigators
Primary Principal Investigator:
Habib Samady, M.D., F.A.C.C., F.S.C.A.I.
Professor of Medicine
Director, Cardiac Catheterization Laboratory
Emory University Hospital
Director, Interventional Cardiology 
Emory University School of Medicine
Atlanta, GA
Tel: (404) 727 7424; Fax: (404) 712 7102
Email: hsamady@emory.edu
Co-Principal Investigators:
Marco A. Costa, M.D., Ph.D., F.A.C.C., F.S.C.A.I.
Director, Center for Research & Innovation, UH Case 
Medical Center
Case Western Reserve University
Cleveland, OH
Tel: 216-368-4737; Fax: 216-368-3959
E-mail: marco.costa@case.edu
Bon-Kwon Koo, M.D., Ph.D.
Seoul National University College of Medicine 
101 Daehang-ro, Chongno-gu, Seoul, 110-744, Korea 
Tel: 82-2-2072-2062(office), 82-2-2072-2677(cath lab) 
Fax: 82-2-3675-0805
Email: bkkoo@snu.ac.kr orbkk1214@gmail.com
Co-Investigators:
Michael Ragosta III, M.D., F.A.C.C., F.S.C.A.I.
Professor of Medicine/Cardiology 
Director, Cardiac Catheterization Laboratories
Division of Cardiovascular Medicine 
University of Virginia Medical Center, Charlottesville, VA 
Tel: (434) 924-2420; Fax: (434) 924-2581
Email: mragosta@virginia.edu
Don P. Giddens, Ph.D.
Dean, College of Engineering
Lawrence L. Gellerstedt, Jr. Chair in Bioengineering
Georgia Research Alliance Eminent Scholar
Georgia Institute of Technology, Atlanta, GA
Tel: (404) 894 1323; Fax: (404) 894 0168
Email: don.giddens@coe.gatech.edu
Alessandro Veneziani, Ph.D.
Associate Professor
Math & Computer Science Department
Emory University, Atlanta, GA
Tel: (404) 727-7925
Email: avenez2@emory.edu
Girum E. Mekonnen, M.D., M.P.H.
Cardiology Fellow
Division of Cardiology
Emory University School of Medicine, Atlanta, GA
Tel: (404) 712 0996
Email: gmekonnen@emory.edu
Olivia Y. Hung, M.D., Ph.D.
Cardiology Fellow
Division of Cardiology
Emory University School of Medicine, Atlanta, GA
Tel: (404) 712 1655
Email: ohung@emory.edu
Javier Escaned, M.D.
Hospital Clinico San Carlos
Cardiovascular Institute
28040 Madrid, Spain
Email: escaned@secardiologia.es

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
4
Chang-Wook Nam, MD
Keimyung University Dongsan Medical Center
Daegu, S. Korea
Email: namcwcv@gmail.com
Ki-Bum Won, MD
Ulsan University Hospital, 
University of Ulsan College of Medicine
Dong-gu, S. Korea
Email: sesim1989@gmail.com,ses@uuh.ulsan.kr
Takashi Akasaka, M.D.
Department of Cardiovascular Medicine, 
Wakayama Medical University, 811-1
Kimiidera, Wakayama, 641-8509, Japan. 
Email akasat@wakayama-med.ac.jp
Hiromasa Otake, M.D., Ph.D.
Division of Cardiovascular and Respiratory Medicne
Kobe University
Kobe, Japan
Email: hiro_yuki15@yahoo.co.jp or hotake@med.kobe-u.ac.jp
Goran Stankovic, M.D.
Department of Cardiology
Clinical Center of Serbia
Visegradska 26
11000 Belgrade, Serbia
Email: goranstan@gmail.com
Shao-Liang Chen, M.D.
Director of Cardiology and Cath Lab, Nanjing First Hospital
Vice President of Nanjing First Hospital, Nanjing Medical 
University,
Professor of Internal Medicine and Cardiology, Nanjing Medical 
University
Tel (office):+86-25-52208048
     (mobile):+86-13605157029, +86-18951670878
Fax: +86-25-52208048
E-Mail: chmengx@126.com
Andrejs Erglis, MD
University of Latvia
Raiņa bulvāris 19, Centra rajons, Rīga, LV-1586, Latvia
E-mail: sjegere@gmail.com
Joo-Myung Lee, MD
Assistant Professor
Division of Cardiology, Department of Internal Medicine, 
Heart Vascular Stroke Institute,
Samsung Medical Center, Sungkyunkwan University 
School of Medicine,
50, Irwon-dong, Gangnam-gu, Seoul 135–710, Republic 
of Korea
C.P; 82-10-8884-8439, Tel; 82-2-3410-3391, Fax; 82-2-
3410-6278
E-mail: drone80@hanmail.net, drone23564@gmail.com, 
joomyung.lee@samsung.com 
Yoshinobu Murasato, MD
Director of Department of Cardiology, Cardiovascular 
Center, Kyushu Medical Center,
1-8-1, Jigyohama, Chuo, Fukuoka, 810-8563, Japan
Phone: +81-92-852-0700, Fax: +81-92-847-8802
E-mail:y.murasato@gmail.com
Yusuke Watanabe, MD
Teikyo University
E-mail: yusuke0831@gmail.com 
Sunao Nakamura, MD
New Tokyo Hospital
E-mail: boss0606@pluto.plala.or.jp

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
5

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
6
Evaluation of Wall Shear Stress and Neointimal Healing Following Percutaneous 
Coronary Intervention of Angulated Vessels with Resolute® 
IntegrityTMZotarolimus Eluting Coronary Stent Compared to XIENCE XPEDITION® 
Everolimus Eluting Coronary Stent (SHEAR-STENT Study)
Rationale
After approval of the Resolute Integrity® Zotarolimus drug-eluting stent (R-ZES) in February 2012 by 
the U.S. Food and Drug Administration, it and the Abbott Vascular’s XIENCE XPEDITION® 
Everolimus drug-eluting stent (X-EES) are expected to be market share leaders. A recent head-to-
head trial (Resolute All Comers Trial) comparing these two stents demonstrated non-inferiority of R-
ZES to X-ESS for the primary endpoint of target lesion failure at 12 months (8.2% and 8.3%, 
respectively, p< 0.001 for non-inferiority) with a non-significantly higher rate of stent thrombosis of R-
ZES compared with X-EES (2.3% vs. 1.5%, respectively; p = 0.17)1. The non-inferiority of the R-ZES 
to X-EES has been reconfirmed in real-world patients by the TWENTE Trial2. While such studies 
provide significant empirical data on the clinical performance and safety of the new R-ZES compared 
with X-ESS1, 3, 4, they do not offer insight into the possible mechanisms relating to early and late stent 
healing that can drive clinical adverse outcomes.
Although drug-eluting stents (DES) have significantly reduced restenosis rates5-10, concerns of late 
stent thrombosis (LST) and timing of re-endothelialization persist11-13. Numerous mechanisms have 
been implicated in the cause for LST, including several aspects of stent design14-17. While the elution 
characteristics of the R-ZES are similar to X-ESS, the BioLinx tri-polymer coating of R-ZES may be 
more biocompatible than the X-EES polymer and preclinical porcine models have demonstrated 
reduced inflammatory scores with R-ZES18. Furthermore, the altered biomechanical environment 
post-stenting (e.g., hemodynamics, arterial straightening) can significantly affect the recovery time of 
endothelial structure and function16, 19. 
The deployment of a stent in an artery significantly affects the near-wall flow patterns, as well as the 
overall flow patterns in the artery17, 20-22. Specifically, the protrusion of the stent strut into the lumen 
results in flow separation and the formation of recirculation zones or eddy currents both proximal and 
distal to each stent strut. These non-physiologic flow characteristics near stent struts persist until re-
endothelization and neointimal tissue growth occurs. The degree to which the flow patterns are 
disrupted depends strongly on the stent design.
Computational fluid dynamics (CFD) techniques have been employed to investigate the 
hemodynamic alterations following stent deployment as they allow for accurate information on flow 
parameters [e.g., wall shear stress (WSS), velocity, pressure]17, 21, 22. Duraiswamy and colleagues 
quantified WSS values near stent struts in four commercially available stents23. Results indicated that 
stent designs whose struts were aligned perpendicular to the flow direction resulted in much lower 
WSS values and greater flow disturbances than designs that did not have these design 
characteristics. Furthermore, stent designs whose struts were aligned primarily in the axial direction 
(i.e., the direction of blood flow) disturb flow the least. Examination of the R-ZES design reveals a 
continuous wire that is molded into a sinusoidal wave and wrapped in a helical pattern and laser-
fused at certain points24. This allows significantly more struts to be aligned in the axial direction than 
the X-EES design.Furthermore, the conformability of the R-ZES may cause less vessel straightening 
and less plaque prolapse, leading to more physiologic shear stress compared to X-EES.  Thus, we 

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
7
hypothesize that R-ZES will result in less disturbed flow and more physiologic WSS at the stent 
edges compared with the X-EES design and promote more complete tissue coverage within the stent.
Specific Aim:
The aim of this proposal is,in patients undergoing PCI to angulated coronary arteries,to:
1) To calculateOCT-derived WSSwithin R-ZES and X-EES stents and relate differences in 
regional in-stent WSS to neo-intimal tissue coverage assessed by OCT at one year. 
2) To calculateIVUS-derived WSSat the R-ZES and X-EES stent edges and relate differences in 
regional WSS at stent edges to change in plaque areaat one year. 
Hypotheses:
In patients undergoing PCI to angulated coronary arteries:
1) With a conformable stent design that is more conducive to physiologic flow characteristics, the 
R-ZES stent will result in less vessel straightening and less plaque prolapse compared to X-
EES. This would result in fewer lowWSS areas within the stent that, in turn, would lead to less 
neo-intimal tissue coverage. 
2) R-ZES will result in less straightening of vessel at the stent edges compared with X-EES, 
yielding fewerlow WSS segments which, in turn, will result in less plaque area at the stent 
edges at one year.  
Design
One hundred twenty six patients from participating US and international study sites Emory University 
Hospital (Atlanta, GA), Hospital Clinico San Carlos (Madrid, Spain), Seoul National University College 
of Medicine (Seoul, S. Korea), Keimyung University Dongsan Medical Center (Daegu, S. Korea), 
Ulsan University Hospital - University of Ulsan College of Medicine (Dong-gu, S. Korea), Wakayama 
Medical University (Wakayama, Japan), Kobe University (Kobe, Japan), Clinical Center of Serbia 
(Belgrade, Serbia), Nanjing Medical University (Nanjing, China), Samsung Medical Center (Seoul, S. 
Korea), Kyushu Medical Center (Fukuoka, Japan), Teikyo University (Tokyo, Japan), New Tokyo 
Hospital (Tokyo, Japan), University of Latvia, (Riga, Latvia)undergoing PCI to angulated coronary 
vessels will be randomized to stent implantation with either the R-ZES or X-EES in a 1:1 ratio. 
Allocation of stent types will be blinded to patients.  Prior to stent deployment, IVUS and OCT will be 
performed to assess the baseline plaque composition. After successful stent deployment, post-stent 
OCT and IVUS will be performed to assess the adequacy of stent deployment. Using OCT, IVUS, and 
angiographic data, computational fluid models will be performed off-line to measure regional WSS. 
Patients will then be followed on optimal medical therapy including dual anti-platelet therapy for one 
year. They will also receive a follow up phone call by study staff at 6 months to assess their clinical 
status and medication compliance. At 1 year follow-up, patients will return to the cardiac 
catheterization laboratory for repeat angiography, OCT, and IVUS. Of the total n=630 subjects 
projected to be enrolled, 80% (n=504) is anticipated to screen fail based on the predefined inclusion 
criteria. Subsequently we anticipate n=126 subjects  to complete baseline evaluation. A 20% drop out 
rate for the 1-year follow-up invasive evaluation has been considered reducing the total number of 
subjects completing the follow-up to n=100. Patients will be stratified on the basis of whether they 
have diabetes or not, as diabetic patients have long been recognized as a complex PCI cohort and 
associated with an increased risk of major adverse cardiovascular events, including death and 
myocardial infarction.

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
8
Figure 1: Schematic of Study Design. CFD: computational fluid dynamic simulations, IVUS: 
Intravascular Ultrasound, OCT: Optical Coherence Tomography, PCI: percutaneous coronary 
intervention, SIHD: stable ischemic heart disease
Fig.2: Flow chart of the SHEAR-STENT Study
Patients with
R-ZES
Baseline OCT
CFD
1 Y
Follow-up 
Assessment of Angulation, Re-
X-EES

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
9
Figure 3: Angulation 
Methodology:
1. Angiography and Percutaneous Coronary Intervention
Patients will undergo routineangiography (bi-planar views if available) and stent deployment per 
standard of care. 
2. Angiographic assessment of angulation
Angulation is the angle created by the intersection of two tangential 
lines at the beginning and end of an index coronary segment with 
the angiogram frozen in end-diastole. In this study, we define an 
angulated vessel as one with >30degrees bend (Figure 3). When 
the angulation is clearly >60 degrees, a visual assessment by the 
investigator will suffice for enrollment. However, for angles <60 
degrees the angiographic image is frozen in end diastole in the 
control room and printed on paper. Subsequently, 2 tangential lines 
are drawn on the vessel at the proximal and distal edge of the lesion 
and the intersecting angle measured with a protractor. In cases 
where the affected artery/stent has more than one curvature 
(assumes an “S” shape, instead of variations of a “C” shape), the 
higher degree of angulation will be analyzed. Stents that overlap or are in very close 
proximity to each other with a gap of less than 5 mm will be assigned to the same 
coronary lesion. 
3. Intravascular Imaging
3.1. Data Acquisition
Optical coherence tomography (OCT) and Intravascular ultrasound (IVUS) will be performed at 
baseline to assess plaque burden prior to and after stent deployment as well as to evaluate stent 
expansion and stent apposition. OCT and IVUS will be repeated at one year follow-up to evaluate 
neo-intimal tissue coverage within the stent and change in plaque area at the stent edges. IVUS 
analysis will be performed with a motorized pullback at 0.5 mm/s. Following IVUS, OCT will be 
performed with a commercially available system (C7-XR™ OCT Intravascular Imaging System, St. 
Jude Medical). The OCT catheter will be positioned distal to the region of interest and automated 
pullback will be performed at 20 mm/s while the blood is removed by the continuous power injection 
of iso-osmolar contrast through the guiding catheter. 
3.2. Data Analysis
Both stent platforms are FDA approved and clinically utilized in the United States and internationally. 
This trial is not powered to detect clinical outcome difference between the two stent platforms but 
rather enhance our understanding of the relationship between biomechanics and stent healing in 
these angulated vessels. We therefore do not think this trial will be discontinued and hence do not 
plan to perform an interim analysis.
3.2.1. Intravascular Ultrasound

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
10
Offline, manual detection of lumen area, stent area, vessel area(external elastic membrane) and the 
media-adventitia interface will be performed for each IVUS cross-section from baseline and follow up 
examinations. Cross sections with rotational distortion artifacts and severe calcifications will be 
excluded from the analysis. Plaque area and plaque burden will be measured at baseline and follow 
up for every IVUS cross-section from the pullback run. Baseline and follow-up IVUS cross-sections 
will be compared, reviewed and co-registered based on a reproducible index side branch atthe distal 
end of the target segment. Changes in external elastic membrane, lumen area, plaque burden and 
plaque area, and fourplaque tissue components defined by IVUS-virtual histology(necrotic core, 
dense calcium, fibrous tissue, and fibrofatty tissue) will be calculated as follow-up values minus 
baseline values for each IVUS segment. The 5 mm segments proximal and distal to the stent edges 
will be defined and analyzed with IVUS. Change in plaque area at the stent edges (secondary IVUS 
endpoint) will be calculated from the change in plaque area in the 5 mm proximal and distal segments 
as described above.  
3.2.2. Intravascular Optical Coherence Tomography
Offline, manual detection of lumen area and stentarea will be performed for each OCT cross-section 
from baseline and follow up examinations. Images with artifacts (e.g. blood) or otherwise 
uninterpretable will be excluded from the analysis. At the strut-level analysis, the struts will be 
classified either as covered or uncovered (a tissue layer over the endoluminal surface is not visible). 
To derive data for the primary study endpoint, from the follow-up OCT images, the total neo-intimal 
tissue coverage area will be calculated as: (stent area − lumen area). For secondary analyses, % 
tissue coverage area will be calculated as: tissue coverage area/stent area × 100; and% tissue 
coverage volume will be calculated as: tissue coverage volume/stent volume × 100. The tissue 
coverage symmetry per frame will be analyzed with the following ratio: (maximum tissue coverage 
thickness per frame – minimum tissue coverage thickness per frame)/maximum tissue coverage 
thickness per frame. This ratio can have values between 0 and 1. The closer the ratio is to 1 the 
higher is the asymmetry of the tissue coverage. Strut tissue coverage will be measured through mean 
tissue coverage thickness, tissue coverage area proportion of tissue coverage area and proportion of 
uncovered struts. Plaque prolapse will be defined as tissue identified between stent struts extending 
inside a circular arc connecting adjacent struts.
4. Wall Shear Stress Calculations
Computational fluid dynamic (CFD) simulations to calculate WSS values have been used extensively 
and validated in our laboratory. Following angiographic, IVUS and OCT acquisition, 3-dimensional 
(3D) coronary geometries will be reconstructed by determining the location of the OCT transducer 
during pullback by using the corresponding angiographic projections. The 3D reconstructed catheter 
core serves as the stem on which to rebuild the 3D geometry. Following image adjustment due to 
rotation, each frame is aligned perpendicular to the catheter core. Lumen boundary points for each 
frame will be determined connected by spline curves to connect consecutive images. The geometry is 
smoothed, meshed, and imported into the commercial solver (Ansys, Inc., Canonsburg, PA), which 
employs the finite volume method for solving the Navier-Stokes equations. Velocity profiles will be 
applied at the inlet, traction-free boundary conditions are applied at all outlets, and a no-slip boundary 
condition (v = 0) is applied at the wall. The fluid (blood) is assumed to be an incompressible 
Newtonian fluid, which is valid under the pulsatile, moderate Reynolds number flow conditions in 
coronary arteries. WSS values are determined as a function of time in the cardiac cycle and the 
evaluation is highly reproducible.

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
11
Nodal WSS values will be extracted from the area of interest (i.e., lesion/stented region and stent 
edges) of computational models at pre- and post-stenting. The stented region and 5-millimeter (mm) 
segments of the proximal and distal edges will be divided into 1- mm segments and WSS values will 
be spatially and temporally averaged. Low WSS will be defined as <10 Dynes/cm2. Corresponding 
regions between the pre-and post-stenting models for a given patient will be examined to assess 
alterations in WSS following stent implantation. Arterial straightening will be assessed by examination 
of the OCT-derived coronary reconstructions. Following reconstruction, centerline data will be 
examined to quantify vessel curvature, average cross-sectional area, maximum/minimum/average 
lumen diameters, and vessel volume will be calculated. 
Patient Selection
Patients planned to be admittedfor coronary angiography and percutaneous coronary artery 
revascularization procedure should be screened for trial eligibilityby a member of the research team 
previously trained to the protocol. The investigator or designee will explain the nature and scope of 
the trial, potential risks and benefits of participation, and answer all questions. Subjects must consent 
to participate in the study and may withdraw their consent at any time without any penalty or loss of 
benefit. 
Patient Inclusion:
1. Patient must be 30 to 80 years old
2. Severe coronary lesion in a vessel with >30o angulation requiring PCI
3. Lesion treatable by a single Resolute Integrity or Onyx or Abbott Xience Xpedition or Sierra 
coronary drug eluting stent.
4. Patients with stable ischemic heart disease or acute coronary syndrome undergoing clinically 
PCI. 
Patient Exclusion:
1. Inability to provide informed consent prior to randomization
2. Anatomy requiring coronary artery bypass surgery (CABG)
3. History of prior CABG in the territory of the vessel being considered for PCI
4. Heavily calcified lesion requiring rotablation or other debulking or scoring device for successful 
stent deployment
5. Large thrombus burden on angiography
6. Previously stented vessels. 
7. Ostial lesions: lesion located within 5mm of the origin of the LAD, LCx, or RCA
8. Lesions at bifurcations and those that occlude side branches>2.5mm
9. Recent (<72 hours) ST-elevation myocardial infarction (STEMI)
10.Planned surgical procedures in the subsequent 12 months
11.History of hypersensitivity or contraindication to device materials and their degradants, 
everolimus, zotarolimus, cobalt, chromium, nickel, platinum, tungsten, acrylic and fluoro 
polymers 
12.History of any solid organ transplantation or subject is on a waiting list for any solid organ 
transplant. 
13.Left ventricular ejection fraction < 30%
14.Known allergies to clinically utilized anti-thrombotic or anti-platelet agents
15.Unable to tolerate long term dual anti-platelet therapy
16.Pregnancy or lactation

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
12
17.Subject has renal insufficiency as defined as an estimated GFR < 30 ml/min/1.73m2.
18.Concurrent enrollment in another clinical trial that has not yet completed its primary endpoint
Study Endpoints
Primary Endpoints (Efficacy):
1. In stent mean cross-sectional area of neo-intimal tissue coverageby OCT at follow-up. 
Secondary Endpoints:
A. In-Stent 
1. Safety: Mean thickness of strut coverage at follow up
2. Mechanistic:
a. Degree of vascular straightening post-PCI (post PCI angulation -baseline angulation) 
b. Plaque prolapse post-PCI (identified by OCT)
c. Percent stent area with low WSSpost-PCI (OCT derived)
B. Stent Edge (5 mm proximal and distal to stent)
1. Efficacy:Change in plaque area at follow up 
2. Mechanistic:
a.
Degree of vascular straightening post-PCI at the stent edges
b.
Percent area with low WSS at stent edges post-PCI (IVUS derived)
Figure 4: Schema of Study endpoints 

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
13
Statistics
OCT cross-section frames will be selected from the stented segments at approximately 1 mm 
intervals for quantitative analysis. Each observed stent strut in each still frame will be classified as 
either completely or incompletely tissue-covered. Furthermore, in those struts where tissue coverage 
is observed, tissue coverage area and tissue coverage thickness will be measured. Previously 
published studies investigating R-ZES and X-EES strut re-endothelialization by OCT in all comers did 
not show statistically significant differences in neointimal thickness or volume, though the studies did 
not concentrate on angulated vessels3, 4.In a sample of 58 patients (30 ZES and 28 EES) with 72 
lesions, 107stents, and 23,197 struts, the OCT sub-study of the RESOLUTE All Comers OCTtrial 
showed the tissue coverage volume of 15.9mm3±11.6mm3 for the ZES and 18.7mm3±14.4mm3 for 
EES (p-value=0.27).3Power calculations were based on the assumption that at 12 months the tissue 
coverage volume for ZES was 14.68mm3and EES 22mm3. Detection of a 20% or more change in 
primary endpoint between the two groups at a power of 80% and a two-sided alpha level of 0.05 will 
requires an enrollment of 50 patients per group. Assuming a dropout rate of 20%, we propose to 
recruit 126 patients.
Continuous variables will be reported as mean and standard deviations (1SD), and a t-test or U-test 
will be employed depending on whether or not the variables are normally distributed and the 
standards of deviations are the same.Analysis of variables at the level of patient, treatment arm, and 
lesion will be performed using multilevel regression models. Chi-square test or Fisher’s exact test will 
be used, as appropriate, to compare categorical variables.
All statistical analyses will be carried out using the Statistical Package for Social Sciences (SPSS) 
software (SPSS, Inc., Chicago, IL). A two-sided p-value of <0.05 will be considered statistically 
significant.
Duration of study
It is estimated that it will take 1 year to enroll patients and collect baseline data and 1 year for follow-
up data collection.
Follow-up
All patients will be followed while in hospital for major adverse events.  Total CK, CK-MB and troponin 
(if available) will be measured 12-24 hours after the procedure.  Patients will be contacted by phone 
at 6 month (±30 days), and undergo follow up cardiac catheterization at 1year (±30 days) after 
enrolment with the specific assessments as outlined in the follow-up table below. During follow-up 
patients will be assessed for any major adverse cardiac events (MACE).
Table 1: Follow-Up Schedule
Baseline
12-24Hr
Post Proc.
Discharge
6 month
(±30 days)
1 year
(±30 days)
Hosp.
Hosp.
Hosp.
Call
Hosp.
Medical History/Demographics
X
Cardiac Enzymes (Tn, CK, MB)
X
X
ECG
X
X
X
Routine Lab Studies
X
X
X
X
Pregnancy Test
X
X

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
14
Baseline
12-24Hr
Post Proc.
Discharge
6 month
(±30 days)
1 year
(±30 days)
Cardiac Medications
X
X
X
X
Angiogram
X
X
OCT
X
X
IVUS
X
X
Adverse Events
X
X
X
X
Data Management
All documents and data shall be produced and maintained in a way that assures control and 
traceability. All documents, and subsequent versions, related to a clinical investigation shall be 
identifiable, traceable and appropriately stored to provide a complete history of the clinical study. The 
principal investigator shall be responsible for the accuracy, legibility, and security of all clinical study 
data, documents, and subject records at the investigator’s participating medical site. The principal 
investigator (or an appropriately designated study staff) is responsible for entering the data from 
source documentation to CRFs.
Data entered on CRFs will be reviewed and verified by the authorized principal investigator and 
promptly submitted to the Primary Site. Any alteration of the data shall be made by only authorized 
personnel. The investigator designee will submit data through the REDCap electronic data capture 
system managed by the Primary Site. Copies of required source documents will be scanned and 
uploaded to the REDCap electronic data capture system in a timely manner where the data will be 
reviewed by the primary site. Subject’s information must be de-identified prior to uploading 
documents on REDCap. Any queries or clarifications requested by the Primary Site will be resolved 
through a documented data clarification process.
Recording Data
The REDCap electronic database system will be utilized for this study. REDCap provides a HIPPA-
compliant, encrypted, backed-up place to store the data and allows online data entry from multiple 
sites, including international sites. Access to the database is limited to certain investigators and 
designees at the study site. Procedures for verification, validation, and securing of electronic clinical 
data will be maintained by the Primary Site under separate cover.
The data reported by the investigator or designee on the CRFs shall be derived from 
sourcedocuments and be consistent with the source documents, any discrepancies shall be 
explained inwriting. The informed consent form shall be signed and dated by the principal investigator 
or his/her authorizeddesignee(s).Electronic CRFs should be entered into REDCap in a timely fashion. 
All imaging data (such as coronary angiography, IVUS and OCT) will be recorded on a compatible 
compact disk (CD-ROM or DVD) and shipped to the Primary Site. A copy of the OCT data will also be 
shipped to the OCT Core Laboratory (Case Western Reserve University).
Source Documents
Source documents shall be created and maintained by the investigation site team throughout 
theclinical study. All findings in this clinical study must be documented as source data, andtherefore 
can be verified (and audited). Source documentation may be paper or electronic, and isdefined as the 
first time the data appears and may include for example; all clinical records,hospital records, surgery 

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
15
reports, autopsy reports, and any other material that contains originalinformation used for clinical 
study data collection or adverse event reporting.The Primary Site representative or site investigator is 
responsible for verifying the CRFs throughout the study toverify adherence to the protocol as well as 
completeness, accuracy, and consistency of the data derived from each site.The Primary Site or 
representative must have access to the source documentation and other studyrelated records to 
verify the entries on the CRFs.
Confidentiality of Data
All subject information collected during the course of this study will be kept strictly 
confidentialaccording 
to 
applicable 
country-specific 
laws 
and 
regulations. 
All 
data 
and 
informationconcerning subjects and their participation in this study are considered confidential. All 
public reporting of the results ofthe study will eliminate identifiable references to the subjects. 
Information on paper will be keptin secured locations. Electronic information will be kept on password-
protected computers.
Personal data, including medical and health information, will be processed both by computer 
andmanually, during and after the study, and its affiliates, its designated third party dataprocessors, 
the IRB, the institution conducting the study, the investigators and otherhealthcare personnel involved 
in the study for the purposes of this study. Subject data will not contain details of study subject 
identity. The datawill be stored on a secure server and backed up routinely. All records and reports 
required by orprepared in connection with this study shall be maintained by the institution and the 
investigators
in a secure location for a minimum period of 15 years post approval or longer as may beotherwise 
required by local law. Personal data will be key-coded to prevent subjectidentification, except by the 
institution, investigators and other healthcare personnel involved inthe study, if necessary for the 
purpose of the study, for regulatory inspections, and to complywith EUH reporting obligations.
Any information about subjects that leaves the institution conducting the study will be modifiedto 
remove certain information that could identify the subject (e.g., subject’s name, age on the dayof 
enrollment, address, and hospital number) and only be identifiable by a study ID code. Studydata 
published in medical journals and/or presented at scientificconferences will not allow the identification 
of study subjects.
Data and Document Retention
The principal investigators shall maintain the clinical study data and documentsas required by 
applicable regulatory requirement(s). They shalltake measures to prevent accidental or premature 
destruction of these documents. The principalinvestigator may transfer custody of records to another 
person/party anddocument the transfer at the study site or at the Primary Site facility.
Amendment to Study Forms
The study forms shall be amended by the Primary Site as needed throughout the clinical study, 
andjustification documented and maintained. The amendments shall be notified to, or approved by, 
the IRBifrequired. The version number and date of amendments shall be documented.

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
16
Deviations from Clinical Study Plan
Investigators are not allowed to deviate from the protocol except when necessary to protect the life 
orphysical well-being of a subject in an emergency. Prior approval by the Primary Site is expected in 
those situations in which the investigator anticipates, contemplates or makes a conscious decision to 
departfrom procedures specified in the clinical investigational plan. Prior approval is generally 
notexpected in situations where unforeseen circumstances are beyond the investigator’s control, but 
isstill considered a deviation (e.g. a clinical investigation subject who fails to attend a 
scheduledfollow-up visit, a clinical study subject too ill to perform a protocol-required test). 
To obtainapproval, the investigator must call or email and discuss the potential deviation with the 
Primary Site Principal Investigator or designee prior to initiating any changes. A Protocol Deviation 
CRF will be completed for eachprotocol deviation. When relevant, the ethics committeesor the 
appropriateregulatory bodies will be informed of protocol deviations.Primary Site will review and 
monitor investigator compliance and determine if there is a need forcorrective action based on the 
severity and/or trends in non-compliance. 
Investigator shall notify Primary Site promptly, and the reviewing IRBwithin 5 working days where 
appropriate of the following:
1. A deviation to protect the life or physical well-being of a subject in an emergency and;
2. Failure to obtain an informed consent.
Investigators or the designee must notify Primary Siteas soon as possible by calling the clinicalstudy 
manager or designee and complete the clinical study deviation case report form.The investigator is 
required to adhere to local IRB or regulatoryrequirements procedures for reporting other deviations.
Monitoring and Reporting
Each site’s evaluation will be carried out by though centralized monitoring by hired research staff at 
the Primary Site. Processes to ensure site record keeping, data entry, and reporting are well-defined 
to ensure timely access to clinical trial data and supporting documentation. Various modes of 
communication (e.g., teleconferences, videoconferencing, email) will be used for specific study time 
points (e.g., study initiation) and activities (e.g., to discuss findings of a monitor’s eCRF review, 
training of new site staff). The sites will regularly upload study documents via the electronic data 
capture which will be remotely verified. An onsite visit could be warranted if concerns regarding 
noncompliance or major safety issues arise.
Investigators are required to keep records on all relevant observations, including records concerning 
adverse effects (whether anticipated or unanticipated. All adverse events and technical observations 
will be captured on an adverse event CRF. It is the responsibility of the investigator to assess the 
subject for adverse events and capture the required adverse event information on a CRF. Adverse 
events will be reported from time of procedure until completion of follow-up. The investigator must 
also notify the responsible IRB regarding new and significant safety information and any event 
identified by Primary Sitethat requires expedited reporting as serious, unexpected, and related to the 
clinical study device.
The general procedure for reporting any adverse event is as follows:
1. If an adverse event occurs, complete the Adverse Event CRF.
2. The Adverse Event CRF must be signed and dated by the investigator.

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
17
For Serious Adverse Event and all Unanticipated Adverse Device Effects, the investigator isrequired 
to document and report to the Primary Site without undue delay, but not longer than 48 hours from 
first knowledge of event. The investigator must notify the IRB, if appropriate,in accordance with 
national and local laws and regulations.
Emergency Contact
In the event that emergent reporting of an adverse event to the Primary Site is necessary, clinical 
siteswill complete a CRF through the electronic database. Once submitted, notification will be sent 
electronically to the Primary Site and the CRF will be immediately available for review.
Publications
The results of this clinical study will be submitted for publication following study completion anddata 
analysis.
Suspension or Premature Termination of the Clinical Study
The Primary Site may suspend or prematurely terminate either a clinical study in an individual site or 
theentire clinical study for significant and documented reasons.A principal investigator, IRB or 
regulatory authority maysuspend or prematurely terminate participation in a clinical study at the study 
sites for which they areresponsible.If suspicion of an unacceptable risk to subjects arises during the 
clinical study, or when so instructedby the IRB or regulatory authority, the Primary Site shallsuspend 
the clinical study while the risk is assessed. The Primary Site shall terminate the clinical study ifan 
unacceptable risk is confirmed.
The Primary Site shall consider terminating or suspending the participation of a particular study site 
orinvestigator in the clinical study if monitoring or auditing identifies serious or repeated deviations 
onthe part of an investigator.If suspension or study termination occurs, the terminating party shall 
justify its decision and providewritten notice of termination in accordance with the study agreement. 
The principal investigator andthe Primary Site shall keep each other informed of any communication 
received from IRB or regulatory authority.If, for any reason, the Primary Site suspends or prematurely 
terminates the study at an individual studysite, the Primary Site shall inform the responsible 
regulatory authority, as appropriate, and ensure that theIRB are notified, either by the principal 
investigator or by thePrimary Site. If the suspension or premature termination was in the interest of 
safety, the Primary Site shallinform all other principal investigators.If suspension or premature 
termination occurs, the Primary Site shall remain responsible for providingresources to fulfill the 
obligations and existing agreements for following up thesubjects enrolled in the clinical study, and the 
principal investigator or authorized designee shallpromptly inform the enrolled subjects at his/her 
study site, if appropriate.
Resuming the Clinical Study after Temporary Suspension
When the Primary Site concludes an analysis of the reason(s) for the suspension, implements 
thenecessary corrective actions, and decides to lift the temporary suspension, the Primary Site shall 
inform the principal investigators, IRB or regulatory authority,where appropriate, and the regulatory 
authority of the rationale, providing them with the relevantdata supporting this decision.Concurrence 
shall be obtained from the, IRB or regulatoryauthority where appropriate, before the clinical study 

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
18
resumes.If subjects have been informed of the suspension, the principal investigator or 
authorizeddesignee shall inform them of the reasons for resumption.

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
19
References
1.
Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van Boven AJ, 
Hofma SH, Linke A, Klauss V, Wijns W, Macaya C, Garot P, DiMario C, Manoharan G, Kornowski R, 
Ischinger T, Bartorelli A, Ronden J, Bressers M, Gobbens P, Negoita M, van Leeuwen F, Windecker S. 
Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med. 
2010;363:136-146
2.
von Birgelen C, Basalus MW, Tandjung K, van Houwelingen KG, Stoel MG, Louwerenburg JH, 
Linssen GC, Said SA, Kleijne MA, Sen H, Lowik MM, van der Palen J, Verhorst PM, de Man FH. A 
randomized controlled trial in second-generation zotarolimus-eluting resolute stents versus everolimus-
eluting Xience Xpedition stents in real-world patients: The twente trial. J Am Coll Cardiol. 
2012;59:1350-1361
3.
Gutierrez-Chico JL, van Geuns RJ, Regar E, van der Giessen WJ, Kelbaek H, Saunamaki K, Escaned J, 
Gonzalo N, di Mario C, Borgia F, Nuesch E, Garcia-Garcia HM, Silber S, Windecker S, Serruys PW. 
Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. A fluoropolymer-coated 
everolimus-eluting stent at 13-month follow-up: An optical coherence tomography substudy from the 
resolute all comers trial. Eur Heart J. 2011;32:2454-2463
4.
Kim JS, Kim BK, Jang IK, Shin DH, Ko YG, Choi D, Hong MK, Cho YK, Nam CW, Hur SH, Choi JH, 
Song YB, Hahn JY, Choi SH, Gwon HC, Jang Y. Comparison of neointimal coverage between 
zotarolimus-eluting stent and everolimus-eluting stent using optical coherence tomography (cover oct). 
Am Heart J. 2012;163:601-607
5.
Kirtane AJ, Gupta A, Iyengar S, Moses JW, Leon MB, Applegate R, Brodie B, Hannan E, Harjai K, 
Jensen LO, Park SJ, Perry R, Racz M, Saia F, Tu JV, Waksman R, Lansky AJ, Mehran R, Stone GW. 
Safety and efficacy of drug-eluting and bare metal stents: Comprehensive meta-analysis of randomized 
trials and observational studies. Circulation. 2009;119:3198-3206
6.
Tu JV, Bowen J, Chiu M, Ko DT, Austin PC, He Y, Hopkins R, Tarride JE, Blackhouse G, Lazzam C, 
Cohen EA, Goeree R. Effectiveness and safety of drug-eluting stents in ontario. N Engl J Med. 
2007;357:1393-1402
7.
Stone GW, Lansky AJ, Pocock SJ, Gersh BJ, Dangas G, Wong SC, Witzenbichler B, Guagliumi G, 
Peruga JZ, Brodie BR, Dudek D, Mockel M, Ochala A, Kellock A, Parise H, Mehran R. Paclitaxel-
eluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med. 2009;360:1946-
1959
8.
Stone GW, Ellis SG, O'Shaughnessy CD, Martin SL, Satler L, McGarry T, Turco MA, Kereiakes DJ, 
Kelley L, Popma JJ, Russell ME. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent 
restenosis within bare-metal stents: The taxus v isr randomized trial. JAMA. 2006;295:1253-1263
9.
James SK, Stenestrand U, Lindback J, Carlsson J, Schersten F, Nilsson T, Wallentin L, Lagerqvist B. 
Long-term safety and efficacy of drug-eluting versus bare-metal stents in sweden. N Engl J Med. 
2009;360:1933-1945
10.
Kelbaek H, Thuesen L, Helqvist S, Clemmensen P, Klovgaard L, Kaltoft A, Andersen B, Thuesen H, 
Engstrom T, Botker HE, Saunamaki K, Krusell LR, Jorgensen E, Hansen HH, Christiansen EH, 
Ravkilde J, Kober L, Kofoed KF, Terkelsen CJ, Lassen JF. Drug-eluting versus bare metal stents in 
patients with st-segment-elevation myocardial infarction: Eight-month follow-up in the drug elution and 
distal protection in acute myocardial infarction (dedication) trial. Circulation. 2008;118:1155-1162
11.
Pilgrim T, Windecker S. Drug-eluting stent thrombosis. Minerva Cardioangiol. 2009;57:611-620
12.
Kalesan B, Pilgrim T, Heinimann K, Raber L, Stefanini GG, Valgimigli M, da Costa BR, Mach F, 
Luscher TF, Meier B, Windecker S, Juni P. Comparison of drug-eluting stents with bare metal stents in 
patients with st-segment elevation myocardial infarction. Eur Heart J. 2012;33:977-987

SHEAR-STENT Study Protocol (H. Samady)                           IRB#: 00066353
Last Updated: September 4, 2020
20
13.
Virmani R, Kolodgie FD, Farb A. Drug-eluting stents: Are they really safe? Am Heart Hosp J. 
2004;2:85-88
14.
Yutani C, Imakita M, Ishibashi-Ueda H, Tsukamoto Y, Nishida N, Ikeda Y. Coronary atherosclerosis 
and interventions: Pathological sequences and restenosis. Pathol Int. 1999;49:273-290
15.
Centemero MP, Stadler JR. Stent thrombosis: An overview. Expert Rev Cardiovasc Ther. 2012;10:599-
615
16.
Pant S, Bressloff NW, Forrester AI, Curzen N. The influence of strut-connectors in stented vessels: A 
comparison of pulsatile flow through five coronary stents. Ann Biomed Eng. 2010;38:1893-1907
17.
LaDisa JF, Jr., Olson LE, Douglas HA, Warltier DC, Kersten JR, Pagel PS. Alterations in regional 
vascular geometry produced by theoretical stent implantation influence distributions of wall shear stress: 
Analysis of a curved coronary artery using 3d computational fluid dynamics modeling. Biomed Eng 
Online. 2006;5:40
18.
Nakazawa G, Finn AV, John MC, Kolodgie FD, Virmani R. The significance of preclinical evaluation 
of sirolimus-, paclitaxel-, and zotarolimus-eluting stents. Am J Cardiol. 2007;100:36M-44M
19.
Timmins LH, Miller MW, Clubb FJ, Jr., Moore JE, Jr. Increased artery wall stress post-stenting leads to 
greater intimal thickening. Lab Invest. 2011;91:955-967
20.
Agostini F, Iannone MA, Mazzucco R, Cionini F, Baccaglioni N, Lettieri C, Belfanti D, Tomasi L, Izzo 
A, Ferrari MR, Brunazzi MC, Zanini R. Coronary flow velocity pattern assessed by transthoracic 
doppler echocardiography predicts adverse clinical events and myocardial recovery after successful 
primary angioplasty. J Cardiovasc Med (Hagerstown). 2006;7:753-760
21.
Chen MC, Lu PC, Chen JS, Hwang NH. Computational hemodynamics of an implanted coronary stent 
based on three-dimensional cine angiography reconstruction. ASAIO J. 2005;51:313-320
22.
LaDisa JF, Jr., Guler I, Olson LE, Hettrick DA, Kersten JR, Warltier DC, Pagel PS. Three-dimensional 
computational fluid dynamics modeling of alterations in coronary wall shear stress produced by stent 
implantation. Ann Biomed Eng. 2003;31:972-980
23.
Duraiswamy N, Schoephoerster RT, Moore JE, Jr. Comparison of near-wall hemodynamic parameters in 
stented artery models. J Biomech Eng. 2009;131:061006
24.
Medtronic resolute integrity™ drug-eluting stent obtains fda approval for treating coronary artery 
disease2012;2012