Assessment of Cutting-Balloon Angioplasty With Novel Bioabsorbable Polymer-Coated, Everolimus-Eluting Stent in the Treatment of Calcified Coronary Lesions Guided by Intravascular Ultrasound
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: Soonchunhyang University Hospital

Study Title 
Assessment of Cutting-Balloon Angioplasty with 
Novel 
Bioabsorbable 
Polymer-Coated, 
Everolimus-Eluting Stent in the Treatment of 
Calcified 
Coronary 
Lesions 
Guided 
by 
Intravascular Ultrasound: Study Design and 
Protocol 
Study Title (Short 
Description)  
CUPID trial 
Principle 
Investigator 
Jon Suh, MD., PhD. 
Institution Name & 
Location 
SoonChunHyang University Hospital 
170 Jomaru-ro, Bucheon-si, Gyeonggi-do, 14584, 
Rep. of KOREA 
Contact 
information 
Email: immanuel@schmc.ac.kr 
Tel.: +82 32 621 5867      
Fax: +82 32 621 5016 
 
 
 
 
 
 
Document date : November 20, 2023 
 
 

1. Study protocol 
 
This clinical trial is designed as a prospective, observational, open-label, multi-center trial that 
will investigate the noninferiority of cutting balloon pre-dilatation compared with NC-balloon 
pre-dilatation in the treatment of calcified lesion who underwent bioabsorbable polymer-coated, 
everolimus-eluting coronary stent implantation. 
# Planned number of sites: 5 institutions in South Korea 
1. SoonChunHyang University Hospital, Bucheon 
2. SoonChunHyang University Hospital, Cheonan 
3. Eulji Medical Center, Eulji University, Daejeon 
4. Seoul St.Mary’s Hospital, Seoul 
5. Hanil General Hospital, Seoul 
 
2. Study Outcomes 
5.1. Primary endpoint: the efficacy of cutting balloon 
① Minimal stent CSA (cross-section area) with IVUS at calcium site 
5.2. Secondary endpoint: comparing the clinical outcomes 

① MACE (major adverse cardiac events): composite of death, MI, TVR at 1yr follow-up 
② TLR (target lesion revascularization) at 1yr follow-up 
③ Procedure time, the total amount of contrast, and the number of balloons 
 
3. Analysis plan 
6.1. Study period: 24 months 
6.2. Enrollment: 12 months 
6.3. Follow-up: 12 months 
6.4. Analysis and result report: 2 months 
 
4. Sample size calculation for the primary analysis 
4.1. Hypothesis:  
This trial is a 1:1 matched comparative cohort clinical trial, with patients being assigned to 
either the cutting balloon or the NC balloon group (1: 1 ratio) during the study period. It will test 
the noninferiority of a strategy of cutting balloon pre-dilatation compared with NC balloon pre-
dilatation in the treatment of calcified coronary lesion. minimal CSA at the calcium site 
assessed by IVUS is the primary endpoint. Limited similar clinical trials on cutting balloon for 
the treatment of de novo various degree calcified coronary lesions have achieved differing 
results. The result of a previous study that investigates the efficacy of cutting balloon indicates 
that the mean CSA after cutting balloon treatment for native coronary artery disease are 
6.26mm and 5.03 mm in the NC balloon group (18). We hypothesize that stent implantation 
after the cutting balloon pre-dilatation will not be inferior to pre-dilatation with NC balloon for 
the treatment of de novo calcified coronary lesions. Using double-sided inspection, α = 0.05 
and β = 0.2, and considering the expected loss to follow-up of 20%, the number of cases to 
be included should be at least 250. Therefore, we aim for 125 cases for each group. 
Nevertheless, the sample size proposed was 250 patients in each group to further increase 
the power and account for possible protocol deviation. 

 
4.2. Assumption 
Data for all endpoints will be evaluated using an intention-to-treat analysis. All data will be 
expressed as mean ± standard deviation. The unpaired Student’s t-test and Mann–Whitney U 
test will be used to compare continuous variables. Categorical variables will be compared 
using the chi-square and Fisher’s exact tests. All time-to-event outcomes of MACEs will be 
summarized using Kaplan–Meier survival estimates and compared between the two groups 
using log-rank tests. p < 0.05 is considered statistically significant. All statistical analyses will 
be performed using SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA). 
 
4.3. Final sample size 
Total number = 250 (Wolverine cutting balloon = 125, Non-compliant balloon = 125) 
 
5. Methods 
5.1. PCI procedure and medication: 
PCI and stent implantation will be performed according to the current guidelines using 
standard interventional techniques (reference). Before PCI, all patients will be administered 
loading doses of aspirin (200–300 mg), clopidogrel (300–600 mg), ticagrelor (180 mg), or 
prasugrel (60 mg). After sheath insertion at the arterial access site, weight-adjusted 
unfractionated heparin will be administered at a bolus dose of 100 U/kg, with an additional 
bolus to maintain an activated clotting time of 250–300 s. Additional intravenous and 
intracoronary injections of platelet glycoprotein IIb/IIIa receptor blockers will be administered 
at the discretion of the operator. The interventional strategy, balloon size, and stent selection 
will be based on the discretion of the same operator for all patients. However, modification 
of the calcific atheroma using rotational atherectomy can be performed at the operator’s 
discretion in cases of balloon-uncrossable lesions, and these cases will be excluded from 
enrollment. All patients who undergo PCI will receive aspirin (100 mg daily) with clopidogrel 
(75 mg daily), ticagrelor (180 mg), or prasugrel (60 mg) because a dual antiplatelet 

maintenance regimen for at least 12 months is recommended. Cilostazol (100–200 mg daily) 
will be administered as an adjunct to the dual antiplatelet regimen at the treating physician’s 
discretion. In-hospital stay and after-discharge medications include aspirin, clopidogrel, 
ticagrelor, prasugrel, beta-blockers, calcium channel blockers, angiotensin-converting 
enzyme inhibitors, angiotensin receptor blockers, and lipid-lowering agents such as statins, 
which will be recorded and entered into a dedicated computerized database with clinical 
information. 
 
5.2. Quantitative coronary angiography: 
Coronary angiography will be digitally recorded at baseline and immediately after the 
procedure (post-ballooning and post-stenting) and assessed offline in the angiographic core 
laboratory. The quantitative coronary angiographic analysis will be performed using an 
automated edge-detection algorithm (CAAS-5; Pie-Medical, Best, Netherlands) with 
conventional methods by independent interventional cardiologists who are blinded to the 
type of balloon used, treatment outcomes, and IVUS analysis. All measurements will be 
performed using cineangiograms recorded after the intracoronary injection of nitroglycerin. 
The interpolated reference diameter will be considered as the reference segment diameter. 
The lesion length is defined as the distance from the proximal shoulder to the distal shoulder 
at the lesion site. Standard qualitative and quantitative analyses and definitions will be used 
for quantitative coronary angiography (QCA) (qca 1, 2 references). 
 
5.3. IVUS procedure and analysis: 
After regular coronary angiography, IVUS will be performed at baseline (before pre-dilatation) 
and repeated immediately after stent implantation in all cases. IVUS will be performed using 
an OptiCross 60 MHz (Scientific Corporation, Maple Grove, MN, USA). After intracoronary 
injection of nitroglycerin, the IVUS catheter will be carefully advanced distal to the culprit 
lesion under fluoroscopic guidance and then withdrawn automatically at 0.5 mm/s to perform 
the imaging sequence, which begins 20 mm distal to the culprit lesion and ends at the aorto-

ostial junction. IVUS imaging will be recorded on the compact disc for offline analysis by a 
single experienced observer who is unaware of the clinical and angiographic information. 
IVUS measurements will be performed in accordance with the American College of 
Cardiology Clinical Expert Consensus Document on the Standards for Acquisition, 
Measurement, and Reporting of Intravascular Ultrasound Studies. The ischemia-related 
vessel is identified as narrow (≥ 70%) using angiography. The culprit lesion site selected for 
analysis is the image slice with the lowest luminal cross-sectional area (CSA). The proximal 
and the distal reference segments are defined as the most normal-looking cross-sections 
within the same arterial segment, typically ≤ 10 mm from the lesion, but before any large 
side branch.  
We will measure the lumen in the minimum lumen area slice. The lumen CSA will be 
measured every 1 mm of the culprit lesion segment, and the average lumen CSA will be 
calculated. The maximum calcium arc, calcium length, and calcium ratio (calcium 
length/lesion length) will be measured. After stent implantation, we will measure the 
minimum stent CSA, minimum and maximum stent diameters, and acute CSA gain. Acute 
CSA gain = minimum stent CSA − minimum CSA. Stent symmetry = minimum stent 
diameter/maximum stent diameter. Stent expansion = minimum stent CSA/reference lumen 
CSA. Incomplete stent apposition is defined as insufficient close contact between the struts 
and the underlying wall. Stent asymmetry is defined as stent symmetry of at least one section 
< 0.7. Stent under expansion is defined as a stent expansion rate of < 0.8. 
 
6. Study device 
1) Wolverine (Boston Scientific, Natrick, MA, USA) cutting balloon 
2) bioabsorbable polymer-coated everolimus-eluting coronary stent (Synergy TM, Boston 
Scientific Corporation, Marlborough, MA, USA) 
3) NC balloon (the type of NC balloon will be decided at the operator's discretion) 
4) IVUS will be performed using an OptiCross 60 MHz (Scientific Corporation, Maple Grove, 
MN, USA). 

 
7. Study Population  
7.1. Inclusion criteria 
1) coronary artery disease including in-stent restenosis (ISR) or de novo lesion with 
stenosis of ≥ 70%,  
2) target lesion calcification confirmed by an imaging study: various degrees of calcium 
deposition along the coronary artery wall (an arch of calcium at least 100 degrees) 
confirmed at baseline coronary angiography, computed tomography, and IVUS),  
3) reference vessel diameter between 2.0 and 4.0 mm, deemed suitable for percutaneous 
coronary intervention (PCI). 
 
 
 
 
 
7.2. Exclusion criteria 
1) extremely tortuous or angulated lesions,  
2) lesions with dissection before balloon pre-dilatation,  
3) lesions within the vein graft,  
4) extremely narrow lesions which need rotational atherectomy,  
5) ST-elevation myocardial infarction (STEMI).  
6) Comorbidities that preclude the achievement of one-year follow-up. 
 
8. Expected study period 
 
▪ 
Enrollment: 12 months  
▪ 
Follow-up: 12 months 
▪ 
Data analysis: 2 months 
▪ 
Publication including target journal and presentation:  
JACC: Cardiovascular Interventions 
Circulation: Cardiovascular Interventions 
TCT 2025 
 

9. Safety Reporting including DSMB 
9.1. Potential risk and adequacy of protection against risks 
In patients undergoing intervention and revascularization, treatment decisions should be based on 
clinical indication, regardless of sex, or race or ethnicity, and efforts to reduce the disparities of care 
are warranted. In patients undergoing revascularization, decision should be patient-centered *that 
is, considerate of the patient’s preferences and goals, cultural beliefs, health literacy, and social 
determinants of health* and made in collaboration with the patient’s support system. In patients 
undergoing coronary angiography and revascularization, adequate information benefits, risks, 
therapeutic consequences, and potential alternatives in the performance of percutaneous and 
surgical myocardial revascularization, when feasible, with sufficient time for informed decision-
making to improve clinical outcomes.  
 
 
9.2. Event adjudication and reporting, data safety and monitoring plan 
 
1) Data safety and monitoring plan 
The principal investigator will make the monitoring manager to visit and examine coordinating 
centers regularly. A designated trial monitor will review data not only for completeness, but 
also for accordance of the hospital data and eCRF data. Compliance with the protocol and 
adverse events will be also examined. This trial monitor may inspect all documents and 
required records that are maintained by the Investigator/site, including medical records (office, 
clinic, or hospital) for the subjects in this trial. The coordinating centers will permit access to 
such records. 
 
Type of Report 
Prepared by Staffs for: 
Time limit of notification 
Serious adverse event 
IRB 
According to IRB regulation of 
Site 
DCC/EC/Principal 
investigator 
DSMB 
Within 48 hours 
Annual progress report 
EC/Principal investigator 
Submitted per 1 year 
Deviations from 
investigational plan 
IRB 
According to IRB regulation of 
Site 
EC/Principal investigator 
Notify within 7 days. 

Final summary report 
EC/Principal investigator 
Within 1 month 
*DCC: Data Coordinating Center, EC: Executive Committee (Co-researchers) 
 
2) Executive Committee 
 
 
Name 
Center 
Position 
Chairman 
Jon Suh 
Department of Cardiology, SoonChunHyang 
University Bucheon Hospital, 
SoonChunHyang University College of 
Medicine 
MD, PhD. 
Committe
e 
members 
Sang Ho Park 
Department of Cardiology, SoonChunHyang 
University Cheonan Hospital, 
SoonChunHyang University College of 
Medicine 
MD, PhD 
Jihun Ahn 
Department of Internal Medicine, Daejeon 
Eulji Medical Center, Eulji University School 
of Medicine 
MD, PhD 
Tae-Hoon Kim 
Department of Cardiology, Hanil General 
Hospital, Seoul 
MD, PhD 
Min Gyu Kong 
Department of Cardiology, SoonChunHyang 
University Bucheon Hospital, 
SoonChunHyang University College of 
Medicine 
MD, PhD 
Kwan Yong Lee 
Department of Cardiology, Seoul St. Mary's 
Hospital, The Catholic University of Korea 
MD, PhD 
Inki Moon 
Department of Cardiology, SoonChunHyang 
University Bucheon Hospital, 
SoonChunHyang University College of 
Medicine 
MD. 
 
3) Serious Adverse Events 
The definition of serious adverse events is in the following paragraph. It must be reported to 
the principal investigator within 48hours after recognition of the event and to the IRB 
according to IRB regulation of site. 
① Results in persistent or significant disability or incapacity (significant, persistent or permanent 
change or disruption in subject’s body function/structure, physical activity or quality of life) 
② Requires in-patient hospitalization or prolongs hospitalization 
③ Results in a congenital anomaly/birth defect or, 
④ Life-threatening events or death 
 
 
4) Event adjudication committee 
 
 
Name 
Center 
Position 
Chairman 
Je Sang Kim 
Cardiovascular Center, Dongguk 
University Ilsan Hospital, Dongguk 
MD, PhD 

University 
Committee 
members 
Jeong-Hun Shin 
Division of Cardiology, Department of 
Internal Medicine, Hanyang University 
Guri Hospital 
MD, PhD 
Ha Wook Park 
Department of Cardiology, Sejong 
General Hospital, Bucheon 
MD. 
 
 
5) Data safety and monitoring board 
 
 
Name 
Center 
Position 
Chairman 
In Hyun Jung 
Department of Cardiology, Yongin 
Severance Hospital, Yonsei University 
College of Medicine 
MD, PhD 
Committee 
members 
Hun Soo Chang 
Department of Microbiology and BK21 
FOUR Project, SoonChunHyang 
University College of Medicine,  
PhD. 
Inki Moon 
Department of Cardiology, 
SoonChunHyang University Bucheon 
Hospital, SoonChunHyang University 
College of Medicine 
MD 
 
The DSMB reviews the safety data and delivers recommendations for it. The DSMB may 
convene a meeting at any time if it deems that there is a safety problem. 
The DSMB Charter is drafted before the DSMB's first data review. The plan defines its 
regulations when clinical trials are suspended due to safety concerns. At the first meeting of 
the DSMB, understanding and discussion of all elements of the plan and determination of the 
frequency of DSMB meetings are made. DSMB develops an understanding of all evaluation 
variables in this clinical trial and all definitions used in the judgment. 
The Commissioners do not directly coordinate the client of this clinical trial. The committee 
members have no interest in the central analysis room or with the researchers of this clinical 
trial. The configuration of the DSMB includes at least two cardiovascular intervention 
specialists. The names of the actual members are not published and can be provided to 
regulators as needed. DSMB functions in accordance with relevant regulations. 
The DSMB Chairman shall notify the DCC if he deems that there is a problem with safety or 
compliance with the plan. The Commission may, if necessary, recommend an early suspension 
in accordance with the safety-related early discontinuation principle determined prior to the 
start of a clinical trial, or if clinically significant results are found in the safety-related data. All 
DSMB reports must be strictly confidential and provided at the request of regulators.