Implementation of a Standardized Algorithm for CoronarY CaLcificatiOn With PlaquE Modification Using UltraSound Guidance to Improve Procedural and Clinical Outcomes (CYCLOPES)
Conditions: Myocardial Ischaemia, Severely Calcified Coronary Stenoses, Coronary Calcification
Sponsor: Royal College of Surgeons, Ireland

 
CYCLOPES 
Clinical Investigation Plan 
 
                                                           
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Implementation of a Standardized Algorithm for 
CoronarY CaLcificatiOn with PlaquE Modification 
using UltraSound Guidance to Improve Procedural 
and Clinical Outcomes (CYCLOPES) 
 
CYCLOPES 
 
 
 
Clinical Investigation Plan 
Version 1.1 
Date: 11 Aug 2024 
 
 
Cardiovascular Research Institute Dublin, 
Mater Private Network & RCSI University 
Dublin, D07KWR1, IRELAND 
 
The information contained in this protocol is CONFIDENTIAL and PROPRIETARY. It may not be provided to any third party 
except as outlined in this protocol without the written consent of CVRI Dublin. 

 
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Clinical Investigation Plan 
 
                                                           
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SPONSOR PROTOCOL AGREEMENT PAGE 
 
The signatories have read and understood the clinical protocol and agree to conduct the clinical 
investigation in compliance with this Clinical Investigation Plan (CIP).  
 
SPONSOR – Royal College of Surgeons Ireland (RCSI) 
 
Name: Prof. Fergal O’Brien 
______________________________________                      
Title: Prof. Fergal O'Brien is Professor of Bioengineering & Regenerative Medicine, Deputy Vice 
Chancellor for Research & Innovation 
 
Date: ______________ 
 
 

 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, any future amendments, and with 
any other clinical conduct procedures provided by the Sponsor. 
• To ensure that the requirements for obtaining informed consent from each subject are met. 
• Not to implement any changes to the protocol without written agreement from the 
Sponsor and prior review and written approval from the independent ethics committee 
(IEC), if applicable, except where necessary to eliminate an immediate hazard to patients. 
• That I am thoroughly familiar with the appropriate use of the study and control devices, as 
described in this protocol and any other information provided by the Sponsor. 
• That I am aware of and will comply with the principles of good clinical practice and all 
applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed about the 
study algorithm and procedures and have been trained in their study-related duties and 
functions as described in the protocol. 
 
Site name: 
 
 
 
 
Principal Investigator Name (print): 
 
 
 
 
 
 
 
Principal Investigator’s Signature: 
 
Date: 
 
 

 
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CLINICAL RESEARCH ORGANIZATION (CRO) PROTOCOL AGREEMENT PAGE 
 
The signatories have read and understood the clinical protocol and agree to conduct the clinical 
investigation in compliance with this Clinical Investigation Plan (CIP).  
 
CVRI (Cardiovascular Research Institute) Dublin, Mater Private Network Dublin  
Address: 73 Eccles Street, Dublin, D07KWR1, IRELAND 
 
Name: Prof. Prof. Robert A. Byrne 
______________________________________                      
Title: Director 
 
Date: ______________ 
 
 
 
CERC (Cardiovascular European Research Center SAS) 
Address: 7 rue du Théâtre, 91300 Massy – France 
 
Name: Dr. Marie-Claude Morice 
______________________________________                      
Title: CEO 
 
Date: ______________ 
 
 

 
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Clinical Investigation Plan 
 
                                                           
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Table of Contents 
SPONSOR PROTOCOL AGREEMENT PAGE ...................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .............................................................................. 3 
REVISION HISTORY .......................................................................................................................... 9 
CONTACT INFORMATION .............................................................................................................. 10 
PROTOCOL SUMMARY .................................................................................................................. 12 
FIGURE 1a: PROPOSED CALCIUM MODIFICATION ALGORITHM ................................................... 17 
FIGURE 1b: PROPOSED CALCIUM MODIFICATION ALGORITHM .................................................. 18 
TABLE 1: TIME SCHEDULE/DATA COLLECTION ............................................................................. 21 
1 
INTRODUCTION ..................................................................................................................... 22 
1.1 
Background Information ................................................................................................ 22 
1.2 
Study Rationale .............................................................................................................. 22 
1.3 
Study Objective .............................................................................................................. 23 
2 
DEVICE INFORMATION .......................................................................................................... 23 
3 
Study Design .......................................................................................................................... 23 
3.1 
General ........................................................................................................................... 23 
3.2 
Study duration ................................................................................................................ 24 
3.3 
Endpoints ........................................................................................................................ 24 
3.3.1 
Co-Primary Endpoint ............................................................................................... 24 
3.3.2 
Secondary Endpoints .............................................................................................. 24 
4 
Study Population ................................................................................................................... 25 
4.1 
Patient Population .......................................................................................................... 25 
4.2 
Eligibility criteria ............................................................................................................. 25 
4.2.1 
Inclusion Criteria ..................................................................................................... 25 
4.2.2 
Exclusion Criteria..................................................................................................... 26 
5 
Study Procedures ................................................................................................................... 26 
5.1 
Screening ........................................................................................................................ 26 

 
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5.2 
Informed Consent .......................................................................................................... 27 
5.3 
Enrollment ...................................................................................................................... 27 
5.4 
Baseline Assessment ...................................................................................................... 28 
5.5 
Pre-Procedure ................................................................................................................ 28 
5.6 
Procedure Visit ............................................................................................................... 28 
5.6.1 
Index Procedure ...................................................................................................... 28 
5.6.2 
Intravascular ultrasound (IVUS) .............................................................................. 28 
5.6.3 
Calcium modification protocol................................................................................ 30 
5.6.4 
Quantitative Coronary Angiography (QCA) ............................................................ 33 
5.6.5 
Antithrombotic Drug Treatment ............................................................................. 33 
5.6.6 
Post-Operative Procedures ..................................................................................... 34 
5.7 
Follow-up ........................................................................................................................ 34 
5.8 
Unscheduled Visit ........................................................................................................... 35 
5.9 
Subject Discontinuation ................................................................................................. 35 
5.9.1 
Withdrawal prior and/or during index procedure .................................................. 35 
5.9.2 
Patient withdrawal .................................................................................................. 36 
5.9.3 
Investigator Withdrawal ......................................................................................... 36 
5.9.4 
Lost to Follow-up .................................................................................................... 36 
5.10 Premature Termination or Suspension of the Study ..................................................... 37 
5.11 Description of Assessments and CRFs ............................................................................ 37 
5.12 Additional Case Report Forms ........................................................................................ 38 
6 
Safety Reporting .................................................................................................................... 39 
6.1 
Definition of Adverse Events (AEs) ................................................................................. 39 
6.1.1 
Adverse Events (AEs)............................................................................................... 39 
6.2 
Adverse Event (AE) Assessment ..................................................................................... 40 
6.3 
Reporting and Documentation....................................................................................... 41 
6.3.1 
Report by Sponsor ..................................................... Error! Bookmark not defined. 

 
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6.3.2 
Report by the investigator to the Sponsor ............................................................. 41 
7 
RISKS EVALUATION ................................................................................................................ 42 
7.1 
Risks ................................................................................... Error! Bookmark not defined. 
7.1.1 
Potential adverse events (AEs) ............................................................................... 42 
7.2 
Methods to Minimize Risks ............................................................................................ 42 
8 
Statistical Consideration/Evaluation ..................................................................................... 43 
8.1 
Statistical Considerations and Analysis .......................................................................... 43 
8.2 
Analysis sets ................................................................................................................... 43 
8.3 
Statistical analyses ......................................................................................................... 43 
8.3.1 
General considerations ........................................................................................... 43 
8.3.2 
Description of baseline variables ............................................................................ 44 
8.3.3 
Primary analysis ...................................................................................................... 44 
8.3.4 
Secondary analysis .................................................................................................. 45 
8.3.5 
CIP deviations .......................................................................................................... 45 
8.3.6 
Subgroup analysis ................................................................................................... 45 
8.4 
Sample size ..................................................................................................................... 45 
8.5 
Missing Data ................................................................................................................... 46 
9 
DATA COLLECTION, HANDLING AND RETENTION ................................................................. 46 
9.1 
Source Documentation (SD) ........................................................................................... 46 
9.2 
Electronic Data Entry ...................................................................................................... 46 
9.2.1 
Data Confidentiality and Data Protection ............................................................... 47 
9.3 
Study Records Retention ................................................................................................ 47 
10 REPORTING ............................................................................................................................ 47 
10.1 Annual Progress Report.................................................................................................. 47 
10.2 End of Study Report ....................................................................................................... 47 
10.3 Other Reporting ............................................................................................................. 47 
11 MONITORING, QUALITY CONTROL AND ASSURANCE ........................................................... 48 

 
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11.1 Site Monitoring Plan ....................................................................................................... 48 
11.2 On-site Audits ................................................................................................................. 48 
11.3 Protocol Deviations ........................................................................................................ 48 
11.4 Protocol Amendments ................................................................................................... 49 
11.5 Core Laboratory.............................................................................................................. 49 
12 ETHICS AND REGULATORY ..................................................................................................... 50 
12.1 Regulation statement ..................................................................................................... 50 
12.2 Informed Consent Procedure ......................................................................................... 50 
12.3 Subject Confidentiality ................................................................................................... 50 
12.4 Selection of Investigators/Sites ...................................................................................... 51 
12.5 Training requirements .................................................................................................... 51 
13 PUBLICATION POLICY ............................................................................................................. 51 
14 STUDY COMMITTEES ............................................................................................................. 52 
14.1 Steering Committee (SC) ................................................................................................ 52 
14.2 Data Safety Monitoring Board (DSMB) .......................................................................... 52 
14.3 Clinical Event Committee (CEC) ...................................................................................... 52 
15 Bibliography ........................................................................................................................... 53 
APPENDIX A - Definitions .............................................................................................................. 54 
APPENDIX B - Abbreviations ......................................................................................................... 61 
 
 

 
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REVISION HISTORY 
 
Version 
Date 
Reason for Change 
1.0 
01 MAR 2024 
First version 
1.1 
11 AUG 2024 
Modifications:  
- Added contact details of Clinical research organizations 
(CROs),  imaging Corelab, EDC provider 
- Added page of signature for CROs, investigation sites 
- Updated study staff 
- Removed incorrect reference to DSMB 
- Clarified timeline requirement for 12 lead ECG prior to 
discharge 
- Clarification on when a pregnancy test should be 
undertaken 
- Amendment of 30 day and 12 month follow-up intervals 
- Include reference to Data Safety Plan 
- Include reference to EU General Data Protection 
Regulation (GDPR 2016/679). 
- Include reference to EU MDR 2017/745 
 
 
 
 

 
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CONTACT INFORMATION 
Responsibility 
Name and Address 
Contact Details 
Study Sponsor  
 
Prof. Fergal O’Brien 
Royal College of Surgeons in Ireland 
RCSI, Anatomy, 123 St Stephens Green, Dublin 2 
Phone: +353 1 402 2149 
E-mail:  fjobrien@rcsi.com 
Co-Principal 
Investigator 
Prof. Robert Byrne 
Cardiovascular Research Institute (CVRI) Dublin, 
Mater Private Network Dublin, 73 Eccles Street, 
Dublin, D07KWR1, IRELAND 
Phone: +353 1 248 1843 
E-mail: robertabyrne@rcsi.ie  
Co-Principal 
Investigator 
Prof. Barbara E. Stähli 
Department of Cardiology, University Heart Center, 
University Hospital Zurich, Rämistrasse 100, 8091 
Zurich, Switzerland 
 
E-mail: barbara.staehli@usz.ch 
Study Chair 
Dr. Colm Hanratty 
Cardiovascular Research Institute (CVRI) Dublin, 
Mater Private Network Dublin, 73 Eccles Street, 
Dublin, D07KWR1, IRELAND 
Phone: +353 1 793 4726 
E-mail: 
colm.hanratty@materprivate.ie 
Clinical 
research 
organizations 
(CRO)  
 
Carmen Lucy Farrelly 
Study Coordinator 
 
Cardiovascular Research Institute (CVRI) Dublin, 
Mater Private Network Dublin, 73 Eccles Street, 
Dublin, D07KWR1, IRELAND 
Phone: +353 (1) 882 2673 
E-mail: 
carmen.farrelly@materprivate.ie 
Cardiovascular European Research Centre (CERC) 
7 Rue du Theatre, 91300 Massy, France 
 
Dr. Marie-Claude MORICE, CEO 
Email: 
mcmorice@cerc-europe.org 
Phone: +33 (0)1 76 73 92 56 

 
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Imaging Core 
Lab 
IVUS:  
CERC Imaging core laboratory 
7 Rue du Theatre, 91300 Massy, France 
 
QCA: 
CVRI Dublin Imaging Core Laboratory 
73 Eccles Street, 
Dublin 7, D07 KWR1, Ireland 
 
Dr. Peter SMITS, Medical Director 
Email: psmits@cerc-europe.org 
 
 
Dr. Himanshu Rai, Director of 
Core Lab 
Email: 
Himanshu.rai@materprivate.ie 
Electronic 
Data Capture 
(EDC) Provider 
Clean web 
Telemedecines Technologies SAS 
121 rue d’Aguesseau 
92100, Boulogne-Billancourt 
France 
Email: hotline@tentelemed.io 
 
 

 
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PROTOCOL SUMMARY 
Title: 
Implementation of a Standardized Algorithm for CoronarY CaLcificatiOn 
with PlaquE Modification using UltraSound Guidance to Improve 
Procedural and Clinical Outcomes (CYCLOPES) 
Investigational 
strategy: 
Calcium modification algorithm (Figure 1) to guide coronary 
intervention with an HD IVUS imaging guided pathway that provides a 
systematic approach to coronary modification. 
Study 
Population:  
Patients with coronary artery disease with evidence of moderate to 
severely calcified coronary arterial lesions that are planned for 
percutaneous intervention requiring calcium modification. 
Design: 
CYCLOPES is a prospective, multicenter, open-label, single arm trial 
assessing the feasibility and efficacy of an intracoronary ultrasound 
guided algorithm (Figure 1) for calcium modification in patients 
undergoing percutaneous coronary intervention (PCI) for chronic calcific 
coronary artery disease. The study will enroll 500 patients who will 
undergo PCI with calcium modification. 
 
Participants will be enrolled prospectively in 25 sites in Ireland, 
Switzerland, the United Kingdom, Spain, France, Italy and Germany (7 
countries). 
 
All patients will have coronary angiography (QCA) and intravascular 
ultrasound (IVUS) imaging with 60MHz HD IVUS of the calcified lesion at 
baseline. The lesion will be characterized based on calcium distribution 
and morphology as assessed by HD IVUS. Depending on the specific 
lesion characteristics, the appropriate method for calcium modification 
will be chosen and performed in line with the CYCLOPES calcium 
modification algorithm included in the study protocol.  
 
The calcific lesion will be imaged for a second time by 60MHz HD IVUS 
following calcium modification. The operator will then proceed, if no 
further lesion preparation is required, to deploy a bioabsorbable 
polymer Everolimus eluting stent using standard stenting techniques, 
post dilatation will be performed at the operator’s discretion. The 
treated lesion will be assessed again using intravascular ultrasound 
following stent deployment and optimization.  

 
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The primary end points will be the post stenting minimal stent area 
(MSA) at the site of maximum calcification relative to reference lumen 
area assessed with 60MHz HD IVUS and target lesion failure (TLF) at 1-
year post-procedure. All HD IVUS determined endpoints will be assessed 
at an independent imaging core laboratory. 
 
Participants will be assessed with clinic or phone visits at hospital 
discharge, 1 month and 12-month time points post procedure. 
 
 
Objectives: 
The aim of this study is to validate a comprehensive and intravascular 
imaging-based calcium modification algorithm for the treatment of 
moderate to severely calcified coronary lesions. 
Primary 
Endpoints: 
The study will have co-primary endpoints: 
1. Minimum stent area (MSA) at the site of maximum calcification 
measured at the end of the index procedure 
2. Target lesion failure (TLF) (cardiovascular death, non-fatal 
myocardial infarction (MI) related to the target vessel, 
unplanned ischemia-driven target lesion revascularization) at 1 
year 
Secondary 
Endpoints: 
1. Individual components of TLF at 1 month and 1 year 
2. Minimum stent area (MSA) at the end of the index procedure 
3. Strategy success defined as: 
a) Successful stent delivery 
b) ≥ 80% stent expansion 
c) Complete stent apposition 
d) No edge dissection 
e) Full lesion coverage with <50% plaque burden at proximal and 
distal references 
f) TIMI 3 flow 
4. Target vessel revascularization (TVR) 
5. Target lesion revascularization (TLR) 
6. Stent thrombosis 
7. Stroke 
8. Cardiovascular death 

 
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9. Acute kidney injury 
10. Major bleeding, categorized as class 3-5 according to the Bleeding 
Academic Research Consortium [BARC] 
11. Procedure time 
12. Fluoroscopy time 
13. Radiation exposure (dose-area-product) 
14.  Cost effectiveness analysis 
Sample size: 
500 patients 
Inclusion 
Criteria: 
1. Documented myocardial ischaemia.  
2. At least one moderate to severely calcified native coronary 
artery lesion confirmed by QCA and/or 60MHz HD IVUS, with the 
presence of significant calcium, ≥70% diameter stenosis by visual 
estimation (in a reference vessel diameter of ≥2.5mm and ≤4.0mm) 
and TIMI 3 flow at baseline that is suitable for PCI.  
a. Significant calcium at the target lesion site is defined as 
either: 
i.The presence of radiopacities involving both sides 
of the arterial wall >10mm and involving the target 
lesion on angiography.  
or  
ii.The presence of >270° arc of superficial calcium on 
HD intravascular imaging with a length >5mm or 
the presence of 360° arc of calcium on HD 
intravascular imaging. [1]  
3. It is possible to cross the calcified lesion with a coronary 
guidewire.  
4. Age ≥ 18 years.  
5. Patient is willing and able to comply with the study procedures 
and follow-up.  
Exclusion 
Criteria: 
1. Patients with cardiogenic shock. 
2. ST-segment elevation myocardial infarction. 
3. Instent re-stenosis. 
4. Stent thrombosis. 
5. Coronary artery dissection. 
6. Chronic total occlusion in a major artery. 
7. Left ventricular ejection fraction ≤30%. 

 
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8. Need for coronary artery bypass graft surgery. 
9. Documented allergy to everolimus or to any stent material 
10. Any contraindication for dual antiplatelet therapy with aspirin 
and a P2Y12 inhibitor for at least 3 months (except for patients 
on oral anticoagulation). 
11. For female, pregnancy, breastfeeding or intend to become 
pregnant within 1 year 
12. Life expectancy <1 year. 
13. Participation in another study with an investigational product. 
14. Inability to provide informed consent. 
Study oversight: An independent clinical events committee (CEC) will adjudicate clinical 
events that are primary or secondary endpoints or components of same. 
The study will be monitored per a monitoring plan, data will be collected 
in an electronic case report form (eCRF). QCA and HD IVUS data will be 
assessed by independent core laboratories.  
Study 
organization: 
- Sponsor: Royal College of Surgeons in Ireland 
- CRO for study management in Ireland: Cardiovascular Research 
Institute (CVRI) Dublin, Mater Private Network Dublin 
- CRO for study management in other countries: CERC (Cardiovascular 
European Research Center)n 
Antiplatelet 
Therapy: 
Dual anti-platelet therapy (DAPT) (P2Y12 inhibitor plus aspirin) should 
be prescribed for 6 months, but the duration may be adjusted in keeping 
with the prescribing physician’s usual clinical discretion and depending 
on clinical bleeding risk. 
Follow-up: 
1. On the day of discharge from the index procedure 
2. 30 days +/- 7-day window (clinic or phone visit) 
3. 12 months +/- 30-day window (clinic or phone visit) 
Study Duration:  
 
The expected duration of the study is approximately 36 months (18 
months to complete enrollment, plus 12 months to complete follow-up 
and 6 months for data freeze, core lab analysis and statistical analysis): 
subjects will be followed for 1 year with clinic or phone visit at 1 month 
and 12 months.  

 
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GCP Statement 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, ISO EN 14155 2020 (as 
well as all national legal and regulatory requirements). [2] 
 
 

 
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FIGURE 1a: PROPOSED CALCIUM MODIFICATION ALGORITHM 
 
Figure 1a CYCLOPES calcium modification algorithm, summary version including set-up. The 
proposed algorithm uses the acronym DMC (Define, Modify, Confirm) to outline the steps to 
successful calcium modification. Step 1: Define, involves intravascular ultrasound to define the 
characteristics of the calcified lesion. Step 2: Modify involves the use of calcium modification 
devices to modify the calcified lesion. Step 3: Confirm requires a repeat intravascular ultrasound 
acquisition to confirm whether the modification process was successful or not. Dependent on 
the outcome of the confirm step, a recommendation to insert a stent or repeat calcium 
modification is made. 

 
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FIGURE 1b: PROPOSED CALCIUM MODIFICATION ALGORITHM 
Figure 1b CYCLOPES calcium modification algorithm. Detailed version. 

 
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FIGURE 1c: PROPOSED CALCIUM MODIFICATION ALGORITHM 
 
Figure 1c Guideline for 60 MHz HD IVUS image interpretation 
 

 
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FIGURE 1d: IVUS Pre-stent Workflow. Adapted from IVUS 1 2 3 Essentials. 
 
 
Figure 1d IVUS Pre-stent Workflow. Adapted from IVUS 1 2 3 Essentials. 

 
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TABLE 1: TIME SCHEDULE/DATA COLLECTION 
 
1 Follow-up assessments may consist of a structured telephone interview, or if standard of care, an office visit. 2 High sensitivity troponin is mandatory for pre-index procedure, 
18-24 hours post-index procedure (or at immediately prior to discharge, if discharged before 18 hours post-procedure) and in case of a clinical event; 3 Full blood count, serum 
creatinine, HbA1c, lipid profile (non-fasting acceptable). 4 For all subjects, coronary angiography and raw 60 MHz HD IVUS image recordings from 3 specified time points (baseline, 
post lesion preparation and post stent insertion) will be sent to the independent Imaging Core Laboratory for evaluation of primary endpoint (MSA). 5 One post-procedural 12 
lead ECG should be performed prior to hospital discharge. A repeat 12 lead ECG may be performed if clinically indicated. 
Study Period 
Screening/ 
Enrollment 
 
 
 
Visit 
1: (day 1/week 0) 
2: (hospital discharge) 
3: (day 30 ± 3 days) 
4: (1 year ± 2 weeks) 
Mode of visit 
Clinical 
Clinical 
Phone 
Phone/Clinical1 
Screening 
x 
 
 
 
Patient information and informed consent 
x 
 
 
 
Review of in-/exclusion criteria 
x 
 
 
 
Demographics 
x 
 
 
 
Medical history 
x 
 
 
 
Physical examination 
x 
 
 
(x) 
Cardiac enzymes2 
x 
x 
 
 
Review of laboratory data3, ECG 
x 
x 
 
(x) 
Review of concomitant medications 
x 
x 
x 
x 
Coronary angiography and PCI (with 60 MHz HD IVUS 
guidance and use of calcium modification devices 
according to a specific algorithm)4 
x 
 
 
 
Adverse event assessment/reporting 
 
x 
x 
x 
Assessment of endpoints 
 
x 
x 
x 
Final status 
 
 
 
x 

 
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1. INTRODUCTION 
1.1. Background Information 
Up to a third of patients undergoing coronary angiography present with coronary artery lesions 
with significant calcium. [3, 4] Given the ageing of the population, the prevalence of calcified 
lesions and the number of patients undergoing complex percutaneous coronary intervention 
(PCI) are expected to rise further. The presence of coronary calcifications is associated with an 
increased procedural complexity, including challenging device delivery and prolonged 
procedures, as well as worse procedural and clinical outcomes.  
 
Coronary lesion modification is important to ensure optimal stent delivery, expansion, 
and apposition. Dedicated devices have been developed and approved to allow for coronary 
calcium modification before stent implantation. These devices include non-compliant balloons, 
super high-pressure balloons, scoring and cutting balloons, rotational atherectomy devices [5] 
and intravascular lithotripsy (IVL) devices. [3, 6] 
 
Cutting balloons are dedicated non-compliant balloons characterized by fixed, 
microsurgical atherotomes that anchor to tissue and precisely dilate calcified lesions at low 
pressures. Rotational atherectomy can effectively ablate calcified plaques, facilitating in many 
cases stent delivery and expansion. Intravascular lithotripsy balloons emit pulsatile sonic 
pressure waves, thereby creating microfractures in intimal and medial calcium in the vessel wall. 
Intravascular lithotripsy balloons have received CE Mark and are available in Europe since 2017, 
following the DISRUPT CAD I and II studies. [6, 7] 60 MHz HD Intravascular ultrasound (IVUS) 
imaging performed after delivering a coronary guidewire allows for a detailed assessment of the 
severity and distribution (concentric or eccentric, deep or superficial, calcium arc) of 
calcifications, thereby facilitating optimal procedural planning and lesion preparation. [8] 
 
Given this armamentarium available in contemporary catheterization laboratories, 
calcium modification algorithms are needed as guidance for optimal device selection. The 
calcium modification algorithm proposed by Oksnes and McEntegart integrates lesion 
assessment by intravascular ultrasound and provides a systematic approach to coronary plaque 
modification. [9] This study aims to evaluate the impact of the systematic utilization of this 
calcium modification algorithm on procedural and clinical outcomes in patients undergoing 
complex PCI. 
 
1.2. Study Rationale 
This study will validate a calcium modification algorithm for coronary lesion preparation in a large 
cohort of patients with complex coronary artery disease and thereby provide evidence for a 

 
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structured approach to the treatment of calcified coronary lesions. Further, the database will 
allow us to identify clinical and imaging risk predictors for procedural success and clinical 
outcomes in patients with calcified coronary lesions undergoing percutaneous coronary 
intervention (PCI). 
1.3. Study Objective 
The aim of this study is to validate a comprehensive and intravascular imaging-based calcium 
modification algorithm for the treatment of moderate to severely calcified coronary lesions.  
2. DEVICE INFORMATION 
All devices are approved for use during percutaneous coronary intervention, including the listed 
specialist calcium modification devices, are used in line with standard clinical practice, and are 
not under investigation. Only CE marked devices are used. 
 
Standard procedural devices used for percutaneous coronary interventions include: 
1. Standard coronary guide catheters 
2. Standard coronary angioplasty wires 
3. Second generation bioabsorbable polymer everolimus-eluting stents 
4. Intravascular ultrasound catheters 
5. Standard compliant and non-compliant angioplasty balloons 
 
Specialist calcium modification devices: 
1. Wolverine™ cutting balloon, Boston Scientific, Marlborough, Massachusetts 
2. Rotablator atherectomy system™, Boston Scientific, Marlborough, Massachusetts 
3. Shockwave Coronary Rx Lithoplasty System™, Shockwave Medical Inc, Santa Clara, 
California 
3. Study Design 
3.1. General 
This study is an international, multi-centre, observational, single-arm study. A total of 500 
patients will be enrolled at 25 centers in Europe. 
Patients will be screened before coronary angiography, and patients with planned PCI for 
moderate to severely calcified native coronary artery lesion will be eligible. 
All procedures will be performed by fully trained operators with at least 50 prior rotablation 
procedures and several years of interventional experience. [5] All procedures will be performed 
according to current guidelines and international standards using a biodegradable-polymer, 

 
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Everolimus-eluting stent. [8, 10] In all patients, HD 60 MHz HD IVUS imaging will be performed 
according to a study-specific algorithm (outlined in section 5.6.3) after 1. crossing the lesion with 
a coronary guidewire, 2. after lesion preparation, and 3. after stent implantation to ascertain an 
optimal procedural result. 
Baseline characteristics, vital signs, concomitant diseases, cardiovascular risk factors, medication, 
routine laboratory analyses, ECG data, coronary angiography, and procedural data (coronary 
angiogram, HD IVUS images, procedural characteristics, and periprocedural complications), and 
follow-up data will be collected. 
The co-primary end points are minimum stent are (MSA) at the site of maximum calcification at 
the end of the index procedure (as assessed by 60MHz HD IVUS imaging) and rates of target 
lesion failure (TLF), a composite of cardiovascular death, non-fatal myocardial infarction related 
to the target vessel, and unplanned ischemia-driven target lesion revascularization, at 1 year.  
Coronary angiograms and HD IVUS images will be analyzed by an independent angiography and 
HD IVUS Core Lab. Follow-up will be performed at discharge, at 30 days, and at 1 year.  
The study will be conducted in accordance with the investigation plan, the current version of the 
Declaration of Helsinki, and national legal and regulatory requirements. [2] 
3.2. Study duration 
The total expected duration of the study is approximately 36 months. 
Enrollment will take place over a period of 18 months. Follow up is planned for 12. There will be 
an additional 6 months for data freeze, core lab analysis and statistical analysis. 
3.3. Endpoints 
3.3.1. Co-Primary Endpoint 
1. Minimum stent area (MSA) at the site of maximum calcification at the end of the index 
procedure  
2. Target lesion failure (TLF) (cardiovascular death, non-fatal myocardial infarction related 
to the target vessel, unplanned ischemia-driven target lesion revascularization) at 1 year 
3.3.2. Secondary Endpoints 
1. Individual components of TLF at 1 month and 1 year. 
2. Minimum stent area (MSA) measured at the end of the index procedure. 
3. Strategy success defined as: 
o Successful stent delivery 
o ≥ 80% stent expansion 

 
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o Complete stent apposition 
o No edge dissection 
o Full lesion coverage with <50% plaque burden at proximal and distal references 
o TIMI 3 flow 
4. Target vessel revascularization (TVR) 
5. Target lesion revascularization (TLR)  
6. Stent thrombosis 
7. Stroke 
8. Cardiovascular death 
9. Acute kidney injury 
10. Major bleeding, categorized as class 3-5 according to the Bleeding Academic Research 
Consortium [BARC] 
11. Procedure time 
12. Fluoroscopy time 
13. Radiation exposure (dose-area-product)  
14. Cost effectiveness analysis 
4. Study Population 
4.1 Patient Population 
Patients with coronary artery disease with evidence of calcified coronary arterial lesions who are 
planned for percutaneous intervention requiring calcium modification. 
4.2 Eligibility criteria 
4.2.1 Inclusion Criteria 
Subjects will be assessed to ensure they meet all the inclusion criteria to be eligible for study 
enrollment:  
1. Clinical indication for PCI in the setting of chronic coronary syndrome or non-ST-segment 
elevation myocardial infarction due to symptoms or documented myocardial ischaemia. 
3. At least one moderate to severely calcified native coronary artery lesion confirmed by 
QCA and/or 60MHz HD IVUS, with the presence of significant calcium, ≥70% diameter 
stenosis by visual estimation (in a reference vessel diameter of ≥2.5mm and ≤4.0mm) and 
TIMI 3 flow at baseline that is suitable for PCI.  
b. Significant calcium at the target lesion site is defined as either: 
ii.The presence of radiopacities involving both sides of the arterial wall >10mm 
and involving the target lesion on angiography.  
or  

 
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iii.The presence of >270° arc of superficial calcium on intravascular imaging 
with a length >5mm or the presence of 360° arc of on intravascular imaging. 
[1]  
2.  It is possible to cross the calcified lesion with a coronary guidewire. 
3. Age ≥ 18 years. 
4. Patient is willing and able to comply with the study procedures and follow-up. 
 
Patient is willing and able to comply with the study procedures and follow-up. [6, 11] 
4.2.2 Exclusion Criteria 
Subjects will be assessed to ensure they do not meet any of the exclusion criteria to be eligible 
for study enrollment:  
1. Patients with cardiogenic shock. 
2. ST-segment elevation myocardial infarction. 
3. Instent re-stenosis. 
4. Stent thrombosis. 
5. Coronary artery dissection. 
6. Chronic total occlusion in a major artery. 
7. Left ventricular ejection fraction ≤30%. 
8. Need for coronary artery bypass graft surgery. 
9. Documented allergy to everolimus or to any stent material 
10. Any contraindication for dual antiplatelet therapy with aspirin and a P2Y12 inhibitor for at 
least 3 months (except for patients on oral anticoagulation). 
11. Female pregnancy, breastfeeding or intend to become pregnant within 1 year 
12. Life expectancy <1 year. 
13. Participation in another study with an investigational product. 
14. Inability to provide informed consent. 
5. Study Procedures 
This chapter describes the procedures the Investigator must follow for each study phase in detail. 
Table 1 summarizes clinical study assessments, procedures, and information collected on case 
report forms (CRFs). 
5.1. Screening 
Patients meeting the general inclusion and exclusion criteria (defined in section 4.2) will be 
informed about the study and asked to read the patient information leaflet. In case they agree 
to participate in the study, they will be asked to sign the consent form.   

 
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All patients who are screened and offered study participation and/or are consented for the study 
and/or are participating in the inclusion/exclusion process must be entered into the subject 
screening log regardless of their study eligibility. Patients must be entered into the log 
sequentially. 
5.2. Informed Consent 
Prior to participation in this study, before collection of any study specific data, the patient must 
complete an informed consent process involving reading the study information leaflet and then 
signing and dating the consent form. Designated center staff will explain the purpose of the study, 
data to be collected, how data will be used, time and travel commitments and other expectations 
of a study subject. The patient will be given the opportunity to discuss the study with the 
investigator, including any medical aspect of their disease or the study treatment. If the patient 
decides to participate, he/she will sign and date the informed consent form along with the 
Investigator and other staff participating in the consent process and the treatment visit will be 
scheduled. A copy of the informed consent form will be given to the subject. 
No patient will be enrolled without signing the informed consent. Any new significant 
information on the study algorithm or procedure that may be relevant to the subject’s willingness 
to participate or to continue participation in the study will be provided to new and existing 
subjects throughout the clinical investigation. If new information that can significantly affect a 
subject’s future health and medical care becomes available, this information shall be provided to 
the subjects affected. If relevant, all affected subjects shall be asked to confirm their continuing 
informed consent in writing.  
5.3. Enrollment 
After completing the informed consent, the final screening check takes place during the 
angiography: this will be confirmed and documented. Only once the below criteria are fulfilled 
can the patient be considered enrolled in the study:  
All angiographic inclusion and exclusion criteria outlined in section 4.2 are fulfilled. 
For the purposes of this clinical study, patients will be considered subjects after enrollment has 
been confirmed. 
If a patient has provided informed consent but has not met one of the above criteria for 
enrollment inclusion into the study, he/she will be considered a screen failure.   

 
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5.4. Baseline Assessment 
Prior to treatment, each patient’s medical history and demographics will be collected. 
Preoperative procedures include a physical examination, documentation of disease, relevant 
medical history and medication or coronary intervention.  
Furthermore, the subject must complete a series of assessments at the time preceding index 
treatment. These assessments include: 
• Laboratory Tests – full blood count, serum creatinine, cardiac troponin (cTn), HbA1c, and 
lipid profile (non-fasting acceptable). 
• Pregnancy test (βHCG subunit) - to be performed for women of childbearing potential if 
the last Menstrual Period does not fall within the last 10 days.  
• If it is not possible to perform the pregnancy test for women of childbearing potential in 
urgent cases, such patients will not be included in the study.   
5.5. Pre-Procedure 
Beyond the anti-platelet regimen, patients are to be medicated as per institutional procedures. 
All anti-platelet and oral medication administered will be captured in the medical notes for 
subsequent capture in the electronic case report form (eCRF).  
5.6. Procedure Visit 
5.6.1. Index Procedure  
Angiography, calcium modification techniques and HD IVUS imaging will be performed according 
to current international guidelines.  
Once the decision to proceed to PCI is made, prior to guidewire insertion, all patients will be 
administered heparin or bivalirudin according to the standard practice. All patients undergoing 
PCI will receive a loading dose of an ADP receptor antagonist. Patients not already receiving 
aspirin will be treated with an oral or intravenous loading dose of aspirin. 
After intracoronary injection of nitroglycerin, baseline angiography of the target vessel (TV) will 
be performed where single worst projection will be recorded for QCA analysis showing the target 
lesion (TL) for all subjects. 
5.6.2. Intravascular ultrasound (IVUS) 
Intravascular imaging of the lesion will then be performed using HD 60 MHz IVUS. Standard HD 
IVUS procedures should be followed as per the product manufacturer guideline during each HD 
IVUS recording. Automated pullback must be performed to image the full extent of the lesion 
from at least 10mm distal to the distal edge of the lesion to at least 10mm proximal to the 

 
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proximal edge of the lesion for each recording. A pullback speed of 0.5-1mm/s should be used. 
Longitudinal and cross-sectional planes must be recorded for each recording. 
The first, baseline HD IVUS recording will take place after the guidewire has crossed the lesion. 
This will allow for determination of baseline lesion characteristics, which can be input into the 
calcium modification algorithm. The characteristics that are to be assessed for the calcium 
modification algorithm include the degree of calcium arc, the lesion length, the reference vessel 
diameter, and the presence/absence of nodular calcium. The individual operator will make their 
assessment of the target lesion calcium characteristics and proceed to use the calcium 
modification algorithm (Section 5.6.3). The operator will then implement the lesion preparation 
method recommended by the calcium modification algorithm. 
Once the recommended calcium modification and lesion preparation has been completed, a 
second HD IVUS imaging recording will be performed using the same protocol as the baseline HD 
IVUS recording. This post lesion preparation HD IVUS recording will assess for calcium fractures 
and for luminal gain as compared to the baseline HD IVUS recording. The lesion characteristics 
assessed by the operator will be input to the next stage of the calcium modification algorithm, 
which will provide the next recommended action. 
If the individual operator is satisfied that optimal lesion preparation has been achieved by the 
presence of calcium fractures or acceptable luminal gain (or at the clinical discretion of the 
operator), they can proceed to treat the lesion with bioabsorbable polymer everolimus eluting 
stent(s). The operator may use their own clinical judgement to choose the appropriate stent type 
for the individual patient and lesion characteristics. If optimal lesion preparation has not been 
achieved by the above criteria, then further lesion preparation is recommended by the calcium 
modification algorithm. Each time that further calcium modification is performed, an additional 
HD IVUS recording is required to assess for optimal lesion preparation. Once optimal lesion 
preparation is achieved, the operator will then proceed to stent insertion. Pre-dilatation and 
post-dilatation may be performed by the operator as per their usual practice. Should the operator 
opt to avoid stent insertion during the index procedure based on their clinical decision, no further 
HD IVUS recordings will be required at this time point. Should a staged procedure be planned, 
and a stent inserted later, the final result should be assessed with HD IVUS, and recordings 
uploaded to the eCRF. 
Following stent insertion, a third and final HD IVUS recording of the target lesion will be 
performed. If additional stent optimization, such as with further post-dilatation with non-
compliant angioplasty balloon is required, this is permitted and must be followed by another HD 
IVUS recording such that the final HD IVUS recording shows the final optimized result. The 
baseline HD IVUS, the post lesion preparation HD IVUS (single or multiple runs) and the final HD 
IVUS recorded images must be uploaded to the eCRF for core lab analysis. 

 
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5.6.3. Calcium modification protocol 
 

 
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The CYCLOPES calcium modification algorithm illustrated in Figure 2 offers a 3-step process for 
the management of coronary calcification “Define, Modify, Confirm” (DMC). The algorithm is 
guided by intravascular ultrasound to be performed with mechanical pullback, using HD IVUS. 
The IVUS 1, 2, 3 Essentials Workflow should be performed at each HD IVUS acquisition 
throughout the algorithm[12]. 
 
Figure 3 Pre-stent workflow based on IVUS 123 Essentials workflow 
 
Figure 2 The CYCLOPES calcium modification algorithm provides a systematic approach to
selection of the appropriate calcium modification device. 

 
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Having met the eligibility criteria outlined in section 4.2, including QCA assessment, the set-up 
step is initiated. This involves crossing the calcified lesion with a coronary guidewire and 
attempting to cross the lesion with the imaging (IVUS) catheter. If the imaging catheter does not 
pass through the lesion, the lesion should be predilated with an angioplasty balloon to facilitate 
crossing the lesion with the imaging catheter at a second attempt. For any lesions that are not 
crossable with an angioplasty balloon, an upfront rotational/orbital atherectomy strategy may 
be required to proceed. 
Once the IVUS catheter is passed distal to the lesion, the first step of the DMC process, “Define” 
is initiated. The first HD IVUS acquisition takes place to define the potential characteristics of 
coronary calcification seen with intravascular imaging. The six features to assess are 
circumferential calcium, long segment of calcification, vessel sizing and reference vessel diameter 
(RVD), wire bias, calcific nodule, and reverberations. Circumferential calcium refers to the 
presence or absence of circumferential calcium. A long segment of calcification is assessed by the 
operator as a segment of calcified disease >20mm. Vessel sizing and reference vessel diameter 
(RVD) is assessed and recorded by the operator using the IVUS 123 Essentials workflow method 
[13]. Wire bias is defined as wire bias towards calcium or away from calcium. Calcific nodule 
refers to the presence or absence of a calcified nodule on HD IVUS. Reverberations refer to the 
presence of reverberations seen on HD IVUS. 
Once the lesion has been defined, move to the “Modify” step. The first part of this step involves 
attempting to pre-dilate the lesion with a non-compliant balloon or cutting balloon. For non-
compliant balloon dilatation, ideally a balloon sized in a 1:1 ratio to the reference vessel diameter 
as assessed by HD IVUS. For cutting balloon dilatation, the cutting balloon size should be chosen 
as 0.5mm smaller than media-to-media measurement of the vessel size as determined by 
intravascular imaging. It is strongly recommended that cutting balloon therapy be delivered to 
the target lesion at high pressure (e.g., ~18-20 atmospheres) as this has been shown to be safe 
and effective in prior studies[1]. 
If 1:1 balloon expansion is achieved with angiographic evidence of complete balloon expansion, 
then the lesion may be sufficiently prepared and additional calcium modification may not be 
required, so proceed to step 3, “Confirm”. If there is incomplete balloon expansion, then 
additional calcium modification methods may be required. Using the characteristics assessed 
with HD IVUS in the “Define” step, choose an additional modality for calcium modification. It is 
important to note that calcium characteristics may be heterogenous, as such, the final choice of 
calcium modification modality is at the discretion of the operator. 

 
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Ideal calcium characteristics for rotational atherectomy include balloon uncrossable lesions and 
long calcific lesions and calcified nodules, particularly if the wire is biased towards the nodule. 
Burr size should be approximately 0.5 x mean RVD. 
Ideal calcium characteristics for intravascular lithotripsy include the presence of a calcium arc 
>270° in large vessels. IVL may also be considered for eccentric or nodular calcium where wire is 
biased away from the nodule. 
Once the chosen modality for calcium modification has been used, move to the “Confirm” step, 
which involves post calcium modification HD IVUS imaging to assess the outcome of the “Modify” 
step. If signs of calcium modification are present, defined as the presence of calcium fractures or 
increased reverberations visualized on HD IVUS, then the algorithm directs the operator to DES 
insertion and optimization. Following DES insertion and optimization, a final HD IVUS acquisition 
takes place to assess the optimal stent implantation criteria. These criteria include at least 80% 
stent expansion, complete stent apposition, no edge dissection and full lesion coverage with less 
than 50% plaque burden at proximal and distal references. 
Further post-dilatation for DES optimization may be required at this point if the optimal stent 
implantation criteria is not met. This should be performed at the operator’s discretion. If 
additional DES optimization is performed, a final HD IVUS acquisition should be obtained showing 
the result.  
If at the “Confirm” step signs of calcium modification are absent, then the algorithm re-directs 
back to the modify step. At this point the choice of calcium modification modality is at the 
discretion of the operator. Multiple modalities may be used. The “Confirm” step must be 
completed after repeating the “Modify” step. 
5.6.4. Quantitative Coronary Angiography (QCA) 
Quantitative coronary angiography (QCA) images will need to be obtained at baseline (pre-
procedure and post-procedure) displaying the coronary lesion in the projection demonstrating 
the severity of the lesion, after intracoronary administration of nitrate (recommended 100-200 
μg, unless clinically contraindicated). At least two orthogonal, or near orthogonal views should 
be obtained.  
Quantitative analysis of the coronary angiographic images will be performed by an independent 
core laboratory for all subjects.  
5.6.5. Antithrombotic Drug Treatment 
Appropriate anticoagulant therapy must be provided to the patient prior to the angioplasty 
procedure and must be maintained during the procedure. 

 
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5.6.6. Post-Operative Procedures 
Following interventional treatment, patients will receive DAPT including a P2Y12 inhibitor in 
combination with aspirin for 6 months. The duration of DAPT may be changed by the prescriber 
at their usual clinical discretion or to account for increased bleeding risk, or co-prescription of 
anticoagulation. 
 
A post-procedural 12 lead electrocardiogram (ECG), will be performed prior to hospital discharge. 
In addition, in the event of development of symptoms after PCI a 12-lead ECG is required to 
document any suspicious cardiac ischemic episode.  
Cardiac troponin (cTn) (per institutional standard) will be measured in all cases at least once post 
procedure with one of the measurements at 18-24 hours post-procedure. If the patient is 
discharged prior to 18 hours post procedure, it will be measured immediately prior to discharge. 
Every effort must be made to obtain cardiac enzyme values within the specified time range to 
help determine presence or absence of MI post-procedure. In the case of multiple measurements 
prior to discharge, the first enzyme measurement and the peak value should be documented on 
the case report forms.  
If any cTn values above the reference range are noted post-procedure, per the Fourth Universal 
Definition, cTn measurements should continue to be performed every 6 hours for 24 hours, as 
per clinical practice starting from when the first elevation is noted. MI will be adjudicated 
according to the Fourth universal definition.  
Clinical status will be assessed at discharge. All cardiac medications will be recorded.  
A letter will be sent to the patient’s referring physician/general practitioner, explaining his/her 
participation in the study and a detailed schedule of required study activities and follow up time 
points. 
5.7. Follow-up 
Follow-up assessment visits will be at the following intervals following the index procedure: 
• Hospital discharge 
• 30 days (± 1 week) 
• 12 Month (± 1 month) 
• Unscheduled visit  
 
The following assessments and information will be collected at all follow-up visits: 

 
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• Review of concomitant medications including antithrombotic medications 
• Endpoint collection 
• Adverse event assessment/reporting 
 
In addition to above assessments, for the 12-month follow-up the following assessments will 
need to be performed as well:  
• Physical examination 
• Review of laboratory data 
• 12-lead ECG 
 
All follow-up time-points, except for 12-month time-point for which the subject needs to attend 
the clinic, may be completed by phone call (or if standard hospital practice during an office visit).  
A summary of required follow-up procedures is listed in Table 1. 
5.8. Unscheduled Visit 
Investigators may see the subjects, at their professional discretion, outside of the visits described 
in the study protocol.  If an SAE is reported during an unscheduled visit, the SAE and its treatment 
(CABG, re-PCI if any) should be documented in the same manner as for a study visit, per section 
6.2.  No additional data collection or CRFs are required at the unscheduled visit.  
5.9. Subject Discontinuation 
Subjects will participate in the study until they complete the 12-month post treatment 
assessments (per protocol). Subjects who do not complete the study per protocol may be 
withdrawn from the study in the following manner: 
5.1.1. Withdrawal prior and/or during index procedure  
Patients who have signed an informed consent form, but that are screen failures, will be 
documented as such on the subject screening log. 
For patients who were declared eligible for the study but who are discontinued for any reason, 
• either, prior to the commencement of PCI procedure or,  
• during the procedure, as it was not possible to cross the lesion with either the guidewire 
or the HD IVUS catheter. 
 

 
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These patients will also be considered screen failures. Data until that period will be collected and 
the patient will be immediately exited from study. The reason for the early withdrawal must be 
documented in the subject screening log. 
Patients that have not passed screening will not be enrolled in the study and further follow-up of 
these patients shall proceed according to the hospital standard procedures. 
5.1.2. Patient withdrawal 
Subjects may withdraw their consent and discontinue participation in the study at any time for 
any reason or no reason, without jeopardizing their medical care. If a subject withdraws consent 
it will be documented on the study exit form, and the reason for withdrawal will be requested.  
All data obtained until the date of withdrawal will be kept and entered into the efficacy and safety 
analysis. If the patient explicitly requests complete deletion of the records, they will be made 
aware that data pertaining to serious adverse events (SAEs) will be retained.  This should be 
documented by the site. Subjects will not be replaced.  
Once the subject is withdrawn, further follow-up of the patients shall proceed according to the 
hospital standard procedures.  
5.1.3. Investigator Withdrawal 
Subjects may be withdrawn by the investigator prior to receiving a study treatment for the 
following reason: 
If, on the day of procedure, it is determined by the investigator that the subject is no 
longer an appropriate candidate for the index procedure then the patient will be 
withdrawn from the study and will not receive the treatment. 
The investigator may decide to withdraw the subject from the study at any time based on medical 
judgment. In all instances of withdrawal, data collected up to the time of subject withdrawal may 
be used in the study. Subjects withdrawn from the study after being treated based on the study 
algorithm or procedures will not be replaced. The site should complete a study exit form. 
5.1.4. Lost to Follow-up 
If the subject cannot be reached for a follow-up visit, at least three telephone contacts (or 
attempts) should be made prior to recording a missed follow-up visit. The subject however 
remains in the study until the 1-year follow-up. The subject will only be considered as ‘Lost to 
follow-up’ if he/she cannot be reached for the final 1-year follow-up.  
NOTE: 
• More than three attempts can be made, but three is the minimum required.  

 
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• In the event contact with the subject cannot be established, the investigator will 
immediately contact the referring physician. If the referring physician has not had contact 
with the subject, information from the subjects identified point of alternative contact will 
be utilized. 
5.10. 
Premature Termination or Suspension of the Study 
The Sponsor may decide to suspend or prematurely terminate the clinical study in one or more 
investigation sites if e.g. information that the risk to the study subjects is higher than initially 
indicated becomes available. 
In the case of an early termination of the study, the regulatory authority(ies) and ethic 
committee(s) (ECs) should be informed according to local and national regulations. The reasons 
for termination should be provided and documented. An appropriate schedule for termination 
will be instituted. 
For patient safety reasons, patients already enrolled in the study will continue to be followed for 
the planned course of study described in this protocol.  
Patients will be informed that the study has been prematurely terminated and about the reason 
for this termination.  
5.11. 
Description of Assessments and CRFs 
All data to be collected is described below. 
Demographic Information  
Demographics collected will include but are not limited to gender, height, weight, age and race 
(if permitted).   
Medical History  
Relevant medical history will be collected but are not limited to conditions as diabetes mellitus, 
atrial fibrillation, peripheral vascular disease, previous MI(s), previous PCI/CABG, congestive 
heart failure, renal insufficiency, hypertension, previous cerebrovascular event and history of 
malignancy.   
Physical examination 
The physical examination is to include evaluations of blood pressure and heart rate as 
appropriate for the subject’s condition.  
Medication review 
Information regarding concomitant medication, clopidogrel, ticlopidine, prasugrel, ticagrelor, 
aspirin and oral anticoagulation medication use will be obtained.  

 
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12-Lead ECG 
Information regarding Q-waves, bundle-branch block and atrial fibrillation will be obtained pre-
procedure at 6-month and in case of a clinical event.   
Laboratory Tests 
Blood tests will be performed to collect information regarding full blood count, serum creatinine, 
HbA1c and lipid profile. Troponin will be collected at time points specified and in case of a clinical 
event. 
Angiography and Intravascular ultrasound (IVUS) 
At baseline (pre-and post-intervention), quantitative coronary angiography and HD IVUS imaging 
is mandatory as outlined in section 5.6 for all subjects and analyzed by Imaging Core Laboratory. 
In case of a clinical event an angiogram may also be acquired.  
 
NOTE: It is left at the discretion of the physician and standard of care of hospital to perform 
coronary angiography at any time point or any other imaging.   
 
Endpoint Collection 
The following events will be adjudicated via the CEC: 
• Death 
• MI 
• Any repeat revascularization 
• Target lesion thrombosis (TLT) 
5.12. 
Additional Case Report Forms  
Adverse Events (AEs) 
AE forms will document a description of the AE, onset date and duration, severity, seriousness, 
treatment, and relatedness. The form will also document whether the event was anticipated or 
unanticipated.  
Study Exit Form  
This form will document termination of each subject’s study participation and capture the reason 
for study exit.  
NOTE: screen failures will not be captured into the eCRF.  
Protocol Deviation Form  
This form will document deviations from the study protocol.  

 
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6. Safety Reporting 
6.1. Definition of Adverse Events (AEs) 
The following definitions are from ISO 14155:2011. 
Adverse Events (AEs) 
Table 2. Classification of AEs 
Non-serious 
Adverse Event (AE) (includes all categories) 
Serious 
Serious Adverse Event (SAE) (includes all categories that are serious) 
 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users, or other persons. 
 
Exceptions include events that are pre-existing (prior to index-procedure) and have not changed 
in severity or intensity. Once a pre-existing complication or event has changed in severity or 
intensity, it should be reported as an AE. 
 
Serious Adverse Event (SAE) 
A SAE is defined as an AE that: 
a. Led to a death, injury or permanent impairment to a body structure or a body function.  
b.  Led to serious deterioration in the health of the subject, that either resulted in 
i. a life-threatening illness or injury, or 
ii. a permanent impairment of a body structure or a body function, or 
iii. in-patient or prolonged hospitalization, or 
iv. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c. Led to foetal distress, foetal death or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a SAE/AE. 
 

 
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Adverse Event (AE) Assessment and Reporting 
As all devices used in this study are CE-mark approved and will only be used within the remit of 
their license, only adverse events, which in the opinion of the investigator, may represent a 
severe adverse advent, need to be reported. 
Each AE record must include a description of the event, date of onset, date investigator (or 
designee) became aware of AE, resolution, severity, action taken, relationship to procedure and 
seriousness criteria. 
Each AE must be recorded separately (each medical condition or symptom if no diagnosis is 
made). 
Severity will be assessed by the investigator using the following definitions: 
• Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• Moderate: minimal, local, or noninvasive intervention indicated; limiting 
• Severe: medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling  
 
Relationship to the study procedure or algorithm will be assessed by the investigator for each 
AE using the following definitions (according to EU MDR 2017/745 and MEDDEV 2.7/3 revision 
3): 
1. Not related: the relationship to the algorithm or procedures can be excluded when: 
• The event is not a known side effect of the study algorithm or procedure. 
• The event has no temporal relationship with the study algorithm or procedure. 
• The event is biologically implausible. 
• The event involves a body-site, or an organ not expected to be affected by the 
study algorithm or procedure. 
• The event can be attributed to another cause (e.g. an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment or other risk 
factors). 
• The event does not depend on a false result given by the study algorithm or 
procedure used for diagnosis, when applicable. 
• Harms to the subject are not clearly due to use error. 
• In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of procedures and the event. 

 
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2. Unlikely: the relationship with the use of the study algorithm or procedure seems not 
relevant and/or the event can be reasonably explained by another cause, but additional 
information may need to be obtained. 
3. Possible: the relationship with the use of the study algorithm or procedure is weak but 
cannot be ruled out completely. Alternative causes are also possible (e.g. an underlying 
or concurrent illness/clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed, or no information has been 
obtained should also be classified as ‘possible’. 
4. Probable: the relationship with the use of the study algorithm or procedure seems 
relevant and/or the event cannot be reasonably explained by another cause, but 
additional information may need to be obtained. 
5. Causal relationship: the event is associated with the study algorithm or procedure is 
beyond reasonable doubt when:  
• The event has a temporal relationship with the study algorithm or procedure. 
• The event follows a known response pattern to the study treatment algorithm or 
procedure (if the response pattern is previously known). 
• Other possible causes (e.g. an underlying or concurrent illness/clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out. 
• Harm to the subject is due to error in the use of the study algorithm or procedure.  
• The event depends on a false result given by the study algorithm or procedure 
used for diagnosis, when applicable. 
• In order to establish the relatedness, not all the criteria listed above might be met 
at the same time, depending on the event. 
Seriousness: If the AE meets any of the SAE criteria mentioned in section 0 it is regarded as 
serious. 
6.2. Reporting and Documentation  
All SAEs that occur either during the index procedure (after calcium modification) or during the 
1-year follow-up phase of the study will be documented as described above and entered into the 
eCRF as soon as possible upon knowledge of the event.  
 
6.2.1. Report by the investigator to the Sponsor 
The Principal Investigator (or designee) shall report all AEs to the Sponsor, or in case of 
discrepancy according to national regulations.  

 
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SAEs must be reported to the Sponsor immediately but in any event no later than 3 calendar days 
of occurrence or of the time the investigator becomes aware of the event. All information on the 
AE form must be made available to the Sponsor as early as possible.   
The Investigator is responsible for reporting all SAEs and new findings/updates in relation to 
already reported events to the EC if required by national regulations or by the EC according to 
local regulations. 
In case of early termination of the study, further follow-up of the study subject shall proceed 
according to this study protocol. 
Further details regarding safety definitions and reporting are described in study safety plan. 
7. RISKS EVALUATION 
7.1. Potential adverse events (AEs) 
The potential AEs that may be associated with the use of a calcium modification devices including 
non-compliant balloons, rotational atherectomy devices, intravascular lithotripsy devices and 
cutting angioplasty balloons in native coronary arteries include, but not limited to, are listed 
below.  
• Haematoma at the 
vascular access site 
• Pseudoaneurysm 
• Acute myocardial 
infarction 
• Pulse arrhythmia 
• Angina pectoris 
• Arterial perforation 
• Spasm of coronary 
arteries 
• Death 
• Cerebral circulatory 
disorders 
• General bleeding 
 
• Side effects due to the 
accompanying medication  
• Thrombus formation 
• Arterial rupture 
• Dissection of the coronary 
vessel 
• Hypotension 
• Ventricular fibrillation 
• Ischaemia 
• Arterio-venous fistulas 
• Palpitations 
• Vascular complications 
which necessitate a 
surgical intervention 
• Infections 
• Vessel trauma requiring 
surgical repair or re-
intervention 
• Emergent Coronary Artery 
Bypass Graft Surgery 
(CABG) 
• Arrhythmia, including 
ventricular fibrillation 
• Total occlusion of a 
coronary artery 
• Restenosis of prior 
treated target vessel 
segment 
7.2. Methods to Minimize Risks 
Several procedures have been incorporated into this protocol to protect study subjects.  

 
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• Specific inclusion/exclusion criteria ensure that patients at increased risk are not enrolled 
in the study (e.g. patients presenting with cardiogenic shock, ACS or left main stenosis).  
• Study subjects will be closely monitored post-procedure to detect and capture events.  
• Qualified physicians will participate as investigators and have experienced staff to 
perform.  
 
8. Statistical Consideration/Evaluation 
8.1. Statistical Considerations and Analysis  
The statistical analysis plan will be finalized prior to data freeze and will include an in-depth 
technical description of the statistical analyses described in this section. This section provides a 
summary of the planned statistical analyses of primary endpoints and key secondary endpoints 
as listed in section 3.3. 
8.2. Analysis sets 
Screened set 
All potentially eligible subjects meeting the general inclusion and exclusion criteria, who have 
signed an informed consent form, have had the index procedure and have been entered into the 
eCRF will be included in this set. These subjects will be followed up until discharge. This set also 
includes subjects who complete 12 months of follow up. 
Full analysis set (FAS) 
This set includes all subjects who have signed an informed consent form, have been entered into 
the eCRF, have had the index procedure completed and have met all inclusion and exclusion 
criteria. These subjects will have been assessed using the CYCLOPES calcium modification 
algorithm and will have been followed up to the end of study (12 months). 
Per protocol set (PP) 
This set will include all subjects from the FAS who have had no major protocol deviations. As 
outlined in section 11.3. 
8.3. Statistical analyses 
8.3.1. General considerations 
The study design aim is to validate a comprehensive, IVUS guided calcium modification algorithm 
for moderate to severely calcified coronary lesions and its effects on the primary and secondary 
outcomes outlined in section 3.3 herein. As such, no statistical hypothesis has been formulated 

 
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in accordance with the single arm, observational design. Descriptive statistics and graphical 
displays will be used to summarize the study findings and outcomes. 
Continuous variables will be summarized by the number of observations, arithmetic mean, 
standard deviation (SD), median, minimum, maximum and interquartile range unless otherwise 
stated. For categorial variables, frequency tables with be produced including counts and 
percentages. Time to event variables will be assessed using Kaplan-Meier curves. There will be 
no imputation of missing values, unless otherwise described in the statistical analysis plan. 
Estimates will be provided with corresponding two-sided 95% Confidence Intervals. No 
adjustments will be made for multiple testing. 
Continuous variables will be reported as mean and standard deviation or median and 
interquartile range, as appropriate. The distribution of continuous variables will be assessed by 
the Shapiro-Wilk test. Categorical variables will be reported as counts and percentages and 
compared by Pearson χ2 or Fisher exact test, as appropriate. In general, the denominator for the 
percentage calculation will be based upon the number of non-missing values available, unless 
otherwise specified.  
For time-to-event analysis other than the primary endpoint for the de-novo patients, Kaplan-
Meier survival curves as well as confidence intervals based on the log-log transformation will be 
reported. 
8.3.2. Description of baseline variables 
Baseline variables will include: 
• Demographic characteristics 
• Medical history 
• Past and concomitant anti-thrombotic medications 
• Clinical status at study entry 
• Baseline lesion characteristics 
8.3.3. Primary analysis 
The study will have co-primary endpoints. The co-primary endpoints are minimum stent area 
(MSA) at the site of maximum calcification measured at the end of the index procedure and target 
lesion failure (TLF) defined as the composite of cardiac death, non-fatal myocardial infarction 
related to the target vessel, and unplanned ischemia-driven target lesion revascularization at one-
year post-procedure. MSA is a numerical measurement in millimeters, measured at the 
independent imaging core laboratory. TLF is a binary endpoint (TLF or no TLF). 
 

 
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The primary analysis will be conducted on the FAS and will estimate the proportion of TLF at 1-
year with corresponding exact two-sided 95% CI. Descriptive analyses for MSA will be performed.  
8.3.4. Secondary analysis 
All secondary endpoints will be summarized by timepoint (see section 7.3 for details) using 
appropriate descriptive statistics as detailed above. 95% two-sided confidence intervals will also 
be calculated for the frequency and mean estimates at each timepoint, as appropriate. Time to 
event endpoints will be assessed using Kaplan-Meier curves. 
Specific details of the analysis of each secondary endpoint, including the rules for handling 
missing values, will be provided in the SAP. 
8.3.5. CIP deviations 
Major CIP deviations are deviations from the CIP which potentially could have a meaningful 
impact on study conduct, or on the primary or secondary outcomes for an individual subject. The 
criteria for identifying major CIP deviations will be defined within the appropriate CIP-specific 
document at study start. Major CIP deviations will be reviewed as part of the ongoing data 
cleaning process and all-important deviations will be identified and documented prior to 
database lock to confirm inclusion or exclusion from analysis sets. The analysis will be conducted 
on the FAS. 
CIP deviations will be summarized for all deviations and by type, with event counts and number 
of subjects with at least one deviation. 
8.3.6. Subgroup analysis 
Analyses will be performed to investigate potential differences in primary and secondary 
outcomes between, but not limited to, the following baseline groups: 
1. Individual subjects, vessel or lesion characteristics defining procedures of increased 
complexity. 
2. Gender (female/male). 
3. Age (<75 years/≥75 years). 
4. Vascular access site (radial/femoral/other). 
8.4. Sample size 
Target recruitment of 500 patients. 

 
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8.5. Missing Data  
There will be imputation for missing data. Partial dates may be handled as follows: if the day is 
missing then it will be imputed as 1, if the month is missing it will be imputed as January. Missing 
years will not be imputed. 
9. DATA COLLECTION, HANDLING AND RETENTION  
9.1. General 
Data will be managed as per EU General Data Protection Regulation (GDPR 2016/679). 
9.2. Source Document Verification (SDV) 
Source document Verification (SDV) for this study will be maintained to capture the course of 
treatment and to substantiate the integrity of the trial data. SDV will include, but is not limited 
to, worksheets, hospital and/or clinic or office records documenting subject visits including study 
and other treatments or procedures, medical history and physical examination information, 
imaging results, device accountability records, medical consultations and laboratory results and 
reports.   
9.3. Electronic Data Entry 
When using electronic data handling or remote electronic trial data systems, the Sponsor or the 
Sponsor’s representative will:  
• Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor established requirements for completeness, accuracy, reliability, and consistent 
intended performance (i.e., validation).  
• Maintain SOPs for using these systems.  
• Ensure that systems are designed to permit changes to the data in such a way that the 
data changes are documented and there is no deletion of any edited or entered data (i.e., 
maintains an audit trail).  
• Maintain a security system to prevent unauthorized access to the data and to uniquely 
identify individuals who access the data entry system.  
• Maintain a list of individuals authorized to make data changes.  
• Maintain adequate data backup.  
Primary data collection based on source-documented hospital and /or clinic chart reviews will be 
performed clearly, timely, adequately, and accurately by site personnel trained on the protocol 
and eCRF completion. Sponsor or designee will perform clinical monitoring as specified in 
Monitoring Plan.  

 
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.1.1. Data Confidentiality and Data Protection  
A role concept with personal passwords (site investigator, statistician, monitor, administrator 
etc.) regulates permission for each user to use the system and database as he/she requires. 
All data entered into the CRFs are transferred to the database. Each data point has attributes 
attached to it identifying the user who entered it with the exact time and date. Retrospective 
alterations of data in the database are recorded in an audit table. Time, table, data field and 
altered value, and the person are recorded (audit trail). Images collected are encrypted.  
9.4. Study Records Retention 
All eCRF information, study records, reports and Source Documents (SD) that support the eCRF 
must be retained in the files of the responsible investigator for a minimum 7 years following 
notification by the Sponsor or designee that all investigations have been completed and will 
further be retained in accordance with local and international guidelines as identified in the 
Investigator Site Agreement. 
The core laboratory will also maintain study records. They will maintain study records until the 
Sponsor notifies them that research is completed/terminated under the clinical investigation in 
compliance with national law. All study data will be archived for a minimum of 7 years after study 
termination or premature termination of the study. 
10. REPORTING  
10.1. 
Annual Progress Report  
Annually, as requested by independent ethics committee (IEC) or national regulations.  
10.2. 
End of Study Report  
The investigator should notify the IEC in writing within three months after completion, 
termination, or discontinuation of the study at the site. The same procedure will be applied to 
regulatory authorities where required.  
10.3. 
Other Reporting  
The reporting requirements of the investigator also include, but are not limited to:  
• Inform the Sponsor of IEC approval withdrawal.  
• Major deviations from the clinical study protocol to the Sponsor  
• Report or ensure the reporting, to the IEC by the Principal Investigator(s) as required by 
national regulations or the clinical study protocol or by the IEC.  

 
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11. MONITORING, QUALITY CONTROL AND ASSURANCE  
11.1. 
Site Monitoring Plan 
The investigators will allow onsite inspection of subjects’ SD as requested by the Sponsor or 
required by an IEC or regulatory authorities.  Monitoring activities may take place at the trial 
center or any ancillary facility where study conduct takes place. The investigators will provide 
access to all SD and adequate workspace. The investigators will be available to the Sponsor, IEC, 
or other regulatory authorities to discuss study issues as requested. 
Sites will be initiated and trained on the clinical study requirements. Assurance of the accuracy 
and reliability of data will consist of checking the consent forms and consent process, on site and 
remote monitoring. All required data for this study will be collected into an eCRF. Appropriate 
computer editing programs will be run to verify the accuracy of the data.  
There will be 100% informed consent verification, and all primary and secondary endpoint events 
up to 1 year will be adjudicated by an independent Clinical Events Committee (CEC). Verification 
of other SD will be performed as specified in the monitoring plan.  
Data monitoring will occur at the Sponsor’s discretion and in all cases where data irregularities 
are identified. As needed, intermittent monitoring visits may be conducted to compare data 
entered into the database to the subjects’ SD.   
Further details are outlined in the Monitoring Plan. 
11.2. 
On-site Audits 
The investigators will allow on-site inspection of subjects’ SD as requested by the Sponsor or 
required by an IEC or regulatory authorities. Monitoring activities may take place at the trial 
center or any ancillary facility where study conduct takes place. The investigators will provide 
access to all SD and adequate workspace. The investigators will be available to the Sponsor, IEC, 
or other regulatory authorities to discuss study issues as requested.  
If an Investigator is contacted by a Regulatory Agency in relation to this clinical trial/investigation, 
the Investigator will notify the Sponsor immediately and EC as appropriate. 
11.3. 
Protocol Deviations 
Investigators are not allowed to deviate from this CIP without prior authorization by the Sponsor 
except under emergency situations when necessary to preserve the rights, safety or well-being 
of study subjects.  

 
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Deviations and non-compliances will be recorded together with an explanation. Deviations or 
non-compliances that impact the rights, welfare, or safety of subjects shall be reported as soon 
as possible to the Sponsor and IEC, as required. 
If appropriate, corrective, and preventive actions will be discussed by the Sponsor, investigator, 
and/or the IEC to determine a suitable course of action.  
Deviations include, but are not limited to the following list: 
• Failure to receive assigned treatment. 
• Failure to obtain informed consent prior to conducting study specific activities. 
• Inclusion/exclusion criteria not met. 
• Incorrect version of the CIP/PIL used. 
• Subject could not be reached for a follow-up visit or follow-up visit was outside window. 
• AEs not reported by investigators in the required timeframe as specified in the protocol. 
• Source data permanently lost. 
Site compliance regarding deviations will be reviewed by the clinical study manager on a regular 
basis. In addition, all deviations from the protocol will be documented in the final report. 
11.4. 
Protocol Amendments 
Investigators will not modify, change, or otherwise amend the protocol without prior written 
consent of the Sponsor. As applicable, if a protocol amendment substantially alters the scientific 
validity of the study or affects the subjects’ rights, safety, welfare, or their willingness to 
continued participation in the study, the subject should generally be re-consented on an updated 
and approved (as required by local law and regulation) ICF. New procedures or processes which 
substantially alter the scientific validity of the study or affects the subjects’ rights, safety, welfare, 
or their willingness to continued participation the study will not be implemented until an 
approval or favorable opinion has been granted by the reviewing IEC, as applicable. 
11.5. 
Core Laboratory 
Two independent core laboratories will be used to perform quantitative coronary analysis (QCA) 
and intravascular ultrasound (IVUS) imaging analysis at: 
- 
Baseline for the index procedure 
- 
Post-calcium modification  
- 
Post-PCI for all subjects  
- 
Endpoints requiring a re-PCI in the treated lesion.  

 
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12. More details can be found in the study specific Core laboratory Plan.ETHICS AND REGULATORY 
12.1. 
Regulation statement 
This protocol has been developed and the study will be run in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki (2013). [1] Further the study will be 
run in compliance with ISO 14155 (2nd edition) 2011. Both investigators and Sponsor will conduct 
this study in accordance with any applicable local or regional laws and regulations. Investigators 
will neither conduct procedures specific to the study nor collect subject data without prior 
approval or favorable opinion of any IEC under whose jurisdiction the conduct of this study falls. 
It is acknowledged that in some geographic areas IEC review and approval of study data collection 
activities may not be required.  
During the conduct of study activity, the investigators and the Sponsor shall act in accordance 
with any further requirements as imposed by an IEC or regulatory agency. 
12.2. 
Informed Consent Procedure 
Any new information or protocol amendment that substantially alters the scientific validity of the 
study or affects the subjects’ rights, safety, welfare, or their willingness to continue participation 
in the study, will result in the re-consenting of currently active subjects on an updated and 
approved (as required by local law and regulation) ICF. 
12.3. 
Subject Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. Subject names will not be 
supplied to the Sponsor. Only the subject number will be recorded in the CRF, and if the subject 
name appears on any other document (e.g. pathologist report), it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. As part of the informed consent process, 
the subjects will be informed in writing that representatives of the Sponsor, IEC, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. If the results of the study are published, the subject’s 
identity will remain confidential. The investigator will maintain a list to enable subjects to be 
identified.  

 
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12.4. 
Selection of Investigators/Sites 
Qualified investigators and their sites will be selected based on experience running clinical 
studies, having adequate numbers of the target subject population and appropriate facilities, 
time and staff and commitment to conduct the clinical study, for participation.  
12.5. 
Training requirements 
Investigators and relevant staff will be trained on the following elements prior to enrollment of 
the first subject at a site: 
• Clinical Investigational Plan (CIP) 
• Electronic data capturing system  
• Informed consent procedure 
• Core lab interaction 
• Study documentation and administration 
• Investigator and Sponsor responsibilities 
• Role of the EC and regulatory authority 
• AE reporting procedures 
• Protocol deviation reporting procedures 
• Monitoring requirements and expectations 
• Applicable regulatory requirements 
 
Training will be done on an individual basis during a site visit before the first enrollment at each 
participating center. Additional training may be provided as needed. A training log will be used 
to document that training has been done. This will be filed in the site binder. When a new 
member joins the study site staff, the investigator/delegate or CRO will provide the appropriate 
training prior to their performing any study related activity.  
13. PUBLICATION POLICY  
CVRI Dublin and RCSI acknowledge that the Institution and/or Investigator may have a legitimate 
interest in publishing relevant parts of the Study Information. If the Institution and/or 
Investigator wants to publish such study information in appropriate scientific journals or other 
professional publications or present such information at scientific conferences/symposia, they 
may do so with respect to the following conditions:  
(a) only if the publication is consistent with the rules and conventions governing clinical 
studies and regulatory submissions in all relevant jurisdictions, and only if drafts of the 
material have been reviewed by CVRI Dublin and the Steering Committee (SC).  
 

 
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(b) Institutional data, sub-analysis or any other experience in the study may not be published 
until the multi-center collective results of primary endpoints at 1 year follow-up, as a whole, 
are published. The results of the study will have no bearing on the submission of the 
manuscript for publication. This publication of the primary endpoints will be submitted to a 
peer-reviewed journal within six (6) months of the outcome of all of the primary measures 
being met (i.e. within six months of all patients having completed one-year follow-up.) In the 
event that the study is terminated early, manuscript submission will occur within 90 days of 
study termination.  
(c) the Investigator and/or the Institution shall deliver the material intended for publication 
to CVRI Dublin at least sixty (60) days prior to the first intended submission for publication. 
CVRI Dublin will review and respond with its comments, if any, within (30) days of receipt of 
such a copy. 
14. STUDY COMMITTEES 
14.1. 
Steering Committee (SC) 
The SC membership will include, but not limited to, the Coordinating Investigator, Director Core 
Lab- CVRI Dublin, CVRI Dublin biostatistician and the CVRI Dublin Project Manager. The role of SC 
is to provide overall supervision of the study. The Coordinating Investigator will review and input 
into the study protocol and any protocol amendments and provide advice to the investigators on 
all aspects of the study. The Project Manager will be responsible for the management of the 
study. This committee will meet periodically by teleconference (TC) or in person to monitor the 
progress of the study, including patient enrollment, clinical site progress and protocol 
compliance. This committee will be responsible for reviewing the final results, determining the 
methods of presentation and publication, and the selection of secondary projects and 
publications. 
14.2. 
Data Safety Monitoring Board (DSMB) 
Due to the nature of the study, specifically that all devices used in this study have received CE-
Mark approval and will only be used within the remit of this approval, DSMB is not applicable for 
this study. 
14.3. 
Clinical Event Committee (CEC) 
The CEC is made up of three (3) interventional cardiologists who are not participants in the study. 
Study Investigators are not permitted to be CEC members to avoid conflict of interest.  

 
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The CEC is responsible for adjudicating all primary and secondary endpoint related events 
reported during the study following established explicit rules in the CEC charter which outlines 
the data required and the algorithm followed in order to classify a clinical event.  
The CEC will adjudicate events using either the independent review method or the consensus 
meeting method described in the study CEC charter. CEC findings will be summarized and 
documented in the CEC reports.  
15. Bibliography 
1. 
Mangieri, A., et al., Cutting balloon to optimize predilation for stent implantation: The 
COPS randomized trial. Catheterization and Cardiovascular Interventions, 2023. 101(4): p. 
798-805. 
2. 
Association, W.M., World Medical Association Declaration of Helsinki: Ethical Principles 
for Medical Research Involving Human Subjects. JAMA, 2013. 310(20): p. 2191-2194. 
3. 
Barbato, E., et al., Management strategies for heavily calcified coronary stenoses: an 
EAPCI clinical consensus statement in collaboration with the EURO4C-PCR group. Eur 
Heart J, 2023. 
4. 
Bourantas, C.V., et al., Prognostic implications of coronary calcification in patients with 
obstructive coronary artery disease treated by percutaneous coronary intervention: a 
patient-level pooled analysis of 7 contemporary stent trials. Heart, 2014. 100(15): p. 1158-
64. 
5. 
Abdel-Wahab, M., et al., High-speed rotational atherectomy before paclitaxel-eluting 
stent implantation in complex calcified coronary lesions: the randomized ROTAXUS 
(Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary 
Artery Disease) trial. JACC Cardiovasc Interv, 2013. 6(1): p. 10-9. 
6. 
Brinton, T.J., et al., Feasibility of Shockwave Coronary Intravascular Lithotripsy for the 
Treatment of Calcified Coronary Stenoses. Circulation, 2019. 139(6): p. 834-836. 
7. 
Ali, Z.A., et al., Safety and Effectiveness of Coronary Intravascular Lithotripsy for 
Treatment of Severely Calcified Coronary Stenoses: The Disrupt CAD II Study. Circ 
Cardiovasc Interv, 2019. 12(10): p. e008434. 
8. 
Neumann, F.J., et al., 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur 
Heart J, 2019. 40(2): p. 87-165. 
9. 
M., Ø.A.M., Intravascular Lithotripsy to Modify Calcified Coronary Artery Disease. How to 
use the Shockwave coronary Rx lithotripsy system. CARDIAC INTERVENTIONS TODAY, 
2020. 14(5). 
10. 
Knuuti, J., et al., 2019 ESC Guidelines for the diagnosis and management of chronic 
coronary syndromes. Eur Heart J, 2019. 

 
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11. 
Abdel-Wahab, M., et al., High-Speed Rotational Atherectomy Versus Modified Balloons 
Prior to Drug-Eluting Stent Implantation in Severely Calcified Coronary Lesions. Circ 
Cardiovasc Interv, 2018. 11(10): p. e007415. 
12. 
Scientific, 
B. 
How 
to 
IVUS. 
 
[cited 
2024 
02/02/2024]; 
Available 
from: 
https://www.bostonscientific.com/en-US/medical-specialties/interventional-
cardiology/coronary-interventions/how-to-ivus.html. 
13. 
How 
to 
IVUS, 
in 
https://www.bostonscientific.com/en-US/medical-
specialties/interventional-cardiology/coronary-interventions/how-to-ivus.html. 
Boston 
Scientific. 
APPENDIX A - Definitions  
 
DEATH   
(Academic Research Consortium-2 [ARC 2] definition) [2] 
 
Type of Death Definition 
- 
Cardiovascular death 
Cardiovascular death is defined as death resulting from cardiovascular causes. The following 
categories may be collected: 
1. Death caused by acute MI 
2. Death caused by sudden cardiac, including unwitnessed, death 
3. Death resulting from heart failure 
4. Death caused by stroke 
5. Death caused by cardiovascular procedures 
6. Death resulting from cardiovascular hemorrhage 
7. Death resulting from other cardiovascular cause  
 
- 
Non cardiovascular Death  
Non cardiovascular death is defined as any death that is not thought to be the result of a 
cardiovascular cause. The following categories may be collected: 
1. Death resulting from malignancy 
2. Death resulting from pulmonary causes 
3. Death caused by infection (includes sepsis) 
4. Death resulting from gastrointestinal causes 
5. Death resulting from accident/trauma 
6. Death caused by other non-cardiovascular organ failure 
7. Death resulting from other non-cardiovascular cause 
 

 
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- 
Undetermined  
Undetermined cause of death is defined as a death not attributable to any other category, 
because of the absence of any relevant source documents. Such deaths will be classified as 
cardiovascular for end point determination.  
 
DISSECTION  
(NHLBI [National Heart, Lung, and Blood Institute] classification) 
Type A 
Small radiolucent area within the lumen of the vessel disappearing with the 
passage of the contrast material. 
Type B 
Appearance of contrast medium parallel to the lumen of the vessel disappearing 
within a few cardiac cycles. 
Type C 
Dissection protruding outside the lumen of the vessel persisting after passage of 
the contrast material. 
Type D 
Spiral shaped filling defect with or without delayed run-off of the contrast 
material in the antegrade flow. 
Type E 
Persistent luminal filling defect with delayed run-off of the contrast material in 
 
the distal lumen. 
Type F 
Filling defect accompanied by total coronary occlusion. 
 
MYOCARDIAL INJURY AND MYOCARDIAL INFARCTION   
(Fourth Universal Definition of Myocardial Infarction 2018)  
 
Criteria for acute myocardial infarction (MI)      
The term myocardial injury should be used when there is evidence of elevated cardiac troponin 
values (cTn) with at least 1 value above the 99th percentile upper reference limit (URL). The 
myocardial injury is considered acute if there is a rise and/or fall of cTn values. 
 
Criteria for acute myocardial infarction (types 1, 2 and 3 MI) 
The term acute myocardial infarction should be used when there is acute myocardial injury with 
clinical evidence of acute myocardial ischemia and with detection of a rise and/or fall of cTn 
values with at least 1 value above the 99th percentile URL and at least 1 of the following: 
- 
Symptoms of myocardial ischemia. 
- 
New ischemic ECG changes. 
- 
Development of pathological Q waves. 
- 
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality in a pattern consistent with an ischemic etiology. 

 
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- 
Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 
MIs). 
Postmortem demonstration of acute atherothrombosis in the artery supplying the infarcted 
myocardium meets criteria for type 1 MI. Evidence of an imbalance between myocardial oxygen 
supply and demand unrelated to acute atherothrombosis meets criteria for type 2 MI. Cardiac 
death in patients with symptoms suggestive of myocardial ischemia and presumed new ischemic 
ECG changes before cTn values become available or abnormal meets criteria for type 3 MI. 
 
Criteria for coronary procedure–related myocardial infarction (types 4 and 5 MI) 
Percutaneous coronary intervention (PCI)–related MI is termed type 4a MI. 
Coronary artery bypass grafting (CABG)–related MI is termed type 5 MI. 
 
Coronary procedure–related MI ≤48 hours after the index procedure is arbitrarily defined by an 
elevation of cTn values >5 times for type 4a MI and >10 times for type 5 MI of the 99th percentile 
URL in patients with normal baseline values. Patients with elevated preprocedural cTn values, in 
whom the preprocedural cTn level are stable (≤20% variation) or falling, must meet the criteria 
for a >5 or >10-fold increase and manifest a change from the baseline value of >20%. 
 
In addition, at least 1 of the following characteristics must be present: 
- 
New ischemic ECG changes (this criterion is related to type 4a MI only. 
- 
Development of new pathological Q waves. 
- 
Imaging evidence of loss of viable myocardium that is presumed to be new and, in a 
pattern, consistent with an ischemic etiology. 
- 
Angiographic findings consistent with a procedural flow-limiting complication such as 
coronary dissection, occlusion of a major epicardial artery or graft, side-branch occlusion-
thrombus, disruption of collateral flow or distal embolization. 
- 
 
Isolated development of new pathological Q waves meets the type 4a MI or type 5 MI criteria 
with either revascularization procedure if cTn values are elevated and rising but less than the 
prespecified thresholds for PCI and CABG. 
Other types of 4 MI include type 4b MI stent thrombosis and type 4c MI restenosis that both meet 
type 1 MI criteria. 
Postmortem demonstration of a procedure-related thrombus meets the type 4a MI criteria or 
type 4b MI criteria if associated with a stent. 
 
Criteria for prior myocardial infarction 
Any 1 of the following criteria meets the diagnosis for prior or silent/unrecognized MI: 
- 
Abnormal Q waves with or without symptoms in the absence of nonischemic causes. 

 
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- 
Imaging evidence of loss of viable myocardium in a pattern consistent with ischemic 
etiology. 
- 
Patho-anatomical findings of a prior MI. 
 
NO REFLOW 
Defined as a sustained or transient reduction in antegrade flow that is not associated with an 
obstructive lesion at the treatment site. 
PERCUTANEOUS CORONARY INTERVENTION (PCI) PROCEDURE 
A PCI procedure will be considered to have commenced at the time the guidewire crosses the 
first lesion to be treated.  
PERFORATION 
Perforations will be classified as follows: 
Angiographic perforation: perforation detected by the clinical site or the core laboratory at any 
point during the procedure. 
Clinical perforation: perforation requiring additional treatment (including efforts to seal the 
perforation or pericardial drainage), or resulting in significant pericardial effusion, abrupt closure, 
myocardial infarction, or death. 
Pericardial haemorrhage/tamponade: perforation resulting in cardiac tamponade. 
REFERENCE VESSEL DIAMETER (RVD) 
Defined as the average diameter of normal segments within 10 mm proximal and distal to the TL 
from two (2) orthogonal views by visual estimate. 
TARGET LESION THROMBOSIS (TLT)  
(ARC II definition)  
Target lesion thrombosis should be reported as a cumulative value over time and at various 
individual time points as specified below. Time 0 is defined as the time point after the guiding 
catheter has been removed and the patient has left the Cath lab.  
We recognize three categories of evidence in defining stent thrombosis inside the target lesion. 
1. Definite stent/scaffold thrombosis 
Angiographic confirmation of stent/scaffold thrombosis* 
The presence of a thrombus† that originates in the stent/scaffold or in the segment 5 mm 
proximal or distal to the stent/scaffold or in a side branch originating from the stented/scaffolded 
segment and the presence of at least 1 of the following criteria: 
- 
Acute onset of ischemic symptoms at rest  
- 
New electrocardiographic changes suggestive of acute ischemia 

 
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- 
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous myocardial 
infarction)  
- 
Or 
Pathological confirmation of stent/scaffold thrombosis 
- 
Evidence of recent thrombus within the stent/scaffold determined at autopsy 
- 
Examination of tissue retrieved following thrombectomy (visual/histology) 
 
2. Probable stent/scaffold thrombosis 
Regardless of the time after the index procedure, any myocardial infarction that is related to 
documented acute ischemia in the territory of the implanted stent/scaffold without angiographic 
confirmation of stent/scaffold thrombosis and in the absence of any other obvious cause.  
 
3. Silent stent/scaffold occlusion 
The incidental angiographic documentation of stent occlusion in the absence of clinical signs or 
symptoms is not considered stent thrombosis. 
 
Timing of ST (duration after stent implantation) 
Acute 0–24 h 
Subacute >24 h–30 d 
Late >30 d–1 y 
Very late >1 y  
Early stent thrombosis is 0 to 30 days (acute plus subacute stent thrombosis). MI indicates 
myocardial infarction. 
*Definite stent/scaffold thrombosis is considered to have occurred by either angiographic or 
pathological confirmation. 
†Occlusive thrombus: Thrombolysis in Myocardial Infarction grade 0 or 1 flow within or proximal 
to a stent/scaffold segment. Nonocclusive thrombus: intracoronary thrombus is defined as a 
(spherical, ovoid, or irregular) noncalcified filling defect or lucency surrounded by contrast 
material (on 3 sides or within a coronary stenosis) seen in multiple projections, persistence of 
contrast material within the lumen, or visible embolization of intraluminal material downstream. 
‡When the stented/scaffolded segment is in the left circumflex coronary artery or in the presence 
of preexisting electrocardiographic abnormalities (e.g. left bundle branch block, paced rhythms), 
definitive evidence of localization may be absent and Clinical Events Committee adjudication is 
based on review of all available evidence. 
§Defined as the moment the patient is undraped and taken off the catheterization table 
TARGET LESION (TL)  
The TL is the portion of the coronary artery that was in immediate contact with the DCB plus a 
margin of 5 mm on both ends. 

 
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TARGET VESSEL (TV) 
The TV is defined as the index coronary artery which was in physical contact with any component 
(guiding catheter, guide wire, balloon catheter, etc.) of the angioplasty hardware during the initial 
procedure. 
TARGET LESION FAILURE (TLF)  
(ARC 2 definition)  
Cardiovascular death, target-vessel myocardial infarction, or clinically driven target-lesion 
revascularization. 
TARGET VESSEL FAILURE (TVF) 
(ARC 2 definition)  
Cardiovascular death, target-vessel myocardial infarction, driven target-vessel revascularization 
 
TARGET LESION REVASCULARIZATION (TLR) 
Defined as any repeat percutaneous intervention of the TL or bypass surgery of the target vessel. 
Clinically driven revascularizations are those in which the patient has a positive functional study, 
ischemic ECG changes at rest in a distribution consistent with the target vessel, or ischemic 
symptoms. Revascularization of a TL with an in-lesion diameter stenosis ≥70% (by QCA) in the 
absence of the above-mentioned ischemic signs or symptoms is also considered clinically driven. 
In the absence of QCA data for relevant follow-up angiograms, the clinical need for 
revascularization is adjudicated using the presence or absence of ischemic signs and symptoms. 
Non-clinically driven repeat target lesion revascularizations are those in which the patient 
undergoes a non-emergent revascularization for a diameter stenosis <50% (by QCA).  Non-
emergent repeat target lesion revascularization for a diameter stenosis <70% (by QCA) in patients 
without either a positive functional study or angina are also considered non-clinically driven 
defined as any repeat revascularization of the target site whether by PCI or bypass surgery. 
 
TARGET VESSEL REVASCULARIZATION (TVR) 
Any target vessel revascularization, death, or MI attributed to the target vessel. 
TIMI CLASSIFICATION 
TIMI 0 
No perfusion. 
TIMI 1 
Penetration with minimal perfusion.  Contrast fails to opacify the entire 
bed distal to the stenosis for the duration of the cine run. 
TIMI 2 
Partial perfusion.  Contrast opacifies the entire coronary bed distal to the 
stenosis.  However, the rate of entry and/or clearance is slower in the 

 
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coronary bed distal to the obstruction than in comparable areas not 
perfused by the dilated vessel. 
TIMI 3 
Complete perfusion. Filling and clearance of contrast equally rapid in the 
coronary bed distal to stenosis as in other coronary beds. 
 
 
 

 
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APPENDIX B - Abbreviations  
ACC 
American College of Cardiology 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
AHA 
American Heart Association 
ARC 
Academic Research Consortium 
BMS 
Bare Metal Stent 
CABG 
Coronary Artery Bypass Grafting 
CAD 
Coronary Artery Disease 
CCS 
Chronic Coronary Syndrome 
CEC 
Clinical Events Committee 
CRO 
Clinical Research Organization 
CIP 
Clinical Investigation Plan 
cTn 
Cardiac Troponin  
CVRI Dublin 
Cardiovascular Research Institute Dublin 
DAPT 
Dual Anti-Platelet Therapy 
DCB 
Drug Coated Balloon 
DCS 
Drug Coated Stent 
DES 
Drug Eluting Stent 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EACTS 
European Association for Cardio-Thoracic Surgery 
ESC 
European Society of Cardiology  
FFR 
Fractional Flow Reserve 
GCP 
Good Clinical Practices 
HbA1c 
Glycated Haemoglobin 
IEC 
Independent Ethics Committee 
iFR 
Instantaneous Free-wave Ratio 
IFU 
Instructions for Use  
ISR 
In-Stent Restenosis 
ITT 
Intent to Treat 
IVUS 
Intravascular Ultrasound 
LLL 
Late Lumen Loss 
MACE 
Major Adverse Cardiac Events 

 
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MB 
Main Branch  
MI 
Myocardial Infarction 
NHLBI 
National Heart, Lung, and Blood Institute 
NOAEL 
No Observed Adverse Effect Level 
Non-TV 
Non-Target Vessel 
OCT 
Optical Coherence Tomography 
%DS 
Percent Diameter Stenosis 
PCI 
Percutaneous coronary intervention 
PK 
Pharmacokinetic  
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QCA 
Quantitative Coronary Analysis 
RCSI 
RCSI University of Medicine and Health Sciences 
RVD 
Reference Vessel Diameter 
SAE 
Serious Adverse Event 
SB 
Side Branch 
SC 
Steering Committee 
SCAI 
Society for Cardiac Angiography and Interventions 
STD 
Standard Deviation 
SD 
Source Documentation 
SDV 
Source Document Verification 
STEMI  
ST-elevation Myocardial Infarction 
ST 
Stent thrombosis 
SVD 
Small Vessel Disease 
TC 
Teleconference 
TL 
Target Lesion 
TLF 
Target Lesion Failure 
TIMI 
Thrombolysis In Myocardial Infarction 
TLR 
Target lesion Revascularization 
TV 
Target Vessel 
TV-MI 
Target Vessel Myocardial Infarction 
TVF 
Target Vessel Failure 
TVR 
Target Vessel Revascularization   
URL 
Upper Reference Limit