Onyx ONE Clear: A Single Arm Trial With Resolute Onyx in ONE-Month DAPT for High-Bleeding Risk Patients Who Are Considered One-Month Clear (Onyx ONE Clear)
Phase: NA
Conditions: Coronary Artery Disease
Sponsor: Medtronic Vascular

Study Name: 
Onyx ONE Clear Study: A Single Arm 
Study with Resolute Onyx in ONE-
Month 
DAPT for High-Bleeding Risk Patients 
who are considered One-Month Clear 
NCT Number: 
NCT03647475 
Document Date:  
V3.0 2019 06 11 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 1 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Clinical Investigation Plan 
Study Title  
Onyx ONE Clear Study: A Single Arm Study with Resolute Onyx in ONE-Month 
DAPT for High-Bleeding Risk Patients who are considered One-Month Clear 
Study Product Name 
Medtronic Resolute Onyx Zotarolimus-Eluting Coronary Stent System  
Sponsor/Local Sponsor 
Medtronic Vascular  
3576 Unocal Place 
Santa Rosa, CA 95403, USA 
Medtronic Japan Co., Ltd.  
1-2-70 Konan, Minato-ku,  
Tokyo Japan 108-0075  
Clinical Investigation Plan Identifier 
MDT18015RES008 
Document Version 
Version 3.0 
Coordinating Investigators 
Co-Principal Investigator: David E. Kandzari, MD, FACC, FSCAI 
Piedmont Heart Institute, Suite 2065, 95 Collier Road, Atlanta, Georgia, 30309, US 
 
Co-Principal Investigator: Ajay Kirtane, MD, SM, FACC, FSCAI 
Columbia University Medical Center / New York-Presbyterian Hospital, 161 Fort 
Washington Avenue, New York, New York, 10032, US 
Program Chair 
Gregg W. Stone, MD 
Columbia University Medical Center / New York-Presbyterian Hospital, 161 Fort 
Washington Avenue, New York, New York, 10032, US 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. Any distribution, copying, or 
disclosure without the prior written authorization of Medtronic is strictly prohibited. Persons to whom the information is disclosed 
must know that it is confidential and that it may not be further disclosed by them. 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 2 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Contents 
1. 
Glossary .............................................................................................................................................................. 4 
2. 
Synopsis ............................................................................................................................................................. 13 
3. 
Introduction ...................................................................................................................................................... 15 
3.1. 
Background .................................................................................................................................................... 15 
3.2. 
Purpose .......................................................................................................................................................... 19 
4. 
Objectives and Endpoints ................................................................................................................................ 19 
4.1. 
Objectives ...................................................................................................................................................... 19 
4.2. 
Endpoints ....................................................................................................................................................... 20 
5. 
Study Design ..................................................................................................................................................... 20 
5.1. 
Duration ......................................................................................................................................................... 21 
5.2. 
Rationale ........................................................................................................................................................ 21 
6. 
Product Description ......................................................................................................................................... 23 
6.1. 
Resolute Onyx Stent and Delivery System .................................................................................................... 23 
6.2. 
Resolute Onyx DES Manufacturing Facility ................................................................................................. 26 
6.3. 
Packaging ...................................................................................................................................................... 26 
6.4. 
Intended Population ....................................................................................................................................... 26 
6.5. 
Equipment ...................................................................................................................................................... 26 
6.6. 
Product Use ................................................................................................................................................... 26 
6.7. 
Product Training Requirements ..................................................................................................................... 27 
6.8. 
Product Storage .............................................................................................................................................. 27 
6.9. 
Product Accountability .................................................................................................................................. 27 
7. 
Selection of Subjects......................................................................................................................................... 27 
7.1. 
Study Population ............................................................................................................................................ 27 
7.2. 
Subject Enrollment ........................................................................................................................................ 27 
7.3. 
Inclusion Criteria ........................................................................................................................................... 28 
7.4. 
Exclusion Criteria .......................................................................................................................................... 28 
8. 
Study Procedures ............................................................................................................................................. 29 
8.1. 
Schedule of Events ........................................................................................................................................ 29 
8.2. 
Subject Screening .......................................................................................................................................... 32 
8.3. 
Subject Consent ............................................................................................................................................. 32 
8.4. 
Revisions in Subject Consent Form ............................................................................................................... 33 
8.5. 
Antiplatelet Medications ................................................................................................................................ 33 
8.6. 
Medication Adherence ................................................................................................................................... 34 
8.7. 
Procedure ....................................................................................................................................................... 34 
8.8. 
Staged Procedures .......................................................................................................................................... 35 
8.9. 
Bailout ........................................................................................................................................................... 35 
8.10. 
Treatment Failure .......................................................................................................................................... 36 
8.11. 
Assessment of Effectiveness .......................................................................................................................... 36 
8.12. 
Assessment of Safety ..................................................................................................................................... 36 
8.13. 
Recording Data .............................................................................................................................................. 36 
8.14. 
Investigator records ....................................................................................................................................... 37 
8.15. 
Investigator reporting responsibilities ........................................................................................................... 38 
8.16. 
Sponsor record maintenance responsibilities ................................................................................................. 39 
8.17. 
Sponsor reporting responsibilities ................................................................................................................. 39 
8.18. 
Deviation Handling ........................................................................................................................................ 40 
8.19. 
Subject Withdrawal or Discontinuation ......................................................................................................... 41 
9. 
Risks and Benefits ............................................................................................................................................ 41 
9.1. 
Potential Risks ............................................................................................................................................... 42 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 3 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
9.2. 
Risks Related to Devices ............................................................................................................................... 43 
9.3. 
Potential Benefits ........................................................................................................................................... 44 
9.4. 
Risk Benefit Rationale ................................................................................................................................... 45 
10. Adverse Events and Device Deficiencies ........................................................................................................ 45 
10.1. 
Definitions/Classifications ............................................................................................................................. 45 
10.2. 
Reporting of Adverse Events ......................................................................................................................... 47 
10.3. 
Recording and Reporting of Device Deficiencies .......................................................................................... 49 
10.4. 
Emergency Contact for Reporting Events and Device Deficiencies .............................................................. 50 
11. Data Review Committees ................................................................................................................................. 50 
11.1. 
Clinical Event Committee .............................................................................................................................. 50 
11.2. 
Data Safety and Monitoring Board ................................................................................................................ 50 
11.3. 
Executive Committee..................................................................................................................................... 51 
12. Statistical Design and Methods ....................................................................................................................... 51 
12.1. 
Primary Endpoint ........................................................................................................................................... 51 
12.2. 
Analysis Populations ..................................................................................................................................... 52 
12.3. 
General Analysis Overview ........................................................................................................................... 52 
12.4. 
Analysis of the Primary Endpoint .................................................................................................................. 53 
12.5. 
Analysis of Secondary Endpoints .................................................................................................................. 53 
12.6. 
Analysis of Baseline Characteristics .............................................................................................................. 53 
12.7. 
Analysis of Subgroups ................................................................................................................................... 53 
12.8. 
Interim Analysis ............................................................................................................................................ 53 
12.9. 
Additional Analysis ....................................................................................................................................... 53 
12.10. Missing Data .................................................................................................................................................. 53 
13. Economic Analysis ........................................................................................................................................... 54 
14. Ethics ................................................................................................................................................................. 54 
14.1. 
Statements of Compliance ............................................................................................................................. 54 
15. Study Administration ...................................................................................................................................... 55 
15.1. 
Investigator / Investigational Site Selection .................................................................................................. 55 
15.2. 
Site Activation/Supply of Study Materials .................................................................................................... 55 
15.3. 
Monitoring ..................................................................................................................................................... 56 
15.4. 
Data Management .......................................................................................................................................... 56 
15.5. 
Direct Access to Source Data / Documents ................................................................................................... 56 
15.6. 
Confidentiality ............................................................................................................................................... 56 
15.7. 
Liability ......................................................................................................................................................... 57 
15.8. 
Clinical Investigation Plan Amendments....................................................................................................... 57 
15.9. 
Record Retention ........................................................................................................................................... 57 
15.10. Publication and Use of Information ............................................................................................................... 57 
15.11. Suspension or Early Termination .................................................................................................................. 58 
15.12. Organizations Involved in Study ................................................................................................................... 59 
16. Version History ................................................................................................................................................ 59 
 
 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 4 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
1. Glossary  
Acronyms / Terms 
Definition 
ACC 
American College of Cardiology 
Acute closure 
Acute closure: The occurrence of new (during the procedure) severely reduced flow (TIMI grade 
0-1) within the target vessel that persisted and required rescue by stenting or other treatment or 
resulted in myocardial infarction or death. Abrupt closure requires proven association with a 
mechanical dissection of the treatment site or instrumented vessel, coronary thrombus, or severe 
spasm. Abrupt closure does not mean “no reflow” (due to microvascular flow limitation), in which 
the epicardial artery is patent but had reduced flow. Abrupt closure also does not mean transient 
closure with reduced flow in which the index treatment application does reverse the closure. 
Subacute closure: Abrupt closure that occurs after the procedure is completed (and the patient left 
the catheterization laboratory) and before the 30-day follow-up evaluation. 
Threatened acute closure: A grade B dissection and ≥50% diameter stenosis or any dissection of 
grade C or higher. 
Acute coronary syndrome 
(ACS) 
An umbrella term where blood supply to the heart muscle is suddenly blocked. Includes unstable 
angina, non ST-elevation myocardial infarction and ST-elevation myocardial infarction 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related 
to the investigational medical device 
NOTE: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE: This definition includes events related to the procedures involved. 
NOTE: For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
AHA 
American Heart Association 
Antiplatelet Therapy 
Prescription or intake of aspirin or a P2Y12 inhibitor (e.g. clopidogrel, ticlopidine, prasugrel, 
ticagrelor). Patients may or may not be on oral anticoagulant medication. 
ARC 
Academic Research Consortium 
Bleeding Academic 
Research Consortium 
(BARC)1 
Type 0: no bleeding 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the patient without consulting a 
healthcare professional  
Type 2: any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for 
a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for 
type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, 
medical intervention by a healthcare professional, (2) leading to hospitalization or increased level 
of care, or (3) prompting evaluation  
Type 3a:  
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to 
bleed)  
Any transfusion with overt bleeding 
Type 3b:  
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) 
Cardiac tamponade  
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) 
                                                            
1 Mehran R, Rao S, Bhatt D, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding Academic 
Research Consortium. Circulation. 2011;123:2736-2747 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 5 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
Bleeding requiring intravenous vasoactive agents  
Type 3c: 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does 
include intraspinal) 
Subcategories confirmed by autopsy or imaging or lumbar puncture  
Intraocular bleed compromising vision 
Type 4:  
CABG-related bleeding+ 
Perioperative intracranial bleeding within 48 h 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
Chest tube output ≥2L within a 24-h period 
Type 5: fatal bleeding 
Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
Type 5b: 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
+CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and 
reported but are not included in these definitions until further information is obtained about the 
relationship to outcomes. If a CABG-related bleed is not adjudicated as at least a type 3 severity 
event, it will be classified as not a bleeding event. If a bleeding event occurs with a clear temporal 
relationship to CABG (i.e., within a 48-h time frame) but does not meet type 4 
severity criteria, it will be classified as not a bleeding event. 
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL hemoglobin) 
†Cell saver products are not counted 
CABG 
Coronary artery bypass graft 
Calcification 
Readily apparent radiopacities within the vascular wall at the site of the stenosis and is classified as 
none/mild, moderate (radiopacities noted only during the cardiac cycle before contrast injection), 
and severe (radiopacities noted without cardiac motion before contrast injection generally 
compromising both sides of the arterial lumen). 
CEC 
Clinical Events Committee 
C.I. 
Confidence Interval 
CK 
Creatine kinase 
CK-MB 
Creatine kinase myocardial-band isoenzyme 
Clinically-driven target 
lesion revascularization 
(CD-TLR) 
Revascularization at the target lesion associated with positive functional ischemia study or 
ischemic symptoms AND an angiographic minimal lumen diameter stenosis ≥50% by QCA, or 
revascularization of a target lesion with diameter stenosis ≥70% by QCA without either angina or 
a positive functional study. 
Clinically-driven target 
vessel revascularization 
(CD-TVR) 
Revascularization in the target vessel associated with positive functional ischemia study or 
ischemic symptoms AND an angiographic minimal lumen diameter stenosis ≥50% by QCA, or 
revascularization of a target vessel with diameter stenosis ≥70% by QCA without either angina or 
a positive functional study. 
cTn 
Cardiac troponin 
CV 
Curriculum Vitae 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 6 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
Death 
Cardiac death:  Any death due to immediate cardiac cause (e.g. MI, low-output failure, fatal 
arrhythmia). Unwitnessed death and death of unknown cause /will be classified as cardiac death. 
This includes all procedure-related deaths including those related to concomitant treatment. 
Vascular death: Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm, or other vascular cause. 
Non-cardiovascular death: Any death not covered by the above definitions, including death due 
to infection, sepsis, pulmonary causes, accident, suicide or trauma. 
DES 
Drug-eluting stent 
Device Success 
Attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 
after the procedure, using the assigned device only. 
Dissection, NHLBI 
(National Heart, Lung, and 
Blood Institute) 
Classification2 
Grade A Small radiolucent area within the lumen of the vessel disappearing with the passage of 
the contrast material.  
Grade B Appearance of contrast medium parallel to the lumen of the vessel disappearing within a 
few cardiac cycles.  
Grade C Dissection protruding outside the lumen of the vessel persisting after passage of the 
contrast material.  
Grade D Spiral shaped filling defect with or without delayed run-off of the contrast material in the 
antegrade flow.  
Grade E Persistent luminal filling defect with delayed run-off of the contrast material in the distal 
lumen.  
Grade F Filling defect accompanied by total coronary occlusion. 
DSMB 
Data and Safety Monitoring Board (may also be referred to as Data Monitoring Committee, or 
DMC) 
DTL 
Delegated Task List 
Dual antiplatelet therapy 
(DAPT) 
Prescription/intake of two anti-platelet medications, with one being aspirin or an aspirin-containing 
drug and the other a P2Y12 inhibitor (e.g. clopidogrel, prasugrel, ticlopidine, ticagrelor).  
eCRF 
Electronic Case Report Form 
ESC 
European Society of Cardiology 
ECG/EKG 
Electrocardiogram 
GP 
Glycoprotein 
High-Bleeding Risk (HBR) 
Patients satisfying one or more of the following criteria:  
• 
Adjunctive chronic oral anticoagulation treatment planned to continue after PCI 
• 
Age ≥ 75 years  
• 
Baseline Hgb <11 g/dl (or anemia requiring transfusion during the 4 weeks prior to 
procedure) 
• 
Any prior documented intracerebral bleed 
• 
Any documented stroke in the last 12 months 
• 
Hospital admission for major bleeding during the prior 12 months 
• 
Active non-skin cancer currently undergoing treatment or surveillance (in lieu of 
treatment). 
• 
Planned daily NSAID (other than aspirin) or steroids for ≥30 days after PCI 
• 
Planned surgery that would require interruption of DAPT (within the next 12 months) 
• 
Renal failure defined as Creatinine clearance <40 ml/min 
• 
Thrombocytopenia (PLT <100,000/mm3) 
                                                            
2 Detre, K., R. Holubkov, S. Kelsey, M. Bourassa, D. Williams, D. Holmes, Jr., G. Dorros, D. Faxon, R. Myler, K. Kent, et al. 1989. One-year follow-up 
results of the 1985-1986 National Heart, Lung, and Blood Institute's Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 80 (3): 421-8.  

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 7 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
• 
Severe chronic liver disease defined as subjects who have developed any of the following: 
variceal hemorrhage, ascites, hepatic encephalopathy or jaundice 
IB 
Investigator’s Brochure 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat: All subjects who signed the informed consent with an attempted implant procedure.  
Time zero begins at the date of the index procedure. 
IVUS 
Intravascular ultrasound 
Lesion Class (American 
College of 
Cardiology/American Heart 
Association Class)3 
Type A Lesions: Minimally complex, discrete (length <10 mm), concentric, readily accessible, 
non-angulated segment (<45°), smooth contour, little or no calcification, less than totally occlusive, 
not ostial in location, no major side branch involvement, and an absence of thrombus.  
Type B Lesions: Moderately complex, tubular (length 10 to 20 mm), eccentric, moderate 
tortuosity of proximal segment, moderately angulated segment (>45°, <90°), irregular contour, 
moderate or heavy calcification, total occlusions <3 months old, ostial in location, bifurcation 
lesions requiring double guidewires, and some thrombus present.  
Type B1: One adverse characteristic.  
Type B2: Two or more adverse characteristics.  
Type C Lesions: Severely complex, diffuse (length >20 mm), excessive tortuosity of proximal 
segment, extremely angulated segments >90°, total occlusions >3 months old and/or bridging 
collaterals, inability to protect major side branches, and degenerated vein grafts with friable 
lesions. 
Lesion success 
The attainment of <30% residual stenosis by QCA (or < 20% by visual assessment) AND TIMI 
flow 3 after the procedure, using any percutaneous method 
LTFU 
Lost-To-Follow-Up 
Major bleeding 
Hospitalization for bleeding that required transfusion or other related evaluation/treatment 
Major adverse cardiac event 
(MACE) 
Death, myocardial infarction, or clinically driven repeat target lesion revascularization by 
percutaneous or surgical methods 
mg 
Milligram 
Third Universal Definition 
of Myocardial Infarction 
 
(3rd UDMI)4 
All composite endpoint data will be reported per 3rd UDMI definitions. 
Criteria for acute myocardial infarction 
The term acute myocardial infarction (MI) should be used when there is evidence of myocardial 
necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any 
one of the following criteria meets the diagnosis for MI: 
• 
Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin 
(cTn)] with at least one value above the 99th percentile upper reference limit (URL) and 
with at least one of the following: 
o 
Symptoms of ischemia. 
o 
New or presumed new significant ST-segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB).  
o 
Development of pathological Q waves in the ECG. 
o 
Imaging evidence of new loss of viable myocardium or new regional wall motion 
                                                            
3 Smith, S. C., Jr., J. T. Dove, A. K. Jacobs, J. W. Kennedy, D. Kereiakes, M. J. Kern, R. E. Kuntz, J. J. Popma, H. V. Schaff, D. O. Williams, et al. 2001. 
ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)--executive summary. A report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous 
transluminal coronary angioplasty). J Am Coll Cardiol 37 (8): 2215-39.   
4 Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third Universal Definition of Myocardial Infarction. Circulation 2012. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 8 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
abnormality. 
o 
Identification of an intracoronary thrombus by angiography or autopsy. 
• 
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were 
obtained, or before cardiac biomarker values would be increased. 
• 
Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by elevation of 
cTn values (>5 x 99th percentile URL) in patients with normal baseline values (≤99th 
percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are 
stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia or (ii) 
new ischemic ECG changes or (iii) angiographic findings consistent with a procedural 
complication or (iv) imaging demonstration of new loss of viable myocardium or new 
regional wall motion abnormality are required. 
• 
Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker 
values with at least one value above the 99th percentile URL. 
• 
Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of 
cardiac biomarker values (>10 x 99th percentile URL) in patients with normal baseline 
cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves or 
new LBBB, or (ii) angiographic documented new graft or new native coronary artery 
occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality. 
Criteria for prior myocardial infarction 
Any one of the following criteria meets the diagnosis for prior MI: 
• 
Pathological Q waves with or without symptoms in the absence of non-ischemic causes. 
• 
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract, in the absence of a non-ischemic cause. 
• 
Pathological findings of a prior MI. 
MLD 
Minimum luminal/lumen diameter 
mm 
Millimeter 
µg 
Microgram 
NQWMI 
Non-Q wave myocardial infarction 
One-month clear 
Subjects who are event-free of any the following within one month after stenting: myocardial 
infarction (MI), repeat coronary revascularization, stroke, stent thrombosis (ARC 
definite/probable), and death. Subject must be adherent to DAPT for the total 1-month period, 
where adherence means without interruption of aspirin and/or P2Y12 inhibitor for >3 days.  
Subjects discontinue either aspirin or P2Y12 inhibitor after one month and continue on single 
antiplatelet therapy (SAPT).* 
 
*Please refer to sections in this protocol on planned staging procedures and anti-coagulant use for 
extended definitions concerning 1-month DAPT use. 
Oral anticoagulant (OAC) 
Type of oral medication used to prevent or reduce coagulation of blood. Includes vitamin K 
antagonists (e.g. warfarin) and novel anticoagulants (NOACs)/ directly acting oral anticoagulants 
(DOACs) (e.g. apixaban, rivaroxaban, dabigatran, edoxaban) 
Percent diameter stenosis 
(%DS) 
The value calculated as 100 x (RVD – MLD)/RVD using the mean values from two orthogonal 
views (when possible). Percent diameter stenosis is visually estimated during angiography by the 
Investigator. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 9 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
Percutaneous coronary 
intervention (PCI) 
All interventional cardiology methods for treatment of coronary artery disease. 
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, acute closure, 
myocardial infarction, or death.  
Pericardial hemorrhage/tamponade: perforation resulting in cardiac tamponade. 
POBA 
Plain old balloon angioplasty 
Procedure success 
Attainment of <30% residual stenosis by QCA (or <20% by visual assessment) AND TIMI flow 3 
after the procedure, using any percutaneous method without the occurrence of MACE during the 
hospital stay. 
PTCA 
Percutaneous transluminal coronary angioplasty 
QCA 
Quantitative coronary angiography 
QWMI 
Q wave myocardial infarction 
RDC 
Oracle Clinical Remote Data Capture 
Restenotic lesion 
A lesion in a vessel segment that has undergone prior percutaneous treatment with or without a 
stent placement. 
Reference vessel diameter 
(RVD) 
The average of normal segments within 10 mm proximal and distal to the target lesion from two 
orthogonal views. RVD is visually estimated during angiography by the Investigator. 
Rx 
Rapid-Exchange 
SADE 
Serious Adverse Device Effects: Adverse device effect that has resulted in any of the consequences 
characteristic of a Serious Adverse Event 
SAE 
Serious Adverse Event: An adverse event that 
a) led to death 
b) led to serious deterioration in the health of the subject, that either resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. 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 fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
Single Antiplatelet Therapy 
(SAPT) 
Prescription/intake of only one anti-platelet drug (aspirin or P2Y12 inhibitor). Patients may or may 
not be on oral anticoagulant medication. 
SOP 
Standard Operating Procedure 
Stent thrombosis 
All stent thrombosis data will be reported per the Academic Research Consortium (ARC) 
definition5: 
 
Stent thrombosis should be reported as a cumulative value over time and at the various individual 
time points as specified below. Time 0 is defined as the time point after the guiding catheter has 
been removed and the subject has left the catheterization lab. 
 
                                                            
5 Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 10 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
Timing 
Acute stent thrombosis* 
 
0 - 24 hours post stent implantation 
Subacute stent thrombosis* 
>24 hours – 30 days post stent implantation 
Late stent thrombosis 
 
>30 days – one year post stent implantation 
Very late stent thrombosis  
>one year post stent implantation 
* Acute or subacute stent thrombosis can be replaced by the term early stent thrombosis 
 
Categories of evidence 
Definite (either by angiographic or pathologic confirmation): 
• 
Angiographic confirmation of stent thrombosis is considered to have occurred if: 
• 
Thrombolysis in Myocardial Infarction (TIMI) flow is: 
• 
TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm 
proximal or distal to the stent region in the presence of a thrombus 
• 
TIMI flow grade 1, 2, or 3, originating in the stent or in the segment 5 mm proximal or 
distal to the stent region in the presence of a thrombus 
• 
AND at least one of the following criteria has been fulfilled within a 48-hour time 
window: 
• 
New onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 
• 
New ischemic ECG changes suggestive of acute ischemia 
• 
Typical rise and fall in cardiac biomarkers (refer to definition non-procedural related MI) 
Note: The incidental angiographic documentation of stent occlusion in the absence of 
clinical signs or symptoms is not considered a confirmed stent thrombosis (silent 
occlusion) 
• 
Pathologic confirmation of stent thrombosis: Evidence of recent thrombus within the stent 
determined at autopsy or via examination of tissue retrieved following thrombectomy 
Probable: Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
• 
Any unexplained death within the first 30 days 
• 
Irrespective of the time after the index procedure any myocardial infarction (MI), which is 
related to documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other obvious 
cause. 
Possible: Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days following intracoronary stenting until end of study follow-up 
Stroke or Cerebrovascular 
Accident (CVA) 
An acute episode of 
focal or global 
neurological 
dysfunction caused 
by brain, spinal cord, 
or retinal vascular 
injury as a result of 
hemorrhage or 
infarction.6 
Categorical 
description of stroke 
Ischemic 
An acute episode of focal cerebral, spinal, or 
retinal dysfunction caused by infarction of 
central nervous system tissue.  
Note: Hemorrhage may be a consequence of 
ischemic stroke. In this situation, the stroke is 
an ischemic stroke with hemorrhagic 
transformation and not a hemorrhagic stroke. 
Hemorrhagic 
Hemorrhagic: An acute episode of focal or 
global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or 
subarachnoid hemorrhage.  
                                                            
6 Adapted from Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from 
the American Heart Association/American Stroke Association. Stroke. 2013;44:2064–89 (19). 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 11 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
type, classified into 1 
of 3 mutually 
exclusive categories 
(ischemic, 
hemorrhagic, 
undetermined) 
Note: Subdural hematomas are intracranial 
hemorrhagic events and not strokes. 
Undetermined 
Undetermined: An acute episode of focal or 
global neurological dysfunction caused by 
presumed brain, spinal cord, or retinal vascular 
injury as a result of hemorrhage or infarction 
but with insufficient information to allow 
categorization as either ischemic or 
hemorrhagic. 
Target lesion (TL) 
Any lesion treated or attempted to be treated during the study procedure with the assigned stent. 
The target lesion is the treated segment starting 5 mm proximal to the stent and ending 5 mm distal 
to the stent. 
Target lesion failure (TLF) 
Cardiac death, target vessel myocardial infarction (Q wave and non-Q wave), or clinically driven 
target lesion revascularization (TLR) by percutaneous or surgical methods. 
Target lesion 
revascularization (TLR) 
Repeat PCI or CABG to the target lesion. See also clinically driven target lesion 
revascularization. 
Target vessel (TV) 
The arterial segment and any branches and/or parent vessel that possess the target lesion. 
 
Note: Side branches less than 2.0 mm in diameter will not be considered ‘significant’ and therefore 
the disease in these vessels will not be considered significant.  
Note: Grafts to the parent vessel will be treated as side branches to that vessel for 
Inclusion/Exclusion Criteria evaluation, and for event evaluation and reporting, such as TVMI and 
TVR assessments 
Target vessel failure (TVF) 
Cardiac death, target vessel myocardial infarction or clinically-driven target vessel 
revascularization.  
Target vessel failure will be reported when ANY of the following events occur:  
• 
Recurrent MI occurs in territory not clearly attributed to a vessel other than the target 
vessel  
• 
Cardiac death not clearly due to a non-target vessel endpoint  
• 
Target vessel revascularization is determined  
Target vessel myocardial 
infarction (TVMI) 
An MI that occurs in a territory that cannot be clearly attributed to a vessel other than the target 
vessel. 
Target vessel 
revascularization (TVR) 
Repeat PCI or CABG to the target vessel. See also clinically driven target vessel 
revascularization. 
Thrombolysis in Myocardial 
Infarction (TIMI) 
Classification7 
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 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. 
Thrombus 
Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) non-
calcified filling defect or lucency surrounded by contrast material (on three sides or within a 
coronary stenosis) seen in multiple projections, or persistence of contrast material within the 
lumen, or a visible embolization of intraluminal material downstream.  
                                                            
7 The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group. 1985. N Engl J Med 312 (14): 932-6.   

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 12 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Acronyms / Terms 
Definition 
Occlusive thrombus: TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent 
proximal side branch or main branch (if originating from the side branch). 
Total occlusion 
A lesion with no flow (TIMI 0). Total occlusions are usually classified as persisting less than or 
more than 3 months (chronic total occlusion). 
Transient ischemic attack 
(TIA) 
A focal neurological abnormality of sudden onset and brief duration (lasting less than 24 hours) 
that reflect dysfunction in the distribution of the effected artery.  
TIAs include transient monocular blindness (e.g., amaurosis fugax defined as a transient episode of 
monocular blindness, or partial blindness, lasting ten minutes or less) and transient hemispheric 
attacks. 
Triple therapy (TT) 
Prescription/intake of dual antiplatelet therapy plus an oral anticoagulant medication  
Unstable angina 
Per the ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina 
and Non ST-Segment Elevation Myocardial Infarction there are three (3) principal presentations of 
unstable angina (UA)8:  
• 
Rest Angina. Angina occurring at rest and prolonged, usually >20 minutes.  
• 
New-onset Angina. New-onset angina of at least CCS Class III Severity.  
• 
Increasing Angina. Previously diagnosed angina that has become distinctly more 
frequent, longer in duration, or lower in threshold (i.e., increased by greater than or equal 
to 1 CCS class to at least CCS Class III severity).  
URL 
Upper Reference Limit, defined as 99th percentile of normal 
USADE 
Unanticipated Serious Adverse Device Effect 
Vascular Complication 
Vascular complications include the following:  
• 
Hematoma at access site > 5 cm  
• 
False aneurysm  
• 
AV fistula  
• 
Retroperitoneal bleed  
• 
Peripheral ischemia/nerve injury  
• 
Any transfusion required will be reported as a vascular complication unless a clinical 
indication clearly other than catheterization complication is present  
• 
Vascular surgical repair  
 
 
                                                            
8 Braunwald, E., E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. 
2002. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--
summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the 
Management of Patients With Unstable Angina). J Am Coll Cardiol 40 (7): 1366-74.   

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 13 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
2. Synopsis 
Title 
Onyx ONE Clear Study: A Single Arm Study with Resolute Onyx in ONE-Month 
DAPT for High-Bleeding Risk Patients who are considered One-Month Clear 
Clinical Study Type 
Prospective, Multi-center, Pre-market Single Arm Study 
Product Name 
Medtronic Resolute Onyx Zotarolimus-Eluting Coronary Stent System (Resolute 
Onyx stent) 
Sponsor  
Medtronic Vascular 
3576 Unocal Place 
Santa Rosa, CA 95403, USA 
Medtronic Japan Co., Ltd.  
1-2-70 Konan, Minato-ku,  
Tokyo Japan 108-0075  
Treatment  
Resolute Onyx stent with short duration of dual antiplatelet therapy (DAPT) in high-
bleeding risk patients 
Purpose 
The purpose of this study is to evaluate the clinical safety and effectiveness of the 
Resolute Onyx stent in subjects deemed at high risk for bleeding and/or medically 
unsuitable for more than one-month DAPT treatment receiving reduced duration (one 
month) of DAPT following stent implantation 
Product Status 
The Resolute Onyx stent is approved for commercial use in the geographies identified 
to execute this study 
Primary Objective 
To evaluate the clinical safety of the Resolute Onyx stent with use of one-month 
DAPT in subjects deemed at high risk for bleeding and/or medically unsuitable for 
more than one-month DAPT treatment 
Secondary Objective 
To evaluate the clinical effectiveness of the Resolute Onyx stent with use of one-
month DAPT in subjects deemed at high risk for bleeding and/or medically unsuitable 
for more than one-month DAPT treatment 
Study Design 
Prospective, multi-center, single arm study enrolling eligible subjects in the United 
States and Japan. The enrollment period is anticipated to be approximately 10 months. 
Subjects will remain in the study with follow-up clinical assessments through 2 years, 
study exit, or death, whichever comes first. 
Blinding 
There is no blinding in this study 
Sample Size 
A total of 700 subjects are required in the US and 100 subjects may additionally be 
enrolled in Japan. Subjects will be enrolled in up to 70 centers 
Trial Sites 
A separate listing will be made available for trial sites 
Inclusion/Exclusion Criteria 
Key Inclusion Criteria:  
All subjects who are acceptable candidates for treatment with a drug-eluting stent in 
accordance with applicable guidelines for percutaneous coronary interventions, who 
additionally meet pre-defined criteria for being high-bleeding risk and are candidates 
for one-month DAPT.  
Key Exclusion Criteria: 
• 
Subjects requiring a planned PCI procedure after one month of index 
procedure 
• 
Subject with planned surgery or procedure necessitating discontinuation of 
DAPT within one month following index procedure 
• 
Subject not expected to comply with long-term single antiplatelet therapy 
• 
Subjects with life expectancy of less than two years 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 14 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Study Procedures and 
Assessments 
Screening and implant (index) procedure; 
Clinic visit health status assessment (every effort should be made for the subject to 
return to the investigative site): 
• 
one month 
Subject contact health status assessments (by telephone, e-mail, or office visit): 
• 
2 months 
• 
6 months 
• 
1 year 
• 
2 years 
Angiography should be performed for cardiovascular-related post-procedure clinical 
events (e.g., MI) to determine if the event is attributable to the target vessel or a non-
target vessel. The reason for any repeat angiography (either clinically driven or non-
clinically driven) must be documented on the electronic case report form (eCRF). 
Safety Assessments 
All Serious Adverse Events (SAEs) and endpoint-related events will be evaluated by 
Medtronic safety department. Quarterly progress reports on study enrollment status 
and rates of cardiac death, MI, cardiac death/MI and stent thrombosis will be provided 
to FDA. 
 
The Clinical Events Committee (CEC) will adjudicate pre-defined clinical endpoint 
events. 
 
The Data and Safety Monitoring Board (DSMB) will evaluate safety data on an 
ongoing basis and will advise Medtronic on the continuing safety of the study, to 
ensure the well-being of the current participants and those yet to be enrolled, as well as 
the continuing validity and scientific merit of the study. 
Primary Endpoint 
Composite of cardiac death and myocardial infarction at one year for a one-month 
clear population [time frame: one month to one year] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 15 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
3. Introduction  
 
3.1. 
Background  
The practice of percutaneous coronary intervention has made considerable technical advancements in the last three decades, 
greatly impacting therapy options for the treatment of coronary artery disease. Extending beyond the initial option of balloon 
angioplasty, the advent of bare metal stents in the 1990s improved the safety and the effectiveness of percutaneous coronary 
intervention compared to balloon angioplasty alone.9,10,11,12 However, there were limitations with bare metal stents. With 
restenosis still occurring with such rates as 20-40% of coronary lesions after implantation of a standard bare metal stent13, 
frequent repeat revascularization procedures were required which, in turn, negatively impacted patients’ quality of life as well 
as society’s health care expenditures.  
 
The introduction of first-generation drug-eluting stents (DES), as marked by the launch of the Cypher stent in 2003, provided 
stents with localized and controlled release of anti-restenotic agents that have resulted in significantly reduced restenosis and 
need for repeat revascularization.14,15 However, as with many early generation devices, early drug-eluting stents were also not 
without their limitations. Due to concerns that these early generation DES may be at risk of increased rates of late (30 days to 
one year) and very late (beyond one year) stent thrombosis, and due to the fact that there was limited clinical evidence to 
demonstrate safety otherwise, guidelines initially recommended at least a full year of dual antiplatelet therapy (DAPT) 
regimen after DES implantation1617.  This drug regimen was meant to reduce the risk for thrombotic complications after stent 
implantation, and typically consisted of aspirin and a thienopyridine. It was only after the technological advancement in 
design and manufacture of newer generation drug-eluting stents, combined with the now available abundance of supportive 
long-term safety data, that clinical practice guidelines have very recently been updated.18,19 Current guidelines have shortened 
the minimum dual-antiplatelet therapy for much of the DES-treated population from one year to six months, with provisions 
for even shorter dual antiplatelet therapy for patients at high risk for bleeding. These “high-bleeding risk” patients are 
estimated to be approximately 15% of those treated, although up to 53%20 of those treated for percutaneous coronary 
                                                            
9 Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J 
Med. Mar 19 1987;316(12):701-706.  
10 Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et al. A randomized comparison of 
coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 
1994;331(8):496-501. 
11 Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, et al. for the Benestent 
Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study 
Group. N Engl J Med. 1994;331(8):489-495.  
12 Kimura T, Yokoi H, Nakagawa Y, Tamura T, Kaburagi S, Sawada Y, Sato Y, Hamasaki N, Nosaka H, et al. Three-year follow-up after implantation of 
metallic coronary-artery stents. N Engl J Med. 1996;334(9):561-566.  
13 Kastrati A, Mehilli J, Dirschinger J, Pache J, Ulm K, Schuhlen H, Seyfarth M, Schmitt C, Blasini R, Neumann FJ, Schomig A. Restenosis after coronary 
placement of various stent types. Am J Cardiol. 2001;87(1):34-39.  
14 Lemos PA, Serruys PW, Sousa JE. Drug-eluting stents: cost versus clinical benefit. Circulation. Jun 24 2003;107(24):3003-3007.  
15 O'Neill WW, Leon MB. Drug-eluting stents: costs versus clinical benefit. Circulation. Jun 24 2003;107(24):3008-3011.  
16 Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary InterventionA Report of the American 
College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and 
Interventions. Journal of the American College of Cardiology 2011;58:e44-e122. 
17 Wijns W, et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology 
(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). European heart journal 2010;31:2501-55. 
18 Levine GN, Bates ER, Bittl JA, Brindis RG, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with 
Coronary Artery Disease. J Thorac Cardiovasc Surg. 2016; 152 (5):1243-1274. 
19 Valgimigli M, Bueno H, Byrne R, et al. 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease developed in collaboration 
with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017; 39(3):213-260. 
20 de Boer SP, Lenzen MJ, Oemrawsingh RM, Simsek C, Duckers HJ, van der Giessen WJ, Serruys PW, Boersma . Evaluating the ‘all-comers’ design: a 
comparison of participants in two ‘all-comers’ PCI trials with non- participants.Eur Heart J. 2011;32(17):2161-7 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 16 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
intervention may be excluded from all-comer studies. These include patients previously excluded from DES procedures due 
to age, underlying comorbidities, (i.e., low ejection fraction, chronic renal insufficiency) and other reasons, who are not able 
to be subjected to longer term dual antiplatelet therapy use.  
 
In the face of increasingly challenging coronary lesion and vessel anatomies, and with newer generation drug-eluting stents 
that have established long term safety and effectiveness and are considered to be the current choice of treatment, Medtronic 
developed the Resolute Onyx Zotarolimus-Eluting Coronary Stent system (Resolute Onyx stent) to answer the demand for 
more flexible, and highly deliverable devices with enhanced radiopacity while maintaining the structural integrity needed to 
safely and efficaciously treat complex disease. 
 
The Resolute Onyx stent represents Medtronic’s fourth generation drug-eluting stent which incorporates thinner stent struts, 
reduced strut lengths, increased strut width to thickness ratio, change to the number of crowns for certain designs, and 
increased radiopacity over predicate stents, while retaining the proven characteristics of the Resolute stent. The thinner stent 
struts are expected to improve acute deliverability performance by way of crossing profile and flexibility. The increased 
radiopacity improves the acute performance by ensuring accurate and complete lesion coverage. The zotarolimus drug and 
drug concentration of approximately 1.6 μg/mm2 of stent surface area remain the same as the predicate Resolute products. 
The BioLinx polymer, polymer thickness and drug coating formulation also remain the same. Additional non-clinical data 
may be found in the Resolute Onyx IFU and Investigator’s Brochure, if applicable.  
 
The RESOLUTE Clinical Program provides clinical evidence on the Resolute Onyx stent and includes the following: the 
RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study and the RESOLUTE Onyx 2.0 mm Clinical Study designed to 
assess the safety and efficacy of the Resolute Onyx stent for the treatment of lesions, amenable to treatment with a Resolute 
Onyx 2.0 mm stent (RESOLUTE ONYX 2.0 mm Clinical Study) and Resolute Onyx 2.25 mm – 4.0 mm stents (RESOLUTE 
ONYX Core (2.25 mm – 4.0 mm) Clinical Study). 
 
The RESOLUTE ONYX Core (2.25 mm – 4.0 mm) Clinical Study outcomes validated the established safety and 
effectiveness of the predicate Resolute stents. The study met the primary endpoint of in-stent late lumen loss (LL) at 8-
months post-procedure as measured by quantitative coronary angiography (QCA), demonstrating non-inferiority (p < 0.001) 
when compared to the historical control in-stent late loss value from the RESOLUTE US Angio/IVUS Sub-study.  
 
The RESOLUTE ONYX 2.0 mm Clinical Study assesses the safety and efficacy of the Resolute Onyx stent for the treatment 
of de novo lesions in native coronary arteries with RVD allowing the use of a 2.0 mm diameter stent. The primary endpoint 
of target lesion failure at 12 months was 5.0%, fulfilling the pre-specified performance criteria. 
 
The RESOLUTE ONYX Post Approval Study (PAS) will augment the body of evidence supporting the safety and 
effectiveness of the Resolute Onyx stent and extend this evidence in a wider global patient population with the full-size 
matrix of Resolute Onyx (2.0 mm - 5.0 mm diameter sizes). The study is currently enrolling subjects in the United States and 
Europe. 
 
Assurance of long term safety and effectiveness data on the Resolute stents is demonstrated in a post hoc pooled analysis of 
patient-level data from the RESOLUTE Clinical Trial Program, designed to collect robust clinical evidence on the Resolute 
stent in both simple and complex clinical presentations. The pooled analysis of 7618 patients, demonstrated a low rate of 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 17 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
cardiac events as well as stent thrombosis, particularly after the first year, that remained stable at 5 years.21 These data 
demonstrate consistent clinical evidence supporting the safe and effective use of the next generation of Resolute Onyx.  
 
While developing safe and effective DES is vital, expanding the clinical evidence with contemporary DES and use of post-
procedural dual antiplatelet therapy (DAPT) is equally important, especially when considering the optimal duration of DAPT. 
Prior ESC recommendations which were supported by earlier generation DES data and very limited DAPT duration data, had 
suggested that DAPT duration for most patients be 6-12 months depending on patient subgroup. Notably, observational data 
have suggested that a significant proportion of patients either interrupt or are unable to tolerate DAPT for such duration.22 
Most recently, the ESC guidelines were updated to incorporate very short DAPT data including data from the LEADERS 
FREE study, a one month randomized, controlled DAPT study comparing BioFreedom DCS against a bare metal stent23. 
Also applicable are the 2016 ACC/AHA guidelines which indicate that in patients at higher risk of bleeding, DAPT 
discontinuation may be reasonable after 3 months in stable patients or after 6 months in ACS patients, based on currently 
available information. Importantly, the guidelines highlight the fact that decisions about duration of DAPT are best made on 
an individual basis and should integrate clinical judgment, assessment of the benefit/risk ratio, and patient preference.24 
 
The generation of clinical evidence supporting recommendations on DAPT duration in diverse populations is important to 
both the physician and to the patient. DAPT related data provide critical information needed for physicians for circumstances 
under which treatment duration decisions post-DES implantation may be complicated by concerns such as for patients’ safety 
(i.e., clinical status, bleeding) or unplanned surgical interventions. For the patient, in addition to a priority of safety and well-
being, concerns may stem from individualized preference as well as affordability.25  
 
While older literature may have focused on the terms under which longer-term DAPT may benefit the patient, there is a 
limited selection of clinical research on short DAPT in the contemporary DES. Contemporary evidence from published 
studies that identified patients with high-bleeding risk from the LEADERS FREE study, ZEUS study, SENIOR study, and 
the RUDI-Free Registry. These studies included a high-bleeding risk patient population that was reflective of real world use 
and included complex patients such as STEMI. For the Resolute Onyx stent, Medtronic has also conducted detailed analysis 
of the RESOLUTE Clinical Trial Program data to better understand the safety outcomes of the Resolute Onyx stent with one-
month DAPT.  
                                                            
21 Yeh RW, Silber S, Chen L, et al. 5-year safety and efficacy of Resolute Zotarolimus-eluting stent: the RESOLUTE Global Clinical Trial Program. JACC 
Cardiovasc Interv. 2017;10(1):247-254. 
22 Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following 
resolute Zotarolimus-eluting stent implantation. Eur Heart J. 2014;35(29):1949-1956 
23 Valgimigli M, Bueno H, Byrne R, et al. 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease developed in collaboration 
with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017;39(3):213-260. 
24 Levine GN, Bates ER, Bittl JA, Brindis RG, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with 
Coronary Artery Disease. J Thorac Cardiovasc Surg. 2016; 152 (5):1243-1274. 
25 Kandzari D, Silber S, Windecker S, Brar S, Lee LC, Kirtane A. Pharmacodynamic considerations and clinical impact of dual antiplatelet therapy 
interruption after Resolute Zotarolimus-eluting stent implantation. Presentation. ACC 2014. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 18 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
The LEADERS FREE Study compared the Biosensors BioFreedom BA9 DES with the Biosensors Gazelle Bare Metal 
Coronary Stent in a 1:1 randomized controlled study.26 The BioFreedom stent consists of a 316L steel bare metal stent 
platform coated with Biolimus A9 drug that is crimped on to a rapid exchange delivery catheter system. This prospective, 
blinded trial randomized 2466 high-bleeding risk (HBR) PCI patients and mandated DAPT for one month only, followed by 
long-term single anti-platelet therapy. LEADERS FREE demonstrated that BioFreedom was superior to a bare-metal stent 
with respect to the primary safety endpoint of cardiac death, MI, definite/probable stent thrombosis and the primary 
effectiveness endpoint of clinically-driven (CD) target lesion revascularization (TLR) at one year. 
 
At one year, with respect to the primary safety endpoint of cardiac death, MI, and definite/probable ST, the BioFreedom stent 
had a reported rate of 9.4% vs. the bare metal stent (BMS) rate of 12.9% (p=0.005 for superiority). Individual components of 
safety include the cardiac death rate of 4.2% vs. 5.3%, MI rate of 6.1% vs. 8.9% (p=0.01), and definite/probable ST rate of 
2.0% vs. 2.2% (p=0.70) for the BioFreedom stent and BMS stent respectively. The primary efficacy endpoint of CD-TLR 
was reported at 5.1% for the BioFreedom stent and 9.8% for the BMS comparator arm (p<0.001 for superiority).  Additional 
secondary efficacy endpoints included urgent TLR rate, 3.3% vs. 5.8% (p=0.004), CD-TLR rate, 5.7% vs. 10.5% (p<0.001), 
any TVR rate 5.8% vs. 10.9% (p<0.001) and any revascularization rate 9.4% vs. 12.9% (p<0.005) for the BioFreedom stent 
vs. the BMS arm respectively.27 
 
The ZEUS study compared BMS to the Endeavor zotarolimus eluting stent (ZES).  One of the study’s findings showed that 
in patients at high-bleeding risk, a treatment strategy of the Endeavor stent followed by a personalized course of DAPT, 
including a 1-month DAPT therapy, resulted in a lower risk of MACE compared with BMS.28,29  CD/MI rates from the ZEUS 
study reflected rates expected from a high-bleeding risk population that included stable as well as acute coronary syndrome 
subjects. 
 
The SENIOR trial is a randomized single-blind trial that compared outcomes between BMS and DES in elderly patients with 
a short duration of DAPT.30 Results showed that for the primary endpoint of major adverse cardiac and cerebrovascular 
events at 1 year, events occurred in 68 (12%) patients in the DES group and 98 (16%) in the BMS. Bleeding complications 
occurred in 26 (5%) in the DES group and 29 (5%) in the BMS group, and stent thrombosis occurred in 3 (1%) in the DES 
group and 8 (1%) in the BMS group. The authors concluded that among elderly patients who have PCI, a DES and a short 
duration of DAPT is better than BMS and a similar duration of DAPT with respect to the occurrent of all-cause mortality, 
myocardial infarction, stroke, and ischemia-driven target lesion revascularization. 
 
                                                            
26 Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. NEJM Oct 14, 2015.  
27 Urban P, Abizaid A, et al. LEADERS FREE Biolimus-coated vs. Bare-metal Coronary Stents in High Bleeding Risk Patients. TCT2015. 
28 Ariotti S, Adamo M, Costa F, et al. Is Bare-Metal Stent Implantation Still Justifiable in High Bleeding Risk Patients Undergoing Percutaneous Coronary 
Intervention?: A Pre-Specified Analysis From the ZEUS Trial. JACC Cardiovasc Interv 2016;9:426-36. 
29 Valgimigli M, et al. J Am Coll Cardiol. 2015;65:805–15 
30 Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. The 
Lancet 2017. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 19 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Recently, outcomes from the RUDI-FREE Registry (an observational, single-arm registry of 1103 subjects at 16 Italian 
centers) were presented at the EuroPCR conference in 2017. RUDI-FREE aimed to assess the safety and efficacy of polymer-
free biolimus-eluting BioFreedom stent in a real-world, all-comer population, evaluating subjects different from LEADERS 
FREE, ie, not only focusing on high-bleeding risk patients, and assessing DAPT use. The primary safety endpoint, a 
composite of cardiac death, MI, and definite/probable stent thrombosis at 12 months was 4.1%.  Additionally, at 12 months 
the TLR rate was 1.4%, TVR rate was 1.8%, TVMI rate was 1.0%, def/prob ST rate was 1.1% and a definite ST rate was 
reported at 0.4%. Patient-oriented outcomes included a BARC ≥3 bleed rate of 1.2% and all-cause death of 3.9%. Although 
this study was not a head-to-head comparison, high-bleeding risk subjects from the RUDI-Free Registry evaluated against the 
LEADERS FREE population for the primary endpoint showed no difference in the risk of the composite of cardiac death, 
MI, and stent thrombosis (p=0.28). 31 
 
To investigate whether early interruption and/or discontinuation of DAPT after implantation of current-generation DES is 
associated with a higher risk of stent thrombosis, Silber et al., performed a post hoc pooled analysis of 4896 patients who 
received the predicate Resolute DES to evaluate DAPT interruption. The investigators found that while interruptions of 
DAPT within one month were associated with high risk of adverse outcomes, interruptions occurring between 1 and 12 
months were associated with low rates of stent thrombosis and adverse cardiac outcomes.32  
 
In light of these data, Onyx ONE Study, a large, multicenter randomized trial enrolling 2000 subjects, has been initiated to 
study the safety and efficacy of the Resolute Onyx stent as compared to the BioFreedom stent in patients at high risk for 
bleeding. Both study arms will have one month of DAPT therapy and study a population that includes stable and acute 
coronary syndrome subjects, including subjects with STEMI, multivessel disease, left main, bifurcations. The trial has 
enrolled over 900 patients as of June 2018 and is expected to complete enrollment by Fall 2018.  
 
3.2. 
Purpose 
The purpose of this study is to evaluate the clinical safety and effectiveness of the Resolute Onyx stent in subjects deemed at 
high risk for bleeding and/or medically unsuitable for more than one-month DAPT treatment receiving reduced duration (one 
month) of DAPT following stent implantation.  
 
 
4. Objectives and Endpoints 
 
4.1. 
Objectives 
4.1.1. 
Primary Objective 
To evaluate the clinical safety of the Resolute Onyx stent with use of one-month DAPT in subjects deemed at high risk 
for bleeding and/or medically unsuitable for more than one-month DAPT treatment with respect to a composite endpoint 
rate of cardiac death and myocardial infarction 
 
                                                            
31 Sardella G, Patients at High Bleeding Risk (HBR): Lessons from LEADERS FREE. Polymer-free biolimus-eluting stents in all-comers patients: analysis 
of DAPT Cessation and Clinical Outcome after BioFreedom Stent Implantation. RUDI-Free Registry. euroPCR 2017. 
32 Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following 
resolute Zotarolimus-eluting stent implantation. Eur Heart J. 2014;35(29):1949-1956 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 20 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
4.1.2. 
Secondary Objective 
To evaluate the clinical effectiveness of the Resolute Onyx stent with use of one-month DAPT in subjects deemed at 
high risk for bleeding and/or medically unsuitable for more than one-month DAPT treatment 
4.2. 
Endpoints 
4.2.1. 
Primary Endpoint 
Composite of cardiac death and myocardial infarction at one year for a one-month clear population [time frame: one 
month to one year] 
 
4.2.2. 
Secondary Endpoints 
The following will be assessed at all follow-up time points (1, 2, 6 months, 1 and 2 years), except acute success: 
• 
Acute success (device, lesion, procedure)  
• 
All deaths, including cardiac death 
• 
Major adverse cardiac event (MACE)  
o 
Defined as death, myocardial infarction, or clinically driven repeat target lesion revascularization by 
percutaneous or surgical methods 
• 
Composite of cardiac death and myocardial infarction 
• 
Target vessel failure (TVF) 
o 
Defined as cardiac death, target vessel myocardial infarction or clinically-driven target vessel 
revascularization 
▪ 
Target vessel failure will be reported when ANY of the following events occur:  
• 
Recurrent MI occurs in territory not clearly attributed to a vessel other than the target 
vessel  
• 
Cardiac death not clearly due to a non-target vessel endpoint  
• 
Target vessel revascularization is determined  
• 
Target lesion failure (TLF)  
o 
Defined as cardiac death, target vessel myocardial infarction (Q wave and non-Q wave), or clinically driven 
target lesion revascularization (TLR) by percutaneous or surgical methods. 
• 
All revascularizations (TLR, TVR and non-TVR) 
• 
Stent thrombosis (def/prob) 
• 
Stroke 
• 
Bleeding per BARC criteria 
o 
BARC 3 to 5 
o 
BARC 2 to 5 
o 
All BARC 
 
5. Study Design  
 
The Onyx ONE Clear Study is a prospective, multi-center, single arm study enrolling eligible subjects at qualified study 
centers. Subjects will remain in the study with follow-up clinical assessments through 2 years, study exit, or death, whichever 
comes first. The study population will consist of subjects with coronary artery disease undergoing stent implantation with 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 21 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
the Resolute Onyx stent receiving DAPT through one month, before transitioning to single antiplatelet therapy (SAPT) 
thereafter.  
 
A total of 700 subjects will be enrolled in the United States, and 100 subjects may additionally be enrolled in Japan. 
Subjects will be enrolled in up to 70 centers over an approximate 10-month period or until study enrollment is completed. 
Subjects may receive treatment of one or more lesions. Planned staged procedures within 30 days of procedure are allowed. 
Subjects who are enrolled will be considered part of the Intent-to-Treat (ITT) population and followed through for two years 
if they receive Resolute Onyx stent only or exit after one year if they receive other non-study device (e.g. non-Resolute 
Onyx stent, POBA and drug-coated balloon).  
 
As this study examines the use of the study devices with one-month DAPT, the medication regimen described in this 
protocol should be strictly adhered to. Longer or shorter duration of DAPT use outside the protocol mandated duration has 
potential impact on the outcomes of the study and will be marked as a study deviation. To prevent or mitigate slow 
enrollment, selection of actively participating study centers and adjusting to an adequate number of study centers will be 
considered. Additionally, enrollment parameters are included in the study to avoid introduction of bias to the study results.  
 
Key measures taken to minimize potential sources of bias: 
• 
Enrollment of subjects is limited by inclusion and exclusion criteria 
• 
An external, independent Clinical Events Committee (CEC) will review and adjudicate, at minimum, all deaths and 
safety-endpoint related adverse events. Endpoint results will be based on CEC adjudications 
• 
An external, independent Data and Safety Monitoring Board (DSMB) will evaluate safety data and advise the 
Sponsor regarding continued safety of the study to ensure the well-being of the subjects 
• 
An independent Angiographic Core Lab will evaluate baseline and all event angiograms 
• 
Statistical analyses will be independently validated 
• 
Study centers are to follow their institutional procedures for maintenance of angiography and laboratory equipment 
used for assessing the study variables 
• 
Study monitors will verify subject data and ensure compliance with this Clinical Investigation Plan and other study 
requirements, (e.g., informed consenting processes, event reporting, etc.) 
 
5.1. 
Duration 
Screening and implant (index) procedures are estimated to take 10 months to enroll 700 subjects. Clinic visit health status 
assessments will be documented at the 1-month time point. Subject contact health status assessments will be documented at 2 
months, 6 months, 1 year, and 2 years. The study will be conducted to allow data collection and analysis for 2 years from 
treatment of the final subject or until the study has been formally terminated. The total study duration is estimated to be 34 
months from first enrolled subject through final follow-up. 
 
5.2. 
Rationale  
DAPT has long been standard of care following DES implantation; however, the duration of DAPT remains widely debated. 
Whereas patients treated with bare metal stents (BMS) were given one month of DAPT, following safety concerns with first 
generation DES over increased risk of very late stent thrombosis, the recommended duration was lengthened. However, with 
the technical advancement of newer generation DES, some of the original concerns, specifically around polymer 
biocompatibility which formed the basis of these longer DAPT recommendations, are no longer relevant.  

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 22 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
After stent implantation, DAPT not only reduces the risk of stent thrombosis and recurrent ischemic events, but it also 
increases the risk for bleeding events. Various studies comparing different shorter and longer DAPT durations have shown 
conflicting results, making decisions on DAPT duration very challenging for physicians. The very latest European guidelines 
incorporates the recent DAPT clinical data to recommend 6 months of DAPT after DES implantation, while shorter DAPT 
duration (one-month DAPT with a Class IIB, Level C recommendation; 3 month DAPT with a Class IIA, Level B 
recommendation) may be considered in stable patients at high-bleeding risk (HBR).33 Similarly, American guidelines also 
state that in stable ischemic heart disease patients, DAPT should be given for at least 6 months, but current data suggests that 
DAPT discontinuation after 3 months may be reasonable in patients who are at high risk of bleeding (e.g. patients on oral 
anticoagulant therapy) or who are at high risk of severe bleeding complication or who develop significant overt bleeding 
(class IIb).34  
 
Historically, most DES trials have excluded HBR patients a population that is estimated at around 15% of PCI patients. 
Studies that enrolled HBR patients specifically have been limited to the ZEUS trial and more recently, the LEADERS-FREE 
Trial. The ZEUS study compared BMS to the Endeavor zotarolimus eluting stent (DES).  One of the study’s findings showed 
that in patients at high-bleeding risk, a treatment strategy of the Endeavor stent followed by a personalized course of DAPT, 
including a 1-month DAPT therapy, resulted in a lower risk of MACE compared with BMS.35 The most recent study that 
focused on HBR patients is the LEADERS-FREE trial, which compared the BioFreedom drug-coated stent (DCS) to a bare 
metal stent platform.36 The trial showed superior outcomes with the BioFreedom stent compared to BMS treatment in HBR 
patients on a 1-month DAPT course.   
 
The Resolute Onyx Zotarolimus-Eluting Coronary Stent System (Resolute Onyx stent) is the latest iteration of the Resolute 
DES platform. The safety and effectiveness of the Resolute DES product family has been demonstrated in over 17,000 
patients that were studied in the RESOLUTE Global Clinical Program, including over 10 clinical studies and non-
randomized registries. Specifically, in an analysis of 7,618 patients, the Resolute stent demonstrated a low rate of cardiac 
events and a 1.2% stent thrombosis rate through five years follow-up.37  
 
A post-hoc analysis of 4,896 patients from the RESOLUTE Global Clinical Program published by Silber et al,38 concluded 
that while randomized clinical trials were needed, DAPT interruptions between 1 to 12 months after Resolute stent 
implantation were associated with low rates of ST and adverse cardiac outcomes. Based on this analysis, the instructions for 
use has the following language approved by Conformité Européenne (CE mark) authorities:  
 
One-year data from the RESOLUTE Clinical Program indicates low stent thrombosis rates for those that 
interrupted or discontinued DAPT any time after one month. While physicians should adhere to current ESC or 
                                                            
33 Valgimigli M, Bueno H, Byrne R, et al. 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease developed in collaboration 
with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017;39(3):213-260. 
34 Levine GN, Bates ER, Bittl JA, Brindis RG, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with 
Coronary Artery Disease. J Thorac Cardiovasc Surg. 2016; 152 (5):1243-1274. 
35 Valgimigli M, et al. J Am Coll Cardiol. 2015;65:805–15 
36 Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. NEJM Oct 14, 2015. 
37 Yeh RW, et al. J Am Coll Cardiol Intv. 2017;10:247–54. 
38 Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following 
resolute Zotarolimus-eluting stent implantation. Eur Heart J. 2014;35(29):1949-1956 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 23 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
ACC/AHA/SCAI Guidelines for PCI, patients who interrupt or discontinue DAPT medication one month or more 
after stent implantation are considered at low risk and showed no increased risk for stent thrombosis. 
 
Optical Coherence Tomography (OCT) imaging is an accepted high-resolution method to evaluate stent strut coverage and 
malapposition once a stent has been implanted. Since incomplete endothelization and positive remodeling has been correlated 
to the incidence of stent thrombosis,39 demonstration of early healing is desirable when considering DAPT discontinuation. 
Data on OCT after Resolute stent implantation from the ORION study showed improved early rapid healing with Resolute 
Integrity DES at 2 months (92.2% strut coverage with Resolute compared to 86.5% with BioMatrix, P=0.06), and at 3 
months (95.4% vs 86.6%; P=0.004).40 In the Onyx 1-Month OCT Study, patients implanted with the Resolute Onyx DES 
demonstrated an excellent early healing profile with an average of 88% of struts covered by neointimal formation (new cell 
growth over stent struts) and 92.3% of the total stented area showing complete strut coverage at one month41. 
 
Both ESC and ACC guidelines acknowledge that there is limited clinical evidence of dedicated DAPT studies in HBR 
patients, especially with existing stents. Therefore, there is a strong need for additional trials that evaluate the optimal DAPT 
duration in HBR patients undergoing implantation of current generation DES. 
 
The Onyx ONE Clear Study is a single-arm study that compares the Resolute Onyx stent with a performance goal. The 
purpose of this study is to demonstrate that DAPT can be discontinued at one month in HBR patients treated with the 
Resolute Onyx stent.  As certain events occurring within the first month after procedure would prevent the subject from 
having the option to be treated with one-month DAPT, and since we have seen historically that most events occur within the 
first month42, to help assess for events relevant to the objectives of this study, the primary analysis focuses on a “one-month 
clear” population. To be deemed one-month clear, subjects need to be event-free of any the following within one month after 
stenting: MI, repeat coronary revascularization, stroke, stent thrombosis (ARC definite/probable), and death. Subject must be 
adherent to DAPT for the total 1-month period, where adherence means without interruption of aspirin and/or P2Y12 
inhibitor for >3 days during the first month after the index PCI or last staged PCI procedure. Subjects discontinue either 
aspirin or P2Y12 inhibitor after one month and continue on single antiplatelet therapy.  
 
 
 
6. Product Description 
 
6.1. 
Resolute Onyx Stent and Delivery System 
The Medtronic device in this clinical study is the Resolute Onyx Zotarolimus Eluting Coronary Stent System (Resolute Onyx 
stent). The size matrix is shown in the table below. Resolute Onyx is a drug-eluting stent (DES) and is comprised of four 
main components: 
 
1. Onyx Bare Metal Stent platform: a pre-mounted cobalt alloy and platinum-iridium alloy based stent 
                                                            
39 Guagliumi G, et al. J Am Coll Cardiol Intv. 2010;3:531–9 
40 Lee SW, et al. Late-Breaking Trials and Trial Updates in Coronary Interventions. Presented at: EuroPCR; May 16-19, 2016; Paris. 
41 Roleder T., Kedhi E., et al. Favourable vessel healing after ONYX stent implantation at 30-day follow-up. Presentation. EuroPCR; May 21-25, 2018; 
Paris. 
42 Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following 
resolute Zotarolimus-eluting stent implantation. Eur Heart J. 2014;35(29):1949-1956 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 24 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
2. Delivery system: Resolute Onyx Rapid Exchange Delivery system; or Resolute Onyx Over-the-Wire Delivery System 
(only available in the US)  
3. Polymer system: BioLinx Polymer System 
4. Zotarolimus: Anti-proliferative drug component/active pharmaceutical ingredient 
 
Table 1. Size Matrix for Resolute Onyx 
Stent 
Length 
(mm) 
Stent Diameter (mm) 
2.00 
2.25 
2.50 
2.75 
3.00 
3.50 
4.00 
4.50 
5.00 
8 
RONYX20008X* RONYX22508X RONYX25008X RONYX27508X RONYX30008X RONYX35008X RONYX40008X 
--- 
--- 
12 
RONYX20012X* RONYX22512X RONYX25012X RONYX27512X RONYX30012X RONYX35012X RONYX40012X RONYX45012X* 
RONYX50012X* 
15 
RONYX20015X* RONYX22515X RONYX25015X RONYX27515X RONYX30015X RONYX35015X RONYX40015X RONYX45015X* 
RONYX50015X* 
18 
RONYX20018X* RONYX22518X RONYX25018X RONYX27518X RONYX30018X RONYX35018X RONYX40018X RONYX45018X* 
RONYX50018X* 
22 
RONYX20022X* RONYX22522X RONYX25022X RONYX27522X RONYX30022X RONYX35022X RONYX40022X RONYX45022X* 
RONYX50022X* 
26 
RONYX20026X* RONYX22526X RONYX25026X RONYX27526X RONYX30026X RONYX35026X RONYX40026X RONYX45026X* 
RONYX50026X* 
30 
RONYX20030X* RONYX22530X RONYX25030X RONYX27530X RONYX30030X RONYX35030X RONYX40030X RONYX45030X* 
RONYX50030X* 
34 
--- 
RONYX22534X* RONYX25034X RONYX27534X RONYX30034X RONYX35034X RONYX40034X 
--- 
--- 
38 
--- 
RONYX22538X* RONYX25038X RONYX27538X RONYX30038X RONYX35038X RONYX40038X 
--- 
--- 
 
---, sizes not available. *: size may not be commercially available in Japan. 
 
Resolute Onyx Stent 
The Onyx stent is similar in design to the Integrity stent and utilizes the same continuous sinusoid manufacturing technology. 
The stent design has been modified to introduce reduced strut dimensions relative to the Integrity stent. The thinner struts 
result in a lower crossing profile which may facilitate easier tracking and crossing to the lesion site, increasing the 
deliverability of the device over the predicate stents. The Onyx stent also has an increased strut width to thickness ratio 
relative to both Integrity and the Driver/MicroDriver stent platform utilized by the Endeavor Resolute product. The Onyx 
stent has a strut to width ratio that allows it to better maintain radial strength. The stent is manufactured from a composite 
wire which has an outer shell of the identical cobalt alloy as used for the Integrity stent and an inner core of a 
platinum/iridium alloy an alternate, more radiopaque material.  
 
Resolute Onyx Delivery System 
The Resolute Onyx stent is mounted on a Rapid Exchange or Over-the-Wire delivery system which incorporates design and 
process improvements to provide enhanced deliverability. Additionally, the Resolute Onyx delivery system offers an increase 
(from the predicate) in nominal burst pressure from 9atm to 12atm and an increase in rated burst pressure, from 16atm to 
18atm for the 2.0 mm – 4.0 mm sizes. The 4.5 mm and 5.0 mm sizes have a 16 atm rated burst pressure. 
 
Graphic representations of the Resolute Onyx Rapid Exchange and Over-the-Wire delivery systems are presented in Figure 1 
and Figure 2, respectively. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 25 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Figure 1. Resolute Onyx Rapid Exchange Delivery System (with Stent)  
 
 
Figure 2: Resolute Onyx Over-the-Wire Delivery System (with Stent) 
 
 
 
BioLinx Polymer System 
The Resolute Onyx stent polymer coating is identical to its predicates, Resolute Integrity and Endeavor Resolute, and 
consists of an inactive Parylene C primer coating and drug-polymer layer containing BioLinx. BioLinx is a blend of the 
proprietary components C10 and C19, and PVP (polyvinyl pyrrolidone). Collectively, these polymer components do the 
following:  
 
• 
The Parylene C aids in adhesion of the subsequent drug-polymer layer onto the stent surface 
• 
The BioLinx controls the elution of zotarolimus from the device.  
 
Zotarolimus Drug Substance 
The therapeutic agent utilized in the Resolute Onyx stent is zotarolimus, a proprietary chemical entity identical to the 
therapeutic agent utilized on the predicate Endeavor Resolute and Resolute Integrity products. It is a tetrazole-containing 
macrocyclic immunosuppressant, and potent antiproliferative agent. The suggested mechanism of action of zotarolimus is to 
bind to FKBP12, leading to the formation of a trimeric complex with the protein kinase mTOR (mammalian target of 
rapamycin) and thus inhibiting its activity. Inhibition of mTOR results in the inhibition of protein phosphorylation events 
associated with translation of mRNA and cell cycle control. Similar to Resolute Integrity and Endeavor Resolute, the 
function of zotarolimus on the Resolute Onyx stent is intended to reduce the incidence of restenosis in coronary 
interventions. The Resolute Onyx stent has a nominal drug dose of approximately 1.6 µg zotarolimus per mm2 of the stent 
surface, identical to Resolute Integrity and Endeavor Resolute, which have been proven to reduce the incidence of restenosis 
in coronary interventions. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 26 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Resolute Onyx Materials 
All materials (inclusive of non-blood and blood contacting materials) used in the Resolute Onyx product are consistent with 
its previously approved predicates or have established precedence through use in other commercially marketed products. 
Therefore, the Resolute Onyx product and the predicate Resolute products share the same the biological characteristics. 
Additionally, all materials in the Resolute Onyx product have successfully completed a full suite of biocompatibility testing 
per ISO 10993. 
 
6.2. 
Resolute Onyx DES Manufacturing Facility  
Medtronic Ireland, 
Parkmore Business Park West,  
Galway, Ireland 
FDA Establishment Registration Number - 9612164 
 
6.3. 
Packaging 
The Onyx ONE Clear Study will be conducted in geographies where the product is commercially available. The packaging 
and labeling are in accordance with local regulations. For detailed information on intended use of the device, indications and 
contraindications, as well as a complete list of warnings, precautions and potential adverse effects, please refer to the 
respective Instructions for Use. 
 
Resolute Onyx stent packaging details: 
• 
Package contains one coronary stent pre-mounted on a custom stent delivery system, sterilized by EtO gas diffusion 
• 
Use by the “Use-By” date noted on the package 
• 
This device is for single use. This device is intended to contact body tissues. Do not reuse, reprocess or resterilize 
 
6.4. 
Intended Population 
The population intended for enrollment are subjects with an indication for percutaneous coronary intervention deemed at high 
risk for bleeding and/or candidates for 1-month DAPT and are acceptable candidates to receive treatment with the Resolute 
Onyx stent.  
 
The Resolute Onyx stent is intended for use in patients eligible for percutaneous transluminal coronary angioplasty. The 
Resolute Onyx stent is intended to improve coronary luminal diameters of either single or multiple vessels as an adjunct to 
coronary interventions and to reduce restenosis. The stent is intended as a permanently implanted device.  All labeling for 
devices will be done in compliance with local regulatory requirements. 
 
6.5. 
Equipment 
Study sites should follow their institutional procedures for maintenance of angiography, diagnostic, and laboratory equipment 
used for assessing the study variables. Maintenance and calibration report will be monitored periodically. 
 
6.6. 
Product Use 
Please refer to the Resolute Onyx stent Instructions for Use for commercially approved product use. The Resolute Onyx stent 
will be used in line with commercially approved intended use.  
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 27 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
6.7. 
Product Training Requirements 
The study investigator(s) will be selected to ensure that he/she is qualified by training, education, and experience to perform 
stenting procedures in coronary arteries. 
 
The stenting procedure should be performed according to this protocol and to the respective Instructions for Use for the 
Resolute Onyx stents. A representative of Medtronic will provide and document initial training on the Onyx ONE Clear 
Clinical Investigation Plan requirements prior to study center activation. Medtronic and/or its designees are responsible for 
training of designated clinical site personnel.  
 
6.8. 
Product Storage 
All information regarding the storage and handling of the devices as indicated in their respective IFUs (and IB, if applicable 
to the region) must be taken into account. 
 
6.9. 
Product Accountability  
The Resolute Onyx stent is a commercialized product. This study will use commercially available product and labeling with 
appropriate documentation of specific device identifiers, e.g. the lot and reference/serial numbers of the used stent(s). 
Commercially available Resolute Onyx stents will be obtained and returned, if applicable, by the centers per routine hospital 
procedures for commercial products. Existing approved procedures for commercial product regarding distribution, shipment, 
storage, handling, of these devices will be followed. For Japan, steps will be taken to ensure product accountability as 
appropriate for the region.  
6.10. 
Product Return 
Any non-functioning devices should be returned to Medtronic following local regulations for return of commercial product.  
 
 
7. Selection of Subjects 
 
7.1. 
Study Population 
Candidates with evidence of coronary artery disease with lesions suitable for stent implantation who are at high risk for 
bleeding or unsuitable for more than one-month DAPT will be considered for further screening and consent to be enrolled 
and take part in this study. The study population will consist of subjects with coronary artery disease who have been 
implanted or are intended to undergo stent implantation with the Resolute Onyx stent receiving DAPT through one month. 
The study is designed to have a similar population to that studied in the randomized controlled global study, Onyx ONE. 
 
 
7.2. 
Subject Enrollment 
A total of 700 subjects in the U.S. are required for this study. Additionally, 100 subjects may be enrolled in Japan. Subjects 
will be enrolled in up to 70 centers over a 10-month period or until study enrollment is completed. Enrollment parameters 
are included in the study to avoid introduction of bias to the study results due to disproportionate enrollment.  
 
A maximum of 140 subjects (approximately 20% of the primary analysis population) may be enrolled at one study center. 
While all sites are expected to contribute to enrollment, there is no set minimum requirement for the number of subjects 
enrolled at each study center; however, it is expected that a minimum of five (5) subjects will be enrolled per study center.  

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 28 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
All subjects who meet eligibility requirements will be asked to participate. Subjects will be considered enrolled into the trial 
after the following criteria have been met:  
1. The signed and dated informed consent has been obtained 
2. The patient and target vessel(s)/lesion(s) have met all of the inclusion and none of the exclusion criteria 
3. The study stent is introduced into the guide catheter 
 
Subjects who undergo consenting and have confirmation of coronary angiography anatomy eligibility and the Resolute Onyx 
stent was attempted but was not implanted will be considered part of the intent-to-treat (ITT) population. These subjects will 
be followed through the one-year endpoint. After the one-year follow-up, the subject will exit the study.  
 
Subjects will complete their participation in the study when all study assessment windows for the duration of the study have 
passed, subjects have completed all study follow-up assessments, or subject exits the study for other reasons (e.g., 
investigator withdrawal or subject death). For all subjects, a study exit form will be completed. 
 
7.3. 
Inclusion Criteria 
All subjects who are acceptable candidates for treatment with a DES in accordance with applicable guidelines for 
percutaneous coronary interventions, per manufacturer’s Instructions for Use, who additionally meet pre-defined criteria for 
being high-bleeding risk and/or are candidates for 1-month DAPT and in the opinion of the investigator, the potential benefit 
of 1-month DAPT to the subject outweighs the potential risk, can be considered. Subjects must be at least 18 years of age.  
 
To qualify as high-bleeding risk and/or a candidate for 1-month DAPT, subject must meet at least one of the following 
criteria:  
• 
Adjunctive chronic oral anticoagulation treatment planned to continue after PCI 
• 
Age ≥ 75 years old 
• 
Baseline Hgb <11 g/dl (or anemia requiring transfusion during the 4 weeks prior to procedure) 
• 
Any prior documented intracerebral bleed 
• 
Any documented stroke in the last 12 months 
• 
Hospital admission for major bleeding during the prior 12 months  
• 
Active non-skin cancer currently undergoing treatment or surveillance (in lieu of treatment) 
• 
Planned daily NSAID (other than aspirin) or steroids for ≥30 days after PCI 
• 
Planned surgery that would require interruption of DAPT (within the next 12 months) 
• 
Renal failure defined as Creatinine clearance <40 ml/min 
• 
Thrombocytopenia (PLT <100,000/mm3) 
• 
Severe chronic liver disease defined as subjects who have developed any of the following: variceal hemorrhage, 
ascites, hepatic encephalopathy or jaundice 
• 
Expected non-compliance for at least 6 months DAPT for other medical reasons 
 
7.4. 
Exclusion Criteria 
• 
Pregnant and breastfeeding women 
• 
Subjects requiring a planned PCI procedure after one month of index procedure 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 29 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
• 
Procedure planned to require non-study stents, stand-alone POBA, or stand-alone atherectomy 
• 
Active bleeding at the time of inclusion 
• 
Cardiogenic shock 
• 
Subject with planned surgery or procedure necessitating discontinuation of DAPT within one month following index 
procedure 
• 
Subject not expected to comply with long-term single antiplatelet therapy 
• 
A known hypersensitivity or contraindication to aspirin, heparin and bivalirudin, P2Y12 inhibitors, mTOR inhibiting 
drugs such as zotarolimus, cobalt, nickel, platinum, iridium, chromium, molybdenum, polymer coatings (e.g., 
BioLinx™), stainless steel (or other metal ions found in 316L stainless steel), zinc, or a sensitivity to contrast media, 
which cannot be adequately pre-medicated. 
• 
PCI during the previous 6 months for a lesion other than the target lesion of the index procedure 
• 
Participation in another clinical study within 12 months after index procedure 
• 
Subjects with life expectancy of less than 2 years 
 
8. Study Procedures 
 
8.1. 
Schedule of Events 
Subjects will undergo initial screening and complete the informed consent process prior to any study-related assessments if 
applicable, i.e., study procedure(s) is not institution’s standard of care.  
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 30 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Table 2. Schedule of Treatments and Assessments 
 
Baseline 
Procedure1 
Post-
procedure 
Discharge 
One Month 
Clinic Visit2 
Follow-up3 
Eligibility criteria 
● 
 
 
 
 
 
Informed consent 
● 
 
 
 
 
 
Medical and cardiac history 
● 
 
 
 
 
 
Angina status 
● 
 
 
 
● 
● 
Pregnancy test4 
● 
 
 
 
 
 
Angiogram 
 
 ●5 
 
 
 
 
Adverse event data6 
● 
● 
● 
● 
● 
● 
Device deficiency data 
● 
● 
● 
● 
● 
● 
Cardiac biomarkers7 
 ●8 
 
 ●9 
 ●9 
 
 
Other lab values (creatinine, 
haemoglobin, WBC, platelet) 
  ●10 
 
 
 
 
 
12 lead ECG11 
● 
 
 
● 
 
 
Anti-platelet medication 
● 
● 
● 
● 
● 
● 
Protocol deviation reporting 
● 
● 
● 
● 
● 
● 
1. End of procedure is defined as removal of the guide catheter. 
2. Clinical visit is planned at one month. See Staged Procedures section for additional details regarding timing of follow-up. 
3. Additional follow-up, as assessed by telephone, email, or office visit, is planned at 2, 6 months and 1, 2 years. See Staged 
Procedures section for additional details regarding follow-up. 
4. For women of childbearing potential only 
5. Submit all angiograms to core lab. Baseline angiograms should be collected if the subject consents pre-procedure or if collected 
per standard of care. All cardiovascular event angiograms should be collected. 
6. Any adverse event related to endpoint (includes all bleeding), SAEs, adverse device effects, or device deficiencies should be 
collected from start of procedure until the completion of study or study exit.  
7. CK/CK-MB and/or Troponin values must be collected post-procedure and when possible (due to consenting), pre-procedure. 
8. Cardiac biomarkers will be collected pre-procedure within 72 hours (for both index and staged procedures) if subject consented 
prior to procedure or per standard of care. 
9. Cardiac biomarkers will be measured post-procedure between 18 and 24 hours for index and staged procedures, or prior to 
discharge, whichever comes first.  
10. Other lab values will be done within 7 days pre-procedure. 
11. A 12-lead ECG will be performed within 72 hours pre-procedure (baseline) and 24 hours post-procedure or prior to discharge if 
<24 hours. Relevant copies of ECGs, which include copies of the baseline ECG at screening and discharge, event ECGs (most 
abnormal ECG and last ECG recorded), angiogram films and medical records (admission, discharge notes, reports, 
documentation for transfusions and cardiac biomarker values) will be collected for death or any (suspected) MI or (suspected) ST 
that occurs after the index procedure for adjudication purposes by a CEC. 
 
8.1.1. 
Clinical Laboratory Procedures and Tests 
It is expected that all sites participating in this study conduct basic standard of care that is required for proper assessment of a 
PCI patients, including 12-lead ECG, cardiac biomarkers, and collection of lab values (creatinine, hemoglobin, WBC, and 
platelet values). Relevant copies of ECGs, which include copies of the baseline ECG at screening and discharge, event ECGs 
(most abnormal ECG and last ECG recorded), angiogram films and medical records (admission, discharge notes, reports, 
documentation for transfusions and cardiac biomarker values) will be collected for death or any (suspected) myocardial 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 31 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
infarction or (suspected) stent thrombosis that occurs after the index procedure for adjudication purposes by a Clinical Events 
Committee (CEC). 
 
Cardiac enzyme values must be collected within the specified times to help determine presence or absence of myocardial 
infarction after procedure. Troponin is preferred, but CK or CK-MB is acceptable if it is collected per institutional standard. 
If the total CK value are utilized and are within normal ranges, CK-MB measurements may not be performed if this is per 
hospital standards. However, CK/CK-MB or troponin must be measured at least once post-procedurally, within an 18-24 
hour window or before discharge. It is encouraged that CK-MB measurements are obtained with every total CK drawn, even 
if CK values are within normal limits. In the case of multiple measurements prior to discharge, first enzyme 
measurement and the peak value should be documented on the case report forms. If the subject is noted to have troponin or 
CK elevation post-procedure, per the Third Universal Definition, troponin or CK/CK-MB treatments should be continued to 
be performed every 6 hours for 24 hours, starting from when the first elevation is noted. Myocardial infarctions will be 
adjudicated to the Third Universal definition43.  
 
Patients who are consented prior to procedure should collect cardiac biomarkers, baseline angiograms, and other laboratory 
tests. Cardiac biomarkers (CK/CK-MB and/or troponin) should be collected within 72 hours pre-procedure (for both index 
and if applicable, staged procedures). Baseline angiograms should be submitted to the Angiographic Core Lab. Other lab 
values (creatinine, hemoglobin, WBC, and platelet values) should be collected within 7 days of procedure and 12-lab ECGs 
should be performed within 72 hours pre-procedure.  
 
For patients who are consented within 24 hours after procedure, baseline cardiac biomarkers and baseline angiograms should 
be collected if following standard of care for the institution. Baseline angiograms (pre-procedure or at procedure) should be 
submitted to the Angiographic Core Lab. Other lab values (creatinine, hemoglobin, WBC, and platelet values) should be 
collected within 7 days of procedure and 12-lab ECGs should be performed within 72 hours pre-procedure.  
 
After procedure, any post-procedure or event angiograms should be submitted to the Angiographic Core Lab. Cardiac 
biomarkers (CK/CK-MB and/or troponin) should be collected between 18 and 24 hours for index and if applicable, staged 
procedures, or prior to discharge, whichever comes first. A 12-lead ECGs should be collected 24 hours post-procedure or 
prior to discharge if less than 24 hours of procedure. 
 
 
Table 3. Follow-up Interval Windows 
Follow-up Interval 
Window 
30 days 
± 5 days 
2 months 
± 10 days 
6 months 
± 14 days 
1 year 
± 30 days 
2 years 
± 30 days 
                                                            
43 Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J, E-pub. August 24, 2012 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 32 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
8.2. 
Subject Screening 
All subjects evaluated for potential PCI should be assessed for study eligibility. A qualified member of the study center’s 
research team will review the subject’s medical history and screen for study eligibility. Study centers may be asked to 
maintain a record of each subject screened by the study center along with the reason(s) for study exclusion. 
 
8.3. 
Subject Consent 
All subjects must complete an Informed Consent Form prior to undergoing any study-related assessments, other than 
procedures conducted per standard treatment at the institution. While consenting should be completed prior to the stent 
placement procedure when possible, subjects may complete informed consent up to 24 hours after receiving a Resolute Onyx 
stent if the subject is receiving standard treatment at the institution, if local regulatory requirements allow this. Study centers 
must comply with local regulatory requirements and Institutional Review Board (IRB) policies for obtaining informed 
consent. 
 
In advance of the consent discussion, the patient should receive the IRB and Medtronic-approved Informed Consent Form. 
During the consent discussion, the investigator or his/her designee (only in geographies where allowed) must fully inform the 
patient of all pertinent aspects and risks of the study.  All items discussed in the Informed Consent Form must be explained 
by study center staff designated on the Delegation Task List.  The language used shall be as non-technical as possible and 
must be understandable, read aloud to the prospective subject and the impartial witness, where applicable. Informed Consent 
Forms should be made available in patient’s native language.  
 
Where allowed by the institution, in the event that the patient is unable to provide written informed consent, verbal consent 
from the patient or written assent from a legally acceptable representative will be accepted to facilitate enrollment. The legal 
representative may provide written consent on behalf of the patient only after having been fully informed about the registry. 
Where a patient is providing verbal consent, an impartial witness must be present during the entire informed consent 
discussion. Once consent has been given, the witness must sign and personally date the consent form, to confirm that the 
information contained within the informed consent and any further information provided by the investigator was explained to 
and apparently understood by the patient and that consent was freely given. Where a patient has initially verbally consented 
or a patient’s legally acceptable representative has assented on behalf of the patient, written consent should be sought from 
the patient as soon as, in the investigator’s opinion, the patient is capable of understanding the process and capable of signing 
the consent form.  
 
Neither the investigator nor the study center staff shall coerce or unduly influence a patient to participate or to continue to 
participate in the clinical study. The informed consent process shall not waive or appear to waive the subject’s rights. The 
patient will be provided ample time to read and understand the Informed Consent Form and to consider participation in the 
study. All questions about the study should be answered to the satisfaction of the subject. 
 
When the patient decides to participate in the clinical study, the site’s current IRB and Medtronic-approved Informed 
Consent Form must be signed and personally dated by the subject and investigator designee. If the patient is consented within 
the allowed time frame after Resolute Onyx DES implantation, the time should be documented along with the date. If 
applicable, a witness shall also sign and personally date the consent form to attest that the information in the Informed 
Consent Form was accurately explained and clearly understood by the subject, and that informed consent was freely given.  
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 33 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
After all required parties have signed and dated the Informed Consent Form, the investigator/or designee must provide the 
subject with a copy of the signed and dated Informed Consent Form. The consent process must be documented in the 
subject’s medical record. 
 
8.4. 
Revisions in Subject Consent Form 
Medtronic will inform the investigators whenever information becomes available that may be relevant to the subject’s 
continued participation in the study. The investigator or designee should inform the subject in a timely manner. 
 
Medtronic will revise the written Informed Consent Form whenever new information becomes available that may be relevant 
to the subject’s continued participation in the study. The revised information will be sent to the investigator for approval by 
the IRB and regulatory authority, if required. After approval by the IRB, a copy of this information must be provided to the 
participating subjects, and the information process as described above, in the section on Subject Consent, needs to be 
repeated. 
 
8.5. 
Antiplatelet Medications 
Antiplatelet medication dosing should be administered per hospital routine and in line with applicable guidelines on 
percutaneous coronary interventions and the IFU of the device. During the index procedure, heparin or bivalirudin will be 
administered as per hospital standard of care. Use of GPIIb/IIIa blockers during the index procedure is left to the discretion of 
the investigator. All antiplatelet and anticoagulant medications will be recorded on the eCRF throughout the study. The 
following are the recommendations for antiplatelet treatment: 
 
Pre-procedure: 
A loading dose of aspirin of 250-500 mg orally or via IV in aspirin-naïve patients. P2Y12 inhibitor pre-treatment and 
loading doses should be performed according to institutional standard practice. Decisions regarding other antiplatelet and 
anticoagulant therapies are left to the discretion of the treating physician. 
 
Post-procedure to ≤30 days: 
• 
Aspirin: daily dose 75-100 mg recommended per DAPT guidelines  
• 
P2Y12 inhibitor: standard daily dose recommended by DAPT guidelines, with clopidogrel, 75mg once daily, being 
the preferred agent 
 
>30 days post-procedure to (indefinite): 
• 
Aspirin 75-100 mg daily or clopidogrel 75 mg daily recommended per DAPT guidelines 
 
Note 1: For staged procedures, DAPT schedule will be calculated from the date of the staged procedure. 
Note 2: Subjects who suffer a stent thrombosis during the first 30 days may be maintained on DAPT beyond 30 days at the 
investigator’s discretion. 
Note 3: The clinical profile of subjects included in the study make it unlikely that more potent antiplatelet agents than 
clopidogrel will be used. Should this be considered justified by the investigator, however, then the dose regimens of 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 34 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
other antiplatelets (e.g. prasugrel or ticagrelor) should follow the regimen recommended by the appropriate DAPT 
guidelines whenever possible. 
Note 4: Subjects being treated with oral anticoagulants may receive single antiplatelet therapy (e.g., clopidogrel) plus an 
oral anticoagulant from the date of the index procedure onwards. 
 
8.6. 
Medication Adherence 
Patient adherence to the one-month DAPT regimen is highly important for this study. The investigator and team should take 
extra steps to ensure this is communicated with the patient. To be deemed one-month clear for DAPT discontinuation at 1-
month, subjects must not interrupt aspirin and/or P2Y12 inhibitor for longer than 3 days during the first month after the index 
PCI or last staged PCI procedure. Subjects must also continue on single antiplatelet therapy (SAPT) after one month of 
DAPT through the end of the study.  Subjects will be provided a medication reminder card and also instructed to inform the 
investigator and team on any changes in medication including medication stop date, reason for stopping medication, 
medication restart date, and medication dosage. Dual antiplatelet therapy compliance will be assessed in the clinic at the 1-
month visit as well as in follow-up contacts and will be recorded in the eCRF. 
 
8.7. 
Procedure 
Treatment of the target lesion(s) should be performed according to the IFU that is provided with each Resolute Onyx stent. 
The beginning of the procedure is defined as the time the guide catheter is inserted into the subject.  
 
There is no limitation to the number of treated vessels and lesions. Full lesion coverage will be ensured by implantation of 
one or multiple stents. Operators are instructed to insert only the Resolute Onyx stent. In the case that multiple stents are 
required, a staged procedure is planned, or revascularization occurs, the Resolute Onyx stent should be used. No mixture of 
DES is permitted in a given subject unless the study stent cannot be placed, in which case the recommendation would be for 
the operator to use another device at Investigator’s discretion. 
 
Optimal technique in placement and in expansion of the assigned DES should be practiced. While recommended, the 
decision to perform predilatation and post dilatation is left to Investigator’s discretion. In the case it is used, post-dilatation 
should be performed with an appropriately sized (length and diameter) non-compliant balloon to assure that the stent is in full 
contact with the vessel wall. Do not use the stent delivery system for post-dilatation.  
 
If the procedure involves treating a bifurcation lesion, a single-stent strategy (the provisional stenting technique) is 
recommended. This provisional technique recommends stent placement in the main branch, finalized with proximal 
optimization technique, followed by placement of a second stent if inadequate results are found in the side branch (such as 
threatened closure of the side branch, dissection type B or worse, cases of TIMI flow <3, or residual stenosis more than 
80%). Provisional stenting is currently sanctioned by both ACC/AHA and ESC revascularization guidelines.44 45 All standard 
ancillary devices (e.g., guidewires, sheaths/guiding catheters, pre-dilatation balloons) used during the preparation and 
procedure should be used in accordance with the manufacturer’s instructions. 
                                                            
44 Kolh P, Windecker S, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization 
of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution 
of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). European Journal of Cardio-Thoracic Surgery 2014; 46(4): 517-92 
45 ACC; Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American 
College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and 
Interventions. J Am Coll Cardiol 2011; 58(24): e44-122 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 35 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Patients receiving non-study stents, or who undergo any non-study procedure for the treatment of coronary artery disease (i.e. 
any procedure other than PCI with Resolute Onyx stent), are considered major protocol deviations and will be followed for 
ITT analysis through one year only. The end of the procedure is defined as the time the guide catheter is removed from the 
subject. 
 
At discharge, clinical status will be assessed. Per informed consent, a letter will be sent to the subject’s referring physician 
providing information on the subject’s participation in the study, including a schedule for follow up time points and 
instructions to transition from DAPT to single antiplatelet therapy after 30 days according to the informed participation by 
the patient.  
 
After the end of the study, subjects will return to routine care as provided by their physician per standard practice. 
 
8.8. 
Staged Procedures 
Treatment of all target lesions with the Resolute Onyx stent within a single PCI is encouraged, if reasonable and safe. 
However, when staging is required for clinical reasons, the staged procedures should be performed within 30 days from 
index procedures and similar to index procedure, with a Resolute Onyx stent. A staged procedure is considered a subsequent 
treatment of a lesion in a vessel not treated at index that is present at the time of the index procedure. Staging should be pre-
specified at the time of the index procedure and follow-up should be calculated from the date of index procedure. Cardiac 
enzymes should be obtained before and after the staged procedure, with the same steps as that taken for the index procedure. 
Lesions and vessels treated with Resolute Onyx stent at the staged procedure are considered target lesions and vessels. 
 
In addition, staged procedures should meet the following requirements: 
• 
Staged procedures must be pre-specified at index procedure AND completed within 30 days of index procedure to 
qualify as a planned staged procedure. Any additional procedure to the index procedure that does not meet these 
requirements may be considered as a revascularization and follow-up will be based on the timing of index 
procedure. 
• 
Resolute Onyx stents should be used at both index and at staged procedures.  
• 
Staged procedures in the target vessel(s) treated at index are NOT allowed.  
• 
Staging should not involve a segment directly adjacent to a segment treated during the index PCI. 
• 
Every urgent coronary reintervention before the planned staged procedure is considered an event. 
• 
Duration of DAPT is one month following the staged procedure. 
• 
For one-month clear analysis, the “clear” definition should be extended to one month beyond the planned staged 
procedure. 
• 
Follow-up for the one month and two month time points will be calculated from the date of staged procedure; 
remaining follow ups will be calculated from the index procedure. 
 
8.9. 
Bailout 
For subjects who consent prior to procedure, bailout procedures should be avoided unless required for subject safety. If 
bailout procedures are performed, justification should be documented on the eCRF. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 36 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
If a subject in this study experiences a major dissection or an occlusive complication (as evidenced by decreased target vessel 
flow, chest pain, or ischemic ECG changes which do not respond to standard rescue techniques), bailout procedures may be 
performed. For these events occurring during the study procedure, additional stenting with the Resolute Onyx DES may be 
employed as a bailout treatment. In the event a Resolute Onyx DES cannot be implanted, the operator may deploy another 
device at Investigator’s discretion to complete the procedure successfully. Subjects with bailout non-study stent(s) will be 
followed for ITT analysis through one year and DAPT is per physician discretion. 
 
Target lesion(s) is/are to be selected with the intent to cover each lesion with a single stent. If incomplete coverage occurs 
during the procedure, additional stenting with assigned study stents may be employed to provide complete coverage. 
 
Refer to IFU for procedural guidelines. 
 
8.10. 
Treatment Failure 
Study stent(s) that enter the guide catheter and fail to be implanted at the intended location are considered treatment failures 
and should be recorded in the eCRF. Treatment failures should be followed-up for safety purposes through one year and these 
subjects and lesions will be included in the ITT population but not the primary analysis. Subjects experiencing total treatment 
failure (i.e., no Resolute Onyx stent treatment) will not be replaced. After the one-year time frame, total treatment failures 
should be exited from the study. 
 
8.11. 
Assessment of Effectiveness 
Assessments of effectiveness will include acute device, lesion, and procedural successes as well as adjudication of any 
revascularizations reported through each subject’s follow-up. 
 
8.12. 
Assessment of Safety 
Reports of all adverse events related to endpoint (including bleeding), SAEs, adverse device effects and device deficiencies, 
with the return of the device when possible, will be evaluated by Medtronic. The Clinical Events Committee (CEC) will 
review and adjudicate clinical events possibly related to study endpoints that need adjudication throughout the duration of the 
study.  
 
8.13. 
Recording Data 
Data collected on each subject will be recorded on a web-based eCRF. This study will utilize an Oracle Clinical Remote Data 
Capture (RDC) system that is the property of Medtronic. Each enrolled subject is assigned a unique study ID number. 
Records of the subject/subject ID relationship will be maintained by the study site. Individual subject medical information 
obtained as a result of this study will be considered confidential.  
 
Authorized site personnel as indicated on the Delegation Task List (DTL) will record the required data on eCRFs. Study 
personnel delegated for eCRF completion and/or approval per the DTL will be trained on the use of the RDC system and 
thereafter be provided with a user name and password to access the system. Passwords are individual and cannot be shared. 
 
The eCRFs must be completed and updated to reflect the latest observations on the subjects participating in the study. The 
investigator (or delegated personnel by investigator) will electronically sign the appropriate pages of each eCRF. In the U.S. 
the delegated personnel will be an approved sub-investigator, and in Japan this may be study staff that has been delegated to 
enter information into the electronic data system as a copy from medical records or other materials. The Oracle Clinical RDC 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 37 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
system maintains an audit trail of entries, changes, and corrections in eCRFs. If a person only authorized to complete eCRFs 
makes changes to an already signed eCRF, the investigator shall re-approve this eCRF.  
 
The hospital files (electronic or paper) will constitute source data. For the purpose of adjudication of events by the CEC, 
relevant event-related source documents (e.g. angiograms, procedural details, worksheets, etc) will be redacted and collected 
for events that need to be adjudicated by the CEC. In Japan, availability of source documentation may be limited due to 
hospital policies. If a specific source document is not available, necessary information may be transcribed on to the relevant 
CRF page. 
 
The eCRFs may not serve as source documents. Source documentation for data elements not routinely captured in medical 
records (e.g., angiogram variables, procedural details) may vary from center to center.  
 
The principal investigator is responsible for ensuring that all sections of each CRF are complete and correct and that those 
entries can be verified against source data. 
 
Medtronic will be responsible for the processing and quality control of the data. Data review, database cleaning and issuing 
and resolving data queries will be done according to Medtronic internal SOPs and the Data Management Plan for this study. 
The study database will employ validation programs (e.g., range and logic checks) on entered data to identify possible data 
entry errors and to facilitate data validation.  
 
8.14. 
Investigator records 
At a minimum, the following records must be kept by the investigator: 
• 
All approved versions of the Clinical Investigation Plan  
• 
Medtronic- and IRB- approved Informed Consent Form 
• 
Fully signed Clinical Trial Agreement and confidentiality agreement (if not included in the Clinical Trial 
Agreement) (for US sites) 
• 
Financial disclosures: if the financial interests change during the course of the study or within one year of 
completion of the study, the investigator is obliged to inform the sponsor of such financial change 
• 
Insurance certificates, if applicable 
• 
Completed Delegated Task List and Curriculum Vitae of all investigational site personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Subject screening log and subject identification log 
• 
Signed, dated, and fully executed Informed Consent Forms 
• 
The investigator will clearly mark clinical records to indicate that the subject is enrolled in this clinical investigation. 
• 
Lab certificates / Lab normal ranges  
• 
Fully executed eCRFs and corrections (in the EDC or as copy on site) 
• 
Reports of Adverse Events and Device Deficiencies 
• 
IRB approval letter, voting list and correspondence 
• 
Clinical Study Report (including statistical analysis), if applicable 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 38 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
8.15. 
Investigator reporting responsibilities 
The investigator is responsible to ensure that all work and services related to this trial described herein, or incidental to those 
described herein, are conducted in accordance with the highest standards of medical and clinical research practice, the 
requirements of the IRB, the investigational plan, the terms of the Investigator Agreement, and all applicable local laws and 
regulations, including (except in Japan):  
• 
21 CFR 812: Investigational Device Exemptions 
• 
21 CFR 50 (Subpart B): Informed Consent of Human Subjects (21 CFR 50.20 General Requirements for Informed 
Consent) 
• 
21 CFR 54 (Part 54): Financial Disclosure by Clinical Investigators  
 
Table 4 describes the Investigator reporting responsibilities.  
 
Table 4. Investigator Reporting and Data Submission Responsibilities 
Report / Data Submission 
Submit to 
Description/Constraints 
CRFs (screening failure, 
inclusion/exclusion, baseline, 
follow-up, non-compliance, event, 
study exit) 
Sponsor 
Submit via EDC (guidelines: within 7 days) 
Angiographic media 
Angiographic Core 
Laboratory 
Submit to Core Laboratory (guidelines: within 7 
days) 
Adverse Events 
Sponsor & IRB 
Refer to Section 10 for reporting requirements 
Progress Report 
Sponsor & IRB 
Provide if required by local law or IRB  
Withdrawal of IRB approval 
Sponsor 
Investigator must report a withdrawal of the 
reviewing IRB within 5 working days of the 
investigator’s part of the investigation. 
Final Report 
IRB 
This report must be submitted within 3 months 
after termination or completion of the 
investigation or the investigator’s part of the 
investigation, or per local IRB requirements. 
Deviations from Investigation Plan 
Deviation from Investigation Plan 
(Other – Non-Emergent) 
Sponsor &IRB 
If the deviation may affect the scientific 
soundness of the plan or the rights, safety and 
welfare of the subjects (and is not an emergency), 
then the deviation must be approved by Medtronic 
and the reviewing authority prior to its 
implementation. If the deviation does not affect 
these issues (study soundness, rights, safety, etc.) 
then only Medtronic must approve it  
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 39 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Deviation from Investigation Plan 
(Emergency) 
Sponsor & IRB 
Notification must be made as soon as possible if 
the deviation was made to protect the life or 
physical well-being of a subject in an emergency 
Failure to Obtain Informed Consent 
(not required for Japan sites) 
Sponsor & IRB 
The Investigator must notify Medtronic and the 
reviewing authority within 5 working days after 
device use. The report must include a brief 
description of the circumstances justifying the 
failure to obtain informed consent. 
 
 
8.16. 
Sponsor record maintenance responsibilities 
At a minimum, the sponsor will keep the following records: 
• 
All essential correspondence related to the clinical study 
• 
Signed Investigator Agreement 
• 
Current curriculum vitae for each Principal Investigator at all sites 
• 
Current curriculum vitae for all other investigators and site team members (for US sites) 
• 
Delegated Task List (DTL) 
• 
SAE, AEs related to endpoint (including bleeding), adverse device effects, and device deficiency information 
• 
All data forms, prepared and signed by the Investigators, and received source documentation and core lab reports 
• 
Clinical investigation protocol and subsequent amendments 
• 
Site monitoring reports 
• 
Financial disclosure information 
• 
Study training records for site participants and internal trial staff members 
• 
Contact lists of all participating investigators/investigative sites, IRB information, study monitors and Sponsor staff 
members including the medical expert; Sponsor will maintain these lists and provide updates to the necessary 
parties. 
• 
Sample of device labeling 
• 
Insurance certificates, if applicable 
• 
IRB approval documentation and voting list and correspondence 
• 
Lab certificates (except in Japan) / Lab normal ranges 
• 
Statistical analyses 
• 
Clinical Investigation Report 
 
8.17. 
Sponsor reporting responsibilities 
 
Sponsor reporting requirements are summarized in Table 5. 
Table 5. Sponsor Reporting Requirements  
Report 
Submitted to 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 40 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Serious Adverse Event (SAE) 
Adverse Device Effect (ADE) or Device Related 
Adverse Event 
Device Deficiency that might have led to a SADE 
Regulatory authorities: Reporting timeframe as per local 
requirement. 
IRB: Reporting timeframe as per local IRB requirement. 
Serious Adverse Device Effects (SADE)  
Unanticipated Adverse Device Effect (UADE) 
Unanticipated Serious Adverse Device Effect (USADE) 
Regulatory authorities: Submit as soon as possible, but 
not later than within 10 working days after the Sponsor 
first receives notice of the event, as per local reporting 
requirement. 
IRB: Reporting timeframe as per local IRB requirement. 
Study enrollment status and rates of cardiac death, MI, 
cardiac death/MI and stent thrombosis 
Progress reports will be provided to FDA on a quarterly 
basis 
 
 
Medtronic will conduct an evaluation of the UADE in accordance with CFR 812.46(b) and shall report the results of such 
evaluation to FDA and to all reviewing IRBs and participating investigators within 10 working days after Medtronic first 
receives notice of the effect. Thereafter, Medtronic shall submit such additional reports concerning the effect as FDA 
requests. Events reported for this study from all geographies will be reviewed and assessed for UADE reporting to the FDA. 
Events deemed to be UADEs will be submitted per local reporting requirements. 
 
A list of potential adverse events related to the Resolute Onyx™ Zotarolimus-Eluting Coronary Stent System can be found in 
the Instructions for Use. 
 
8.18. 
Deviation Handling 
A study deviation is defined as an event where the investigator or site personnel did not conduct the study according to the 
Clinical Investigation Plan, applicable laws or regulations, IRB, or the investigator agreement.  
 
Regulations require that investigators maintain accurate, complete and current records, including documentation of any 
deviations from the investigation plan including the date of and reason for the deviation. The deviations must be reported to 
the sponsor on the eCRF.  
 
Investigators are required to obtain prior approval from the Medtronic Clinical Research Department before initiating 
changes in or deviations from the investigation plan, except where necessary to protect the life or physical well-being of a 
subject in an emergency. Such approval will be documented in writing and maintained in the study files.  
 
Deviations shall be reported to Medtronic regardless of whether medically justifiable, pre-approved by Medtronic, or taken to 
protect the subject in an emergency. Deviations to protect the life or physical wellbeing of the subject in an emergency must 
be reported to Medtronic and the IRB within five working days. 
 
Subject-specific deviations will be reported on the non-compliance eCRF. Deviations that are not subject specific (e.g., 
unauthorized use of an investigational device by a physician who has not signed an Investigator Agreement) will be reported 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 41 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
to Medtronic in writing. Investigators will also adhere to procedures for reporting study deviations to their IRB in accordance 
with their IRB requirements. 
 
The study center’s compliance with the clinical investigation plan will be assessed on an ongoing basis. Corrective and 
preventive action plans will be developed and implemented to secure compliance. In cases of serious non-compliance, the 
sponsor may decide to stop subject enrollment and site participation at an investigational site based on its assessment of 
repeated occurrences of significant non-compliance. 
 
Examples of deviations include but are not limited to the following: 
• 
Failure to obtain informed consent prior to participation 
• 
Incorrect version of the Informed Consent used 
• 
Failure to obtain IRB approval before the start of the study 
• 
Treated subject did not meet inclusion/exclusion criteria  
• 
Follow-up visit not done 
• 
Reportable adverse events not reported in the required time frame as required by regulation or as specified in 
protocol 
• 
Source data permanently lost 
• 
Enrollment of patients during lapse of IRB approval 
 
8.19. 
Subject Withdrawal or Discontinuation 
A study subject has the right to discontinue participation in the study at any time without penalty or loss of benefits to which 
the subject is otherwise entitled. A withdrawn subject will be treated according to standard of medical care and will not be 
replaced. Subjects will be included in the analyses up to the time that consent was withdrawn.  
 
If an investigator decides to withdraw a subject or if the subject decides to withdraw from the study, the investigator will 
document the reason for withdrawal, if known, and indicate any rationale for the withdrawal from the study in the subject’s 
file. If a subject is withdrawn from the study due to problems related to the investigational device, continued follow-up may 
be requested by the sponsor to assess subject safety. In all other cases, no additional data will be captured after the subject 
withdraws or is removed from the study, unless the information is publicly available. Subjects have the right to withdraw 
from the study at any time without explaining why and without any consequences. 
 
Subject Lost-To-Follow-Up (LTFU) should be avoided as much as possible and investigators are urged to do their utmost 
best to maintain subject follow-up compliance. Continuous attempts (e.g., phone, email, certified letter) throughout the final 
follow-up period should be made to contact the subject, the subject’s family or referring physician before documenting a 
subject LTFU (at least three documented attempts must be made). It is recommended that death study databases (e.g. SSDI) 
should be checked before subjects are considered LTFU. A subject is not considered LTFU until the subject’s final follow-up 
window has closed. Once a subject has completed their final follow-up visit, a study exit form must be completed. 
 
 
9. Risks and Benefits 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 42 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
9.1. 
Potential Risks 
This study assesses the use of a shorter duration of DAPT use for a specific patient population treated with DES. Stent drug, 
stent materials, and technique related standard percutaneous coronary diagnostic and treatment procedures will not be 
changed. Therefore, the risks associated with this study are related to a reduced duration of DAPT in subjects. As recent 
evidence have suggested that major bleeding is correlated with adverse events46, this study balances the potential risks of 
shorter DAPT such as a higher risk for thrombotic complications after stent implantation, with the potential benefit of reducing 
the bleeding risk in a population that is at high risk for bleeding complications. These “high-bleeding risk” patients are 
estimated to be approximately 15% of those treated for PCI and include patients excluded due to age, underlying 
comorbidities, (i.e. low ejection fraction, chronic renal insufficiency) and other reasons, who are not able to be subjected to 
longer term dual antiplatelet therapy use. In many drug-eluting stent studies, these high-bleeding risk patients have been 
excluded from the study population. 
 
While there is early clinical evidence suggesting that the clinical risks around usage of a shorter DAPT treatment after DES 
implantation may be low47, there is limited conclusive evidence in a wider population suggesting short DAPT duration may 
be safe and effective for all patients. However, the high-bleeding risk population has been identified in published guidelines 
as a subgroup that may be suitable for shorter DAPT compared to other patients treated with DES, with evidence supporting 
DAPT duration as short as one month.48 49 In addition, the LEADERS FREE study was conducted with a population of high-
bleeding risk patients with the understanding that these included patients with potential to be at higher clinical risk and still 
demonstrated safety and effectiveness with 1-month DAPT when compared to a bare-metal stent. This high-bleeding risk 
population in the LEADERS FREE study included subjects who had clinical or anatomic features that posed a higher ischemic 
risk, including subjects who had multivessel disease (1493/2399 (62.2%)), ACS (659/2432 (27.1%)), diabetes (805/2427 
(33.2%)), hypertension (1913/2427 (78.8%)), bifurcation (15.5%), in-stent restenosis (2.5%) and chronic total occlusion 
(4.7%). While rates of adverse clinical outcomes were higher in these subgroups as compared to treatment of simple lesions, 
the investigators did not find patients to be at higher risk in these subgroups that would trigger concern. These data were pre-
specified and also published by the LEADERS FREE investigators. 50  51  Given that the Onyx ONE Clear Study 
inclusion/exclusion criteria are similar to that of LEADERS FREE, it is expected that similar proportions will be enrolled and 
have clinical or anatomic features that pose a higher ischemic risk.  
 
In addition, the study design will minimize the risks through observance of strict study center and investigator selection 
criteria, careful subject selection and management, rigorous adherence to a standardized schedule of evaluations and adverse 
event monitoring. Risks may be further limited by continued monitoring of subjects following the index procedure. The 
investigators are also expected to perform continuous monitoring, assessment and documentation of any risks. The device 
used in this study is commercially available and has a proven safety record. 
 
                                                            
46 Morice, LEADERS FREE 1 year Presentation. TCT 2017. 
47 Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following 
resolute Zotarolimus-eluting stent implantation. Eur Heart J. 2014;35(29):1949-1956 
48 Levine GN, Bates ER, Bittl JA, Brindis RG, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with 
Coronary Artery Disease. J Thorac Cardiovasc Surg. 2016; 152 (5):1243-1274. 
49 Valgimigli M, Bueno H, Byrne R, et al. 2017 ESC Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease developed in collaboration 
with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017;39(3):213-260. 
50 Naber CK, Urban P, Ong PJ, et al. Biolimus-A9 polymer-free coated stent in high bleeding risk patients with acute coronary syndrome: a LEADERS 
FREE ACS sub—study. EHJ. 2017:38, 961-969.  
51 Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. NEJM Oct 14, 2015. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 43 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Standard risks associated with the medical device used in this study and risks associated with percutaneous treatment 
procedures are provided in the device IFU. Additional risks, which are not known at this time, may also exist.  
 
In addition, all efforts will be made to minimize these risks by selecting investigators who are experienced and skilled in 
interventional procedures including stenting, by clearly defining inclusion/exclusion criteria to ensure only appropriate 
subjects are enrolled, and by ensuring that treatment and follow-up of the subject are consistent with current medical 
practices. 
 
9.2. 
Risks Related to Devices 
The risks associated with using the study device are related to the drug, the stent materials, and risks associated with 
standard percutaneous coronary diagnostic and treatment procedures.  
 
As outlined in the commercially available IFU for the study device, physicians should make decisions about duration of 
DAPT on an individual basis and should integrate clinical judgment, assessment of the benefit/risk ratio, and subject 
preference. While there are no new risks identified specific for this study, risks from product commercial IFU include the 
following: 
 
Percutaneous Coronary Diagnostic and Treatment Procedures 
Risks associated with using these products are those associated with percutaneous treatment procedures for a stenotic coronary 
artery. The complications relating to standard PTCA and stenting include, but are not limited to the following: 
• 
Abrupt vessel closure 
• 
Access site pain, hematoma or hemorrhage 
• 
Allergic reaction to anti-coagulation and/or anti-thrombotic therapy, contrast material, or stent and/or delivery 
system materials, drug, and polymer coating 
• 
Aneurysm, pseudoaneurysm, or arteriovenous fistula 
• 
Arrhythmias (including ventricular fibrillation) 
• 
Balloon rupture 
• 
Bleeding 
• 
Cardiac tamponade 
 
• 
Coronary artery occlusion, perforation, rupture, or dissection 
• 
Coronary artery spasm 
• 
Death 
 
• 
Embolism (air, tissue device or thrombus) 
• 
Emergency surgery: peripheral vascular or coronary bypass 
• 
Failure to deliver the stent  
• 
Hemorrhage requiring transfusion 
• 
Hypotension / hypertension 
• 
Incomplete stent apposition 
• 
Increased risk of restenosis of stented segments 
• 
Infection or fever 
• 
Myocardial infarction 
• 
Pericarditis 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 44 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
• 
Peripheral ischemia / peripheral nerve injury 
• 
Renal failure 
• 
Shock / pulmonary edema 
• 
Stable or unstable angina 
• 
Stent deformation, collapse, or fracture 
• 
Stent migration or embolization 
• 
Stent misplacement 
 
• 
Stroke or transient ischemic attack 
• 
Thrombosis (acute, sub-acute, or late) 
 
Additional Potential Risks Related to Resolute Onyx stent 
Additional potential adverse events that have been associated with zotarolimus include but are not limited to: 
• 
Anemia  
• 
Diarrhea 
• 
Dry Skin 
• 
Headache 
• 
Hematuria 
• 
Infection 
• 
Injection site reaction 
• 
Pain (abdominal, arthralgia) 
• 
Rash 
 
The types of risks of the BioLinx polymer coating are expected to be no different than those of other stent coatings. These 
additional risks may include, but are not limited to, the following: 
• 
Allergic reaction 
• 
Focal inflammation at the site of stent implantation 
• 
Restenosis of the stented artery 
 
9.3. 
Potential Benefits 
Clinical practice guidelines have been updated recently to reduce the duration of DAPT after technological advancements in 
design and manufacture of newer generation DES, while leveraging the now available abundance of supportive long-term 
safety data of currently marketed DES. This study identifies a specific population which may benefit from shorter DAPT 
treatment due to a high risk for bleeding. Risk of major bleeding may prevent these patients from receiving a DES and limit 
treatment to a POBA or a bare-metal stent which may not be the preferred treatment. Reducing the duration of DAPT to one 
month may allow high bleeding patients to be treated with a DES as it may reduce the bleeding risks for this patient 
population. Recent evidence such as presented on the LEADERS FREE trial relating to the occurrence of major bleeding to 
higher mortality rates suggests also that shorter DAPT may have a positive impact on the risk of the patient to have adverse 
events.52 In addition, study participation contributes to expanding the knowledge base with respect to the use of the Resolute 
Onyx stent systems with a specific time frame for DAPT. As highlighted by recent changes in both the ESC/EACTS and 
ACC/AHA guidelines on DAPT, the generation of clinical evidence supporting recommendations on DAPT duration in 
                                                            
52 Morice. LEADERS FREE at 1 year Presentation. TCT 2017 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 45 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
diverse populations is important to both the physician and to the patient. DAPT related data provide critical information 
needed for physicians for circumstances under which treatment duration decisions post-DES implantation may be 
complicated by concerns such as patient safety (e.g., clinical status, bleeding) or unplanned surgical interventions. For the 
patient, in addition to a priority of safety and well-being, concerns may stem from individualized preference as well as 
affordability.  
 
Importantly, as highlighted by current guidelines, decisions about duration of DAPT are best made on an individual basis and 
should integrate clinical judgement, assessment of the benefit/risk ratio, and patient preference. However, there are strong 
potential benefits for the subject, especially one that is at higher risk for bleeding or who would otherwise not be able to 
receive treatment with a DES. 
 
9.4. 
Risk Benefit Rationale 
Appropriate risk management activities have been performed on the Resolute Onyx stent, resulting in a positive risk-to-
benefit rationale as confirmed by previous regulatory approvals in different global regions.  
 
Ultimately, it is the balance between the need for DAPT use after DES implantation and the risk for bleeding that provides 
the basis for this study. Based on our current knowledge, while the included patient population is at higher risk for bleeding, 
participation in this study does not impose significant additional risks to the subject when compared to the existing DAPT 
treatment regime based on current guidelines and clinical evidence that has been obtained in recent studies, including 
LEADERS FREE. Subjects at high-bleeding risks may benefit from a shorter duration of DAPT due to the reduced risk of 
bleeding events and potential sequelae that exist with prolonged DAPT. As recent studies have shown that the occurrence of 
major bleeding events can be linked to higher rates of mortality, the opportunity to reduce the risk of such bleeding events is 
important to patient safety. Furthermore, the use of DES compared to bare-metal stents has been compared in many studies 
and have led to general consensus that DES is preferred to bare-metal stents. Under these premises, the availability of clinical 
evidence on short DAPT use in a high-bleeding risk population provides opportunities for patients for potentially safer 
treatment.  In this carefully selected population of patients with high risk for bleeding, it is anticipated that the potential 
benefits of the study outweigh the potential risks. 
 
10. Adverse Events and Device Deficiencies 
 
10.1. 
Definitions/Classifications 
For the purpose of this clinical investigation, Medtronic defines adverse events as shown below. In case country specific 
definitions and safety reporting regulations are stricter than mandated, reporting will be done in compliance with the country 
specific safety regulations. For Japan, please also refer to the investigator’s brochure for additional reference to possible AEs 
and device deficiencies.  
 
While ISO14155:2011 has been carefully considered for this study, due to the nature and regulatory strategy of this study, 
including the post-approval status of the Resolute Onyx product, the scope of adverse event reporting has been limited to 
reporting of all endpoint-related AEs (including all minor bleeding), SAEs, adverse device effects, and device deficiencies.   
 
Medical occurrences that are inherent to a surgical procedure and expected to occur in the majority of subjects for a projected 
duration may be considered unavoidable. Such events include, but are not limited to, those listed in Table 6. These medical 
occurrences should not be reported as adverse events during this study. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 46 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Table 6. Expected, non-reportable events related to a surgical procedure 
Event Description 
Timeframe (hours) from the procedure 
Anesthesia related nausea / vomiting (with or without treatment) 
24 
Low-grade fever (<37.8°C) 
48 
Pain at access site (with or without standard treatment and patient 
not returning to clinic to have additional treatment) 
72 
Sleep problems (insomnia) (with or without treatment) 
72 
Back pain related to laying on table (with or without treatment) 
72 
 
For the purposes of the clinical report, Medtronic will classify the following adverse events according to ISO 
14155:2011. Where the definition indicates “device,” it refers to any component of the Resolute Onyx stent used in the study. 
 
Table 7. Adverse Event Definitions  
Adverse Event (AE): (ISO14155:2011 3.2) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users or other persons, whether or not related to the investigational medical device 
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical devices. 
Adverse Device Effect (ADE): (ISO14155:2011 3.1) 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
Serious Adverse Event (SAE): (ISO 14155:2011 3.37) 
An adverse event that 
a) led to death 
b) led to serious deterioration in the health of the subject, that either resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. 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 fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered a serious adverse event. 
Serious Adverse Device Effect (SADE): (ISO 14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious Adverse Event 
Unanticipated Serious Adverse Device Effect (USADE): (ISO 14155:2011 3.42) 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 47 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current 
version of the risk analysis report. 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or outcome 
has been identified in the risk analysis report 
Device deficiency: (ISO 14155:2011 3.15) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labelling 
 
10.2. 
Reporting of Adverse Events 
Investigators are required to report adverse events and device deficiencies as described in the table below, from the start of 
procedure until subject’s exit from the study. Reportable adverse events will be reported to the sponsor and documented on 
the Adverse Event eCRF and in the subject’s medical records. All assessments prior to subject enrollment are considered 
standard of care. 
 
Reportable events will be followed until the event has resolved (in the case of permanent impairment, the event will be 
followed until it stabilizes and the overall clinical outcome has been ascertained). The investigator will report events that may 
occur to the Sponsor, and will assess seriousness, relationship (relatedness to the device, procedure and therapy where 
applicable), subsequent intervention required, resolution status and whether or not the adverse event resulted in the subject’s 
discontinuation from the study. The following table outlines the five different levels of causality for every adverse event to be 
classified against. 
 
Table 8. Causality Assessment53 
Not related 
Relationship to the device or procedures can be excluded when: 
 - the event is not a known54 side effect of the product category the device belongs to or of similar 
devices and procedures; 
 - the event has no temporal relationship with the use of the investigational device or the 
procedures; 
 - the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
 - the discontinuation device application or the reduction of the level of activation/exposure – 
when clinically feasible – and reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
 - the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
 - the serious 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); 
                                                            
53 Guidelines on Medical Devices. Clinical Investigations: Serious Adverse Event Reporting Under Directives 90/385/EEC/and 93/42/EEC; MEDDEV 2.7/3 
revision 3; May 2015 
54 When the event is not a known side effect of the product category the device belongs to or of similar devices and procedures, generally is considered “not 
related”. Yet, the unexpected effect shall not be excluded from evaluation and reporting.   
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 48 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 - the event does not depend on a false result given by the investigational device used for 
diagnosis55, 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 device/procedures and the serious event. 
Unlikely 
The relationship with the use of the device seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possible 
The relationship with the use of the investigational device 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. 
Probable 
The relationship with the use of the investigational device seems relevant and/or the event cannot 
be reasonably explained by another cause, but additional information may be obtained. 
Causal relationship 
The serious event is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
 - the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
 - the event has a temporal relationship with investigational device use/application or procedure; 
 - the event involves a body-site or organ that 
• 
the investigational device or procedures are applied to; 
• 
the investigational device or procedures have an effect on; 
 - the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
 - the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
 - 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 use; 
 - the event depends on a false result given by the investigational device used for diagnosis56, 
when applicable; 
 - in order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
 
The investigator will provide further information regarding reportable adverse events as requested by the Sponsor. Previously 
reported Adverse Events information should be updated when the status of the event changes, including change in actions 
taken, change in outcome, or change in relatedness. Adverse events that occur during and are recorded in this study are 
required to be reported to Medtronic via the AE or device deficiency eCRF, as per the timeframes listed in Table 9. 
                                                            
55 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment and incur all the risks that 
accompany that treatment, or might be incorrectly diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment 
(thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease or condition.   
56 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment and incur all the risks that 
accompany that treatment, or might be incorrectly diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment 
(thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease or condition.   

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 49 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Table 9. Investigator AE Reporting Requirements to Medtronic and IRB 
Event Type 
Investigator Timeframe for Reporting to Medtronic 
Serious Adverse Event (SAE) and 
any adverse-event related to endpoint 
(including all bleeding) 
Immediately, but no later than 7 calendar days of the investigator’s / 
site’s first knowledge of the event  
Adverse Device Effect (ADE) 
(Device or procedure Related 
Adverse Event) 
Submit in a timely manner (15 calendar days) of the investigator’s / 
site’s first knowledge of the event 
Serious Adverse Device Effect 
(SADE) 
Immediately, but no later than 7 calendar days of the investigator’s / 
site’s first knowledge of the event  
Unanticipated Serious Adverse 
Device Effect (USADE) 
Immediately, but no later than 2 calendar days of the investigator’s / 
site’s first knowledge of the event 
Device Deficiency that might have 
led to an SADE 
Immediately, but no later than 7 calendar days of the investigator’s / 
site’s first knowledge of the event 
Device Deficiency 
Submit in a timely manner (15 calendar days) of the investigator’s / 
site’s first knowledge of the event 
 
In addition, investigators are obliged to report appropriate adverse events to their IRB in accordance with the requirements 
and local regulations. 
 
All events and complaint reporting will be reviewed by Medtronic. This process is part of postmarket vigilance. Medtronic 
will review and report all reportable events (including device deficiencies) according to national regulations in acceptably 
timely conditions. For events, this review will include the determination whether the SAE meets regulatory reporting 
requirements. The Sponsor will ensure timely SAE reporting to meet global regulatory requirements. The Medtronic 
employee who first becomes aware of an SAE/Device Deficiency related to a Medtronic device will immediately report this 
device-related SAE/Device Deficiency to the Medtronic Product Experience Management (PXM) Galway, Ireland. The 
Medtronic PXM Galway, Ireland will ensure prompt review, and appropriate reporting. 
 
10.3. 
Recording and Reporting of Device Deficiencies 
Device deficiencies are defined as inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance. Device deficiencies include malfunctions, use errors, and inadequate labeling.  
 
Malfunction is defined as the failure of a device to meet its performance specifications or otherwise perform as intended. 
Performance specifications include all claims made in the labeling for the device. The intended performance of a device 
refers to the intended use for which the device is labeled or marketed. Product labels, Instructions for Use, User Manuals, and 
if appropriate an IB, for this study are provided separately. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 50 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Device deficiency information will be collected throughout the study and reported to Medtronic. Device deficiencies that did 
not lead to an AE should be reported on the Device Deficiency eCRF. Device deficiencies that result in an adverse device 
effect (ADE) to the subject should be captured as an adverse event only. Device deficiencies that did not lead to an AE but 
could have led to a serious adverse device effect (SADE) (i.e., if suitable action had not been taken, if intervention had not 
been made, or if the circumstances had been less fortunate) require immediate reporting. All reportable device deficiencies 
and malfunctions will be documented on the appropriate eCRF, one form for each deficiency, and further reported to the IRB 
(if required) within the IRB required timeframe and local and national regulations.  
 
 
10.4. 
Emergency Contact for Reporting Events and Device Deficiencies 
Investigators should contact their responsible Medtronic study contact if they have any questions regarding reportable AEs or 
device deficiencies. Sponsor contact information (including name, title, address, and telephone number(s) is subject to 
change and will be maintained in a document separate from the clinical investigation plan and provided to sites. 
 
For reportable AEs or device deficiencies that require immediate reporting (see Table 7), initial reporting shall be done by 
completing the appropriate eCRF. If the eCRF is not available during the required reporting period, the reportable AE or 
device deficiency should be reported to Medtronic by alternate means, such as the responsible site manager. In due time, the 
reportable AE or device deficiency needs to be entered in the eCRF as well. 
 
 
11. Data Review Committees 
 
11.1. 
Clinical Event Committee 
The Clinical Event Committee (CEC) is composed of independent cardiologists who are not participants in the study. The 
CEC is charged with the development of specific criteria used for the categorization of clinical events and clinical endpoints 
in the study. Criteria will be established for selected complications and clinical events. At the onset of the study, the CEC will 
establish explicit rules outlining the minimum amount of data required, and the algorithm followed in order to classify a 
clinical event. The CEC will meet regularly to review and adjudicate pre-defined clinical endpoint events. If needed, the 
adjudication committee will require collection of additional source documentation from the clinical centers. The procedures 
by which the CEC will operate will be documented in a separate CEC charter. 
 
11.2. 
Data Safety and Monitoring Board 
The Data Safety and Monitoring Board (DSMB) will evaluate safety data on an ongoing basis and advise Medtronic about 
the continuing safety of the study, to ensure the well-being of the current participants and those yet to be enrolled as well as 
the continuing validity and scientific merit of the study. The primary responsibility of the DSMB is to monitor the health, 
safety, and welfare of subjects. The DSMB will be composed of physicians from the fields of cardiology and interventional 
cardiology and at least one biostatistician with experience in analysis of clinical studies. The members of the DSMB will not 
be investigators in the study and will be independent of Medtronic.  
 
Prior to the first DSMB review, guidelines for the identification and evaluation of significant safety findings and/or increased 
frequency of events that may impact the rights, safety or welfare of subjects will be established. All materials, discussions, 
and proceedings of the DSMB are completely confidential. The proceedings of each DMSB meeting will be recorded in 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 51 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
minutes. The DSMB Chairperson will be responsible for providing a written recommendation regarding study conduct (e.g., 
continue as planned, specify a modification, or termination) to Medtronic and the Study Principal Investigators. All final 
decisions, regarding study modifications rest with the Executive Committee and Sponsor. Details around the procedures of 
the DSMB are documented in a separate DSMB charter. 
 
11.3. 
Executive Committee 
The Executive Committee is composed of the study governance members including the study leadership and committee 
members. Their role is to provide overall supervision of the study, advise in study design, provide feedback on current 
practice and to assist in communications with clinical investigational sites.  This committee will meet periodically by 
teleconference or in person to monitor the progress of the study, including subject enrollment, clinical site progress, and 
protocol compliance. The Executive committee will also be responsible for reviewing the final results and determining the 
methods of presentation and publication. 
 
12. Statistical Design and Methods 
 
The Onyx ONE Clear Study is a prospective, multi-center, single arm study for a commercially approved product. A total of 
700 US subjects deemed at high risk for bleeding and/or medically unsuitable for more than one month DAPT treatment will 
be treated with the Resolute Onyx stent and studied for a one month DAPT treatment. Additionally, 100 subjects may be 
enrolled in Japan. 
 
The primary objective is to evaluate the clinical safety of the Resolute Onyx stent as compared to the Performance Goal (PG) 
with use of one-month DAPT in subjects deemed at high risk for bleeding and/or medically unsuitable for more than one-
month DAPT treatment. 
 
12.1. 
Primary Endpoint 
The primary endpoint in this trial is the composite of cardiac death and myocardial infarction at one year for a one-month 
clear population [timeframe: one month to one year]. 
 
12.1.1. 
Primary Hypothesis 
The primary endpoint of the study will be compared to a PG of 9.7%. The study hypotheses are: 
H0: π ≥ 9.7% 
HA: π < 9.7% 
Where π denotes the binary rate of cardiac death and myocardial infarction at one year in a one-month clear population 
[timeframe: one month to one year]. This one-sided test will be carried out at the 0.025 significance level using the binomial 
exact test. 
 
12.1.2. 
Hypothesis 
Based on historical short DAPT studies with high-bleeding risk patient populations (LEADERS FREE, ZEUS, and 
SENIOR), the weighted average of cardiac death and myocardial infarction at one year was 9.6%. As disproportionally 
higher rates of STEMI, unstable angina, and multi-vessel disease were identified in the ZEUS study population which could 
have led to a higher rate of cardiac death, the ZEUS rate was revised. Similarly, the SENIOR rate contribution was derived 
from the published rates based on subjects with planned one-month DAPT use.  

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 52 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Approximately 3% of CD/MI events occurred in LEADERS FREE study at 30 days. To account for a “one-month clear” 
population, the weighted CD/MI rate at 12 months will be discounted by 3%, resulting in an average rate of 6.6%. In 
addition, to account for the 3% population that will also be removed from the denominator of the rates, the expected CD/MI 
rate between 30 days and one year is more accurately represented as 6.8%.  
 
The performance goal (9.7%) incorporated a clinically acceptable margin of 2.9% to the expected rate.  
 
In defining a “one-month clear” population, an attrition rate of 20% will be applied to account subjects who interrupted or 
discontinued DAPT (greater than 3 cumulative days) within the first one month of procedure, who were excluded due to 
events that would prohibit them from discontinuing DAPT beyond one month, who failed to transition from DAPT to SAPT 
one month after procedure, and who were lost to follow-up. Peri-procedural MIs will not exclude the patient from being 
considered as “one month clear”. For the secondary endpoints like TLF, all available biomarkers (including peri-procedural) 
will be forwarded to the CEC to be used towards the adjudication of events. 
 
12.1.3. 
Sample Size Calculation and Methods 
Assuming a one-sided alpha level of 0.025 and a true event rate of 6.8%, an effective sample size of 1360 subjects will yield 
a greater than 97% power to reject the null hypothesis. Assuming a 20% attrition rate, a total sample size of 1700 subjects 
will be needed.   
 
The outcomes from 700 US subjects enrolled in this study will be combined with those of 1000 subjects from the Resolute 
Onyx arm of the Onyx ONE Study to form the total sample size of 1700. In addition, subjects enrolled in Japan who have 
completed their one-year follow-up at the time when the 700 US subjects have completed their one year follow up will also 
be included in the primary analysis.  
 
12.2. 
Analysis Populations 
Intent-to-Treat (ITT): All subjects who signed the informed consent with an attempted implant procedure.  Time zero begins 
at the date of the index procedure.  
 
Primary Analysis: ITT subjects who are one-month clear and received the Resolute Onyx stent only.  Time zero begins at the 
date of the index procedure.  
 
 
12.3. 
General Analysis Overview 
Descriptive statistics of continuous outcomes will be presented with sample size, mean, median, standard deviation, 
minimum and maximum. Categorical variables will be summarized with frequencies and percentages. All statistical analyses 
will be performed using SAS for Windows (version 9.1 or higher) or other widely accepted statistical or graphical software. 
Patient data listings and tabular and graphical presentations of results will be provided. Statistical analyses will be 
independently validated. Additional details on the analysis will be provided in the Statistical Analysis Plan (SAP) for this 
study. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 53 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
12.4. 
Analysis of the Primary Endpoint 
Cardiac death and myocardial infarction will be adjudicated by the CEC. The CD/MI rate at one year in a one-month clear 
population [timeframe: one month to one year] will be compared with the performance goal of 9.7%, with a one-sided 
binomial exact test at the 0.025 significance level. The analysis for the primary endpoint will be performed in ITT subjects 
who are one-month clear and received the Resolute Onyx stent only. 
12.5. 
Analysis of Secondary Endpoints 
For secondary endpoints, event/success rates, and 95% two-sided confidence interval will be provided. The time-sensitive 
nature of any response variable may be displayed by using a Kaplan-Meier plot. Further details on the secondary endpoints 
will be included in the Statistical Analysis Plan.  
 
12.6. 
Analysis of Baseline Characteristics 
All clinically relevant baseline variables will be tabulated and reported. Categorical variables will be reported using counts 
and percentages, and continuous variables will be reported by giving the number of known values, the mean, standard 
deviation, minimum and maximum values. 
 
12.7. 
Analysis of Subgroups 
Subgroup analyses of the primary endpoint include but are not limited to the following patient characteristics. Further details 
on subgroup analysis are included in the Statistical Analysis Plan. 
• 
Acute Coronary Syndrome 
• 
Diabetes 
• 
Sex 
• 
Age 
• 
Stent / Lesion Characteristics (multiple vessels, multiple lesions, overlapping stents) 
 
12.8. 
Interim Analysis 
Interim analyses are not planned in this trial. 
 
12.9. 
Additional Analysis 
There may be additionally 100 subjects enrolled in Japan. Once all enrolled subjects (US and Japan) have had the chance to 
complete 1-year follow up, an additional report (including subjects from Onyx ONE Clear as well as the Onyx-arm of Onyx 
ONE Global Study) may be prepared as requested by PMDA.  
 
12.10. Missing Data  
Deviations from original statistical plan will be avoided, and every effort will be undertaken to minimize missing data. In 
time-to-event outcomes, dropouts will be censored at the time of discontinuation, consistent with the Kaplan-Meier approach. 
Unless otherwise specified, no statistical techniques will be used to impute missing data for continuous or categorical 
outcomes. The number of subjects included in each analysis will be reported so that the reader can assess the potential impact 
of missing data. Further details are provided in the Statistical Analysis Plan. 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 54 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
13. Economic Analysis 
Economic analysis of Resolute Onyx stent in specific study centers may be assessed to determine the relative cost 
effectiveness after treatment including procedural cost estimated from the viewpoint of the hospital including quality of life 
instruments. Analysis may include medical costs, procedural aspects of the study such as the use of pre- and post- dilatation, 
the number of DES attempted to be used, length of stay and any other ancillary devices utilized. Additional details will be 
listed in the statistical analyses plan.  
 
Access to health economic source documents at each center, if needed, should be made available to the Sponsor in order to 
enable collection of relevant clinical and cost data.  
 
14. Ethics 
14.1. 
Statements of Compliance 
• 
In the United States, this study will be conducted in compliance with the protocol, good clinical practice (GCP) and 
21CFR812. This study is designed to reflect the GCP principles outlined in ISO 14155:2011. These include the 
protection of the rights, safety and well-being of human subjects, controls to ensure the scientific conduct and 
credibility of the clinical investigation and the definition of responsibilities of the sponsor and investigators. 
ISO14155 will not be followed for full device accountability and Adverse Event reporting except in regions where 
noted.  
• 
The study will also be conducted in accordance with the Declaration of Helsinki. The principles of the Declaration 
of Helsinki (2013) are implemented in this study by means of the Informed Consent (IC) process, IRB approval, 
study training, clinical study registration, pre-clinical testing, risk benefit assessment, and publication policy.  
• 
In Japan, the trial will be conducted in accordance with the ethical principles of the Japan GCP Ordinance, the 
Pharmaceutical and Medical Device Act as well as ISO 14155:2011. 
• 
Regulatory agency approval to conduct the study will be obtained in participating geographies (where applicable). 
Study centers will not be activated nor begin enrolling subjects until the required approval/favorable opinion from 
the respective regulatory agency has been obtained (as appropriate). Additionally, any requirements imposed by a 
local regulatory agency or IRB shall be followed, as appropriate.  
• 
Each study center must provide Medtronic with a copy of the study center’s IRB approval letter and the IRB-
approved Informed Consent Form. 
• 
If applicable, approvals for the continuation of the study at each study center must be kept current in accordance 
with the IRB review schedule. All study center communications to and from the IRB must be forwarded to 
Medtronic as they are sent/received. 
• 
The Sponsor will be informed by the IRB and/or the investigator in case any action is taken by an IRB with respect 
to this investigation. 
• 
Study reimbursement is outlined in the Clinical Study Agreement. Indemnification will be done according to local 
laws. Reimbursement of travel cost will be considered if allowed by local regulations 
• 
This study will be publicly registered on www.clinicaltrials.gov prior to first enrollment.  
• 
Medtronic maintains appropriate clinical study liability insurance coverage if required under applicable laws and 
regulations and will comply with applicable law and custom concerning specific insurance coverage. If required, a 
clinical study insurance statement/certificate will be provided to the EC. 
• 
Study centers should follow their institutional procedures for maintenance of angiography, diagnostic, and 
laboratory equipment used for assessing the study variables 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 55 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
15. Study Administration 
 
15.1. 
Investigator / Investigational Site Selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical study as well as 
ensure data integrity and the rights, safety and well-being of the subjects involved in the clinical study. 
 
An investigator may be included in the clinical study if compliant with the following requirements: 
• 
Investigator is qualified, educated and has experience in the interventional treatment of coronary arteries 
• 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions. 
• 
Investigator/site expects to have adequate time and resources to conduct the study throughout the duration of the 
study. Each site must have a designated research coordinator assigned to the study. 
• 
Investigator/site has access to an adequate number of eligible subjects. 
• 
Investigator/site has the ability to comply with applicable IRB and regulatory requirements. 
• 
Lack of potential conflict(s) of interest 
• 
Anticipated study startup timeline, including contracting and IRB and regulatory submission and approval (if 
applicable) is acceptable. 
• 
Anticipated competition for same subject population from competitive ongoing studies is at an acceptable rate. 
 
A list of participating study centers, including contact information, and investigators, including titles, will be available as a 
separate document. 
 
Prior to study start, a recent CV shall be collected from each principal investigator and key members of the study center team 
participating in this study (if required for the region), evidencing the required qualifications, including the year and where 
obtained, and shall include their current position at the study center.  
 
15.2. 
Site Activation/Supply of Study Materials 
Study centers will receive a formal letter of site activation upon receipt of or completion of the following: 
• 
Curriculum vitae of the principal and sub-investigators and all key site staff (as required by the region) 
• 
A signed trial agreement 
• 
Financial disclosure from the investigators 
• 
A copy of the IRB approval letter, along with the voting roster 
• 
The IRB approved subject information and Informed Consent Form 
• 
Documented training of the investigative team 
• 
Delegated Task List 
• 
Confirmation of calibration and maintenance of equipment and maintenance of facilities 
 
Medtronic will control the supply of study materials and will only grant site activation when above activation criteria are met, 
and the site receives a formal activation letter from Medtronic. 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 56 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
15.3. 
Monitoring 
Monitoring visits will be conducted during the course of the study in accordance with Medtronic SOPs and the Monitoring 
Plan. The monitor will be identified for each site and contact information will be provided as appropriate. The initiation visit 
will be performed before the first subject is enrolled once it has been verified that the site is prepared for the study and the 
requirements for starting subject enrollment are met. Subject-level data will be 100% monitored by a representative of 
Medtronic through the one-year primary endpoint, and a risk based plan will be in place for the remainder of the study.  
 
Documentation of the training of site research personnel will be collected during the site initiation visit. In order to ensure a 
high degree of data quality, periodic monitoring will be performed at all recruiting clinical centers. Site monitoring will be 
conducted to monitor compliance with the protocol and adherence to the data collection procedures, to assess the accuracy 
and completeness of submitted clinical data, and to verify that records and documents are being properly maintained for the 
duration of the study. 
 
The monitor will perform source data verification by reviewing subject documents through each subject’s one-year time 
point. All Informed Consent Forms will be checked. The monitor will perform review of key variables for all enrolled 
subjects (including but not limited to, inclusion/exclusion criteria, endpoints and safety) on the eCRFs against subject’s 
source documents per the Monitoring Plan. In addition, all available source documentation will be reviewed for potential 
serious adverse events and device effects. Any discrepancies will be noted and resolved. The principal investigator(s), his/her 
delegate(s) and the study coordinator(s) shall be accessible to Medtronic study personnel during these visits or other times 
when questions arise regarding subject information.  
 
15.4. 
Data Management 
All records and other information about subjects participating in this study will be treated as confidential. 
 
Medtronic will collect data and monitor study records. Auditors, IRB members, inspectors (governmental regulatory 
authorities) may also have access to the study records. Participating subjects will not be identified by name in any published 
reports about this study. 
 
The investigator must ensure accuracy, completeness and timeliness of the data reported in the eCRFs and in all other 
required reports. Data reported on the eCRFs which are derived from source documents must be consistent with the source 
documents and discrepancies need to be justified in a documented rationale, signed and dated by the (principal) investigator, 
and filed in the subject medical file. Only authorized persons can complete eCRFs. eCRFs shall be signed by investigators 
(physicians only) as specified on the Delegated Tasks List included in the Investigator Site File. 
 
15.5. 
Direct Access to Source Data / Documents 
The Investigator must be willing to give direct source data access to study monitors, auditors, EC members and inspectors, 
and have appropriate facilities to retain relevant study documents. 
 
15.6. 
Confidentiality 
Subject confidentiality will be maintained throughout the clinical study to the extent permitted by law. Every attempt will be 
made to remove subject identifiers from clinical study documents. For this purpose, a unique subject identification code (site 
number and subject number) will be assigned and used to allow identification of all data reported for each subject. This will 
also ensure that the information can be tracked back to the source data. 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 57 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
 
Study data may be made available to third parties, e.g., in the case of an audit performed by regulatory authorities, provided 
the data are treated confidentially and that the subject’s privacy is guaranteed. The identity of a subject will never be 
disclosed in the event that study data are published. 
 
15.7. 
Liability 
The sponsor and local sponsors are wholly own subsidiaries of Medtronic. Medtronic (including all wholly owned 
subsidiaries) maintains appropriate clinical study liability insurance coverage as required under applicable laws and 
regulations and will comply with applicable law and custom concerning specific insurance coverage. If required, a Clinical 
Study Insurance statement or certificate will be provided to the IRB. 
 
Medtronic will provide subject indemnification according to local laws where this study will be conducted. 
 
15.8. 
Clinical Investigation Plan Amendments 
All clinical investigation plan updates need to be approved by Medtronic and respective IRB. Medtronic is responsible for 
regulatory authority approval or notification of clinical investigation plan updates or amendments if applicable according to 
local regulations.  
 
15.9. 
Record Retention 
Medtronic records and reports will be stored at Medtronic during the course of the study. After the closure of the study, all 
records and reports will be archived by Medtronic permanently. Investigators’ records will be retained for at least two years 
after the formal discontinuation of clinical development of the device, and according to the local requirements of the country.  
 
15.10. Publication and Use of Information 
Medtronic will form a Publications Committee with the purpose of providing direction and support for the development of 
the publication plan. The scientific validity and timing of all publications (manuscripts and presentations) will be evaluated in 
order to maximize the benefits derived from the publication of the clinical data of the study. 
 
Members of the Publication Committee may include, but are not limited to, the principal investigators, members of the 
Executive Committee, the Clinical Program Director and other Medtronic personnel as appropriate. 
 
Authorship selection for publications using multi-center data will be determined based on the International Committee of 
Medical Journal Editors (ICMJE) published guidelines. Specific authorship criteria required by the scientific journal or other 
forum for publication submission must also be met. Authors must meet the following four conditions: 
• 
Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of 
data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy 
or integrity of any part of the work are appropriately investigated and resolved  
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 58 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
At the conclusion of the study, a multi-center manuscript on the study primary results may be prepared for publication in a 
reputable scientific journal. The publication of the principal results from any single site experience within the study is not 
allowed until the preparation and publication of the multi-center results. Investigators may submit publication ideas through 
the Publication Committee and may author publications approved by Medtronic and the Committee. 
 
15.11. Suspension or Early Termination 
Suspension: A temporary postponement of study activities related to enrollment. This is possible for the whole study or a 
single investigational site. 
 
Early termination: Closure of a clinical study that occurs prior to meeting defined endpoints. This is possible for the whole 
study or a single center. If a center is terminated or suspended, no additional enrollments will be allowed at the center until, 
in the case of suspension, issues can be resolved. Possible reasons for clinical investigator or center termination or suspension 
include but are not limited to: 
• 
Non-compliance to obtain Informed Consent 
• 
Non-compliance to the inclusion/exclusion criteria 
• 
Failure to follow subjects per scheduled follow-ups 
• 
Failure to submit data in a timely manner 
• 
IRB approval expiration 
• 
IRB suspension of the center 
 
If the study is terminated prematurely or suspended: 
• 
Medtronic will promptly inform the investigators of the termination or suspension and the reasons, and inform the 
regulatory authority(ies) (where required by applicable regulatory requirements) 
• 
The IRB will also be promptly informed and provided with the reasons(s) for termination or suspension by the 
sponsor or by the clinical investigator 
• 
The investigator will promptly inform the subjects if appropriate and assure appropriate therapy and follow-up for 
the subjects 
• 
In the case of suspension, when Medtronic concludes an analysis of the reason(s) for the suspension, implements 
the necessary corrective actions, and decides to lift the temporary suspension, Medtronic will inform the clinical 
investigator and the appropriate IRB of the rationale and provide relevant data to support this decision. 
• 
In case of early termination, the investigator agreement will be terminated 
• 
In case of early termination, the subjects need to be followed until at least 30 days after the index procedure 
 
 
 
 
 
 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 59 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
15.12. Organizations Involved in Study 
 
Image Transfer: 
Medidata Medical Imaging 
700 W. Pete Rose Way, Suite 436 
Cincinnati, OH 45202 
Data Safety 
Monitoring Board: 
Cardiovascular Research Foundation 
1700 Broadway, Floor 8 
New York, NY 10019 
Clinical Events 
Committee: 
Cardiovascular Research Foundation 
1700 Broadway, Floor 8 
New York, NY 10019 
Angiographic Core 
Lab: 
 
Cardiovascular Research Foundation 
1700 Broadway, Floor 8 
New York, NY 10019 
 
Statistical Analysis 
(Independent 
Statistician) 
BAIM Institute 
930-W Commonwealth Ave 
Boston, MA 02215 
 
 
 
 
 
16. Version History 
 
Version 
Location of Change 
Summary of Changes 
Author 
1.0 
Not applicable 
Not applicable – initial release 
Lilian C Lee 
2.0 
See Summary of Changes Table 
– Onyx ONE Clear CIP v1.0 to 
v2.0 
See Summary of Changes Table – 
Onyx ONE Clear CIP v1.0 to v2.0 
Lilian C Lee 
3.0 
See Summary of Changes Table 
– Onyx ONE Clear CIP v2.0 to 
v3.0 
See Summary of Changes Table – 
Onyx ONE Clear CIP v2.0 to v3.0 
Lilian C Lee, Zhen 
Meng 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 60 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Summary of Changes Table– Onyx ONE Clear CIP v1.0 to v2.0 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
Page 4 
Glossary 
-- 
• 
Antiplatelet Therapy: Prescription or intake of aspirin or a 
P2Y12 inhibitor (e.g. clopidogrel, ticlopidine, prasugrel, 
ticagrelor). Patients may or may not be on oral anticoagulant 
medication. 
Addition of text 
Antiplatelet therapy 
definition was added. 
Page 6 
Glossary 
-- 
• 
Dual antiplatelet therapy (DAPT): Prescription/intake of two 
anti-platelet medications, with one being aspirin or an aspirin-
containing drug and the other a P2Y12 inhibitor (e.g. 
clopidogrel, prasugrel, ticlopidine, ticagrelor).  
Move and modification 
of text 
Dual antiplatelet therapy 
definition was modified and 
moved on page 6. 
Page 7 
Glossary 
-- 
• 
Major Bleeding: Hospitalization for bleeding that required 
transfusion or other related evaluation/treatment. 
Move and modification 
of text 
Major bleeding definition 
was modified moved from 
page 4 to page 7. 
Page 9 
Glossary 
• 
Oral anticoagulant (OAC): Type of oral 
medication used to prevent or reduce coagulation 
of blood. Includes vitamin K antagonists and novel 
anticoagulants (NOACs)/ directly acting oral 
anticoagulants (DOACs) 
• 
Oral anticoagulant (OAC): Type of oral medication used to 
prevent or reduce coagulation of blood. Includes vitamin K 
antagonists (e.g. warfarin) and novel anticoagulants 
(NOACs)/ directly acting oral anticoagulants (DOACs) (e.g. 
apixaban, rivaroxaban, dabigatran, edoxaban) 
Addition of text 
Added examples of oral 
anticoagulant 
Page 10 
Glossary 
SAPT: Single Antiplatelet Therapy: prescription/intake 
of only one anti-platelet drug (aspirin or P2Y12 
inhibitor). Patients may or may not be on OAC 
• 
Single Antiplatelet Therapy (SAPT): Prescription/intake of 
only one anti-platelet drug (aspirin or P2Y12 inhibitor). 
Patients may or may not be on oral anticoagulant medication. 
Modification 
Modification of acronyms 
 
Page 12 
Glossary 
-- 
• 
Triple therapy (TT): Prescription/intake of dual antiplatelet 
therapy plus an oral anticoagulant medication  
Addition of text 
Added triple therapy 
definition 
Page 15 
Synopsis 
All Serious Adverse Events (SAEs) and endpoint-
related events will be evaluated by the Medtronic. 
All Serious Adverse Events (SAEs) and endpoint-related events 
will be evaluated by Medtronic safety department. Quarterly 
progress reports on study enrollment status and rates of 
cardiac death, MI, cardiac death/MI and stent thrombosis will 
be provided to FDA. 
Addition of text 
Added quarterly safety 
reports  
Page 22 
5.2 Rationale 
The Onyx ONE Clear Study is a single-arm study that 
compares the Resolute Onyx stent with objective 
performance criteria. 
The Onyx ONE Clear Study is a single-arm study that compares 
the Resolute Onyx stent with a performance goal. 
Modification 
Clarification 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 61 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
Page 25 
6.1 Resolute Onyx Stent 
and Delivery 
System 
The Resolute Onyx stent is mounted on a Rapid 
Exchange delivery system which incorporates design 
and process improvements to provide enhanced 
deliverability. 
The Resolute Onyx stent is mounted on a Rapid Exchange or 
Over-the-Wire delivery system which incorporates design and 
process improvements to provide enhanced deliverability. 
Addition of text 
Description to match figures 
Page 26 
6.1 Resolute Onyx Stent 
and Delivery 
System 
Figure 1 caption 
Figure 1. Delivery System and Resolute Onyx Stent 
Figure 1. Resolute Onyx Rapid Exchange Delivery System (with 
Stent) 
Modification 
Added identification of 
delivery system 
Page 28 
6.9 Product 
Accountability 
This study will use commercially available product and 
labeling with appropriate documentation of specific 
device identifiers, e.g. the lot/batch numbers of the 
used stent(s). 
This study will use commercially available product and labeling 
with appropriate documentation of specific device identifiers, e.g. 
the lot and reference/serial numbers of the used stent(s). 
Modification 
Clarification of device 
identifiers to be recorded 
Page 29 
7.3 Inclusion Criteria 
All subjects who are acceptable candidates for 
treatment with a DES in accordance with applicable 
guidelines for percutaneous coronary interventions, per 
manufacturer’s Instructions for Use, who additionally 
meet pre-defined criteria for being high-bleeding risk 
and/or are candidates for 1-month DAPT can be 
considered. 
All subjects who are acceptable candidates for treatment with a 
DES in accordance with applicable guidelines for percutaneous 
coronary interventions, per manufacturer’s Instructions for Use, 
who additionally meet pre-defined criteria for being high-bleeding 
risk and/or are candidates for 1-month DAPT and who in the 
opinion of the investigator, the potential benefit of 1-month 
DAPT to the subject outweighs the potential risk can be 
considered.  
Addition of text 
Added additional emphasis 
on importance of risk-benefit 
assessment for one-month 
DAPT 
Page 35 
8.6 Medication 
Adherence 
Subjects must also continue on single antiplatelet 
therapy (SAPT) after one month of DAPT through the 
end of the study.   
Subjects must also continue on single antiplatelet therapy (SAPT) 
after one month of DAPT through the end of the study.  Subjects 
will be provided a medication reminder card and also 
instructed to inform the investigator and team on any changes 
in medication including medication stop date, reason for 
stopping medication, medication restart date, and medication 
dosage. Dual antiplatelet therapy compliance will be assessed 
in the clinic at the 1-month visit as well as in follow-up contacts 
and will be recorded in the eCRF. 
Addition of text 
Added methods to track 
medication adherence to 
protect against DAPT 
interruption 
Page 40 
8.16 Sponsor record 
maintenance 
responsibilities 
Competent Authority notification and approval 
documentation and correspondence 
-- 
Deletion of text 
Correction 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 62 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
Page 41 
8.17 Sponsor reporting 
responsibilities 
Table 5. Sponsor 
Reporting 
requirements 
-- 
Report: 
Study enrollment status and rates of cardiac death, MI, cardiac 
death/MI and stent thrombosis 
 
Submitted to: 
Progress reports will be provided to FDA on a quarterly basis 
Addition of text 
Added sponsor responsibility 
of submitting quarterly 
progress reports 
Page 43 
9.1 Potential Risks 
This high-bleeding risk population in the LEADERS 
FREE study included complex lesion subgroups such 
as in the senior and in ACS (STEMI/NSTEMI) 
patient population. While rates of adverse clinical 
outcomes were higher in these subgroups as compared 
to treatment of simple lesions, the investigators did not 
find patients to be at higher risk in these subgroups that 
would trigger concern. These data were pre-specified 
and also published by the LEADERS FREE 
investigators. 
This high-bleeding risk population in the LEADERS FREE study 
included subjects who had clinical or anatomic features that 
posed a higher ischemic risk, including subjects who had 
multivessel disease (1493/2399 (62.2%)), ACS (659/2432 
(27.1%)), diabetes (805/2427 (33.2%), hypertension (1913/2427 
(78.8%)), bifurcation (15.5%), in-stent restenosis (2.5%) and 
chronic total occlusion (4.7%). While rates of adverse clinical 
outcomes were higher in these subgroups as compared to treatment 
of simple lesions, the investigators did not find patients to be at 
higher risk in these subgroups that would trigger concern. These 
data were pre-specified and also published by the LEADERS 
FREE investigators. Given that the Onyx ONE Clear Study 
inclusion/exclusion criteria are similar to that of LEADERS 
FREE, it is expected that similar proportions will be enrolled 
and have clinical or anatomic features that pose a higher 
ischemic risk.  
Modification 
Added proportions of 
enrolled subjects who had 
clinical or anatomic features 
that pose a higher ischemic 
risk in LEADERS FREE 
study and an estimate of 
similar proportion of this 
population in the current 
study 
 
Page 44 
9.2 Risks Related to 
Devices 
Percutaneous 
Coronary 
Diagnostic 
and 
Treatment Procedures 
Risks associated with using these products are 
those associated with percutaneous treatment 
procedures for a stenotic coronary artery. The 
complications relating to standard PTCA and 
stenting include, but are not limited to the 
following: 
• 
Abrupt stent / vessel closure 
• 
Access 
site 
pain, 
hematoma 
or 
hemorrhage 
Percutaneous Coronary Diagnostic and Treatment 
Procedures 
Risks associated with using these products are those 
associated with percutaneous treatment procedures for a 
stenotic coronary artery. The complications relating to 
standard PTCA and stenting include, but are not limited to 
the following: 
• 
Abrupt vessel closure 
• 
Access site pain, hematoma or hemorrhage 
• 
Allergic reaction to anti-coagulation and/or anti-
thrombotic therapy, contrast material, or stent 
Modification 
Correction of risk section to 
align with the Resolute Onyx 
US IFU 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 63 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
• 
Acute myocardial infarction 
• 
Allergic reaction to anti-coagulation 
and/or anti-thrombotic therapy, contrast 
material, or stent and/or delivery system 
materials, drug, and polymer coating 
• 
Aneurysm, 
pseudoaneurysm, 
or 
arteriovenous fistula 
• 
Arrhythmias 
(including 
ventricular 
fibrillation and ventricular tachycardia) 
• 
Balloon rupture 
• 
Bleeding 
• 
Cardiac tamponade 
• 
Cardiogenic shock 
• 
Coronary artery occlusion, perforation, 
rupture, or dissection 
• 
Coronary artery spasm 
• 
Death 
• 
Damage to the stent or injury to the 
artery requiring emergency coronary artery 
bypass grafting (CABG) 
• 
Embolism, emboli (blockage), distal 
(air, tissue or thrombotic emboli) 
• 
Emergency surgery: peripheral vascular 
or coronary bypass 
• 
Failure to deliver the stent 
• 
Fever 
• 
Hemorrhage requiring transfusion 
• 
Hypotension / hypertension 
• 
Incomplete stent apposition 
• 
Increased risk of restenosis of stented 
segments 
and/or delivery system materials, drug, and 
polymer coating 
• 
Aneurysm, pseudoaneurysm, or arteriovenous 
fistula 
• 
Arrhythmias (including ventricular fibrillation) 
• 
Balloon rupture 
• 
Bleeding 
• 
Cardiac tamponade 
• 
Coronary artery occlusion, perforation, rupture, or 
dissection 
• 
Coronary artery spasm 
• 
Death 
• 
Embolism (air, tissue device or thrombus) 
• 
Emergency surgery: peripheral vascular or 
coronary bypass 
• 
Failure to deliver the stent 
• 
Hemorrhage requiring transfusion 
• 
Hypotension / hypertension 
• 
Incomplete stent apposition 
• 
Increased risk of restenosis of stented segments 
• 
Infection or fever 
• 
Myocardial infarction 
• 
Pericarditis 
• 
Peripheral ischemia / peripheral nerve injury 
• 
Renal failure 
• 
Shock / pulmonary edema 
• 
Stable or unstable angina 
• 
Stent deformation, collapse, or fracture 
• 
Stent migration or embolization 
• 
Stent misplacement 
• 
Stroke or transient ischemic attack 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 64 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
• 
Infection 
and/or 
pain 
at 
catheter 
insertion site, fever 
• 
Pericarditis 
• 
Peripheral ischemia / peripheral nerve 
injury 
• 
Renal failure 
• 
Shock / pulmonary edema 
• 
Stable or unstable angina 
• 
Stent deformation, collapse, or fracture 
• 
Stent migration or embolization 
• 
Stent misplacement 
• 
Stent thrombosis or occlusion 
• 
Stroke or transient ischemic attack 
• 
Thrombosis (acute, sub-acute, late, or 
very late) 
• 
Total occlusion of coronary artery 
 
Additional Potential Risks Related to Resolute 
Onyx stent 
Additional potential adverse events that have 
been associated with zotarolimus include but are 
not limited to: 
• 
Anemia 
• 
Circumoral paresthesia 
• 
Diarrhea 
• 
Dry Skin 
• 
Headache 
• 
Hematuria 
• 
Pain (abdominal, arthralgia) 
• 
Rash 
 
• 
Thrombosis (acute, sub-acute, or late) 
Additional Potential Risks Related to Resolute Onyx 
stent 
Additional potential adverse events that have been 
associated with zotarolimus include but are not limited to: 
• 
Anemia 
• 
Diarrhea 
• 
Dry Skin 
• 
Headache 
• 
Hematuria 
• 
Infection 
• 
Injection site reaction 
• 
Pain (abdominal, arthralgia) 
• 
Rash 
The types of risks of the BioLinx polymer coating are 
expected to be no different than those of other stent 
coatings. These additional risks may include, but are not 
limited to, the following: 
• 
Allergic reaction 
• 
Focal inflammation at the site of stent implantation 
• 
Restenosis of the stented artery 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 65 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v1.0 
New wording in Onyx ONE Clear v2.0 
The types of risks of the BioLinx polymer coating 
are expected to be no different than those of other 
stent coatings. These additional risks may 
include, but are not limited to, the following: 
• 
Local inflammation at the site of stent 
implantation 
• 
Restenosis of the stented artery 
 
Page 43 
Footnote 
Morice  MC, Talwar S, Gaemperli O, et al. Drug-coated 
versus bare-metal stents for elderly patients: A 
predefined sub-study of the LEADERS FREE trial. Int 
J Cardiol. 2017; 243:110-115. 
Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated 
coronary stents in patients at high bleeding risk. NEJM Oct 14, 
2015. 
Modification 
Reference modification 
Page 53 
12.1.2 Hypothesis 
-- 
Peri-procedural MIs will not exclude the patient from being 
considered as “one month clear”. For the secondary endpoints like 
TLF, all available biomarkers (including peri-procedural) will be 
forwarded to the CEC to be used towards the adjudication of 
events. 
Addition of text 
Clarification of the exclusion 
of peri-procedural MI from 
one-month clear  
Page 57 
15.3 Monitoring 
Subject-level data will be 100% monitored by a 
representative of Medtronic through the one-year 
primary endpoint. 
Subject-level data will be 100% monitored by a representative of 
Medtronic through the one-year primary endpoint, and a risk 
based plan will be in place for the remainder of the study. 
Addition of text 
Clarification that there is a 
rigorous monitoring plan in 
place through completion of 
study 
 
 
 
 
 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 66 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Summary of Changes Table– Onyx ONE Clear CIP v2.0 to v3.0 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v2.0 
New wording in Onyx ONE Clear v3.0 
Footer 
Medtronic Confidential 
056-F275 v3.0 Clinical Investigation Plan Template 
Medtronic Controlled Information 
056-F275 v A Clinical Investigation Plan Template 
Modification 
Template update 
Page 4 
Glossary 
AE 
Adverse Event (AE) 
Modification 
Modification of acronyms 
Page 21 
5. Study Design 
Subjects who are enrolled will be considered part of the 
Intention-to-Treat (ITT) population and followed 
through for two years. 
Subjects who are enrolled will be considered part of the Intent-to-
Treat (ITT) population and followed through for two years if they 
receive Resolute Onyx stent only or exit after one year if they 
receive other non-study device (e.g. non-Resolute Onyx stent, 
POBA and drug-coated balloon). 
Modification 
 
Addition 
Typo 
 
This same information was 
previously only captured in 
Section 8.7 (p. 35); Added 
same information to section 
5 
Page 28 
7.2. Subject Enrollment 
Subjects who undergo consenting and have 
confirmation of coronary angiography anatomy 
eligibility and the Resolute Onyx stent was attempted 
but was not implanted will be considered part of the 
intention-to-treat (ITT) population. 
Subjects who undergo consenting and have confirmation of 
coronary angiography anatomy eligibility and the Resolute Onyx 
stent was attempted but was not implanted will be considered part 
of the intent-to-treat (ITT) population. 
Modification 
Typo 
Page 32 
8.3. Subject Consent 
Where a patient has initially verbally consented…, 
written consent should be sought form the patient as 
soon as, ... 
Where a patient has initially verbally consented …, written consent 
should be sought from the patient as soon as, … 
Modification 
Typo 
Page 33 
8.3. Subject Consent  
The consent process should be documented in the 
subject’s medical record. 
The consent process must be documented in the subject’s medical 
record. 
Modification 
 
Emphasis on the requirement 
of consent process to 
increase to patient rights, 
safety or welfare 
Page 35 
8.8. Staged Procedure 
Staging should be pre-specified at the time of the index 
procedure and follow-up should be calculated from 
the date of index procedure…. Lesions and vessels 
treated at the staged procedure are considered target 
lesions and vessels. 
Staging should be pre-specified at the time of the index procedure. 
... Lesions and vessels treated with Resolute Onyx stent at the 
staged procedure are considered target lesions and vessels. 
Deletion 
 
Addition 
 
Deletion of text since 
complete follow-up 
requirements are list in the 
following paragraph 
 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 67 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v2.0 
New wording in Onyx ONE Clear v3.0 
Clarification on target lesion 
and vessel definitions at 
staged procedure 
Page 36 
8.12. Assessment of 
Safety 
Reports of all adverse events related to endpoint 
(including bleeding), SAEs, and device deficiencies, 
with the return of the device when possible, will be 
evaluated by Medtronic. 
Reports of all adverse events related to endpoint (including 
bleeding), SAEs, adverse device effects and device deficiencies, 
with the return of the device when possible, will be evaluated by 
Medtronic. 
Addition  
“adverse device effects” was 
missing and added to aligned 
with other sections 
Page 50 
10.3. Recording and 
Reporting of Device 
Deficiencies 
All reportable device deficiencies and malfunctions will 
be documented on the appropriate eCRF, one more 
each deficiency, and further reported to the IRB (if 
required) within the IRB required timeframe and local 
and national regulations. 
All reportable device deficiencies and malfunctions will be 
documented on the appropriate eCRF, one form for each 
deficiency, and further reported to the IRB (if required) within the 
IRB required timeframe and local and national regulations. 
Modification 
Typo 
Page 52  
12.1.1. Primary 
Hypothesis 
The primary endpoint of the study will be compared to 
a PG of 9.9%. The study hypotheses are: 
H0: π ≥ 9.9% 
HA: π < 9.9% 
… 
This one-sided test will be carried out at the 0.025 
significance level using the Fisher’s exact test. 
The primary endpoint of the study will be compared to a PG of 
9.7%. The study hypotheses are: 
H0: π ≥ 9.7% 
HA: π < 9.7% 
… 
This one-sided test will be carried out at the 0.025 significance 
level using the binomial exact test. 
Modification 
 
Updated performance goal 
and test name as consistent 
with Statistical Analysis 
Plan 
 
Page 52  
12.1.2. Hypothesis 
As disproportionally higher rates of STEMI, unstable 
angina, and multi-vessel disease were identified in the 
ZEUS study population which could have led to a 
higher rate of cardiac death. Hence, the ZEUS rate was 
revised. 
As disproportionally higher rates of STEMI, unstable angina, and 
multi-vessel disease were identified in the ZEUS study population 
which could have led to a higher rate of cardiac death, the ZEUS 
rate was revised. 
Deletion 
Typo 
Page 52  
12.1.2. Hypothesis 
The performance goal incorporated a clinically 
acceptable margin of 3.1% to the expected rate. 
The performance goal (9.7%) incorporated a clinically acceptable 
margin of 2.9% to the expected rate. 
Modification 
Updated the margin as 
consistent with Statistical 
Analysis Plan 

 
Onyx ONE Clear Clinical Investigation Plan 
 
              
MDT18015RES008                                                                    Version 3.0 
 
Page 68 of 68 
 
 
Medtronic Controlled Information 
This document is electronically controlled  
 
056-F275, v A Clinical Investigation Plan Template 
 
 
 
 
Section/Page 
Description of Change 
Type of Change 
Rationale for Change 
Previous wording in Onyx ONE Clear v2.0 
New wording in Onyx ONE Clear v3.0 
Page 52  
12.1.3. Sample Size 
Calculation and 
Methods 
Assuming a one-sided alpha level of 0.025 and a true 
event rate of 6.8%, an effective sample size of 1360 
subjects will yield a greater than 98% power to reject 
the null hypothesis. 
Assuming a one-sided alpha level of 0.025 and a true event rate of 
6.8%, an effective sample size of 1360 subjects will yield a greater 
than 97% power to reject the null hypothesis. 
Modification 
 
Updated the power as 
consistent with Statistical 
Analysis Plan 
 
Page 53 
12.4. Analysis of the 
Primary Endpoint 
The CD/MI rate at one year in a one-month clear 
population [timeframe: one month to one year] will be 
compared with the performance goal of 9.9%, with a 
one-sided Fisher’s exact test at the 0.025 significance 
level. 
The CD/MI rate at one year in a one-month clear population 
[timeframe: one month to one year] will be compared with the 
performance goal of 9.7%, with a one-sided binomial exact test at 
the 0.025 significance level. 
Modification 
 
Updated performance goal 
and test name as consistent 
with Statistical Analysis 
Plan 
Page 53 
12.5. Analysis of 
Secondary 
Endpoints 
For secondary endpoints, event/success rates, and 95% 
confidence interval will be provided. 
For secondary endpoints, event/success rates, and 95% two-sided 
confidence interval will be provided. 
Addition 
Clarification on the 
confidence interval 
Page 53 
12.7. Analysis of 
Subgroups 
Subgroup analyses of the primary endpoint include the 
following patient characteristics. 
Subgroup analyses of the primary endpoint include but are not 
limited to the following patient characteristics. 
Addition 
Clarification on the 
subgroup analyses as 
consistent with Statistical 
Analysis Plan