Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Medtronic Cardiac Ablation Solutions

PULSED AF Clinical Investigation Plan  
 
 
MDT16027
 
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Medtronic Controlled Information
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056-F275, v A Clinical Investigation Plan Template 
 
Clinical
 Investigation
 Plan 
Clinical
 Investigation
 Plan/Study
 Title
  Pulsed
 Field
 Ablation
 to
 Irreversibly
 
Electroporate
 Tissue
 and
 Treat
 AF
 (PULSED
 AF) 
Clinical
 Investigation
 Plan
 Identifier MDT16027 
Study
 Product
 Name Pulsed
 Field
 Ablation
 (PFA) 
system 
Sponsor/Local
 Sponsor United
 States
 of
 America 
Medtronic,
 Inc. 
8200
 Coral
 Sea
 Street
 NE 
Mounds
 View,
 MN
 U.S.A.
 55112 
1-800-328-2518 
 
Australia 
Medtronic
 Australasia
 Pty
 Ltd. 
2
 Alma
 Road
  
Macquarie
 Park,
 NSW
 2113,
 Australia 
+61-2-9857-9000 
 
Canada 
Medtronic
 Canada 
ULC 
99
 Hereford
 Street 
Brampton,
 Ontario,
 L6Y
 0R3,
 Canada
  
+1-905-460-3800 
 
Europe 
Medtronic,
 Bakken
 Research
 Center
 B.V. 
Endepolsdomein
 5 
6229
 GW
 Maastricht,
 The
 Netherlands 
+31-43-3566566 
 
Japan 
Medtronic
 Japan
 Co.
 Ltd. 
1-2-70
 Konan,
 Minato-ku,
  
Tokyo,
 Japan
 108-0075 
+81-3-6776-0056 
Document
 Version Version
 2.0,
 24-OCT-2019 

PULSED AF Clinical Investigation Plan  
 
 
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Lead
 Principal/Coordinating 
Investigator 
 
 
 
 
 
 
  
 
Atul
 Verma,
 MD 
Staff
 Cardiac
 Electrophysiologist/Cardiologist
 
Southlake
 Regional
 Health
 Centre 
 
 
 
 
 
Confidentiality
 Statement 
The 
information 
contained 
in 
this 
document 
is 
confidential 
and 
the 
proprietary 
property 
of 
Medtronic. 
Any 
distribution, 
copying, 
or 
disclosure 
without 
the 
prior w
ritten 
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. 
 
 

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056-F275, v A Clinical Investigation Plan Template 
Table of Contents  
 
Table of Contents 
...................................................................................................................... 3 
Listing of Tables 
........................................................................................................................ 8 
Listing of Figures 
....................................................................................................................... 9 
Listing of Appendices 
................................................................................................................ 9 
Sponsor Contact Information.................................................................................................... 9 
Steering Committee ................................................................................................................ 11 
Contract Research Organizations............................................................................................ 12 
1. Glossary ............................................................................................................................ 13 
2. Synopsis ........................................................................................................................... 17 
3. Introduction 
..................................................................................................................... 29 
3.1. Background ........................................................................................................................ 29 
3.2. Purpose 
.............................................................................................................................. 32 
4. Objectives and Endpoints 
................................................................................................. 33 
4.1. Pilot Phase Objectives 
.......................................................................................................... 33 
4.1.1.  Pilot Phase Safety Objective 
.................................................................................................. 
33 
4.1.2.  Pilot Phase Effectiveness Objective ...................................................................................... 
33 
4.2. Pivotal Phase Objectives ...................................................................................................... 33 
4.2.1.  Primary Objectives 
................................................................................................................ 
33 
4.2.1.1.  Primary Safety Objective 
................................................................................................... 
33 
4.2.1.2.  Primary Effectiveness Objective 
........................................................................................ 
33 
4.2.2.  Secondary Objective.............................................................................................................. 
33 
 
 
5. Study Design 
.................................................................................................................... 35 
5.1. Duration 
............................................................................................................................. 37 
5.2. Rationale 
............................................................................................................................ 37 
5.3. Minimization of Bias 
............................................................................................................. 38 
6. Product Description.......................................................................................................... 39 
6.1. General 
.............................................................................................................................. 39 
6.1.1.  System Description 
................................................................................................................ 
41 

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6.2. PFA Generator .................................................................................................................... 42 
6.3. Catheter Electrode Distribution System (CEDS) 
...................................................................... 43 
6.4. Remote Control 
................................................................................................................... 43 
6.5. Cable, Generator to Remote Control ..................................................................................... 43 
6.6. Cable, Generator to CEDS 
.................................................................................................... 44 
6.7. Cable, CEDS to EP Recording System (EGM) 
.......................................................................... 44 
6.8. Cable, Sterile, Catheter to CEDS 
........................................................................................... 44 
 
6.10. Cardiac Trigger Monitor and Cables 
................................................................................. 44 
6.11. Power Cord 
................................................................................................................... 44 
6.12. Uninterruptible Power Supply (UPS) ................................................................................ 45 
6.13. Power Cord – C14M-C13F 
............................................................................................... 45 
6.14. Packaging 
..................................................................................................................... 45 
6.15. Product Training Requirements 
....................................................................................... 46 
6.16. Product Receipt, Tracking and Return 
.............................................................................. 46 
6.17. Product Storage 
............................................................................................................. 48 
7. Selection of Subjects 
........................................................................................................ 49 
7.1. Study Population 
................................................................................................................. 49 
7.2. Subject Enrollment 
.............................................................................................................. 49 
7.2.1.  Roll-in Subjects 
...................................................................................................................... 
49 
7.3. Inclusion Criteria 
................................................................................................................. 50 
7.4. Exclusion Criteria................................................................................................................. 50 
8. Study Procedures 
............................................................................................................. 52 
8.1. Schedule of Events 
.............................................................................................................. 52 
8.2. Subject Consent 
.................................................................................................................. 53 
8.3. Enrollment, Baseline, and Pre-ablation 
.................................................................................. 55 
8.4. Procedure 
........................................................................................................................... 57 
8.4.1.  Esophageal Visualization and Temperature Monitoring 
....................................................... 
58 
8.4.2.  Diaphragm Movement 
.......................................................................................................... 
58 
8.4.3.   Peri-procedural Anticoagulation 
........................................................................................... 
58 
8.4.4.  Pulmonary Vein (PV) Ablation with the PFA system 
............................................................. 
58 

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8.4.5.  Other Ablations during Index Procedure 
.............................................................................. 
59 
8.4.6.  Procedure Documentation 
.................................................................................................... 
59 
8.4.7.  Cardioversion ........................................................................................................................ 
60 
8.4.8.   Role of Medtronic Personnel at Study Procedure ................................................................ 
60 
8.5. Hospital Discharge .............................................................................................................. 60 
8.6. Medications ........................................................................................................................ 61 
8.6.1.  Paroxysmal AF Cohort 
........................................................................................................... 
61 
8.6.2.  Persistent AF Cohort ............................................................................................................. 
62 
8.7. Repeat Ablations with PFA ................................................................................................... 62 
8.8. Post-Procedural Cardioversions 
............................................................................................. 63 
8.9. Scheduled Follow-up Visits 
................................................................................................... 64 
8.9.1.  Thirty Day Visit 
...................................................................................................................... 
64 
8.9.2.  Three Month Visit ................................................................................................................. 
65 
8.9.3.  Six Month Visit ...................................................................................................................... 
65 
8.9.4.  Twelve Month Visit ............................................................................................................... 
65 
8.10. Unscheduled Office Visits ............................................................................................... 66 
8.11. Holter and Patient Activated Ambulatory ECG Monitor Management 
................................... 66 
8.12. 12-lead Electrocardiograms ............................................................................................ 66 
8.13. Assessment of Safety 
..................................................................................................... 66 
8.14. Assessment of Effectiveness 
........................................................................................... 67 
 
 
 
 
8.17. Recording Data.............................................................................................................. 67 
8.18. Deviation Handling ........................................................................................................ 67 
8.19. Subject Withdrawal or Discontinuation (Subject Exit) 
........................................................ 69 
9. Risks and Benefits 
............................................................................................................ 70 
9.1. Potential Risks .................................................................................................................... 70 
9.2. Risk Minimization ................................................................................................................ 70 
9.3. Potential Adverse Events from Risk Assessment 
..................................................................... 75 
9.4. Potential Benefits 
................................................................................................................ 76 
9.5. Risk-Benefit Rationale 
.......................................................................................................... 77 

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10. Adverse Events and Device Deficiencies ....................................................................... 78 
10.1. Adverse Event Assessment 
............................................................................................. 78 
10.2. Device Deficiencies Assessment ...................................................................................... 78 
10.3. Definitions/Classifications ............................................................................................... 78 
10.4. Reporting of Adverse Events, including Death .................................................................. 84 
10.4.1.  Subject Death .................................................................................................................... 
86 
10.4.2.  Adverse Event Reporting Requirements ........................................................................... 
87 
10.5. Reporting of Product Complaints 
..................................................................................... 91 
11. Data Review Committees .............................................................................................. 93 
11.1. Data Monitoring Committee (DMC) 
.................................................................................. 93 
11.2. Clinical Events Committee (CEC) ..................................................................................... 94 
12. Statistical Design and Methods 
..................................................................................... 95 
12.1.  Pilot Phase 
............................................................................................................................. 
96 
12.1.1.  Pilot Phase Safety Objective 
.............................................................................................. 
96 
12.1.2.  Pilot Phase Effectiveness Objective 
................................................................................... 
98 
12.2.  Pivotal Phase 
......................................................................................................................... 
99 
12.2.1.  Planned Analyses 
............................................................................................................... 
99 
12.2.2.  Primary Safety Objective 
................................................................................................. 
100 
12.2.3.  Primary Effectiveness Objective 
...................................................................................... 
105 
12.2.4.  Overall Study Sample Size Rationale 
............................................................................... 
116 
12.3.  Secondary Objective............................................................................................................ 
117 
12.3.1.  Secondary Objective: Quality of Life ............................................................................... 
117 
12.3.1.1.  Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
..................................................... 
118 
12.3.1.2.  EQ-5D Questionnaire 
................................................................................................... 
120 
 
 
 
 
 
 
 
 
 
 
 
 

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13. Ethics ........................................................................................................................... 129 
13.1. Statement(s) of Compliance ......................................................................................... 129 
14. Study Administration 
................................................................................................... 132 
14.1. Monitoring .................................................................................................................. 132 
14.2. Data Management ....................................................................................................... 132 
14.3. Confidentiality ............................................................................................................. 134 
14.4. Liability 
....................................................................................................................... 134 
14.5. CIP Amendments 
......................................................................................................... 134 
14.6. Record Retention and Reports ...................................................................................... 135 
14.6.1.  Investigator Records 
........................................................................................................ 
135 
14.6.2.  Investigator Reports 
........................................................................................................ 
136 
14.6.3.  Sponsor Records 
.............................................................................................................. 
141 
14.6.4.  Sponsor Reports .............................................................................................................. 
141 
14.7. Publication and Use of Information 
................................................................................ 146 
14.8. Investigator / Site Selection 
.......................................................................................... 148 
14.9. Site Activation 
............................................................................................................. 148 
14.10. Suspension or Early Termination 
................................................................................... 149 
14.10.1. Early Termination or Suspension 
..................................................................................... 
149 
14.10.2. Study-wide Termination or Suspension .......................................................................... 
149 
14.10.3. Investigator/Center Termination or Suspension 
............................................................. 
150 
14.10.4. Procedures for Termination or Suspension 
..................................................................... 
150 
14.10.4.1.  Medtronic-Initiated and Regulatory Authority-Initiated 
............................................. 
150 
14.10.4.2.  Investigator-Initiated ................................................................................................... 
151 
14.10.4.3.  Ethics Committee-Initiated .......................................................................................... 
151 
15. References 
................................................................................................................... 152 
16. Appendices .................................................................................................................. 156 
17. Version History ............................................................................................................ 170 
 
 
 

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Listing of Tables  
Table 1: Study Sponsor and Monitoring Contact Information 
...................................................................... 
9 
Table 2: Steering Committee Contact Information..................................................................................... 
11 
Table 3: Contract Research Organization Information 
............................................................................... 
12 
Table 4: Complication Occurrence Rates for Catheter Ablation 
................................................................. 
31 
Table 5: PFA System Components .............................................................................................................. 
39 
Table 6: PFA System Accessories 
................................................................................................................ 
40 
Table 7: Study Procedures and Data Collection per Subject Visit 
............................................................... 
52 
Table 8: Follow-up Schedule 
....................................................................................................................... 
64 
Table 9: Potential Risks and Mitigation Strategies ..................................................................................... 
70 
Table 10:  Adverse Event and Device Deficiency Definitions 
...................................................................... 
79 
Table 11: Adverse Event Classification Responsibilities ............................................................................. 
85 
Table 12: Adverse Event and Device Deficiency Reporting Requirements 
................................................. 
88 
Table 13: Analysis of Serious Adverse Events for Pilot Phase Subjects 
...................................................... 
96 
Table 14: Summary of Published Literature on Safety Rates of Catheter Ablation for AF 
....................... 
103 
Table 15: Summary of Published Literature on Catheter Ablation for Paroxysmal AF 
............................. 
110 
Table 16: Summary of Published Literature on Catheter Ablation for Persistent AF 
............................... 
113 
Table 17: Investigator Reports Applicable for All Geographies per Medtronic Requirements 
................ 
137 
Table 18: Additional Investigator Reports Applicable to Australia 
........................................................... 
137 
Table 19: Additional Investigator Reports Applicable to Europe 
.............................................................. 
138 
Table 20: Additional Investigator Reports Applicable to Japan 
................................................................ 
139 
Table 21: Additional Investigator Reports Applicable to the United States 
............................................. 
140 
Table 22: Sponsor Reports for Australia 
................................................................................................... 
142 
Table 23: Sponsor Reports for Canada ..................................................................................................... 
142 
Table 24: Sponsor Reports for Europe 
...................................................................................................... 
143 
Table 25: Sponsor Reports for Japan 
........................................................................................................ 
144 
Table 26: Sponsor Reports for the United States ..................................................................................... 
145 
 
Table C- 1: Foreseeable Adverse Events 
................................................................................................... 
163 
Table D- 1: Adverse Event Definitions ...................................................................................................... 
166 
 
 

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Listing of Figures  
Figure 1: Subject-Level Study Design   
........................................................................................................ 
35 
Figure 2: Phased Study Design 
.................................................................................................................... 
36 
 
Figure 4: Current Safety Rates in Catheter Ablation Technologies for Paroxysmal AF and Persistent AF 
102 
Figure 5: Current 12-Month Effectiveness Rates in Approved Catheter Ablation Technologies for 
Paroxysmal AF 
........................................................................................................................................... 
109 
Figure 6: Current 12-Month Effectiveness Rates in Catheter Ablation Technologies for Persistent AF .. 
112 
 
 
Listing of Appendices  
Appendix A: Study-Specific Requirements by Country 
............................................................................. 
156 
 
Appendix C: Foreseeable Adverse Events 
................................................................................................. 
163 
Appendix D: Endpoint-Related Adverse Event Definitions 
....................................................................... 
166 
Appendix E: Instructions For Use 
.............................................................................................................. 
168 
Appendix F: Data Collection Elements (Case Report Forms) 
.................................................................... 
168 
Appendix G: Informed Consent Template 
................................................................................................ 
168 
Appendix H: Participating Investigators and Institutions ......................................................................... 
168 
Appendix I: IRB/REB/EC List 
...................................................................................................................... 
168 
Appendix J: Pre-Clinical Testing 
................................................................................................................ 
168 
Appendix K: Centers for Medicare and Medicaid Services (CMS) IDE Study Criteria 
............................... 
169 
 
Sponsor Contact Information 
Medtronic
 contact
 information
 is
 provided
 in 
Table
 1.
 This 
information
 is
 subject
 to
 change
 during
 
the
 course
 of
 the
 clinical
 study.
 Periodic
 updates
 to
 study
 contact
 information
 will
 be
 sent
 to
 study
 
sites 
as
 needed.
  
Table
 1:
 Study
 Sponsor
 and
 Monitoring
 Contact
 Information 
Study
 Contacts 
 
 
 
 
 
Worldwide
 Clinical
 Study
 Leader 
Kirsten
 Rasmussen,
 Senior
 Clinical
 Research
 Specialist 
 
 
 
 

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Study
 Contacts 
(continued) 
Australia 
John
 Porreca,
 Associate 
Clinical
 Research
 Specialist 
 
 
 
Canada 
Aarthi
 Kamath,
 Senior
 Clinical
 Research
 Specialist 
 
 
 
Europe
 
Enneke
 Prinsen,
 Clinical
 Research
 Specialist 
 
 
 
Japan 
Yoshiko
 Ishiwatari,
 Clinical
 Research
 Manager 
 
 
 
 
 
US 
Josh Treadway,
 Clinical
 Research
 Specialist
 
 
 
Monitoring
 
Contacts 
US,
 Canada 
Shane
 Taylor,
 Senior 
Clinical
 Research
 Monitor 
 
 
 
Europe,
 Australia 
Anja
 Hesse,
 Monitoring
 Portfolio
 Specialist 
 
 
 
Japan 
Kenji
 Shinkai,
 Senior
 Clinical
 Research
 Monitor 
 
 
 
 
 
 

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2. Synopsis 
Title 
Pulsed
 Field
 Ablation
 to
 Irreversibly
 Electroporate
 Tissue
 and
 Treat
 AF
 
(PULSED
 AF) 
Clinical
 Study
 
Type 
Phased
 Study
 Design
  
Product
 Name  Pulsed
 Field
 Ablation
 (PFA)
 system 
Sponsor
   
United
 States
 of
 America 
Medtronic,
 Inc. 
8200
 Coral
 Sea
 Street
 NE 
Mounds
 View,
 MN
 U.S.A.
 55112 
1-800-328-2518 
Local
 Sponsors  Canada 
Medtronic
 Canada 
ULC 
99
 Hereford
 Street 
Brampton,
 Ontario,
 L6Y
 0R3,
 Canada
  
+1-905-460-3800 
 
Europe 
Medtronic,
 Bakken
 Research
 Center
 B.V. 
Endepolsdomein
 5 
6229
 GW
 Maastricht,
 The
 Netherlands 
+31(0)43-3566566 
 
Australia 
Medtronic
 Australasia
 Pty
 Ltd. 
2
 Alma
 Road
  
Macquarie
 Park,
 NSW
 2113,
 Australia 
+61-2-9857-9000 
Japan 
Medtronic
 Japan
 Co.
 Ltd. 
1-2-70
 Konan,
 Minato-ku,
  
Tokyo,
 Japan 
108-0075 
+81-3-6776-0056 
Indication
 under
 
investigation
  
The
 planned
 indication
 for
 the
 PFA
 system
 evaluated
 in
 this
 Study
 is
 as
 
follows: 
 
The
 PFA
 system,
 which
 includes
 a
 compatible
 Medtronic
 multi-electrode
 
cardiac
 ablation
 catheter,
 is
 indicated
 for
 the
 treatment
 of
 atrial
 fibrillation.
 
The
 Medtronic
 multi-electrode
 cardiac
 ablation
 catheter
 is
 also
 intended
 to
 
be
 used
 for
 cardiac
 electrophysiological
 (EP)
 mapping
 and
 measuring
 of
 
intracardiac
 electrograms,
 delivery
 of
 diagnostic
 pacing
 stimuli
 and
 verifying
 
electrical
 isolation
 post-treatment. 

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Power
 Cord  
1038N
 - 
North
 
America;
 Japan 
1038K
 -
 
Australia 
1038E
 -
 EU 
 
CAN:
 not
 regulated
  
EU:
 self-certified 
AUS:
 not
 regulated
  
US:
 FDA
 approved 
JPN:
 PMDA
 approved 
Investigational
 when
 used
 with
 
PFA
 system 
Uninterruptible
 
Power
 Supply
 (UPS) 
SMART1200XL
HG
 (120V) 
SMX1200XLHG
 
(230V) 
CAN:
 not
 regulated 
EU:
 not
 regulated 
AUS:
 not
 regulated 
US:
 not
 regulated 
JPN:
 not
 regulated 
Investigational
 when
 used
 with
 
PFA
 system 
Power
 Cord
 – 
C14M-C13F 
P004-006-ABL  CAN:
 not
 regulated 
EU:
 not
 regulated 
AUS:
 not
 regulated 
US:
 not
 regulated 
JPN:
 not
 regulated 
Investigational
 when
 used
 with
 
PFA
 system 
Study
 Design  
The
 study
 is
 a
 prospective,
 multi-center,
 non-randomized,
 unblinded
 
worldwide
 pre-market 
clinical
 study.
 The
 study
 is
 designed
 to
 have
 a
 
continuously
 growing
 body
 of
 evidence
 across
 two
 phases,
 with
 data
 
analyses
 planned
 at
 pre-specified
 timepoints.
 The
 data
 collected
 in
 this
 
study
 will
 be
 used
 to
 support
 regulatory
 submissions
 around
 the
 world
 to
 
obtain
 market
 approval
 for
 the
 PFA
 system,
 including,
 but
 not
 limited
 to,
 CE
 
Mark,
 Health
 Canada,
 Therapeutic
 Goods
 Administration
 (TGA),
 
Pharmaceutical
 and
 Medical
 Devices
 Agency
 (PMDA)
 and
 U.S.
 Food
 and
 Drug
 
Administration
 (FDA)
 market
 applications.
 
  
Description
 of
 
Phased
 Study
 
Design 
Pilot
 Phase 
 
The
 Pilot
 Phase
 of
 the
 PULSED
 AF
 study
 will
 include
 an
 early
 assessment
 of
 
safety
 and
 confirmation
 of
 acute
 procedural
 success
 of
 pulmonary
 vein
 
isolation
 (PVI)
 ablation
 with
 the
 PFA
 system.
 Specifically,
 this
 phase
 will
 
include 
treatment
 of
 20
 subjects
 (paroxysmal
 AF
 or
 persistent
 AF)
 across 
up
 
to 
4
 clinical
 sites.
 
 
 
 
 
 
 
 

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The
 Pilot
 Phase
 subjects
 will
 not
 be
 included
 in
 the
 Pivotal
 Phase
 primary 
or
 
secondary
 endpoint
 analyses
 but
 will
 be
 treated
 and
 followed
 in
 accordance
 
with
 all
 other
 protocol
 requirements. 
In
 addition,
 the
 Pilot
 Phase
 subjects
 will
 
complete
 a
 cardiac
 CT
 or
 MRI
 scan
 at
 baseline
 and
 3
 months
 to
 allow
 
characterization
 of
 any
 potential
 occurrences
 of
 pulmonary
 vein
 (PV)
 
stenosis.
 If
 PV
 stenosis
 (>70%
 diameter
 reduction)
 is
 identified
 in
 any
 of
 
these
 20
 subjects,
 an
 additional
 report
 will
 be
 generated
 containing
 the
 3-
month
 PV
 stenosis
 analysis
 once
 all
 20
 subjects
 have
 completed
 their
 3-
month
 follow-up
 or
 exited. The
 report
 will
 be
 sent
 to
 regulatory
 authorities
 
(as
 requested)
 while 
enrollment
 in
 the
 Pivotal
 Phase
 of
 the
 study
 continues. 
 
 
Pivotal
 Phase 
 
The
 purpose
 of
 the
 Pivotal
 Phase
 of
 the
 study
 is
 to 
provide
 data
 
demonstrating
 the
 safety
 and
 effectiveness
 of
 the
 PFA
 system
 for
 the
 
treatment
 of
 atrial
 fibrillation.
 Specifically,
 this
 phase
 will
 include 
treatment
 
of
 315 
subjects
 (165 p
aroxysmal 
AF
 and
 150
 persistent 
AF)
 for
 analysis
 of
 
primary 
objectives, 
across
 up
 to
 40
 total
 sites
 worldwide 
(including
 the
 4
 Pilot
 
Phase
 sites).
 For
 the
 Pivotal
 Phase
 of
 the
 study,
 subjects
 will
 be
 separated
 
into
 paroxysmal
 AF
 and
 persistent
 AF
 arms
 and
 analyzed
 separately.
 
 It
 is
 
expected
 that
 at
 least
 50%
 of
 the
 treatments
 and 
supporting
 clinical
 data
 will
 
come
 from
 the
 United
 States
 with
 no
 single
 site
 contributing
 more
 than
 15%
 
of
 the
 treatments
 to
 each 
arm
 of
 the
 Pivotal
 Phase.
 Each
 arm
 will
 have
 a
 
primary
 safety
 objective
 and
 a
 primary
 effectiveness
 objective,
 in
 addition
 to
 
secondary
  
 objectives.
 
 
To
 facilitate
 the
 investigators’
 familiarity 
with
 the
 system,
 a
 cohort
 of
 roll-in
 
subjects
 will
 also
 be
 included
 in 
the
 Pivotal
 Phase.
 There
 will
 be
 up
 to
 80
 roll-in
 
subjects 
(up
 to
 2
 per
 site).
 Roll-in
 subjects
 will
 not
 be
 included
 in
 the
 Pivotal
 
Phase
 primary 
or
 secondary
 endpoint
 analyses
 but
 will
 be
 treated
 and
 
followed
 in
 accordance
 with
 all
 other
 protocol
 requirements. 
 
Sample
 Size  
The
 primary effectiveness
 objectives drive
 the
 sample size, as for both
 arms,
 
the
 effectiveness
 sample
 sizes
 (165 
for
 paroxysmal
 AF
 and
 150 
for
 persistent 
AF) are higher than the sample size needed to adequately power the safety 
objective
 (n=138
 in
 each
 arm).
 
 
Overall, up to 475 subjects will be enrolled to ensure there are 20 Pilot Phase 
subjects,
 up
 to
 80
 Pivotal
 Phase
 roll-in 
cohort 
subjects,
 and
 315
 Pivotal
 Phase
 
primary
 analysis
 cohort
 subjects 
treated
 with
 the
 PFA
 system,
 and
 to
 account
 
for
 subjects
 not
 treated
 prior
 to
 exit. 

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Pilot
 Phase
 
Objectives 
Safety
 Objective:
 
 Assess
 the
 incidence
 of
 PFA
 system-related
 and
 PFA 
procedure-related
 serious
 adverse
 events
 (SAEs)
 within
 30
 days
 post-
ablation:
 
 
Serious
 Adverse
 Event 
Method
 of
 Analysis 
pulmonary
 vein
 stenosis
 (>70%
 diameter
 
reduction); 
Review
 of
 symptoms
 
post-procedure
 and
 at
 
30-day
 visit 
phrenic
 nerve
 injury/diaphragmatic
 paralysis
 
(ongoing
 at
 30
 days
 post-ablation); 
atrioesophageal
 fistula; 
cardiac
 tamponade/perforation;
  
cerebrovascular
 accident; 
Review
 of
 symptoms
 
post-procedure
 and
 at
 
30-day
 visit; 
Confirmed
 by
 formal
 
neurology
 assessment
 
if 
required
 due
 to
 
NIHSS 
assessments 
major
 bleeding
 requiring
 transfusion;
  
Review
 of
 symptoms
 
post-procedure
 and
 at
 
30-day
 visit 
myocardial
 infarction;
  
pericarditis
 requiring
 intervention; 
transient
 ischemic
 attack;
  
vagal
 nerve
 injury
 resulting
 in
 esophageal
 
dysmotility
 or
 gastroparesis; 
vascular
 access
 complications
 requiring
 
intervention; 
death;
 
any
 PFA
 system-related
 or
 PFA
 procedure-related
 
cardiovascular
 and/or 
pulmonary
 adverse
 event
 
that
 prolongs
 or
 requires
 hospitalization
 for
 more
 
than
 48
 hours
 (excluding
 recurrent
 AF/AFL/AT) 
 
 
 
 
 
 

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Effectiveness
 Objective:
 
 Assess
 the
 acute
 procedural
 success
 of
 PVI
 
ablation
 with
 the
 PFA
 system.
  
 
Acute
 procedural
 failure
 is
 defined
 as:
  
 
•  Inability
 to
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (minimally
 
assessed
 for
 entrance
 block
 and,
 where
 assessable,
 exit
 block)
 during
 
the
 index
 procedure
  
•  Ablation
 using
 a
 non-study
 device
 to
 isolate
 any 
pulmonary
 vein 
 
Acute
 procedural
 success
 is
 the
 opposite
 of
 acute
 procedural
 failure. 
Pivotal
 Phase
 
Primary
 
Objectives
  
Primary
 objectives,
 which
 will
 be
 reported
 separately
 by
 paroxysmal
 AF
 and
 
persistent
 AF,
 are
 as
 follows:
 
 
 
Safety
 Objective:
 Demonstrate
 an
 acceptable
 safety
 profile
 of
 PVI
 ablation
 
with
 the
 PFA
 System.
  
 
Effectiveness
 Objective:
 
 Demonstrate
 an
 acceptable
 chronic
 effectiveness
 
of
 PVI
 ablation
 with
 the
 PFA
 System,
 based
 on
 freedom
 from
 treatment
 
failure.
  
 
 
Pivotal
 Phase 
Secondary
 
Objectives 
The
 following
 secondary
 objective 
will
 be
 reported
 separately
 by
 paroxysmal
 
AF
 and
 persistent
 AF: 
 
1. Assess
 changes
 in
 quality
 of
 life
 from
 baseline
 through
 12
 months 
after
 the
 index
 ablation
 procedure.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Primary
 Safety
 
Endpoint 
The
 primary
 safety
 endpoint
 definition,
 as
 follows,
 is
 identical
 for
 each
 arm
 
(paroxysmal
 AF
 and
 persistent
 AF) 
of
 the
 Pivotal
 Phase.
 
 
The
 following
 PFA
 system-related
 and
 PFA 
procedure-related
 serious 
adverse
 events
 (SAEs),
 as
 adjudicated
 by
 the
 Clinical
 Events
 Committee
 
(CEC),
 will
 be
 considered
 a
 primary
 safety
 event: 
 
Within
 6
 months
 post-ablation: 
•  Pulmonary
 vein
 stenosis
 (>70%
 diameter
 reduction) 
•  Phrenic
 nerve
 injury/diaphragmatic
 paralysis
 (ongoing
 at
 6
 months) 
•  Atrioesophageal
 fistula
  
 
Within
 30
 days
 of
 ablation
 procedure: 
•  Cardiac
 tamponade/perforation
  
•  Cerebrovascular
 accident
  
•  Major
 bleeding
 requiring
 transfusion 
•  Myocardial
 infarction
  
•  Pericarditis
 requiring
 intervention 
•  Transient
 ischemic
 attack 
•  Vagal
 nerve
 injury
 resulting
 in
 esophageal
 dysmotility
 or
 gastroparesis
  
•  Vascular
 access
 complications
 requiring
 intervention
  
•  Death 
•  Any PFA system-related
 or
 PFA
 procedure-related cardiovascular 
and/or pulmonary adverse event that prolongs or requires 
hospitalization for more than 48 hours (excluding recurrent 
AF/AFL/AT)
  
Primary
 
Effectiveness
 
Endpoints 
The
 definition
 of
 treatment
 success
 and
 failure
 differs
 slightly
 between
 the
 
paroxysmal
 and
 persistent
 arms
 of
 the
 Pivotal
 Phase.
 
 
Primary
 Effectiveness
 Endpoint
 for
 Paroxysmal
 AF 
 
Treatment
 success
 is
 defined
 as
 freedom
 from
 treatment
 failure.
 The
 study
 
requires 
24-hour
 Holter
 monitoring
 at
 6
 and
 12
 months
 in
 addition
 to
 weekly
 
and
 symptomatic
 patient
 activated
 ambulatory 
monitoring 
transmissions
 
from
 3
 through
 12
 months,
 and
 12-lead
 ECGs
 at
 all
 follow
 up
 visits.
 
Treatment
 failure
 is
 defined
 as
 any
 of
 the
 following
 components:
  
 

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•  Acute
 procedural
 failure
 (see
 definition
 below) 
•  Documented
 AF/AT/AFL
 on
 Holter/patient
 activated
 ambulatory 
monitoring/12-lead
 ECG
 after
 the
 90-day
 post-ablation
 blanking
 
period
  
•  Minimum
 of
 30
 seconds
 on
 Holter/patient
 activated
 ambulatory 
monitoring 
or
 10
 seconds
 on
 12-lead
 ECG
 recording 
•  Note:
 Documented
 occurrence
 and
 treatment
 of
 typical
 right-sided
 
cavotricuspid
 isthmus
 dependent
 atrial
 flutter
 is
 not
 considered
 a
 
failure.
 
•  Any
 subsequent
 AF
 surgery
 or
 ablation
 in
 the
 left
 atrium,
 except
 for
 
repeat
 PVI
 ablations
 using
 PFA
 within
 the
 90-day
 blanking
 period.
 
•  Direct
 current
 cardioversion
 for
 atrial
 tachyarrhythmia
 recurrences
 
after
 the
 90-day
 blanking
 period. 
•  Class
 I
 or
 III
 antiarrhythmic
 drug
 (AAD)
 use
 after
 the
 90-day
 blanking
 
period.
  
Blanking
 period
 is
 defined
 as
 the
 first
 90
 days
 after
 the
 index
 ablation
 
procedure.
 Recurrences
 of
 atrial
 arrhythmias
 during
 the
 blanking
 period
 will
 
not
 be
 counted
 in
 the
 determination
 of
 the
 first
 clinical
 failure
 for
 the
 primary
 
endpoint.
 Within
 the
 blanking
 period,
 recurrent
 arrhythmias
 can
 be
 managed
 
with
 antiarrhythmic
 drugs
 or
 cardioversions.
 Titration
 of
 Class
 I
 and
 III
 
antiarrhythmic
 medications
 are
 allowed
 during
 the
 blanking
 period.
  
 
Acute
 procedural
 failure
 is
 defined
 as:
  
 
•  Inability
 to
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (minimally
 
assessed
 for
 entrance
 block
 and,
 where
 assessable,
 exit
 block)
 during
 
the
 index
 procedure
  
•  Ablation
 using
 a
 non-study
 device
 to
 isolate
 any 
pulmonary
 vein
 
 
Primary
 Effectiveness
 Endpoint
 for
 Persistent
 AF 
 
Treatment
 success
 is
 defined
 as
 freedom
 from
 treatment
 failure.
 The
 study
 
requires 
24-hour
 Holter
 monitoring
 at
 6
 and
 12
 months
 in
 addition
 to
 weekly
 
and
 symptomatic
 patient
 activated
 ambulatory 
monitoring 
transmissions
 
from
 3
 through
 12
 months,
 and
 12-lead
 ECGs
 at
 all
 follow
 up
 visits.
 
Treatment
 failure
 is
 defined
 as
 any
 of
 the
 following
 components:
  
 
•  Acute
 procedural
 failure
 (see
 definition
 below) 
•  Documented
 AF/AT/AFL
 on
 Holter/patient
 activated
 ambulatory 
monitoring/12-lead
 ECG
 after
 the
 90-day
 post-ablation
 blanking
 
period
  
•  Minimum
 of
 30
 seconds
 on
 Holter/patient
 activated
 ambulatory 
monitoring 
or
 10
 seconds
 on
 12-lead 
ECG
 recording 

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056-F275, v A Clinical Investigation Plan Template 
•  Note:
 Documented
 occurrence
 and
 treatment
 of
 typical
 right-sided
 
cavotricuspid
 isthmus
 dependent
 atrial
 flutter
 is
 not
 considered
 a
 
failure. 
•  Any
 subsequent
 AF
 surgery
 or
 ablation
 in
 the
 left
 atrium,
 except
 for
 
repeat
 PVI
 ablations
 using
 PFA
 within
 the
 90-day
 blanking
 period.
 
•  Direct
 current
 cardioversion
 for
 atrial
 tachyarrhythmia
 recurrences
 
after
 the
 90-day
 blanking
 period. 
•  Class
 I
 or
 III
 antiarrhythmic
 drug
 (AAD)
 dose
 increase
 from
 the
 
historic
 maximum
 ineffective
 dose
 (prior
 to
 the
 ablation
 procedure)
 
or
 initiation
 of
 a
 new
 Class
 I
 or
 III
 AAD
 after
 the
 90-day
 blanking
 
period.
 Note:
 remaining
 on
 the
 same
 pre-ablation
 dose
 or
 decreased
 
dose
 of
 a
 previously
 failed
 or
 not
 tolerated
 Class
 I
 or
 III
 AAD
 after
 the
 
90-day
 blanking
 is
 not
 considered
 a
 failure.
  
 
Blanking
 period
 is
 defined
 as
 the
 first
 90
 days
 after
 the
 index
 ablation
 
procedure.
 Recurrences
 of
 atrial
 arrhythmias
 during
 the
 blanking
 period
 will
 
not
 be
 counted
 in
 the
 determination
 of
 the
 first
 clinical
 failure
 for
 the
 primary
 
endpoint.
 Within
 the
 blanking
 period,
 recurrent
 arrhythmias
 can
 be
 managed
 
with
 antiarrhythmic
 drugs
 or
 cardioversions.
 Titration
 of
 Class
 I
 and
 III
 
antiarrhythmic
 medications
 are
 allowed
 during
 the
 blanking
 period.
  
 
Acute
 procedural
 failure
 is
 defined
 as:
  
 
•  Inability
 to
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (minimally
 
assessed
 for
 entrance
 block
 and,
 where
 assessable,
 exit
 block)
 during
 
the
 index
 procedure
  
•  Ablation
 using
 a
 non-study
 device
 to
 isolate
 any 
pulmonary
 vein 
Inclusion/
 
Exclusion
 
Criteria 
Inclusion
 Criteria 
1. Failure
 of
 at
 least
 one
 AAD
 (class
 I
 or
 III)
 for
 AF
 as
 evidenced
 by
 
recurrent
 symptomatic
 AF,
 or
 intolerable
 side
 effects
 due
 to
 AAD. 
2. A
 diagnosis
 of
 recurrent
 symptomatic
 paroxysmal
 or
 persistent
 AF
 
with
 the
 following
 documentation:
  
a. Paroxysmal:
 (1)
 physician’s
 note
 indicating 
symptoms
 
consistent
 with 
recurrent
 self-terminating
 (within
 7
 days)
 AF
 or
 
paroxysmal
 AF;
 and
 (2)
 any
 ECG
 documented
 AF
 episode(s)
 
within
 12
 months
 prior
 to
 enrollment
  
OR 
b. Persistent:
 (1)
 physician’s
 note
 indicating
 symptoms
 consistent
 
with
 continuous
 AF
 episode
 lasting
 longer
 than
 7
 days
 but
 less
 
than
 1
 year;
 and
 (2)
 any
 24-hour
 continuous
 ECG
 recording
 
documenting
 persistent
 AF
 within
 6
 months
 of
 enrollment;
 OR
 
(2)
 two
 ECGs
 from
 any
 form
 of
 rhythm
 monitoring
 showing
 
continuous
 AF
 taken
 at
 least
 7
 days
 apart
  
3. Age
 18
 through
 80
 years
 old 
(or
 older
 than
 18
 if
 required
 by
 local
 law)
 
 

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Exclusion
 Criteria 
1. Long-standing
 persistent
 AF
 (continuous
 AF
 that
 is
 sustained
 >12
 
months)
  
2. Left
 atrial
 diameter
 >
 5.0
 cm
 (anteroposterior)
 
 
3. Prior
 left
 atrial
 ablation
 or
 surgical
 procedure
 (including
 left
 atrial
 
appendage
 closures)
 
4. Planned
 LAA
 closure
 procedure
 or
 implant
 of
 a
 permanent
 pacemaker,
 
biventricular
 pacemaker,
 loop
 recorder/insertable
 cardiac
 monitor
 
(ICM),
 or
 any
 type
 of
 implantable
 cardiac
 defibrillator
 (with
 or
 without
 
biventricular
 pacing
 function) 
for
 any
 time
 during
 the
 follow-up
 period
 
5. Patient
 who
 is
 not
 on
 oral
 anticoagulation
 therapy
 for
 at
 least
 3
 weeks
 
prior
 to
 the
 ablation
 procedure
 
6. Presence
 of
 a
 permanent
 pacemaker,
 biventricular
 pacemaker,
 loop
 
recorder/insertable
 cardiac
 monitor
 (ICM),
 or
 any
 type
 of
 implantable
 
cardiac
 defibrillator
 (with
 or
 without
 biventricular
 pacing
 function) 
7. Presence
 of
 any
 pulmonary
 vein
 stents 
8. Presence
 of
 any
 pre-existing
 pulmonary
 vein
 stenosis 
9. Pre-existing
 hemidiaphragmatic
 paralysis 
10. Presence
 of
 any
 cardiac
 valve
 prosthesis 
11. Moderate
 to
 severe
 mitral
 valve
 stenosis
  
12. More
 than
 moderate
 mitral
 regurgitation
 (i.e.,
 3+
 or
 4+
 MR) 
13. Any
 cardiac
 surgery,
 myocardial
 infarction,
 PCI
 /
 PTCA
 or
 coronary
 
artery
 stenting
 which
 occurred
 during
 the
 3-month
 interval
 preceding
 
the
 consent
 date 
14. Unstable
 angina 
15. NYHA
 Class
 III
 or
 IV
 congestive
 heart
 failure
 or
 documented
 left
 
ventricular
 ejection
 fraction
 (LVEF)
 less
 than
 or
 equal
 to
 35%
 measure
 
by
 acceptable
 cardiac
 testing
 (e.g.
 TTE) 
16. Primary
 pulmonary
 hypertension 
17. Rheumatic
 heart
 disease 
18. Thrombocytosis,
 thrombocytopenia 
19. Any
 condition
 contraindicating
 chronic
 anticoagulation 
20. Active
 systemic
 infection 
21. Hypertrophic
 cardiomyopathy 
22. Known
 reversible
 causes
 of
 AF,
 including
 but
 not
 limited
 to
 
uncontrolled
 hyperthyroidism,
 severe
 untreated
 obstructive
 sleep
 
apnea,
 and
 acute
 alcohol
 toxicity 
23. Any
 cerebral
 ischemic
 event
 (strokes
 or
 TIAs)
 which
 occurred
 during
 
the
 6-month
 interval
 preceding
 the
 consent
 date 
24. History
 of
 thromboembolic
 event
 within
 the
 past
 6
 months
 or
 evidence
 
of
 intracardiac
 thrombus
 at
 the
 time
 of
 the
 procedure 
25. Any
 woman
 known
 to
 be
 pregnant
 or
 breastfeeding,
 or
 any
 woman
 of
 
child
 bearing
 potential
 who
 is
 not
 on
 a
 reliable
 form
 of
 birth
 regulation
 
method
 or
 abstinence 

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26. Patient
 with
 life
 expectancy
 that
 makes
 it
 unlikely
 12
 months
 of
 follow-
up
 will
 be
 completed
  
27. Current
 or
 anticipated
 participation
 in
 any
 other
 clinical
 trial
 of
 a
 drug,
 
device
 or
 biologic
 during
 the
 duration
 of
 the
 study
 not
 pre-approved
 by
 
Medtronic 
28. Known
 allergies
 or
 hypersensitivities
 to
 adhesives 
29. Unwilling
 or
 unable
 to
 comply
 fully
 with
 study
 procedures
 and
 follow-up 
30. Unable
 to
 provide
 own
 informed
 consent 
Study
 
Procedures
 and
 
Assessments 
Adult
 subjects
 with
 history
 of
 drug
 refractory
 recurrent
 symptomatic
 atrial
 
fibrillation
 (AF)
 will
 undergo
 ablation
 of
 pulmonary
 veins
 and
 confirmation
 of
 
entrance
 block
 and,
 where
 assessable,
 exit
 block
 with
 the
 PFA
 system.
 
Following
 the
 index
 ablation
 procedure
 and
 hospital
 discharge,
 all
 study
 
subjects
 from
 all
 participating
 geographies
 will
 be
 followed
 at
 30
 days,
 3
 
months,
 6
 months,
 and
 12
 months,
 and
 will
 be
 exited
 from
 the
 study
 at
 the
 
conclusion
 of
 the
 12-month
 follow-up
 visit
 and
 associated
 24-hour
 Holter. 
Safety
 
Assessments 
All 
adverse
 events
 will
 be
 collected 
starting
 at
 the
 time
 of
 signing
 the
 IC
 Form
 
through
 the
 duration
 of
 the
 subject’s
 participation
 in
 the
 study. 
 
Clinical
 Events
 Committee 
(CEC):
 
An
 independent
 committee
 comprised
 of
 electrophysiologists
 not
 
participating
 in
 the
 study
 will
 review
 and
 adjudicate,
 at
 a
 minimum,
 all
 
procedure-
 and
 system-related
 adverse
 events, 
as
 well
 as
 adverse
 events
 
resulting
 in 
death. 
Additional
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
Planned
 Primary
 
Analyses 
 
 
 
 
The
 paroxysmal
 and
 persistent
 arms
 will
 be
 analyzed
 separately.
 
 
  
 
 
 
 
 
 
 

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all
 subjects
 will
 be
 
followed
 for
 12
 months,
 and
 a
 final
 report
 will
 be
 prepared
 for
 each
 arm. 
 
 
 

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3. Introduction  
3.1. Background  
Atrial
 fibrillation
 (AF)
 is
 a
 common
 and
 disabling
 cardiac
 arrhythmia
 with
 a
 heterogeneous
 clinical
 
presentation.
 The
 fundamental
 pathophysiology
 consists
 of
 atrial
 wavelets
 propagating
 in
 
different
 directions,
 causing
 disorganized
 atrial
 depolarizations
 without
 effective
 atrial
 contraction,
 
with
 concomitant
 rapid
 and
 irregular
 ventricular
 contractions.
 As
 published
 in
 the
 2017
 
HRS/EHRA/ECAS/APHRS/SOLAECE
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 Surgical
 
Ablation
 of
 Atrial
 Fibrillation,
 there
 are
 several
 classifications
 for
 AF:
 paroxysmal
 AF
 (PAF)
 is
 defined
 
as
 AF
 that
 terminates
 spontaneously
 or
 with
 intervention
 within
 7
 days
 of
 onset;
 persistent
 AF
 is
 
defined
 as
 continuous
 AF
 that
 is
 sustained
 beyond
 7
 days;
 and
 long-standing
 persistent
 AF
 is
 
defined
 as
 continuous
 AF
 of
 greater
 than
 12-month
 duration.1 
 
AF
 is
 the
 most
 common
 of
 the
 sustained
 arrhythmias
 affecting
 millions
 of
 people
 worldwide.
 The
 
estimated
 global
 prevalence
 of
 AF
 is
 33
 million
 patients,
 and
 the
 number
 of
 AF
 patients
 in
 the
 US
 is
 
expected
 to
 double
 by
 2035.2,3 
Prolonged
 AF
 may
 lead
 to
 electrical,
 mechanical,
 and
 structural
 
changes
 to
 the
 left
 atrium,
 which
 may
 then
 progress
 to
 tachycardia-induced
 cardiomyopathy,
 
heart
 failure
 and
 persistent
 AF.
 Persistent
 AF
 represents
 approximately
 25%
 of
 AF
 cases.4 
The
 
prognosis
 is
 related
 to
 the
 underlying
 cause
 of
 the
 disease,
 with
 idiopathic
 causes
 having
 the
 best
 
prognosis
 and
 ischemic
 cardiomyopathy
 having
 a
 poor
 prognosis.
 The
 mortality
 rate
 in
 patients
 
with
 AF
 is
 twice
 that
 of
 patients
 without
 AF,
 and
 the
 risk
 of
 AF-related
 stroke
 is
 5-fold
 compared
 to
 
the
 risk
 in
 patients
 without
 AF.
5 
In
 comparison
 to
 patients
 with
 paroxysmal
 AF,
 patients
 with
 
persistent
 AF
 are
 at
 a
 significantly
 greater
 risk
 for
 cardiac
 mortality
 (hazard
 ratio
 [HR],
 2.37;
 95%
 
confidence
 interval
 [CI],
 1.19-4.73)
 and
 all-cause
 mortality
 (HR,
 1.89;
 CI,
 1.30-2.74).6 
 
Catheter
 ablation
 is
 established
 as
 an
 acceptable
 line
 of
 treatment
 for
 patients
 with
 recurrent
 
symptomatic
 atrial
 fibrillation
 (both
 paroxysmal
 and
 persistent) 
who
 have
 failed
 anti-arrhythmic
 
drug
 therapy.
 In
 2017,
 the
 HRS/EHRA/ECAS/APHRS/SOLAECE
 Expert
 Consensus
 Statement
 on
 
Catheter
 and
 Surgical
 Ablation
 of
 Atrial
 Fibrillation
 continued
 the
 Class
 I
 Level
 A
 recommendation
 
(as
 previously
 published
 in
 the
 2012
 HRS/EHRA/ECAS
 Expert
 Consensus
 Statement
 on
 Catheter
 
                                                           
 
1 
Calkins H, et al., 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical
 
Ablation
 of
 Atrial
 Fibrillation,
 Heart
 Rhythm
 (2017),
 doi:10.10106/j.hrthm.2017.05.012. 
2 
Chugh,
 S.
 S.,
 et
 al.
 Worldwide
 epidemiology
 of
 atrial
 fibrillation:
 a
 Global 
Burden
 of
 Disease
 2010
 Study.
 Circulation
 129,
 
837-847,
 doi:10.1161/circulationaha.113.005119
 (2014).
 
3 
Naccarelli, G. V., Varker, H., Lin, J. & Schulman, K. L. Increasing prevalence of atrial fibrillation and flutter in the United
 
States.
 The
 American
 journal
 of
 cardiology
 104,
 1534-1539,
 doi:10.1016/j.amjcard.2009.07.022
 (2009). 
4 
Zoni-Berisso
 M,
 et
 al.
 Epidemiology
 of
 atrial
 fibrillation:
 European
 perspective.
 Clinical
 Epidemiology. 
2014;6:213-220. 
doi:10.2147/CLEP.S47385. 
5 
Wolf
 P,
 et
 al.
 Atrial
 fibrillation
 as
 an
 independent
 risk
 factor
 for
 stroke:
 the
 Framingham
 Study.
 Stroke. 
1991;22(8):983-
988. 
6 
Ghanbari
 H,
 et
 al.
 Mortality
 and
 cerebrovascular
 events
 after
 radiofrequency
 catheter
 ablation
 of
 atrial
 fibrillation.
 Heart
 
Rhythm.
 2014;11:1503-1511. 

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and
 Surgical
 Ablation
 of
 Atrial
 Fibrillation7)
 for
 catheter
 and
 surgical
 ablation
 of
 AF
 for
 symptomatic
 
paroxysmal
 AF
 (refractory
 or
 intolerant
 to
 at
 least
 one
 Class
 I
 or
 III
 AAD).
 Although
 in
 the
 US
 there
 
are
 no
 approved
 catheter
 ablation
 options
 for
 treating
 persistent
 AF,
 there
 is
 a
 growing
 body
 of
 
evidence
 supporting
 catheter
 ablation
 as
 a
 reasonable
 option
 for
 this
 patient
 population.
 The
 2017
 
HRS/EHRA/ECAS/APHRS/SOLAECE
 Expert
 Consensus
 Statement
 continued
 the
 Class
 IIa
 Level
 B
 
recommendation
 for
 catheter
 and
 surgical
 ablation
 of
 AF
 for
 symptomatic
 persistent
 AF
 
(refractory
 or
 intolerant
 to
 at
 least
 one
 Class
 I
 or
 III
 AAD),
 stating
 “the
 benefits
 of
 an
 AF
 ablation
 
procedure
 exceed
 the
 risks,
 and
 that
 it
 is
 reasonable
 to
 perform
 AF
 ablation”.1 
In
 the
 previously
 
published
 2014
 AHA/ACC/HRS
 Guideline
 for
 the
 Management
 of
 Patients
 with
 Atrial
 Fibrillation,
 
the
 level
 of
 evidence
 supporting
 the
 recommendation
 moved
 to
 Class
 IIa,
 Level
 A.
8 
 
 
Catheter
 ablation
 treatment
 strategies
 for
 AF
 have
 evolved
 over
 time
 and
 currently
 include
 
pulmonary
 vein
 isolation
 (PVI)
 as
 the
 cornerstone
 of
 ablation
 therapy
 in
 all
 types
 of
 AF
 (paroxysmal
 
and
 persistent),9,
 10 
with
 several
 recent
 studies
 reporting
 benefit
 using
 a
 minimal
 PVI-only
 type
 
strategy.11,12,13,14 
AF
 arises
 primarily
 from
 the
 left
 side
 of
 the
 heart
 in
 the
 atrium,
 particularly
 where
 
the
 pulmonary
 veins
 (PVs)
 join
 the
 atrium.
 The
 fundamental
 basis
 for
 the
 AF
 ablation
 procedure
 is
 
the
 elimination
 of
 initiating
 triggers
 and
 the
 creation
 of
 myocardial
 lesions
 that
 block
 the
 
propagation
 of
 AF
 wave
 fronts
 from
 the
 triggering
 source.
 The
 muscular
 sleeves
 both
 within
 and
 
near
 the
 PVs
 have
 been
 established
 as
 a
 critical
 source
 of
 AF
 triggers.15 
 
Currently
 approved
 catheter
 ablation
 options
 for
 the
 treatment
 of
 drug
 refractory
 recurrent
 
symptomatic
 paroxysmal
 AF
 include
 radiofrequency
 (RF)
 ablation,
 cryoablation,
 and
 visually
 guided
 
                                                           
 
7 
Calkins
 H,
 et
 al.
 2012
 HRS/EHRA/ECAS
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 Surgical
 Ablation
 of
 Atrial
 
Fibrillation:
 Recommendations
 for
 Patient
 Selection,
 Procedural
 Techniques,
 Patient
 Management
 and
 Follow-up,
 
Definitions,
 Endpoints,
 and
 Research
 Trial
 Design.
 Heart
 Rhythm
 2012;9:632-696. 
8 
January C, Wann L, Alpert J, Calkins H, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial 
fibrillation:
 a
 report
 of
 the
 American
 College
 of
 Cardiology/American
 Heart
 Association
 Task
 Force
 on
 Practice
 Guidelines
 
and
 the
 Heart
 Rhythm
 Society.
 J
 Am
 Coll
 Cardiol. 
2014. 
9 
Raviele,
 et
 al.
 Venice
 Chart
 International
 consensus
 Document
 on
 Atrial
 Fibrillation:
 2011
 Update.
 J
 Cardiovasc
 
Electrophysiol,
 2012;23:890-923. 
10 
Jais
 P,
 et
 al.
 Stepwise
 Catheter
 Ablation
 of
 Chronic
 Atrial
 Fibrillation:
 Importance
 of
 Discrete
 Anatomic
 Sites
 for
 
Termination.
 J
 Cardiovasc
 Electrophysiol.
 2006;17:
 S28-S36,
 Suppl.
 3. 
11 
Dong JZ, Sang CH, Yu RH, et al. Prospective randomized comparison between a fixed “2C3L” approach vs. stepwise 
approach
 for
 catheter
 ablation
 of
 persistent
 atrial
 fibrillation.
 Europace.
 doi:10.1093/europace/euv067. 
12 
Wynn GJ, Panikker S, Morgan M, et al. Effect of linear ablation in substrate-based AF: Results of the substrate 
modification
 with
 ablation
 and
 antiarrhythmic
 drugs
 in
 non-permanent
 atrial
 fibrillation
 trial.
 Heart
 Rhythm.
 2015;12:1715. 
13 
Verma A, Jiang CY, Betts TR, et al, STAR AF II Investigators. Approaches to Catheter Ablation for Persistent Atrial 
Fibrillation.
 N
 Engl
 J
 Med.
 2015;372:1812-1822. 
14 
Scott P, Silberbauer J, Murgatroyd F. The impact of adjunctive complex fractionated atrial electrograms ablation and 
linear
 lesions
 on
 outcomes
 in
 persistent
 atrial
 fibrillation:
 a
 meta-analysis.
 Europace
 2016;
 18,
 359-367. 
15 
Calkins
 H,
 et
 al.
 HRS/EHRA/ECAS
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 Surgical
 Ablation
 of
 Atrial
 Fibrillation:
 
Recommendations
 for
 personnel,
 Policy,
 Procedures
 and
 Follow-Up.
 Europace.
 2007;9(6):335-379. 

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Reducing
 safety
 risks
 as
 compared
 to
 current
 catheter
 ablation
 technologies
 is
 warranted.
 The
 
Medtronic
 Pulsed
 Field
 Ablation
 (PFA)
 system
 is
 a
 novel
 method
 of
 PVI
 ablation
 that
 has
 the
 
potential
 to
 offer
 a
 safer
 and
 more
 effective
 treatment 
option
 for
 AF
 over
 existing,
 approved
 
methods
 of
 AF
 ablation.
 Medtronic
 proposes
 there
 is
 a
 need
 to
 investigate
 PVI
 ablation
 with
 a
 novel
 
technology
 (i.e.,
 PFA
 system)
 that
 is
 capable
 of
 potentially
 reducing
 or
 eliminating
 collateral
 
damage,
 improving
 lesion
 formation
 and
 durability,
 and
 reducing
 the
 AF
 ablation
 procedure
 time.
 
The
 PFA
 system
 is
 expected
 to
 be
 a
 safe
 and
 effective
 alternative
 to
 the
 currently
 approved
 
technologies
 used
 to
 achieve
 PVI
 ablation
 in
 a
 paroxysmal
 AF
 patient
 population.
 Indication 
in
 the
 
US
 would
 fulfill
 an
 unmet
 clinical
 need
 for
 symptomatic
 persistent
 AF
 patients
 in
 which
 
antiarrhythmic
 drugs
 fail
 or
 are
 not
 tolerated.
 
 
 
 
 
  
3.2. Purpose 
The
 purpose
 of
 the
 study
 is
 to
 provide
 data
 demonstrating
 the
 safety
 and
 effectiveness
 of 
the
 PFA
 
system 
for
 the
 treatment
 of
 atrial
 fibrillation.
 The
 study
 will
 also
 provide 
first
 in
 human
 insights
 into
 
clinical
 safety
 and
 device
 function
 of
 the
 PFA
 system
 for
 pulmonary
 vein
 isolation
 as
 a
 treatment
 for
 
AF. 
To
 this
 end,
 the
 clinical
 study
 has
 been
 designed
 into
 phases 
(Pilot
 and
 Pivotal),
 with
 each
 phase
 
comprising
 a
 separate
 data
 set
 that
 will
 be
 analyzed
 and
 reported
 on
 per
 the
 below
 objectives. 
The
 proposed
 indication
 for
 the
 PFA
 system
 evaluated
 in
 this
 Study
 is
 as
 follows: 
The
 PFA
 system,
 which
 includes
 a
 compatible
 Medtronic
 multi-electrode
 cardiac
 ablation
 catheter,
 
is
 indicated
 for
 the
 treatment
 of
 atrial
 fibrillation.
 The
 Medtronic
 multi-electrode
 cardiac
 ablation
 
catheter
 is
 also
 intended
 to
 be
 used
 for
 cardiac
 electrophysiological
 (EP)
 mapping
 and
 measuring
 of
 
intracardiac
 electrograms,
 delivery
 of 
diagnostic
 pacing
 stimuli
 and
 verifying
 electrical
 isolation
 
post-treatment.
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. Objectives and Endpoints 
Endpoint
 definitions
 for
 all
 study
 objectives
 are
 described
 in
 Section
 12.
 
 
 
4.1. Pilot Phase Objectives 
4.1.1.  Pilot Phase Safety Objective 
Assess
 the
 incidence
 of
 PFA
 system-related
 and
 PFA 
procedure-related
 serious 
adverse
 events
 
(SAEs)
 within
 30
 days
 post-ablation.
 
4.1.2.  Pilot Phase Effectiveness Objective 
Assess
 the
 acute
 procedural
 success
 of
 PVI
 ablation
 with
 the
 PFA
 system.
 
4.2. Pivotal Phase Objectives 
4.2.1.  Primary Objectives 
Primary
 objectives,
 which
 will
 be
 reported
 separately
 by
 paroxysmal
 AF
 and
 persistent
 AF,
 are
 as
 
follows: 
4.2.1.1.  Primary Safety Objective 
Demonstrate
 an
 acceptable
 safety
 profile
 of
 PVI
 ablation
 with
 the
 PFA
 system. 
4.2.1.2.  Primary Effectiveness Objective 
Demonstrate
 an
 acceptable
 chronic
 effectiveness 
of
 PVI
 ablation
 with
 the
 PFA
 system,
 based
 on
 
freedom
 from
 treatment
 failure.
 
  
4.2.2.  Secondary Objective 
The
 following
 secondary
 objective 
will
 be
 reported
 separately 
by
 paroxysmal
 AF
 and
 persistent
 AF:
 
1. Assess
 changes
 in
 quality
 of
 life
 from 
baseline
 through
 12 
months 
after
 the
 index
 ablation
 
procedure.
 

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056-F275, v A Clinical Investigation Plan Template 
include 
treatment
 of
 315 
subjects
 (165 p
aroxysmal 
AF
 and
 150
 persistent 
AF)
 for
 analysis
 of
 
primary 
objectives,
 across
 up
 to
 40
 sites
 worldwide
 (including
 the
 4
 Pilot
 Phase
 sites).
 For
 the
 
Pivotal
 Phase
 of
 the
 study,
 subjects
 will
 be
 separated
 into
 paroxysmal
 AF
 and
 persistent
 AF
 arms
 
and
 analyzed
 separately.
 
 It
 is
 expected
 that
 at
 least
 50%
 of
 the
 treatments
 and 
supporting
 clinical
 
data
 will
 come
 from
 the
 United
 States
 with
 no
 single
 site
 contributing
 more
 than
 15%
 of
 the
 
treatments
 to
 each 
arm
 of
 the
 Pivotal
 Phase.
 Each
 arm
 will
 have
 a
 primary
 safety
 objective
 and
 a
 
primary
 effectiveness
 objective,
 in
 addition
 to
 secondary
  
 objectives.
 
For
 each
 study
 
arm
 to
 be
 considered
 a
 success,
 both
 the
 primary
 safety
 and
 effectiveness
 objectives 
must
 be
 met. 
To
 facilitate
 the
 investigators’
 familiarity 
with
 the
 system,
 a
 cohort
 of
 roll-in
 subjects
 will
 also
 be
 
included
 in
 the
 Pivotal
 Phase.
 It
 is
 estimated
 that
 there
 will
 be
 up
 to
 80
 roll-in
 subjects 
(up
 to
 2
 per
 
site).
 Roll-in
 subjects
 will
 not
 be
 included
 in
 the
 Pivotal
 Phase
 primary 
or
 secondary
 endpoint
 
analyses
 but
 will
 be
 treated
 and
 followed
 in
 accordance
 with
 all
 other
 protocol
 requirements.
 Roll-in
 
subjects
 are
 defined
 in
 Section
 7.2.1.
 
5.1. Duration 
Subjects
 will
 be
 followed
 for
 12
 months
 after
 the
 index
 ablation
 procedure
 and
 then
 be
 considered
 
exited
 from
 the
 study 
upon
 completion
 of
 the
 12-month
 visit.
 Accordingly,
 the
 expected
 total
 
study
 duration
 is
 approximately
 2
 years
 and
 4
 months,
 representing
 16 
months
 of
 enrollment
 and
 
12
 months
 of
 subject
 follow-up.
 
 Subjects
 will
 not
 be
 replaced
 with
 newly
 enrolled
 subjects
 upon
 
early
 study
 exit. 
 
 
5.2. Rationale  
The
 study
 has
 primary
 objectives
 designed
 to
 evaluate
 the
 safety
 and
 effectiveness
 of 
the
 PFA
 
system 
for
 treatment
 of
 AF.
 This
 evaluation
 will
 support
 the
 proposed 
indication 
of
 the
 PFA
 
system.
 The
 study
 will be
 
scientifically
 sound
 and
 successful
 if
 it
 meets 
both 
primary
 safety
 and
 
effectiveness
 objectives
 for
 one
 or
 both
 arms
 (paroxysmal
 and/or
 persistent). 
 
The
 potential
 benefits
 related
 to
 the
 use
 of
 the
 PFA
 system
 have
 been
 determined
 to
 outweigh
 any
 
potential
 risks,
 providing 
justification 
to
 proceed
 with
 clinical
 investigation.
 Clinical
 data
 are needed
 
to
 demonstrate
 that
 the
 safety
 profile
 and
 proper
 lesion
 creation
 established
 in
 preclinical
 testing
 
is
 confirmed
 in
 a
 clinical
 setting.
 Also,
 as
 demonstrated
 in
 preclinical
 studies20,21,
 22,
 the
 PFA
 system
 
                                                           
 
20 
Stewart, Mark T., et al.  Intracardiac pulsed field ablation: proof of feasibility in a chronic porcine model.  Heart
 rhythm.
 
16.5
 (2019):
 754-764. 
21 H
oward,
 Brian
 T.,
 et
 al.
  Pulsed
 Field
 Ablation
 Reduces
 Pulmonary
 Vein
 Stenosis
 Risk:
 An
 Advanced
 Model
 for
 Assessment
 
of
 PV
 Stenosis.
  Circulation
 138.Suppl_1
 (2018):
 A16516-A16516.
 
22 
Verma, A., et al.  Pulsed field ablation-feasibility, safety and comparison to radiofrequency.  EUROPEAN HEART 
JOURNAL.
 Vol.
 39.
 GREAT
 CLARENDON
 ST,
 OXFORD
 OX2
 6DP,
 ENGLAND:
 OXFORD
 UNIV
 PRESS,
 2018. 

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056-F275, v A Clinical Investigation Plan Template 
offers
 potential
 advantages
 over
 existing
 approved
 or
 cleared
 alternatives
 such
 as 
reducing/eliminating
 collateral
 damage,
 improving
 lesion
 formation
 and
 durability,
 and
 reducing
 
the
 AF
 ablation
 procedure 
time.
 A
 phased
 clinical
 study
 design
 with
 continuous
 enrollment
 and
 
prospective
 data
 collection
 to
 demonstrate
 safety
 and
 effectiveness
 of
 the
 PFA
 system
 potentially
 
reduces
 the
 time
 to
 patient
 access 
for
 this
 breakthrough
 device,
 as
 opposed
 to
 running
 separate
 
pilot
 and
 pivotal
 studies.
 A
 multi-site,
 multi-national
 design 
helps
 to
 ensure
 a
 representative
 
sample
 of
 the
 global
 population
 as
 well
 as
 maintain
 a
 reasonable
 enrollment
 duration. 
5.3. Minimization of Bias 
Selection
 of
 subjects,
 treatment
 of
 subjects,
 and
 evaluation
 of
 study
 data
 are
 potential
 sources
 of
 
bias.
 Methods
 incorporated
 in
 the
 study
 design
 to
 minimize
 potential
 bias
 include
 (but
 are
 not
 
limited
 to): 
•  Subjects
 will
 be
 screened
 to
 confirm
 eligibility
 for
 enrollment
 with
 defined
 
inclusion/exclusion
 criteria
 prior
 to
 enrollment.
 
•  Subject
 demographics
 will
 be
 collected
 at
 baseline
 in
 order
 to
 later
 assess
 possible
 
characteristics
 that
 may
 influence
 endpoints.
 
 
•  All
 investigational
 site personnel
 
and
 Medtronic
 personnel
 will
 be
 trained
 on
 their
 respective
 
aspects
 of
 the
 study
 using
 standardized
 training
 materials.
 
•  All
 investigational
 site personnel
 
will
 be
 trained
 on
 and
 required
 to
 follow
 the
 CIP.
 
•  An
 independent
 Clinical
 Events
 Committee
 (CEC)
 will
 be
 utilized
 to
 regularly
 review
 and
 
adjudicate
 reported 
adverse
 events 
and
 deaths
 in
 the
 study. 
•  An
 independent
 core
 lab
 will
 be
 utilized
 to
 regularly
 review
 and
 adjudicate
 the
 arrhythmia
 
component
 of
 the
 primary
 endpoints. 
•  A
 statistical
 analysis
 plan
 (SAP)
 will
 be
 developed
 prior
 to
 analyzing
 data.
 The
 plan 
will
 
document
 all
 pre-specified
 analyses
 and
 analysis
 methods.
 
•  Monitoring
 will
 be
 conducted
 to
 review
 adherence
 to
 the
 CIP
 and
 perform
 source
 data
 
verification
 per
 the
 Monitoring
 Plan. 
•  No
 single
 site
 may
 contribute
 more
 than
 15%
 of
 the
 treatments
 to
 each
 arm
 of
 the
 Pivotal
 
Phase
 (25 
paroxysmal
 AF
 subjects
 and
 23 
persistent
 AF
 subjects,
 excluding
 Pilot
 Phase
 and
 
roll-in
 subjects) 
to
 ensure
 a
 reasonable 
distribution
 of
 subjects
 across
 sites. 
•  An
 independent 
core
 laboratory 
will
 be
 used
 
 to
 evaluate
 b
aseline
 and
 3-
month
 cardiac
 CT
 or
 MRI
 scans
 to
 characterize
 of
 any
 potential
 occurrences
 of
 PV
 stenosis 
for
 Pilot
 Phase
 subjects.
 
 
In
 summary,
 potential
 sources
 of
 bias
 that
 may
 be
 encountered
 in
 this
 clinical
 study
 have
 been
 
considered
 and
 minimized
 by 
thorough, 
careful
 study
 design. 

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It
 is
 anticipated
 that
 at
 least
 415
  
 catheters
 and
 415
 
Sterile,
 Catheter
 to
 CEDS,
 Cables
 
will
 be
 used 
to
 ensure
 the
 study
 sample
 size
 is
 met.
 It
 is
 anticipated
 that
 at
 least
 one
 each
 of
 the
 
remaining
 PFA
 system
 components
 and
 accessories
 will
 be
 used
 per
 site
 in
 the
 study. 
6.1.1.  System Description  
The
 Medtronic
 Pulsed
 Field
 Ablation
 (PFA)
 system
 applies
 bipolar,
 biphasic
 pulsed
 electric
 fields
 
through
 a
 circular
 multi-electrode
 array
 catheter
 to
 perform
 cardiac
 tissue
 ablation
 through
 
irreversible
 electroporation.
 The
 system
 is
 intended
 to
 be
 used
 for
 the
 treatment
 of
 atrial
 
fibrillation
 in
 humans
 by
 isolation
 of
 the
 major
 cardiac
 veins. 
Each
 PFA
 therapeutic
 delivery
 consists
 of
 a
 series
 of
 electric
 pulses
 delivered
 as
 a
 pulse
 train
 
containing
 individual 
brief
 biphasic
 pulses.
 During
 each
 pulse,
 current
 flows
 in
 a
 bipolar
 manner
 
between
 individual
 electrodes
 on
 the
 multi-electrode
 catheter
 array
 which
 radiates
 an
 electric
 field
 
that
 surrounds
 the
 array.
 Cardiac
 tissue
 within
 the
 electric
 field
 undergoes
 cellular
 hyper-
permeabilization,
 which
 irreversibly
 disrupts
 the
 integrity
 of
 the
 cellular
 membrane
 leading
 to
 cell
 
death
 in
 the
 targeted
 tissue
 site.
 This
 mechanism
 of
 cell
 death
 is
 known
 as
 irreversible
 
electroporation
 (IRE).
 The
 ablated
 myocardium
 then
 undergoes
 replacement
 fibrosis
 over
 a
 period
 
of
 days
 to
 weeks
 creating
 a
 fibrotic
 lesion. 
 
 
 catheters
 are
 sterile,
 single
-use
 only
 intravascular
 devices
 designed
 for
 short-term
 
use
 (<
 24
 hours)
 within
 the
 human
 vasculature
 and
 heart.
 
 makes
 contact
 with
 the
 
central
 circulatory
 system
 (blood
 contact).
  
 is
 also
 intended
 for
 cardiac
 EP
 mapping
 of
 
pulmonary
 vein
 potentials,
 delivery
 of
 diagnostic
 pacing
 stimuli
 and
 verifying
 electrical
 isolation
 of
 
the
 pulmonary
 veins
 post-treatment.
 The
 PFA
 system
 is
 utilizing
 this
 catheter
 as
 a
 platform
 to
 
deliver
 pulsed
 electric
 fields
 to
 cardiac
 tissue.
  
The
 PFA
 system
 is
 for
 use
 by
 physicians
 in
 a
 clinical
 setting
 (e.g.
 a
 fully
 equipped
 electrophysiology
 
laboratory)
 and
 has
 been
 developed
 for
 use
 under
 a
 clinical
 protocol
 and
 not
 for
 general
 commercial
 
use. 
 
 

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6.2. PFA Generator 
 
 
 
 
 
 
 
 

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6.3. Catheter Electrode Distribution System (CEDS) 
 
 
 
 
 
 
 
 
 
 
 
6.4. Remote Control 
 
 
 
 
 
 
 
 
 
 
 
6.5. Cable, Generator to Remote Control 
 
 

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6.6. Cable, Generator to CEDS 
 
 
 
 
6.7. Cable, CEDS to EP Recording System (EGM) 
 
 
  
6.8. Cable, Sterile, Catheter to CEDS 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
6.10. Cardiac Trigger Monitor and Cables 
 
 
 
 
 
 
6.11. Power Cord 
 
 

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6.12. Uninterruptible Power Supply (UPS) 
 
 
 
 
 
 
 
 
 
6.13. Power Cord – C14M-C13F 
 
 
6.14. Packaging 
In
 all
 geographies,
 the
 following
 PFA
 system
 components
 will
 be
 provided
 to
 sites
 and
 will
 be
 
labeled
 as
 investigational: 
•  PFA
 Generator 
•  CEDS 
•  Remote
 Control 
•  Cable,
 Generator
 to
 CEDS 
•  Cable,
 Generator
 to
 Remote
 Control 
 
In
 the
 US 
and
 Japan,
 the
 following
 PFA
 system
 accessories 
will
 be
 provided
 to
 sites
 and
 will
 be
 
labeled
 as
 investigational: 
• 
 catheter
 
•  Sterile
 catheter
 to
 CEDS
 cable 
•  CEDS
 to
 EP
 recording
 cable
 (EGM
 cable) 
 
In
 Australia,
 Canada 
and
 Europe,
 the
 following
 PFA
 system
 accessories 
are
 commercially
 available
 
and
 will
 not
 be
 provided
 to
 sites,
 but
 will
 be
 considered
 investigational
 upon
 opening
 to 
be
 used
 
with
 the
 PFA
 system
 per
 the
 CIP.
 
 
• 
 catheter
 
•  Sterile
 catheter
 to
 CEDS
 cable 
•  CEDS
 to
 EP
 recording
 cable
 (EGM
 cable) 
 
 

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In
 Australia,
 Canada,
 Europe,
 and
 US,
 the
 Cardiac
 Trigger
 Monitor
 is
 commercially
 available.
 At
 
study
 start,
 the
 Cardiac
 Trigger
 Monitor
 is
 not
 commercially
 available
 in
 Japan.
 In
 all
 geographies, 
this
 accessory 
will
 be
 provided
 to
 sites
 and
 will
 be
 considered
 investigational
 upon
 opening
 to
 be
 
used
 with
 the
 PFA
 system
 per
 the
 CIP.
  
 
In
 all
 geographies,
 the
 power
 cords
 (models
 1038N,
 1038K,
 1038E,
 P004-006-ABL)
 are 
commercially
 available,
 but
 will
 be
 provided
 to
 sites
 and
 will
 be
 considered
 investigational
 upon
 
opening
 to
 be
 used
 with
 the
 PFA
 system
 per
 the
 CIP.
 Medtronic
 personnel
 trained
 on
 the
 study
 will
 
affix
 a
 sticker 
denoting
 the
 accessory 
model
 number.
 The
 appropriate
 geography-specific
 model
 
cord
 should
 be
 used
 by
 each
 study
 site. 
In
 all
 geographies,
 the
 UPS 
is
 commercially
 available,
 but
 will
 be
 provided
 to
 sites
 and
 will
 be
 
considered
 investigational
 upon
 opening
 to
 be
 used
 with
 the
 PFA
 system
 per
 the
 CIP.
 
 
Market
 released
 components
 used
 in
 this
 study
 will
 be
 labeled
 investigational
 according
 to
 local
 
requirements.
 See
 Appendix
 A 
(Study-Specific
 Requirements
 by
 Country)
 for
 details
 of
 
investigational
 labeling
 of
 market
 released
 components.
 
6.15. Product Training Requirements 
Investigators
 responsible
 as
 operators
 for
 the
 PFA
 system
 ablation
 procedure
 will
 be
 required
 to
 
undergo
 product
 training
 (to
 include
 hands
 on
 experience)
 prior
 to
 treating
 any
 subject
 with
 the
 
PFA
 system.
 A
 separate
 training
 document
 will
 overview
 topics
 and
 include
 details
 on
 the
 format
 of
 
delivery. 
6.16. Product Receipt, Tracking and Return 
In
 Canada,
 Australia
 and
 Europe,
 the
 study
 will
 utilize
 the
 commercially
 available
  
 
catheter,
 sterile
 catheter
 to
 CEDS
 cable,
 and
 CEDS
 to
 EP
 recording
 cable
 (EGM
 cable)
 with
 no
 study
 
driven
 changes
 to
 the
 product
 or
 labeling,
 except
 as
 noted
 in
 Section 
6.14.
 These
 devices
 will
 not
 
be
 provided
 to
 the
 sites
 in
 these
 geographies
 where
 the
 devices
 are
 commercially
 available,
 but
 
sites
 may
 be
 reimbursed
 for
 device
 use
 in
 the
 clinical
 study. 
 
Investigational
 product
 will
 be
 distributed
 to
 a
 site
 only
 when
 Medtronic
 has
 received
 all
 required
 
documentation,
 has
 notified
 the
 site
 of
 site
 activation
 and
 the
 site
 has
 been
 authorized
 to
 enroll
 in
 
the
 study.
 Distribution
 of
 the
 investigational
 product
 to
 study
 sites
 during
 the
 clinical
 study
 will
 be
 
managed
 by
 Medtronic.
 Investigational
 product
 can
 only
 be
 ordered
 by
 Medtronic
 personnel.
 
Investigational
 product
 must
 be
 stored
 in
 a
 secure
 location
 at
 the
 site.
 Investigational
 products
 will
 
be
 used
 only
 in
 the
 study
 according
 to
 the
 CIP 
and
 PFA
 system
 IFU.
 In
 Japan,
 the
 device
 control
 
manager,
 assigned
 by
 the
 Head
 of
 Medical
 Institution
 controls
 the
 investigational
 device
 once
 the
 
product
 arrives
 at
 the
 study
 site. 
 
The
 principal
 investigator
 or
 an
 authorized
 designee
 shall
 keep
 records
 documenting
 the
 receipt,
 
use,
 return
 and
 disposal
 of
 the
 investigational
 devices,
 which
 shall
 include:
 

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•  The
 date
 of
 receipt 
•  Identification
 of
 each
 investigational
 device
 (batch
 number/serial
 number
 or
 unique
 code) 
•  The
 expiration
 date
 (if
 applicable) 
•  The
 date(s)
 of
 use 
•  Subject
 identification 
•  The
 date
 of
 return
 of
 unused,
 expired
 or
 malfunctioning
 investigational
 devices
 (if
 
applicable) 
 
All
 PFA
 system
 components
 and
 accessories
 are
 to
 be
 returned
 to
 Medtronic
 by
 each
 study
 site 
at
 
the
 following
 timepoints:
 
 
After
 each
 study
 ablation
 procedure: 
• 
 catheter
 
•  Sterile
 catheter
 to
 CEDS
 cable 
Note:
 
 In
 US
 and
 Japan,
 these
 PFA
 system
 accessories
 are
 shipped
 to
 sites
 as
 investigational;
 
therefore,
 unopened
 or
 expired
 accessories
 are
 required
 to
 be
 returned
 to
 Medtronic.
 In
 Australia,
 
Canada
 and
 Europe, 
these 
PFA
 system
 accessories
 are
 only
 considered
 investigational
 upon
 
opening
 to
 be
 used
 with
 the
 PFA
 system
 per
 the
 CIP;
 therefore,
 there
 is
 no
 requirement
 to
 return
 
unopened
 product
 to
 Medtronic. 
Upon
 completion
 of
 the
 study,
 unless
 otherwise
 directed
 by
 the
 Medtronic
 study
 team: 
•  PFA
 Generator 
•  CEDS 
•  Remote
 Control 
•  Cable,
 Generator
 to
 CEDS 
•  Cable,
 Generator
 to
 Remote
 Control 
•  CEDS
 to
 EP
 recording
 cable
 (EGM
 cable) 
•  Cardiac
 Trigger
 Monitor 
•  Power
 cord 
(models
 1038N,
 1038K,
 1038E,
 P004-006-ABL)
 
•  Uninterruptible
 Power
 Supply
 (UPS) 
Note:
 
 In
 all
 geographies,
 these
 PFA
 system
 components
 and
 accessories
 (including
 unopened
 or
 
expired
 product)
 are
 required
 to
 be
 returned
 to
 Medtronic. 
The
 one
 exception
 is
 in
 Australia,
 
Canada
 and
 Europe,
 the
 CEDS
 to
 EP 
recording
 cable
 (EGM
 cable)
 is 
only
 considered
 investigational
 
upon
 opening
 to
 be
 used
 with
 the
 PFA
 system
 per
 the
 CIP;
 therefore,
 there
 is
 no
 requirement
 to
 
return
 this
 product
 to
 Medtronic
 if
 unopened. 
Any
 sheath
 or
 guidewire
 used
 in
 conjunction
 with
 the
 PFA
 system
 with
 a
 reportable
 device
 
deficiency
 should
 be
 returned
 to
 Medtronic
 following
 the
 study
 ablation
 procedure. 
 
Device
 disposition
 logs
 will
 be
 provided
 to
 all
 sites
 and
 used
 for
 tracking
 of
 all
 investigational
 
product
 throughout
 the 
duration
 of
 the
 study.
 The
 logs
 must
 be
 maintained
 and
 updated
 when
 
product
 is
 disposed
 of
 or
 returned
 to
 Medtronic.
 If
 the
 products
 are
 not
 returned
 to
 Medtronic,
 a
 
justification
 is
 required
 to
 be
 reported
 on
 the
 appropriate
 case
 report
 form(s)
 or
 disposition
 log(s). 

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6.17. Product Storage 
The
 PFA
 system
 is
 investigational
 and
 will
 be
 maintained
 in
 locked,
 secure
 storage
 with 
access
 limited
 only
 to
 approved
 study
 staff. 
 
 
 

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7. Selection of Subjects 
7.1. Study Population 
The
 population
 being
 studied
 has
 documented
 drug
 refractory
 recurrent
 symptomatic
 paroxysmal
 
or
 persistent
 atrial
 fibrillation
 with
 generally
 otherwise
 good
 cardiovascular
 health.
 The
 AF
 
classifications
 that
 will
 be
 used
 for
 this
 study
 are
 defined
 in
 the
 2017
 
HRS/EHRA/ECAS/APHRS/SOLAECE
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 Surgical
 
Ablation
 of
 Atrial
 Fibrillation.
1 
 
 
Paroxysmal
 AF
 is
 defined
 as
 AF
 that
 terminates
 spontaneously
 or
 with
 intervention
 within
 7
 days
 of
 
onset. 
 
Persistent
 AF
 is
 defined
 as
 continuous
 AF
 that
 is
 sustained
 beyond
 7
 days. 
 
Patients
 in
 long-standing
 persistent
 AF
 are
 excluded
 from
 the
 study.
 Long-standing
 persistent
 AF
 
is
 defined
 as
 continuous
 AF
 of
 greater
 than
 12
 months’
 duration. 
7.2. Subject Enrollment 
Patients
 will
 be
 screened
 to
 ensure
 they
 meet
 all
 of
 the
 inclusion
 and
 none
 of
 the
 exclusion
 criteria
 
prior
 to
 study
 enrollment.
 IRB/MEC
 and
 Medtronic
 approval
 of
 the
 Clinical
 Investigation
 Plan
 and
 
the
 Patient
 Informed
 Consent
 Form
 must
 be
 obtained
 prior
 to
 enrolling
 subjects
 in
 the
 study.
 
Enrollment
 of
 the
 subject
 must
 occur
 prior
 to
 performing
 any
 study
 procedures.
 Subjects
 are
 
enrolled
 at
 the
 time
 the
 Patient
 Informed
 Consent
 Form
 is
 signed
 and
 dated. 
Pilot
 and
 Pivotal
 Phase
 
subjects
 must
 meet
 the
 same
 inclusion 
and
 exclusion
 criteria
 and
 will
 follow
 the
 same
 consent
 
process.
  
7.2.1.  Roll-in Subjects 
To
 facilitate
 the
 investigators’
 familiarity 
with
 the
 system,
 a
 cohort
 of
 roll-in
 subjects
 will
 be
 
included
 in
 the
 Pivotal
 Phase
 enrollments.
 The
 roll-in
 subjects
 will
 not
 be
 included
 in
 the
 315 
subjects
 included
 in
 the
 analysis
 for 
the 
Pivotal
 Phase
 primary
 and
 secondary
 objectives
 but 
will
 be
 
consented,
 enrolled,
 treated,
 and
 followed
 in
 accordance
 with
 all
 other
 protocol
 requirements.
 
Sites
 that
 do
 not
 have
 previous
 experience
 with
 the
 catheter
 will
 utilize
 up
 to
 two
 roll
-
in
 subjects;
 Medtronic
 approval
 is
 required
 to
 utilize
 fewer
 than
 two
 roll-in
 subjects.
 Sites
 having
 
prior
 recent
 experience
 with
 the
 
 catheter
 may
 be
 allow
ed
 to
 waive
 the
 roll-in
 
requirement,
 with
 Medtronic
 approval,
 prior
 to
 enrolling
 subjects
 into
 the
 primary
 analysis
 cohort.
 
Investigators
 that
 participate
 as
 PFA
 system
 operators
 in
 the
 Pilot
 Phase
 will
 not
 be
 required
 to
 
utilize
 roll-in
 subjects.
 Since
 paroxysmal
 AF
 and
 persistent
 AF
 subjects
 will
 be
 treated
 with
 the
 
same
 ablation
 procedure
 approach
 (PVI-only),
 subjects
 with
 either
 AF
 type
 can
 contribute
 to
 the
 

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roll-in
 cohort.
 Subjects
 will
 be
 identified
 as
 roll-in
 subjects
 prior
 to
 the
 ablation
 procedure. 
There 
will
 be
 up
 to
 80
 total
 roll-in
 subjects.
  
7.3. Inclusion Criteria 
1. Failure
 of
 at
 least
 one
 AAD
 (class
 I 
or 
III)
 for
 AF
 as
 evidenced
 by
 recurrent
 symptomatic
 AF,
 
or
 intolerable
 side
 effects
 due
 to
 AAD. 
 
2. A
 diagnosis
 of
 recurrent
 symptomatic
 paroxysmal
 or
 persistent
 AF
 with
 the
 following
 
documentation: 
a. Paroxysmal:
 (1)
 physician’s
 note
 indicating
 symptoms
 consistent
 with
 recurrent
 
self-terminating
 or
 terminating
 with
 intervention
 (within
 7
 days)
 AF
 or
 paroxysmal
 
AF;
 and
 (2)
 any
 ECG
 documented
 AF
 episode(s)
 within
 12
 months
 prior
 to
 
enrollment
  
OR 
b. Persistent:
 (1)
 physician’s
 note
 indicating
 symptoms
 consistent
 with
 continuous
 AF
 
episode
 lasting
 longer
 than
 7
 days
 but
 less
 than
 1
 year;
 and
 (2)
 any
 24-hour
 
continuous
 ECG
 recording
 documenting
 persistent
 AF
 within
 6
 months
 of
 
enrollment;
 OR
 (2)
 two
 ECGs
 from
 any
 form
 of
 rhythm
 monitoring
 showing
 
continuous
 AF
 taken
 at
 least
 7
 days
 apart 
3. Age
 18
 through
 80
 years
 old 
(or
 older
 than
 18
 if
 required
 by
 local
 law) 
7.4. Exclusion Criteria 
1. Long-standing
 persistent
 AF
 (continuous
 AF
 that
 is
 sustained
 >12
 months)
  
2. Left
 atrial
 diameter
 >
 5.0
 cm
 (anteroposterior)
  
3. Prior
 left
 atrial
 ablation
 or
 surgical
 procedure
 (including
 left
 atrial
 appendage
 closures) 
4. Planned
 LAA
 closure
 procedure
 or
 implant
 of
 a
 permanent
 pacemaker,
 biventricular
 
pacemaker,
 loop
 recorder/insertable
 cardiac
 monitor
 (ICM),
 or
 any
 type
 of
 implantable
 
cardiac
 defibrillator
 (with
 or
 without
 biventricular
 pacing
 function) 
for
 any
 time
 during
 the
 
follow-up
 period
  
5. Patient
 who
 is
 not
 on
 oral
 anticoagulation
 therapy
 for
 at
 least
 3
 weeks
 prior
 to
 the
 ablation
 
procedure
  
6. Presence
 of
 a
 permanent
 pacemaker,
 biventricular
 pacemaker,
 loop
 recorder/insertable
 
cardiac
 monitor
 (ICM),
 or
 any
 type
 of
 implantable
 cardiac
 defibrillator
 (with
 or
 without
 
biventricular
 pacing
 function)
  
7. Presence
 of
 any
 pulmonary
 vein
 stents 
8. Presence
 of
 any
 pre-existing
 pulmonary
 vein
 stenosis 
9. Pre-existing
 hemidiaphragmatic
 paralysis 
10. Presence
 of
 any
 cardiac
 valve
 prosthesis 
11. Moderate
 to
 severe
 mitral
 valve
 stenosis
  
12. More
 than
 moderate
 mitral
 regurgitation
 (i.e.,
 3+
 or
 4+
 MR) 

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13. Any
 cardiac
 surgery,
 myocardial
 infarction,
 PCI
 /
 PTCA
 or
 coronary
 artery
 stenting
 which
 
occurred
 during
 the
 3-month
 interval
 preceding
 the
 consent
 date 
14. Unstable
 angina 
15. NYHA
 Class
 III
 or
 IV
 congestive
 heart
 failure
 or
 documented
 left
 ventricular
 ejection
 fraction
 
(LVEF)
 less
 than
 or
 equal
 to
 35%
 measure
 by
 acceptable
 cardiac
 testing
 (e.g.
 TTE) 
16. Primary
 pulmonary
 hypertension 
17. Rheumatic
 heart
 disease 
18. Thrombocytosis,
 thrombocytopenia 
19. Any
 condition
 contraindicating
 chronic
 anticoagulation 
20. Active
 systemic
 infection 
21. Hypertrophic
 cardiomyopathy 
22. Known
 reversible
 causes
 of
 AF,
 including
 but
 not
 limited
 to
 uncontrolled
 hyperthyroidism,
 
severe
 untreated
 obstructive
 sleep
 apnea,
 and
 acute
 alcohol
 toxicity 
23. Any
 cerebral
 ischemic
 event
 (strokes
 or
 TIAs)
 which
 occurred
 during
 the
 6-month
 interval
 
preceding
 the
 consent
 date 
24. History
 of
 thromboembolic
 event
 within
 the
 past
 6
 months
 or
 evidence
 of
 intracardiac
 
thrombus
 at
 the 
time
 of
 the
 procedure 
25. Any
 woman
 known
 to
 be
 pregnant
 or
 breastfeeding,
 or
 any
 woman
 of
 child
 bearing
 
potential
 who
 is
 not
 on
 a
 reliable
 form
 of
 birth
 regulation
 method
 or
 abstinence 
26. Patient
 with
 life
 expectancy
 that
 makes
 it
 unlikely
 12
 months
 of
 follow-up
 will
 be
 completed
  
27. Current
 or
 anticipated
 participation
 in
 any
 other
 clinical
 trial
 of
 a
 drug,
 device
 or
 biologic
 
during
 the
 duration
 of
 the
 study
 not
 pre-approved
 by
 Medtronic 
28. Known
 allergies
 or
 hypersensitivities
 to
 adhesives 
29. Unwilling
 or
 unable
 to
 comply
 fully
 with
 study
 procedures
 and
 follow-up 
30. Unable
 to
 provide
 own
 informed
 consent 
 
 

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5 
TEE
 must
 be
 performed
 in
 all
 subjects.
 The
 TEE
 should
 occur
 within
 one
 day
 (on
 the
 day
 of
 or
 within
 the
 day
 prior
 to)
 the
 planned
 
ablation
 procedure.
 
6 S
ubjects
 taking
 a
 vitamin
 K
 antagonist
 (VKA)
 are
 required
 to
 have
 a
 therapeutic
 INR
 (2-3.5)
 on
 the
 day
 of
 the
 planned
 ablation
 
procedure.
 INR
 assessment
 is
 not
 required
 for
 subjects
 on
 other
 types
 of
 anticoagulants. 
 
8
 Subjects shall submit ECG transmissions weekly and whenever symptoms occur after the post-ablation blanking period 
through
 12-month
 follow-up.
 
  
8.2. Subject Consent 
Patient
 informed
 consent
 (IC)
 is
 defined
 as
 a
 legally
 effective
 documented
 confirmation
 of
 a
 
subject’s
 voluntary
 agreement
 to
 participate
 in
 a
 particular
 clinical
 study
 after
 information
 has
 been
 
given
 to
 the
 subject
 on
 all
 aspects
 of 
the
 clinical
 study
 that
 are
 relevant
 to
 the
 subject’s
 decision
 to
 
participate.
 This
 process
 includes
 obtaining
 an 
IC
 Form
 and
 an
 Authorization
 to
 Use
 and
 Disclose
 
Personal
 Health
 Information
 (US
 only)
 that
 has
 been
 approved
 by
 the
 study
 site’s
 IRB/REB/MEC
 and
 
signed
 and
 dated
 by
 the
 subject.
 A
 subject
 may
 only
 consent
 after
 information
 has
 been
 given
 to
 
the
 subject
 on
 all
 aspects
 of
 the
 clinical
 investigation
 that
 are
 relevant
 to
 the
 subject’s
 decision
 to
 
participate.
  
 
Prior
 to
 enrolling
 subjects,
 the
 IC
 Form
 must
 have
 been
 approved
 by
 each
 site’s
 IRB/REB/MEC.
 
Each
 site
 must
 also
 use
 an
 Authorization
 to
 Use
 and
 Disclose
 Personal
 Health
 
Information/Research
 Authorization
 (US
 only)
 or
 other
 privacy
 language
 as
 required
 by
 law.
 The
 IC
 
Form
 must
 be
 controlled
 (i.e.
 versioned
 and
 dated)
 to
 ensure
 it
 is
 clear
 which
 version(s)
 were
 
approved
 by
 the
 IRB/REB/MEC.
 Any
 adaptation
 of
 the
 sample
 IC
 Form
 must
 be
 reviewed
 and
 
approved
 by
 Medtronic
 and
 the
 IRB/REB/MEC
 reviewing
 the
 application
 prior
 to
 enrolling
 subjects.
  
 
The
 Investigator
 must
 notify
 the
 subject
 of
 any
 significant
 new
 findings
 about
 the
 study
 that
 
become
 available
 during
 the
 study
 which
 are
 pertinent
 to
 the
 safety
 and
 well-being
 of
 the
 subject.
 
This
 could
 impact
 a
 subject’s
 willingness
 to
 participate
 in
 the
 study.
 If
 relevant,
 approval
 may
 be
 
requested
 from
 subjects
 to
 confirm
 their
 continued
 participation. 
 
Prior
 to
 initiation
 of
 any
 study-specific
 procedures,
 documented
 informed
 consent
 must
 be
 
obtained
 from
 the
 subject.
 Likewise,
 privacy
 or 
health
 information
 protection
 regulation
 may
 
require
 subjects
 to
 sign
 additional
 forms
 to
 authorize
 sites
 to
 submit
 subject
 information
 to
 the
 
study
 sponsor.
 The
 informed
 consent
 process
 must
 be
 conducted
 by
 the
 Principal
 Investigator
 or
 
an
 authorized
 designee,
 and
 the
 IC
 Form
 and
 the
 Authorization
 to
 Use
 and
 Disclose
 Personal
 Health
 
Information/Research
 Authorization/other
 privacy
 language
 (US
 only)
 as
 required
 by
 law
 must
 be
 
given
 to
 the
 subject
 in
 a
 language
 he/she
 is
 able
 to
 read
 and
 understand.
 The
 process
 of
 informed
 
consent
 must
 be
 conducted
 without
 using
 coercion,
 undue
 or
 improper
 influence
 on,
 or
 
inducement
 of
 the
 subject
 to
 participate
 by
 the
 Investigator
 or
 other
 site 
personnel.
 The
 informed
 
consent
 process
 shall
 not
 waive
 or
 appear
 to
 waive
 the 
subject’s
 legal
 rights.
 The
 language
 used
 
shall
 be
 as
 non-technical
 as
 possible
 and
 must
 be
 understandable
 to
 the
 subject
 and
 the
 impartial
 
witness,
 where
 applicable. 
 

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The
 subject
 must
 have
 ample
 time
 and
 opportunity
 to
 read
 and
 understand
 the
 IC
 Form,
 to 
inquire
 
about
 details
 of
 the
 study,
 and
 to
 decide
 whether
 to
 participate
 in
 the
 clinical
 study.
 All
 questions
 
about
 the
 study
 should
 be
 answered
 to
 the
 satisfaction
 of
 the
 subject.
  
 
When
 the
 subject
 decides
 to
 participate
 in
 the
 clinical
 study,
 the
 IC
 Form
 and
 the
 Authorization
 to
 
Use
 and
 Disclose
 Personal
 Health
 Information/Research
 Authorization/other
 privacy
 language
 (US
 
only)
 as
 required
 by
 law
 must
 be
 signed
 and
 personally
 dated
 by
 the
 subject
 and
 either
 the
 
Investigator
 or
 the
 Investigator’s
 authorized
 designee,
 as
 required
 by
 local
 law.
 If
 applicable,
 
independent
 witness
 must
 be
 present
 throughout
 the
 entire
 informed
 consent
 process,
 and
 the
 
written
 informed
 consent
 form
 and
 any
 other
 information
 related
 to
 the
 study
 must
 be
 read
 aloud
 
and
 explained 
to
 the
 prospective
 subject.
 If
 applicable,
 witness
 shall
 also
 sign
 and
 personally
 date
 
the
 consent
 form
 to
 attest
 that
 the
 information
 in
 the
 IC
 Form
 was
 accurately
 explained
 and
 clearly
 
understood
 by
 the
 subject,
 and
 that
 informed
 consent
 was
 freely
 given. 
 
 
A
 copy
 of
 the
 IC
 Form
 and
 the
 Authorization
 to
 Use
 and
 Disclose
 Personal
 Health
 
Information/Research
 Authorization/other
 privacy
 language
 as
 required
 by
 law
 (US
 only),
 signed
 
and
 dated
 as
 required
 by
 law,
 must
 be
 provided
 to
 the
 subject.
  
 
If
 consent
 is
 obtained
 the
 same
 day
 the
 subject
 begins
 participating
 in
 study-related
 procedures,
 it
 
must
 be
 documented
 in
 the
 subject’s
 case
 history
 that
 consent
 was
 obtained
 prior
 to
 participation
 
in
 any
 study
 related
 procedures.
 It
 is
 best
 practice
 for
 the
 informed
 consent
 process
 to
 be
 
documented
 in
 the
 subject’s
 case
 history,
 regardless
 of
 circumstance. 
 
In
 the
 event
 the
 subject
 cannot
 read
 and/or
 write,
 a
 witnessed
 (impartial
 third
 party)
 IC
 Form
 will
 be
 
allowed,
 provided
 detailed
 documentation
 of
 the
 process
 is
 recorded
 in
 the
 subject’s
 case
 history
 
and
 the
 witness
 signs
 and
 dates
 the
 IC
 Form. 
 
The
 original
 of
 the
 signed
 IC
 Form
 and
 the
 Authorization
 to
 Use
 and
 Disclose
 Personal
 Health
 
Information/Research
 Authorization/other
 privacy
 language
 (US
 only) 
as
 required
 by
 law
 must
 be
 
filed
 in
 the
 hospital/clinical
 chart
 and/or
 with
 the
 subject’s
 study
 documents
 and
 should
 also
 be
 
available
 for
 monitoring
 and
 auditing.
 Any
 Medtronic
 Field
 personnel
 who
 support
 the
 study
 
procedure
 must
 be
 able
 to
 review
 the
 subject’s
 signed
 and
 dated
 IC
 Form
 and
 verify
 its
 
completeness
 prior
 to
 proceeding
 with
 the
 procedure.
 In
 the
 event
 the
 Medtronic
 Field
 personnel
 
identify
 an
 IC
 Form
 as
 being
 incomplete,
 the
 study
 procedure
 will
 not
 be
 allowed
 to
 occur
 until
 the
 
consent
 of
 the
 subject
 can
 be
 adequately
 and
 appropriately
 obtained. 
 
 

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056-F275, v A Clinical Investigation Plan Template 
8.3. Enrollment, Baseline, and Pre-ablation 
When
 a
 patient
 and
 the
 Principal
 Investigator
 or
 authorized
 designee,
 as
 required,
 have
 signed
 and
 
dated
 the
 IC
 Form,
 the
 patient
 is
 considered
 a
 subject
 enrolled
 in
 the
 study.
 
 The
 date
 the
 subject
 
signed
 the
 IC
 Form
 and
 Authorization 
to
 Use
 and
 Disclose
 Personal
 Health
 Information/Research
 
Authorization/other
 privacy
 language
 as
 required
 by
 law
 must
 be
 documented
 in
 the
 subject’s
 
medical
 records. 
The
 baseline 
visit
 can
 be
 a
 standalone
 visit
 or
 can
 be
 performed
 on
 the
 same
 day
 but
 prior
 to
 the
 
PFA
 system
 ablation
 procedure.
 The
 following
 evaluations
 will
 be
 performed
 after
 consent,
 unless
 
previously
 performed
 as
 part
 of
 routine
 clinical
 evaluations
 within
 the
 specified
 windows: 
Within
 6
 months
 prior
 to
 consent
 date: 
•  Trans-thoracic
 echocardiogram
 (TTE)
 for
 the
 collection
 of
 left
 atrial
 size,
 left
 ventricular
 
ejection
 fraction,
 and
 mitral
 valve
 impairment.
 
 A
 repeat
 TTE
 procedure
 for
 the
 purpose
 of
 
the
 study
 after 
the
 consent
 date
 is
 not
 required
 if
 a
 TTE
 was
 performed
 within
 6
 months
 of
 
the
 consent
 date
 and
 all
 data
 are
 available. 
•  Pilot
 Phase
 subjects
 only:
 cardiac
 Magnetic
 Resonance
 Imaging
 (MRI)
 or
 Computerized
 
Tomography
 Scanning
 (CT
 scan)
 of
 the
 four
 PVs
 or
 their
 anomalous
 equivalent. 
Within
 30
 days
 prior
 to
 consent
 date: 
•  12-lead
 ECG
  
•  Physical
 examination 
•  CHA2DS2-VASc
 Score 
•  Demographics 
•  Medical
 history
 
  
 
After
 consent
 date
 but
 prior
 to
 procedure:
  
Note:
 The
 time
 between
 the
 consent
 date
 and
 the
 procedure
 should
 not
 exceed
 30
 days. 
If
 30
 days
 
are
 exceeded,
 the
 subject
 must
 be
 re-evaluated
 against
 inclusion
 and
 exclusion
 criteria
 to
 ensure
 
they
 still
 qualify
 for
 the
 study. 
•  Final
 assessment
 of
 all
 factors
 specified
 for
 evaluation
 under
 Inclusion
 Criteria
 and
 
Exclusion
 Criteria
 (Section
 7)
 
o Note:
 After
 required
 study
 testing,
 if
 a
 subject
 no
 longer
 meets
 the
 inclusion
 criteria
 
or
 now
 meets
 exclusion
 criteria,
 the
 subject
 will
 be
 exited
 from
 the
 study. 
•  Pregnancy
 screen
 (female
 subjects
 of
 child
 bearing
 potential
 only)
  
o Note:
 For
 this
 study,
 a
 woman
 of
 childbearing
 potential
 is
 defined
 as
 a
 
premenopausal
 female
 capable
 of
 becoming
 pregnant 

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•  Review
 of
 AF
 symptoms 
•  Review
 of
 medications
 to
 treat
 atrial
 arrhythmias
 and
 anticoagulation
 medications
  
o Amiodarone
 use
 must
 be
 discontinued
 at
 least
 14
 days
 prior
 to
 the
 ablation
 
procedure
 and
 not
 restarted
 after
 the
 ablation
 procedure.
  
•  EQ-5D
 (5L
 version)
 and
 AFEQT
 Questionnaires 
•  INR
 assessment 
o Subjects
 taking
 a
 vitamin
 K
 antagonist
 (VKA)
 are
 required
 to
 have
 a
 therapeutic
 INR
 
(2-3.5)
 on
 the
 day
 of
 the
 planned
 ablation
 procedure.
  
o INR
 assessment
 is
 not
 required
 for
 subjects
 on
 other
 types
 of
 anticoagulants.
 
•  Transesophageal
 Echocardiogram
 (TEE)
  
o A
 TEE
 must
 be
 performed
 in
 all
 subjects.
 The
 TEE
 should
 occur
 within
 one
 day
 (on
 
the
 day
 of
 or
 within
 the
 day
 prior
 to)
 the
 planned
 ablation
 procedure. 
o The
 subject
 will
 not
 proceed
 with
 the
 study
 ablation
 procedure
 and
 will
 be
 exited
 
from
 the
 study
 if
 a
 left
 atrial
 thrombus
 is
 visualized. 
•  National
 Institute
 of
 Health
 Stroke
 Scale
 (NIHSS)
 Assessment 
o The
 NIHSS
 will
 be
 administered
 to
 all
 subjects
 within
 3
 days
 prior
 to,
 including
 day 
of,
 planned
 ablation
 procedure.
 
o The
 NIHSS
 will
 be
 administered
 by
 study
 site
 personnel
 who
 have
 been
 certified
 to 
perform
 the
 NIHSS
 assessment
 and
 are
 delegated
 by
 their
 respective
 site
 to 
perform
 such
 assessment 
 
 
 
 
 
 
 

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056-F275, v A Clinical Investigation Plan Template 
8.4. Procedure 
Note:
 The
 time
 between
 the
 consent
 date
 and
 the
 procedure
 should
 not
 exceed
 30
 days. If
 30
 days
 
are
 exceeded,
 the
 subject
 must
 be
 re-evaluated
 against
 inclusion
 and
 exclusion
 criteria
 to
 ensure
 
they
 still
 qualify
 for
 the
 study. 
 
Perform
 the
 pulmonary
 vein
 isolation
 procedure
 using
 the
 PFA
 system
 with
 the
  
 
cardiac
 ablation
 catheter.
 
 
 
 
The
 Investigator
 is
 to
 perform
 the
 procedure
 
according
 to
 the
 procedural
 steps
 in
 this
 CIP
 and
 the
 PFA
 system 
Instructions
 For
 Use.
 Appropriate 
sedation
 and
 venous
 access
 should 
be
 attained
 at
 the
 Investigator’s
 standard
 practice
 according
 to
 
their
 institution’s
 pre-established
 procedures/guidelines
 at
 the
 time
 of
 the
 procedure.
 Investigator
 
may
 choose
 compatible
 guidewires,
 sheaths
 and
 mapping
 catheters
 at
 their
 discretion. 
ACT
 
analyzer
 calibration
 records
 must
 be
 made
 available
 for
 sponsor
 review
 prior
 to
 each
 PFA 
ablation
 
procedure. 
 
The
 anticoagulation
 protocol 
for
 PULSED
 AF
 is
 as
 follows: 
•  Pre-procedure 
o Subjects
 who
 are
 not
 on
 oral
 anticoagulation
 therapy
 for
 at
 least
 3
 weeks
 prior
 to
 
the
 ablation
 procedure
 are
 excluded
 from
 the
 study. 
 
 
o If
 VKA
 is
 used,
 1
 therapeutic
 INR
 reading
 (2-3.5)
 is
 required
 day
 of
 procedure.
 
o Prior
 to
 ablation,
 TEE
 is
 required
 of
 all
 patients
 regardless
 of
 CHA2DS2-VASc
 score
 
or
 anticoagulation.
 
•  Procedure 
o Continuous,
 uninterrupted
 oral
 anticoagulation
 (e.g.
 no
 bridging
 with
 low
 molecular
 
weight
 heparin) 
is
 required. 
o Administer
 heparin
 bolus
 prior
 to
 (or
 immediately
 after)
 the
 transseptal
 puncture
 
and
 start
 continuous
 heparin
 infusion
 to
 maintain
 a
 target
 ACT
 ≥
 350
 seconds.
  
o The
 ACT
 level
 should
 be
 checked 
at
 approximately
 15–30
 minute
 intervals
 for
 the
 
duration
 of
 the
 procedure. 
o In
 the
 event
 of
 persistent
 bleeding
 or
 cardiac
 tamponade,
 protamine
 may
 be
 
administered
 to
 reverse
 heparin.
 If
 bleeding
 resolves,
 reversal
 of
 oral
 anticoagulant
 
is
 not
 recommended. 
•  Post-procedure 
o Oral
 anticoagulation
 must 
be
 continued
 for
 at
 least
 2
 months
 post-procedure
 (e.g.
 
no
 bridging
 post-procedure)
 for
 all
 subjects
 unless
 contraindicated.
 
o Discontinuation
 of
 systemic
 anticoagulation
 therapy
 after
 2
 months
 post
 ablation
 is
 
not
 recommended
 in
 male
 subjects
 with
 a
 CHA
2DS2-VASc
 score
 >1
 or
 female
 
subjects
 with
 a
 CHA
2DS2-VASc
 score
 >2. 

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056-F275, v A Clinical Investigation Plan Template 
8.4.1.  Esophageal Visualization and Temperature Monitoring 
a. An
 esophageal
 temperature
 monitor
 is
 not
 required
 to
 be
 used
 for
 PFA
 therapy
 profile
 
applications.
 If
 an
 esophageal
 temperature
 monitor
 is
 used,
 it
 should
 have
 an
 insulated
 
tip. 
8.4.2.  Diaphragm Movement 
a. Prior
 to
 the
 first
 PFA
 application,
 the
 Investigator
 must
 confirm
 absence
 of
 pre-
existing
 hemidiaphragmatic
 paralysis.
 
8.4.3.  Peri-procedural Anticoagulation 
a. Heparin
 should
 be
 administered
 prior
 to
 (or
 immediately
 following)
 transseptal
 
puncture
 during
 AF
 ablation
 procedures
 and
 adjusted
 to
 achieve
 and
 maintain
 a 
target 
ACT
 of
 at
 least
 350 
 
seconds.
 ACT
 should
 be
 checked
 approximately
 every
 15-30
 
minutes. 
b. Performance
 of
 AF
 ablation
 in
 a
 subject
 systemically
 anticoagulated
 with
 VKA 
or
 novel
 
oral
 anticoagulants
 (NOACs)
 does
 not
 alter
 the
 need
 for
 intravenous
 heparin
 to
 
maintain
 a
 therapeutic
 ACT
 during
 the
 procedure.
  
c. Performance
 of
 the
 ablation
 procedure
 on
 continuous,
 uninterrupted
 oral
 
anticoagulation
 (e.g.
 no
 bridging
 with
 low
 molecular
 weight
 heparin)
 is
 required. 
 
d. In
 the
 event
 of
 persistent
 bleeding
 or
 cardiac
 tamponade,
 protamine
 may
 be
 
administered
 to
 reverse
 heparin.
 If
 bleeding
 resolves,
 reversal
 of
 oral
 anticoagulant
 is
 
not
 recommended.
 
8.4.4.  Pulmonary Vein (PV) Ablation with the PFA system 
a. Deploy
 diagnostic
 catheters
 and
 perform
 transseptal
 puncture.
 Introduction
 of
 the
 
 catheter
 should
 be
 performed
 according
 to
 the
 
PFA
 system
 IFU. 
 
b. Every
 effort
 consistent
 with
 subject
 welfare
 should
 be
 made
 to
 treat
 all
 PVs
 or
 their
 
anomalous
 equivalents. 
c. The
 
 catheter
 will
 be
 advanced
 into
 the
 left
 atrium
 and
 tracked
 over
 the
 
guidewire
 so
 that
 it
 is 
positioned
 at
 the
 entrance
 of
 the
 PV. 
d. Assess
 the
 catheter’s
 spiral
 array
 positioning
 at
 the
 PV
 by
 fluoroscopy
 or
 other
 
imaging
 technique.
 Reposition
 as
 needed. 
e. Map
 for
 pulmonary
 vein
 potentials.
 

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056-F275, v A Clinical Investigation Plan Template 
f. If
 desired
 due
 to
 proximity
 to
 phrenic
 nerve,
 deliver
 the
 test
 pulse
 while
 monitoring
 for
 
stimulation
 of
 the 
diaphragm.
  
 
 
 
 
 
 
h. Verify
 isolation
 of
 each
 pulmonary
 vein
 a
 minimum
 of 
20 
minutes
 after 
the
 last
 PFA
 
application
 of
 the
 initial
 PVI
 in
 that
 PV.
 Each
 pulmonary
 vein
 should
 be
 minimally
 
assessed
 for
 entrance
 block
 and,
 where
 assessable,
 exit
 block
 to
 demonstrate
 
electrical
 isolation.
 
  
i.  Upon
 the
 Investigator’s
 assessment
 of
 procedure
 completion,
 Isoproterenol
 and/or
 
adenosine
 may
 be
 used
 to
 assess
 pulmonary
 vein
 isolation.
 
j.  In
 the
 event
 of
 an
 inability
 to
 electrically
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 
with
 the
 PFA
 system,
 any
 commercially
 released
 catheter
 deemed
 appropriate
 for
 the
 
procedure
 may
 be
 used
 to
 complete
 the
 ablation
 procedure.
 Ablation
 using
 a
 non-
study
 device
 to
 isolate
 any
 pulmonary
 vein
 will
 be
 considered
 a
 primary
 endpoint
 
failure.
 
8.4.5.  Other Ablations during Index Procedure 
a. Ablation
 of
 the
 cavotricuspid
 isthmus,
 with
 the
 goal
 of
 achieving
 bi-directional
 
isthmus
 block,
 is
 recommended
 for
 subjects
 with
 a
 history
 of
 typical
 atrial
 flutter
 or
 
inducible
 cavotricuspid
 isthmus
 dependent
 atrial
 flutter.
 
 It
 is
 recommended
 to
 
attempt
 an
 induction
 of
 cavotricuspid
 isthmus
 dependent
 atrial
 flutter
 if
 the
 subject
 
does
 not
 have
 a
 history
 of
 this
 arrhythmia.
 
 Any
 commercially
 released
 catheter
 
deemed
 appropriate
 for
 the
 procedure
 may
 be
 used. 
b. Additional
 right
 atrial
 ablations
 may
 be
 performed
 if
 clinically
 necessary. 
Any
 
commercially
 released
 catheter
 deemed
 appropriate
 for
 the
 procedure
 may
 be
 used. 
8.4.6.  Procedure Documentation  
During
 the
 procedure,
 the
 following
 data
 will
 be
 collected:
  
•  Catheters
 used 
•  Vein
 location
 for
 each
 PFA
 application
 (e.g.
 right
 superior
 PV) 
•  Use
 of
 test
 pulse
 or
 other
 phrenic
 nerve
 monitoring
 technique
 for
 each
 PFA
 application 

PULSED AF Clinical Investigation Plan  
 
 
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056-F275, v A Clinical Investigation Plan Template 
•  PFA
 therapy
 profile
 and
 electrode 
configuration
 used
 for
 each
 PFA
 application 
•  Procedural
 sedation
 methods/type,
 including
 any
 modifications
 to
 procedural
 sedation
 as
 a
 
result
 of
 subject
 reaction
 to
 PFA
 applications 
•  Stimulation
 of
 diaphragm
 or
 skeletal
 muscle
 as
 a
 result
 of
 PFA
 applications 
•  Demonstrated
 electrical
 block
 and
 the
 device
 used
 to
 demonstrate 
•  Adjunctive
 catheters,
 mapping
 or
 visualization
 devices,
 procedure
 information,
 ACT,
 
cardioversion
 use
 and
 fluoroscopy
 time
 will
 be
 collected;
 esophageal
 temperature
 may
 be
 
collected 
8.4.7.  Cardioversion 
Direct
 Current
 (DCCV)
 or
 pharmacological
 cardioversion
 may
 be
 considered
 at
 any
 point
 during
 the 
procedure
 when
 restoration
 of
 SR 
will
 assist
 in
 assessing
 the
 effectiveness
 of
 PFA
 or
 deemed
 
necessary
 for
 the
 benefit
 of
 the
 patient.
 Electrical
 or
 pharmacological
 cardioversion
 to
 sinus
 
rhythm
 must
 be
 attempted
 at
 the
 conclusion
 of
 the
 procedure
 if
 sinus
 rhythm
 was
 not
 restored. 
8.4.8.  Role of Medtronic Personnel at Study Procedure 
Medtronic
 personnel
 will
 provide
 technical
 support
 at
 the
 ablation
 procedures
 under 
the 
supervision
 of
 a
 study
 investigator,
 but
 no
 data
 entry
 into
 the
 electronic 
database
 shall
 be
 
performed
 by
 Medtronic
 personnel
 at
 sites.
 Medtronic 
personnel
 may
 support
 completion
 of
 the
 
study
 worksheets.
 Medtronic
 personnel
 will
 collect
 procedural
 data
 from
 the
 PFA
 generator
 post-
procedure
 via
 data 
download.
 It
 is
 the
 responsibility
 of
 the
 study
 site 
to 
ensure
 the
 subject
 is
 
identified
 via
 subject
 ID
 number
 to
 prevent
 the
 distribution
 of
 personally
 identifiable
 information.
 
8.5. Hospital Discharge 
At
 or
 shortly
 before
 hospital
 discharge,
 the
 following
 will
 be
 performed
 and
 collected: 
•  Adverse
 event
 assessment 
•  Review
 medications 
•  12-lead
 ECG 
•  NIHSS
 Assessment 
o The
 NIHSS
 will
 be
 administered
 by
 study
 site
 personnel
 who
 have
 been
 certified
 
to
 perform
 the
 NIHSS
 assessment
 and
 are
 delegated
 by
 their
 respective
 site
 to
 
perform
 the
 assessment.
 The
 discharge
 NIHSS
 assessment
 will
 be
 conducted
 
no
 earlier
 than
 the
 day
 following
 the
 procedure
 and
 no
 later
 than
 the
 subject’s
 
discharge.
 If
 the
 subject
 is
 discharged
 the
 same
 day
 as
 the
 ablation
 procedure,
 
the
 NIHSS
 assessment
 will
 be
 conducted
 no
 earlier
 than
 6
 hours
 following
 the
 
procedure.
 If
 the
 subject’s
 discharge
 NIHSS
 total
 score
 is
 higher
 (worse)
 than
 
the
 baseline
 NIHSS
 total
 score,
 a
 formal
 neurology
 consult
 will
 be
 initiated
 by
 
the
 study
 site
 team
 to
 confirm
 the
 presence
 or
 absence
 of
 stroke
 or
 TIA.
 If
 the
 
site’s
 neurology
 team
 deems
 it
 necessary,
 imaging
 will
 be
 performed. 

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•  Review
 study
 requirements
 with
 the
 subject
 to
 help
 ensure
 compliance
 with
 follow-up
 
procedures.
 
 
 
 
 
 
 
 
 
 
8.6. Medications 
Oral
 anticoagulation
 must 
be
 continued
 for
 at
 least
 two 
months
 post-ablation 
(e.g.
 no
 bridging
 
post-ablation)
 for
 all
 subjects
 unless
 contraindicated.
 Decisions
 regarding
 the
 continuation
 of
 
anticoagulation
 therapy
 more
 than
 two
 months
 following
 ablation
 should
 be
 based
 on
 the
 subject’s
 
risk
 factors
 for
 stroke
 as
 estimated
 by
 the
 CHA
2DS2-VASc
 score
 and
 not
 on
 the
 presence
 or
 type
 of
 
AF.
 Discontinuation
 of
 systemic
 anticoagulation
 therapy
 after
 two
 months
 post-ablation
 is
 not
 
recommended
 in
 male
 subjects
 with
 a
 CHA
2DS2-VASc
 score
 >1
 or
 female
 subjects
 with
 a
 
CHA2DS2-VASc
 score
 >2. 
 
Information
 regarding
 medications
 prescribed
 for
 anticoagulation
 or
 to
 treat
 atrial
 arrhythmias
 will
 
be
 collected
 from
 subject
 enrollment
 through
 study
 exit.
 The
 following
 information
 will
 be
 collected
 
for
 medications
 to
 treat
 atrial
 arrhythmias:
 medication
 name,
 purpose
 for
 use,
 start
 and
 stop
 
dates,
 dose,
 dosage
 changes
 (and
 reasons
 for
 changes),
 and
 route
 of
 administration.
 Data
 
collection
 for
 anticoagulation
 medication
 will
 be
 limited
 to
 medication
 name
 and
 start
 and
 stop
 
dates. 
 
Requirements
 for
 use
 of
 antiarrhythmic
 medications
 are
 described
 below
 for
 the
 Paroxysmal
 AF
 
and
 Persistent
 AF
 cohorts.
 Use
 of
 amiodarone
 is
 not
 permitted
 for
 any
 subject
 post-ablation.
 All
 
other
 medications
 (those
 that
 are
 not
 specified
 below)
 are
 permitted
 in
 the
 study,
 with
 the
 
exception
 of
 investigational
 drugs
 that
 may
 confound
 the
 study
 results.
 Beta-blockers
 may
 be
 
prescribed
 per
 standard
 of
 care. 
8.6.1.  Paroxysmal AF Cohort 
Per
 physician
 discretion,
 class
 I
 or
 III
 antiarrhythmic,
 including
 sotalol,
 medication
 use
 is
 permitted
 
for
 up
 to
 80
 days
 following
 the
 ablation
 procedure.
 Prescriptions
 for
 these
 drugs
 should 
not
 allow
 a
 
quantity
 that
 will
 last
 longer
 than 
80
 days
 post-procedure.
 It
 is
 recommended
 that
 site
 personnel
 
contact
 subjects
 on
 day
 80
 post-ablation
 procedure
 to
 ensure
 they
 have
 stopped
 taking
 class
 I
 or
 III
 
antiarrhythmic
 drugs.
 Class
 I
 or
 III
 antiarrhythmic
 drug
 use
 after
 the
 90-day
 blanking
 period
 will
 be
 
considered
 a
 primary
 endpoint
 failure.
 
 

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8.6.2.  Persistent AF Cohort 
Up-titration
 of
 the 
Class
 I
 or 
III
 antiarrhythmic
 medication 
dose
 is
 allowed
 only
 in
 the
 90-day
 post-
procedure
 blanking
 period.
 
Class
 I
 and
 III
 antiarrhythmic
 medication
 use
 after
 the
 90-day
 post-procedure
 blanking
 period: 
•  Subjects
 are 
allowed
 to
 remain
 on
 Class
 I
 or
 III
 antiarrhythmic
 medications
 at
 or
 lower
 than 
the
 historic
 maximum
 ineffective
 dose
 (prior
 to
 the
 ablation
 procedure)
 after
 the
 90-day
 
post-procedure
 blanking
 period. 
•  Re-initiation,
 at
 any
 point
 during
 follow-up,
 of
 a
 Class
 I
 or
 III
 antiarrhythmic
 medication
 that
 
was
 failed
 or
 was
 not
 tolerated 
prior
 to
 the
 ablation
 procedure
 at
 any 
dose 
will
 be
 
considered
 a
 primary
 endpoint
 failure.
 
•  Initiation
 of
 a
 new
 Class
 I
 or
 III
 antiarrhythmic
 medication
 after
 the
 90-day
 post-procedure
 
blanking
 period 
will
 be
 considered
 a
 primary
 endpoint
 failure. 
•  Remaining
 on
 a
 dose
 higher
 than
 the
 historic
 maximum
 ineffective
 dose
 (prior
 to
 the
 
ablation
 procedure)
 after
 the
 90-day
 post-procedure
 blanking
 period 
will
 be
 considered
 a
 
primary
 endpoint
 failure. 
8.7. Repeat Ablations with PFA 
Repeat
 PVI
 ablations
 using
 PFA
 are
 permissible
 within
 the
 90-day
 blanking
 period.
 Any
 repeat
 PVI
 
using
 the
 PFA
 system
 throughout
 the
 study
 follow-up
 period
 should
 be
 performed
 according
 to
 the
 
procedural
 steps 
in
 Section 
8.4.
 Note,
 a
 repeat
 ablation
 after
 the
 90-day
 blanking
 period
 will
 be
 
considered
 a
 primary
 endpoint
 failure.
 Any
 repeat
 ablation
 in
 the
 left
 atrium
 using
 a
 non-study
 
device 
at
 any
 time
 after
 the
 index
 PFA
 ablation
 procedure
 will
 be
 considered
 a
 primary
 endpoint
 
failure.
 
Subsequent
 ablations
 in
 the
 right
 atrium
 are
 allowed
 (e.g.,
 typical
 atrial
 flutter
 ablation) 
at
 any
 time
 
throughout
 the
 study
 follow-up
 period.
  
 
If
 a
 repeat
 left
 atrial
 ablation
 is
 deemed
 necessary
 and
 performed
 by
 the
 Investigator,
 the
 following
 
should
 be
 performed: 
 
 
 
 
•  Review
 medications
  
•  Adverse
 event
 assessment 
•  Review
 symptoms
 suggestive
 of
 recurrent
 AF/AT/AFL 
•  NIHSS
 Assessment 
o An
 NIHSS
 assessment
 will
 be
 administered
 to
 all
 subjects
 within
 3
 days
 prior
 to,
 
including
 day
 of,
 repeat
 ablation
 procedure. 

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o The
 NIHSS
 will
 be
 administered
 by
 study
 site
 personnel
 who
 have
 been
 certified
 to
 
perform
 the
 NIHSS
 assessment
 and
 are
 delegated
 by
 their
 respective
 site
 to
 
perform
 such
 assessment. 
•  Discharge
 procedures
 will
 be
 completed
 in
 accordance
 with
 Section 
8.5.
 
 
 
 
 
Repeat
 ablation
 procedures
 will
 be
 documented
 on
 an
 electronic
 case
 report
 form
 (eCRF) 
and
 as
 
described
 in
 accordance
 with
 Section 
8.4.6.
 
 The
 subject’s
 procedures
 and
 follow-up
 windows 
will
 
continue
 based
 on
 the
 index
 PFA
 ablation
 procedure
 date.
 
  
8.8. Post-Procedural Cardioversions 
Electrically and
 pharmacologically
 cardioverting
 the
 subject
 to
 sinus
 rhythm
 is
 allowed
 in
 the
 90-
day
 post-procedure
 blanking
 period 
at
 the
 discretion
 of
 the
 Investigator.
 Electrically
 or
 
pharmacologically
 cardioverting
 the
 subject
 to
 sinus
 rhythm
 after
 the
 90-day
 blanking
 period 
will
 
be
 considered
 a
 primary
 endpoint
 failure. 
 
 

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8.9.2.  Three Month Visit 
•  Review
 medications
  
•  Adverse
 event
 assessment 
•  Review
 symptoms
 suggestive
 of
 recurrent
 AF/AT/AFL 
•  12-lead
 ECG 
•  Provide
 the
 subject
 with
 patient
 activated
 ambulatory
 monitoring
 equipment
 and
 provide
 
instructions
 for
 weekly
 and
 symptomatic
 transmissions
  
•  Cardiac
 MRI
 or 
CT
 scan:
 
•  Pilot
 Phase
 subjects
 are
 required
 to
 complete
 a 
cardiac
 MRI
 or
 CT
 scan
 (whichever
 
technology
 was
 used
 at
 Baseline)
 of
 all
 PVs
 or
 their
 anomalous
 equivalents.
  
•  All
 subjects:
 only
 in
 the
 case
 of
 suspected
 PV
 stenosis,
 is
 cardiac
 MRI
 or
 CT
 scan
 required.
 It
 
is
 not
 required
 at
 this
 visit
 if
 it
 was
 already
 completed
 at
 an
 earlier
 visit
 where
 PV
 stenosis
 
was
 confirmed. 
 
 
 
 
8.9.3.  Six Month Visit 
•  Review
 medications
  
•  Adverse
 event
 assessment 
•  Review
 symptoms
 suggestive
 of
 recurrent
 AF/AT/AFL 
•  12-lead
 ECG 
•  Remind
 subject
 of
 instructions
 on
 patient
 activated
 ambulatory
 monitoring
 equipment
 for
 
weekly
 and
 symptomatic
 transmissions 
•  Only
 in
 the
 case
 of
 suspected
 PV
 stenosis,
 is
 cardiac
 MRI
 or
 CT
 scan 
required.
 It
 is
 not
 
required
 at
 this
 visit
 if
 it
 was
 already
 completed
 at
 an
 earlier
 visit
 where 
PV
 stenosis
 was
 
confirmed. 
•  24h
 continuous
 monitoring
 with
 Holter 
•  EQ-5D
 and
 AFEQT
 Questionnaires 
8.9.4.  Twelve Month Visit 
•  Review
 medications
  
•  Adverse
 event
 assessment 
•  Review
 symptoms 
suggestive
 of
 recurrent
 AF/AT/AFL 
•  12-lead
 ECG 
•  Only
 in
 the
 case
 of
 suspected
 PV
 stenosis,
 is
 cardiac
 MRI
 or
 CT
 scan 
required.
 It
 is
 not
 
required
 at
 this
 visit
 if
 it
 was
 already
 completed
 at
 an
 earlier
 visit
 where 
PV
 stenosis
 was
 
confirmed. 
•  24h
 continuous
 monitoring
 with
 Holter 
•  EQ-5D
 and
 AFEQT
 Questionnaires 
•  Collect
 or
 ensure
 return
 of
 ambulatory
 monitoring
 equipment
  

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8.10. Unscheduled Office Visits 
An
 unscheduled
 visit
 is
 defined
 as
 any
 unplanned
 cardiovascular-related
 office
 visit
 or
 early
 study
 
exit
 at
 the
 study
 site 
that
 occurs
 between
 CIP
 required
 visits.
 
 If
 the
 subject
 exits
 the
 study
 early,
 
the
 site
 should
 attempt
 to
 complete
 an
 unscheduled
 office
 visit.
 
 The
 following
 information
 is
 
required
 to
 be
 collected
 at
 unscheduled
 follow-up
 visits: 
•  Review
 medications
  
•  Adverse
 event
 assessment 
•  Review
 symptoms
 suggestive
 of
 recurrent
 AF/AT/AFL 
•  12-lead
 ECG 
8.11. Holter and Patient Activated Ambulatory ECG Monitor 
Management 
Market-released
 Holters
 will
 be
 distributed
 by
 a
 core
 lab
 to
 sites
 after
 activation
 has
 occurred.
 
 All
 
subjects
 will
 wear
 a
 Holter
 in
 conjunction
 with
 their
 6-
 and
 12-month 
office
 visits.
 
 Holters
 will
 be
 
sent
 back
 to
 the
 core
 lab
 after
 they
 have
 been
 worn
 by
 the
 subject.
 
 The
 core
 lab
 will
 be
 responsible
 
for
 adjudication
 of
 atrial
 arrhythmias
 for
 the
 primary
 objective
 of
 the
 study.
 
 The
 core
 lab
 will
 
manage
 maintenance,
 calibration
 and
 tracking
 of
 the
 Holters.
  
Market-released
 Patient
 Activated
 Ambulatory
 ECG
 Monitors
 will
 be
 distributed
 by
 a
 core
 lab
 to
 
sites
 after
 activation
 has
 occurred.
 
 All
 subjects
 will
 transmit
 weekly
 and
 symptomatic
 ECGs
 
following
 their
 3-month 
office
 visit.
 
 The
 monitors
 will
 be
 returned
 to
 the
 core
 lab
 at
 the
 end
 of
 the
 
study.
 
 The
 core
 lab
 will
 be
 responsible
 for
 adjudication
 of
 atrial
 arrhythmias
 for
 the
 primary
 
effectiveness
 objectives
 of
 the
 study.
 
 The
 core
 lab
 will
 manage
 maintenance,
 calibration
 and
 
tracking
 of
 the
 monitors.
  
8.12. 12-lead Electrocardiograms 
All
 12-lead
 ECGs
 will
 be
 sent
 to
 the
 core
 lab.
 The
 core
 lab
 will
 be
 responsible
 for
 adjudication
 of
 
atrial
 arrhythmias
 for
 the
 primary
 objectives
 of
 the
 study.
 
 Copies
 of
 additional
 source
 documents
 
may
 be
 requested.
  
8.13. Assessment of Safety 
The
 Pilot
 Phase
 safety 
objective
 is
 based
 on
 the
 data
 collected
 as
 discussed
 in
 Sections
 4.1 
and
 
12.1.
 
 
The
 Pivotal
 Phase
 primary
 safety
 objective
 is
 based
 on
 the
 Adverse
 Event
 data
 collected.
 Further
 
information
 on
 the
 collection
 of
 Adverse
 Events
 is
 discussed
 in
 Section 
10.
 

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8.14. Assessment of Effectiveness 
The
 Pilot
 Phase
 effectiveness
 objective
 is
 based
 on
 the
 data
 collected
 as
 discussed
 in
 Sections
 4.1 
and
 12.1.
 
The
 Pivotal
 Phase
 primary
 effectiveness 
objectives
 are
 based
 on
 the
 data
 collected
 as
 discussed
 in
 
Sections
 4.2 
and
 12.2.
 
 
  
 
 
 
 
 
 
8.17. Recording Data 
The
 study
 will
 collect
 data
 using
 an
 electronic
 data
 management
 system
 for
 clinical
 studies.
 Sites
 
will
 enter
 data
 onto
 case 
report
 forms
 (CRFs)
 within
 the
 electronic
 database.
 The
 Holter/Patient
 
Ambulatory
 Monitoring/12-lead
 ECG
 core
 lab
 will
 also
 provide
 data
 in
 the
 electronic
 database. 
 
Data
 reported
 on
 the
 CRFs
 shall
 be
 derived
 from
 source
 documents,
 which
 may
 include,
 but
 is
 not
 
limited
 to, 
worksheets,
 quality
 of
 life
 questionnaires,
 patient
 medical
 records
 and
 ECG
 data.
 These
 
source
 documents
 must
 be
 maintained
 by
 the
 site 
personnel.
 Further
 detail
 on
 data
 management
 
is
 provided
 in
 Section 
14.2.
 
8.18. Deviation Handling 
A
 study
 deviation
 is
 defined
 as
 an
 event 
within
 a
 study
 that
 did
 not
 occur
 according
 to
 the
 CIP
 or
 the
 
Clinical
 Trial
 Agreement.
 Prior
 approval
 by
 Medtronic
 is
 expected
 in
 situations
 where
 the
 
Investigator
 anticipates,
 contemplates,
 or
 makes
 a
 conscious
 decision
 to
 deviate.
 
 Prior
 approval
 
for
 study
 deviations
 will
 be
 reported
 to
 local
 authorities
 and
 ethics
 boards
 per
 local
 requirements.
 
Prior
 approval
 is
 not
 required
 when
 a
 deviation
 is
 necessary
 to
 protect
 the
 safety,
 rights
 or
 well-
being
 of
 a
 subject
 in
 an
 emergency
 or
 in
 unforeseen
 situations
 beyond
 the
 Investigator’s
 control
 
(e.g.
 subject
 failure
 to
 attend
 scheduled
 follow-up
 visits,
 inadvertent
 loss
 of
 data
 due
 to
 computer
 
malfunction,
 inability
 to
 perform
 required
 procedures
 due
 to
 subject
 illness).
  
If 
the
 deviation
 
affects
 subject’s
 rights,
 safety
 and
 well-being,
 or
 the
 scientific
 integrity
 of
 the
 study,
 prior
 approval
 
from
 IRB/REB/MEC
 may
 also
 be
 required,
 depending
 on
 local
 requirement.
 
 Subjects’
 failure
 to
 
submit
 ambulatory
 monitoring
 transmissions
 per
 the
 CIP
 does
 not
 require
 a
 deviation
 to
 be
 

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reported.
 Ambulatory
 monitoring
 transmission
 compliance
 will
 be
 tracked
 by
 Medtronic
 personnel
 
and
 the
 Core
 Lab. 
 
For
 medically
 justifiable
 conditions
 which
 preempt
 a
 subject’s
 ability
 to
 complete
 a
 study-required
 
procedure,
 it
 may
 be
 permitted
 to
 report
 only
 one
 deviation
 which
 will
 apply
 to
 all
 visits
 going
 
forward.
 This
 may
 also
 apply
 for
 other
 unforeseen
 situations
 (e.g.
 the
 subject
 permanently
 refuses
 
to
 complete
 a
 study
 required
 procedure
 and
 the
 data
 will
 not
 contribute
 to
 the
 primary
 endpoint
 
analysis).
 However,
 prior
 approval
 from
 Medtronic
 is
 required
 for
 such
 situations.
 
  
All
 study
 deviations
 must
 be
 reported
 on
 the
 eCRF
 regardless
 of
 whether
 medically
 justifiable,
 pre-
approved
 by
 Medtronic,
 an
 inadvertent
 occurrence,
 or
 taken
 to
 protect
 the
 subject
 in
 an
 
emergency.
 
 The
 deviation
 description
 must
 be
 recorded
 with
 an
 explanation
 for
 the
 deviation. 
In
 the
 event
 the
 deviation
 involves
 a
 failure
 to
 obtain
 a
 subject’s
 consent
 or 
is
 made
 to
 protect
 the
 
life
 or
 physical
 well-being
 of
 a
 subject
 in
 an
 emergency,
 the
 deviation
 must
 be
 reported
 to
 the
 
IRB/REB/MEC
 as
 well
 as
 Medtronic
 within
 five
 (5)
 working
 days,
 or
 earlier
 according
 to
 local
 
requirements. 
 
In
 Japan,
 the
 deviation
 must
 be
 immediately
 reported
 to
 Head
 of
 Medical
 Institute
 
(HOMI),
 to
 the
 Ethics
 Board
 via
 the
 HOMI,
 and
 to
 Medtronic.
 
 Reporting
 of
 all
 other
 study
 deviations
 
should
 comply
 with
 IRB/REB/MEC
 policies,
 local
 laws
 and/or
 regulatory
 agency
 requirements
 and 
must 
be
 reported
 to
 Medtronic
 as
 soon
 as
 possible
 upon
 the
 site 
becoming
 aware
 of
 the
 deviation.
 
 
Refer
 to
 Investigator
 Reports,
 Section 
14.6.2,
 for
 specific
 deviation
 reporting
 requirements
 and
 
timeframes
 for
 reporting
 to
 Medtronic
 and/or
 regulatory
 bodies.
  
 
Medtronic
 is
 responsible
 for
 analyzing
 deviations,
 assessing
 their
 significance,
 and
 identifying
 any 
additional
 corrective
 and/or
 preventive
 actions
 (e.g.
 amend
 the
 CIP,
 conduct
 additional
 training,
 
and
 terminate
 the
 investigation).
 Repetitive
 or
 serious
 Investigator
 compliance
 issues
 may
 result
 in 
initiation
 of
 a
 corrective
 action
 plan
 with
 the
 Investigator
 and
 site,
 and
 in
 some
 cases, 
necessitate
 suspending
 enrollment
 until
 the
 problem
 is
 resolved
 or
 ultimately
 terminating
 the 
Investigator's
 participation
 in
 the
 study.
 Medtronic
 will
 provide
 site-specific
 reports
 to 
Investigators
 summarizing
 information
 on
 deviations
 that
 occurred
 at
 the
 investigational
 site 
on 
a
 periodic
 basis. 
 
 

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8.19. Subject Withdrawal or Discontinuation (Subject Exit) 
A
 subject
 can
 exit
 from
 the
 study
 at
 any
 time 
and
 is
 not
 obliged
 to
 provide
 a
 reason.
 If
 the
 subject
 
wishes
 to
 exit
 early
 from
 the
 study,
 the
 site 
is
 required
 to
 document
 the
 reason,
 if
 available,
 for
 exit
 
on
 an
 eCRF
 and
 in
 the
 subject’s
 medical
 record.
 In
 addition,
 sites
 shall
 follow
 the
 regulations 
set
 
forth
 by
 their
 IRB/REB/MEC.
 It
 is
 recommended
 that
 Investigators
 follow
 the
 subject
 until
 all
 device
 
and/or
 procedure-related
 adverse
 events
 are
 recovered
 /
 resolved.
 For
 countries
 following
 ISO 
14155:2011,
 permission
 may
 be
 requested
 to
 follow-up
 with
 the
 subject
 outside
 of
 the
 study
 based
 
on
 problems
 related
 to
 the
 study
 device
 safety
 or
 performance.
 Following
 completion
 of
 the
 12-
month
 visit
 or
 early
 study
 exit,
 subjects
 will
 continue
 to
 receive
 standard
 medical
 care.
 All
 data
 
available
 through
 the
 time
 of
 the
 subject’s
 exit
 will
 be
 available 
for
 analysis. 
 
Potential
 reasons
 for
 early
 study
 exit
 include: 
•  Subject
 lost
 to
 follow-up 
•  Subject
 did
 not
 meet
 inclusion/exclusion
 criteria
 after
 consent
 and
 did
 not
 undergo
 an 
ablation
 procedure 
•  The
 PFA
 system
 was
 not
 used
 during
 the
 subject’s
 ablation
 procedure 
•  Subject
 did
 not
 provide
 proper
 consent
 or
 data
 use
 protection
 authorization 
•  Subject
 chooses
 to
 withdraw
 (e.g.,
 consent
 withdrawal,
 relocation
 to
 another
 geographic 
location) 
•  Investigator
 deems
 withdrawal
 necessary
 (e.g.,
 medically
 justified,
 failure
 of
 subject
 to
 
maintain
 adequate
 study
 compliance) 
•  The
 sponsor
 decides
 the
 study
 will
 be
 closed
 or
 a
 particular
 site 
will
 be
 closed 
 
In
 the
 case
 that
 the
 subject
 is
 determined
 to
 be
 lost
 to
 follow-up,
 details
 of
 a
 minimum
 of
 two 
attempts
 and
 the
 method
 of
 attempt
 (e.g.,
 one
 letter
 and
 one
 phone
 record
 or
 two
 letters)
 to 
contact
 the
 subject
 must
 be
 recorded. 
 
An
 unscheduled
 office
 visit
 should
 be
 attempted
 if
 the
 subject
 exits
 the
 study
 outside
 of
 a
 
scheduled
 follow-up
 visit.
 Subjects
 treated
 with
 the
 PFA
 system
 who
 exit
 from
 the
 study
 should
 
continue
 to
 be
 followed
 by
 an
 electrophysiologist
 for
 follow-up
 of
 any
 potential
 adverse
 events
 at
 
the
 recommended
 interval
 of
 12
 months
 from
 the
 index
 PFA
 system
 ablation
 procedure. 
 
 

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i
 Per
 PULSED
 AF
 clinical
 study
 protocol
 in
 the
 interest
 of
 prioritizing
 patient
 care,
 in
 the
 event
 of
 an
 
inability
 to
 electrically
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 with
 the
 PFA
 system,
 any
 
commercially
 released
 catheter
 deemed
 appropriate
 for
 the
 procedure
 may
 be
 used
 to
 complete
 
the
 ablation
 procedure. 
9.3. Potential Adverse Events from Risk Assessment  
 
The
 current
 PFA
 system
 IFU
 should
 be
 referenced
 as
 the
 list
 below
 may
 be
 updated
 during
 the
 
course
 of
 the
 study.
 Possible
 additional
 risks
 for
 participating
 in
 the
 study
 include
 the
 following
 
(although
 others
 are
 possible)
 and
 are
 further 
defined 
in 
Appendix
 C:
 
 
•  Access
 site
 complications
 (e.g.
 bruising,
 ecchymosis,
 AV
 fistula,
 hematoma,
 
pseudoaneurysm) 
•  Allergic
 reaction
 to
 x-ray
 contrast
 media 
•  Anesthesia
 reactions 
•  Anemia 
•  Arrhythmias,
 proarrhythmia
 (e.g.
 atrial
 flutter,
 bradycardia,
 heart
 block,
 tachycardia) 
•  Back
 pain 
•  Bleeding,
 possibly
 requiring
 transfusion 
•  Body
 temperature
 elevation 
•  Cardiac
 perforation
 of
 the
 heart
 or
 other
 organs
 during
 transseptal
 puncture
 or
 other
 
procedures 
•  Cardiac
 tamponade 
•  Chest
 discomfort 
•  Cough 
•  Embolism 
•  Catheter
 entrapment
 in
 cardiac
 structures
 requiring
 intervention 
 
•  Cerebrovascular
 accident
 (CVA) 
•  Transient
 ischemic
 attack
 (TIA) 
•  Collateral
 damage
 to
 the
 conduction
 system
 or
 coronary
 vasculature 
•  Death 
•  Esophageal 
damage
 (including
 atrial
 esophageal
 fistula) 
•  Hemoptysis 
•  Hypotension/
 hypertension 
•  Infections 
•  Myocardial
 infarction
 or
 ischemia 
•  Nerve
 injury
 or
 nerve
 damage
 (e.g.
 phrenic
 nerve
 injury) 
•  Obstruction,
 perforation,
 damage,
 or
 spasm
 of
 the
 vascular
 system
 including
 the
 coronary
 
circulation
 system 
•  Pericarditis
 or
 endocarditis 
•  Pleural
 effusion
  
•  Pericardial
 effusion 
•  Pneumonia 

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•  Pneumothorax 
•  Pulmonary
 vein
 stenosis 
•  Radiation
 injury
 or
 damage
 and
 late
 malignancy 
•  Respiratory
 depression 
•  Sore
 throat 
•  Unintended
 complete
 or
 incomplete
 atrioventricular
 node
 (AV-Node)
 or
 sinus
 node
 block
 or
 
damage 
•  Valvular
 insufficiency
 or
 damage 
•  Vasovagal
 reaction 
 
There
 are
 additional
 potential
 risks
 to
 the
 patient
 that
 are
 outside
 of
 the
 ablation
 procedure.
 
These
 are
 due
 to
 PULSED
 AF
 clinical
 study
 requirements
 and
 are
 not
 related
 to
 the
 PFA 
procedure
 or
 the
 PFA
 system.
 Potential
 additional
 risks
 identified
 for
 participation
 in
 this
 study
 
include:
 
•  Claustrophobia
 (sense
 of
 anxiety
 in
 small
 areas)
 related
 to
 an
 MRI
 scan
  
•  Skin
 discomfort
 or
 irritation
 related
 to
 the
 Holter
 recorder 
•  Exposure
 to
 radiation
 or
 allergic
 reaction
 to
 the
 contrast
 dye
 related
 to
 a
 CT
 scan
  
9.4. Potential Benefits 
The
 PFA
 system
 utilizes
 a
 novel
 energy
 source
 that
 may
 increase
 efficacy
 through
 field-based
 
ablation
 without
 the
 dependency
 on
 tissue
 contact,
 which
 is
 expected
 to
 lead
 to
 higher
 clinical
 
success
 by
 effectively
 treating
 patients
 with
 AF.
 PFA
 has
 the
 potential
 to
 create 
contiguous
 lesions
 
in
 highly
 trabeculated
 anatomical
 locations
 with
 varying
 tissue
 thickness
 or
 blood
 flow
 conditions
 
that
 limit
 the
 effectiveness
 of
 thermal
 ablation
 technologies.
 PFA
 requires
 the
 catheter
 to
 be
 in
 
close
 proximity
 to
 the
 target
 locations,
 but
 not
 in
 contact
 with
 tissue.
  
PFA
 potentially
 increases
 the
 safety
 of
 catheter
 ablation
 for
 AF
 through
 applying
 a
 refined
 
waveform
 with
 parameters
 (e.g.
 pulse
 width,
 number
 of
 pulses,
 voltage
 amplitude)
 that
 result
 in
 
selective
 ablation
 of
 myocardial
 tissue.
 This
 could
 reduce
 collateral
 damage
 to
 extracardiac
 tissues
 
such
 as
 the
 phrenic
 nerve,
 vagus
 nerve,
 and
 smooth
 muscle. 
The
 safety
 profile
 of
 the
 Medtronic
 PFA
 delivery
 may
 also
 be
 improved
 over
 other
 commercially
 
available
 ablation
 energy
 sources
 due
 to
 the
 bipolar
 energy
 delivery
 method
 through
 the
 multi-
electrode
 array
 catheter
 that
 minimizes
 exposure
 of
 extracardiac
 tissue
 to
 the
 electric
 field
 
compared
 to
 unipolar
 energy. 
PFA
 also
 potentially
 improves
 safety
 due
 to
 its
 non-thermal
 field-based
 ablation
 approach.
 
Operators
 using
 currently
 available
 technology
 must
 be
 careful
 to
 balance
 optimal
 contact
 force
 
required
 for
 transmural
 lesion
 formation
 with
 potential
 adverse
 events
 associated
 with
 thermal
 

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mechanisms
 of
 catheter
 ablation.
 Overall,
 the
 potential
 improvement
 in
 the
 safety
 profile
 of
 PFA
 is
 
due
 to
 the
 refined
 waveform,
 bipolar
 delivery,
 and
 non-thermal
 field-based
 approach
 which
 may
 
reduce
 collateral
 damage. 
PFA
 delivery
 is
 performed
 within
 milliseconds
 and
 is
 predicted
 to
 achieve
 pulmonary
 vein
 isolation
 
in
 approximately
 1
 minute.
 PFA
 may
 reduce
 both
 time
 to
 isolation
 and
 overall
 procedure
 time
 
compared
 to
 standard
 of
 care
 ablation
 procedures
 that
 take
 up
 to
 10
 minutes
 and
 in
 some
 cases
 
more
 than
 10
 minutes,
 to
 isolate
 each
 pulmonary
 vein23.
 The
 efficiency
 of
 PFA
 energy
 delivery
 is
 
potentially
 increased
 in
 comparison
 to
 existing
 ablation
 technologies. 
Ablation
 with
 the
 PFA
 system
 may
 reduce
 or
 eliminate
 atrial
 fibrillation
 in
 subjects;
 however,
 some
 
subjects
 may
 not
 receive
 this
 benefit.
 Clinical
 benefit
 has
 not
 been
 demonstrated
 as
 this
 study
 is
 
the
 first
 in
 human
 use
 of
 the
 PFA
 system.
 The
 information
 gained
 from
 the
 study
 could
 result
 in
 
improved
 management
 of
 atrial
 fibrillation. 
9.5. Risk-Benefit Rationale 
PFA
 therapy 
offers
 the
 opportunity
 to
 reduce
 the
 episodes
 of
 atrial
 fibrillation
 and
 therefore
 reduce
 
the
 subject’s
 risk
 of
 stroke
 and
 symptoms.
 Results
 of
 the
 PULSED
 AF
 study
 are
 expected
 to
 be
 
used
 to
 guide
 subsequent
 product
 development
 activities
 for
 the
 PFA
 system.
  
 
The
 PFA
 system
 has
 been
 examined
 and
 tested
 via
 modeling,
 bench,
 and
 preclinical
 animal
 testing
 
and
 the
 residual
 risks
 associated
 with
 the
 PFA
 system
 have
 been
 found
 to
 be
 acceptable.
 These
 
residual
 risks
 have
 been
 mitigated
 to
 the
 fullest
 extent
 possible
 through
 design,
 manufacturing,
 
labeling
 and
 training.
 The
 potential
 benefits
 related
 to
 the
 use
 of
 the
 PFA
 system
 have
 been
 
determined
 to
 outweigh
 any
 potential
 risks 
and
 justify
 this
 investigation.
  
 
 
 
 
                                                           
 
23 
Attanasio, P. et al. Pain Reactions during Pulmonary Vein Isolation under Deep Sedation: Cryothermal versus 
Radiofrequency
 Ablation.
 Pacing
 and
 clinical
 electrophysiology:
 PACE
 39,
 452-457,
 doi:10.1111/pace.12840
 (2016). 

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10. Adverse Events and Device Deficiencies 
Timely,
 accurate,
 and
 complete
 reporting
 and
 analysis
 of
 safety
 information
 for
 clinical
 studies
 are
 
crucial
 for
 the
 protection
 of
 subjects.
 
 Reporting
 and
 analysis
 of
 safety
 data
 are
 mandated
 by
 
regulatory
 authorities
 worldwide.
 Medtronic
 has 
established
 procedures
 in
 conformity
 with
 
worldwide
 regulatory
 requirements
 to
 ensure
 appropriate
 reporting
 of
 safety
 information.
 
 The
 
study
 is
 conducted
 in
 accordance
 with
 these
 procedures
 and
 regulations. 
Since
 the
 safety
 reporting
 requirements
 and
 classification
 systems
 vary
 for
 each
 regulatory
 
agency,
 requirements
 from
 all
 geographies
 are
 taken
 into
 account
 for
 the
 collection
 and
 reporting
 
of
 safety
 information.
  
10.1. Adverse Event Assessment  
For
 the
 purposes
 of
 the
 study,
 all 
Adverse
 Events
 will
 be
 collected
 starting
 at
 the
 time
 of
 signing
 the
 
IC
 Form
 through
 the
 duration
 of
 the
 subject’s
 participation
 in
 the
 study. 
10.2. Device Deficiencies Assessment 
Device
 deficiency
 (DD)
 information
 will
 be
 collected
 throughout
 the
 study
 and
 reported
 to
 
Medtronic,
 as
 per
 Table 12.
 A
 Medtronic
 representative
 will
 review
 the
 device
 deficiency
 for
 
completeness
 and
 accuracy
 and
 when
 necessary
 will
 request
 clarification
 and/or
 additional
 
information
 from
 the
 Investigator.
 Note
 that
 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.
 
 For
 device
 deficiencies
 that
 
require
 immediate
 reporting,
 initial
 reporting
 may
 be
 done
 by
 contacting
 the
 study
 sponsor
 per
 the
 
sponsor
 contact
 information.
  
 
10.3. Definitions/Classifications 
Where
 the
 definition
 indicates
 “device”,
 it
 refers
 to
 any
 device
 used
 in
 the
 study.
 This
 might
 be
 any
 
component
 of
 the
 system
 under
 investigation,
 or
 any
 market-released
 component 
or
 accessory
 of
 
the
 system.
 Adverse
 events
 (AE)
 will
 be
 classified
 according
 to
 the
 definitions
 below. 

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System
 related 
An
 Adverse
 Event
 that
 results
 from
 the
 presence
 or
 
performance
 (intended
 or
 otherwise)
 of
 the
 PFA
 system
 
(including
 the
 PFA
 Generator,
 Catheter
 Electrode
 
Distribution
 System
 (CEDS),
 Remote
 Control,
 Cable-
Generator
 to
 Remote
 Control,
 Cable-Generator
 to
 CEDS,
 
Cable-CEDS
 to
 EP
 Recording
 System,
 Cable-Catheter
 to
 
CEDS,
 
 catheter,
 Cardiac
 Trigger
 Monitor
 and
 
Cable,
 Uninterruptible
 Power
 Supply,
 Power
 Cord)
 or
 any
 
other
 device
 used
 during
 the
 procedure. 
 
NOTE:
 Only
 those
 Adverse
 Events
 that
 result
 from
 the
 
presence
 or
 performance
 (intended
 or
 otherwise)
 of
 the
 PFA
 
system 
will
 be
 considered
 as
 PFA
 system
 related. 
Not
 related 
Relationship
 to
 the
 device
 or
 procedures
 can
 be
 excluded
 
when: 
•  The
 event
 is
 not
 a
 known
 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
 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
 of
 medical
 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
 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); 
•  The
 event
 does
 not
 depend
 on
 a
 false
 result
 given
 by
 
the
 device
 used
 for
 diagnosis
 (when
 applicable); 
•  Harms
 to
 the
 subject
 are
 not
 clearly
 due
 to
 use
 error; 
•  In
 order
 to
 establish
 the
 non-relatedness,
 not
 all
 the
 
criteria
 listed
 above
 might
 be
 met
 at
 the
 same
 time,
 
depending
 on
 the
 type
 of
 device/procedures
 and
 the
 
event. 

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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
 were
 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
 reasonably
 be
 
explained
 by
 another
 cause,
 but
 additional
 information
 may
 
be
 obtained. 
Causal
 Relationship 
The
 event
 is
 associated
 with
 the
 device
 or
 study
 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
 device
 
use/application
 or
 procedures; 
•  The
 event
 involves
 a
 body-site
 or
 organ
 that
 the
 
device
 or
 procedures
 are
 applied
 to
 or
 the
 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
 
device
 used
 for
 diagnosis
 (when
 applicable); 
•  In
 order
 to
 establish
 the
 relatedness,
 not
 all
 the
 
criteria
 listed
 above
 might
 be
 met
 at
 the
 same
 time,
 
depending
 on
 the
 type
 of
 device/procedures
 and
 the
 
serious
 event. 

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Medtronic Controlled Information
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056-F275, v A Clinical Investigation Plan Template 
10.4.1.  Subject Death 
All
 subject
 deaths
 must
 be
 reported
 by
 the
 Investigator
 to
 Medtronic
 on
 an
 adverse
 event
 eCRF
 (AE
 
with
 outcome
 of
 fatal)
 as
 soon
 as
 possible
 after
 the
 Investigator
 first
 learns
 of
 the
 death.
 
 There
 
should
 be
 one
 SAE
 with
 the
 outcome
 of
 fatal.
  
A
 de-identified
 copy
 of
 the
 death
 certificate,
 if
 available
 and
 allowed
 by
 state/local
 law,
 should
 be
 
sent
 to
 the
 Medtronic
 clinical
 study
 team.
 When
 a
 death
 occurs
 in
 a
 hospital,
 a
 copy
 of
 the
 death
 
summary
 report
 and
 all
 relevant
 hospital
 records
 should
 be
 sent
 to
 Medtronic,
 if
 available.
 If
 an
 
autopsy
 is
 conducted,
 the
 autopsy
 report
 should
 also
 be
 sent
 to
 Medtronic
 if
 available
 and
 allowed
 
by
 state/local
 law.
 When
 the
 death
 occurs
 at
 a
 remote
 site,
 it
 is
 the
 investigative
 site’s
 
responsibility
 to
 attempt
 retrieval
 of
 information
 about
 the
 death.
 In
 summary,
 the
 following
 data
 
will
 be
 collected: 
•  Date
 of
 death 
•  Detailed
 description
 of
 death 
•  Cause
 of
 death
  
•  Relatedness
 to
 system 
and/or
 procedure 
•  Death
 summary/hospital
 records
 (if
 available
 and
 allowed
 by
 state/local
 law)
 
•  Autopsy
 report
 (if
 available
 and
 allowed
 by
 state/local
 law) 
•  Death
 certificate
 (if
 available
 and/or
 allowed
 by
 state/local
 law) 
 
Sufficient 
information
 will
 be
 required
 in
 order
 to
 properly
 classify
 the
 subject’s
 death.
 The
 
Investigator
 shall
 classify
 each
 subject
 death
 per
 the
 following
 definitions: 
•  Cardiac
 Death:
 A
 death
 directly
 related
 to
 the
 electrical
 or
 mechanical
 dysfunction
 of
 the
 
heart. 
•  Sudden
 Cardiac
 Death
 (SCD): 
Natural
 death
 due
 to
 cardiac
 causes,
 indicated
 by
 abrupt
 loss
 
of
 consciousness
 within
 one
 hour
 of
 the
 onset
 of
 acute
 symptoms;
 preexisting
 heart
 
disease
 may
 have
 been
 known
 to
 be
 present,
 but
 the
 time
 and
 mode
 of
 death
 are
 
unexpected.
 If
 time
 of
 onset
 cannot
 be
 determined,
 SCD
 will
 alternatively
 be
 defined
 as
 any
 
unexpected
 cardiac
 death
 occurring
 out
 of
 the
 hospital
 or
 in
 the
 emergency
 room
 as
 dead
 
on
 arrival. 
•  Non-sudden
 Cardiac
 Death:
 All
 cardiac
 deaths
 that
 are
 not
 classified
 as
 sudden
 deaths,
 
including
 all
 cardiac
 deaths
 of
 hospitalized
 subjects
 on
 inotropic
 support. 
•  Non-cardiac
 Death:
 A
 death
 not
 classified
 as
 a
 cardiac
 death. 
•  Unknown
 Classification:
 Unknown
 death
 classification
 is
 intended
 for
 use
 only
 when
 there
 is
 
insufficient
 or
 inadequate
 information
 to
 classify
 the
 death.
 
  
 
The
 CEC
 will
 review
 all
 deaths
 and
 provide
 an
 adjudication
 of
 the
 primary
 cause
 of
 death
 and
 death 
classification.
 Regulatory
 reporting
 of
 Subject
 Deaths
 will
 be
 completed
 according
 to
 local
 
regulatory
 requirements. 

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10.4.2.  Adverse Event Reporting Requirements 
Regulatory
 reporting 
of
 AEs
 will
 be
 completed
 according
 to
 local
 regulatory
 requirements.
 Refer
 to 
Table 12 
for
 a 
list
 of
 required
 investigator 
reporting
 requirements
 and
 timeframes,
 and
 of
 required
 
Medtronic
 reporting
 requirements
 and
 timeframes. 
The
 investigator
 is
 required
 to
 report
 all
 SAEs
 to
 Medtronic
 immediately,
 and
 to
 the
 Ethics
 
Committee 
per
 local
 requirements.
 It
 is
 the
 responsibility
 of
 the
 investigator
 to
 abide
 by
 any
 
additional
 AE
 reporting
 requirements
 stipulated
 by
 the
 Ethics
 Committee 
responsible
 for
 oversight
 
of
 the
 study.
 Additionally,
 Medtronic
 is
 required
 to
 report
 these
 events
 to
 the
 local
 regulatory
 
authority
 based
 on
 their
 requirements.
 In
 the
 case
 that
 the
 AE
 is
 related
 to
 a
 market-released
 
device
 used
 during
 the
 study,
 post
 market
 surveillance
 is
 also
 applicable
 and
 the
 Investigator
 is
 
responsible
 for
 immediate
 reporting
 of
 the
 product
 complaint
 via
 the
 regular
 channels
 for
 market-
released
 products. 
For
 AEs
 that
 require
 immediate
 reporting,
 initial
 reporting
 may
 be
 done
 by
 contacting
 the
 study
 
sponsor
 per
 the
 sponsor
 contact
 information
 provided
 in
 this
 document. 
 
 

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It
 is
 the
 responsibility
 of
 the
 Investigator
 to
 report
 all
 product
 complaint(s)
 associated
 with
 a
 
medical
 device
 distributed
 by
 Medtronic,
 regardless
 whether
 they
 are
 related
 to
 intended
 use,
 
misuse
 or
 abuse
 of
 the
 product.
 Reporting
 must
 be
 done
 immediately
 and
 via
 the
 regular
 channels
 
for
 market-released
 products. 
Medtronic
 will
 notify
 the
 regulatory
 authorities
 (e.g.
 FDA)
 as
 applicable
 for
 the
 following
 incidents
 
immediately
 upon
 learning
 of
 them: 
•  Any
 malfunction
 or
 deterioration
 in
 the
 characteristics
 and/or
 performance
 of
 a
 device,
 as
 
well
 as
 any
 inadequacy
 in
 the
 labeling
 or
 instructions
 for
 use
 which
 led
 or
 might
 have
 led
 to
 
the
 death
 or
 serious
 deterioration
 in
 the
 state
 of
 health
 of
 a
 patient,
 user,
 or
 other
 person. 
•  Any
 technical
 or
 medical
 reason
 resulting
 in
 withdrawal
 of
 a
 device
 from
 the
 market
 by
 the
 
manufacturer. 
•  A
 serious
 deterioration
 in
 the
 state
 of
 heath
 includes: 
o Life-threatening
 illness
 or
 injury 
o Permanent
 impairment
 of
 a
 body
 function
 or
 permanent
 damage
 to
 a
 body
 
structure 
o A
 condition
 necessitating
 medical
 or
 surgical
 intervention
 to
 prevent
 permanent
 
impairment
 of
 a
 body
 function
 or
 permanent
 damage
 to
 a
 body
 structure 
 
 

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056-F275, v A Clinical Investigation Plan Template 
11. Data Review Committees  
11.1. Data Monitoring Committee (DMC) 
Study
 Oversight
  
Ongoing
 oversight
 for
 this
 study
 will
 be
 provided
 by
 an
 independent
 Data
 Monitoring 
Committee. 
Who
 will
 be 
involved 
The
 DMC
 will
 have
 one
 statistician
 with
 experience
 in
 the
 evaluation
 of
 clinical
 trials 
and
 at
 least
 two
 
physicians 
that
 are
 not
 participating
 Investigators
 for
 the
 study.
 A 
chairperson
 from
 among
 those
 
members
 will
 be
 identified. 
 
Responsibility
 of 
the
 DMC 
The
 DMC
 will
 be
 responsible
 for
 assessing
 the
 accumulating
 data
 on
 safety
 of
 the 
therapy
 during
 
the
 study.
 The
 DMC
 will
 be
 responsible
 for
 safeguarding
 the
 interests 
of
 study
 subjects,
 assessing
 
the
 safety
 of
 the
 PFA 
system
 during
 the
 study,
 and
 for 
monitoring
 the
 overall
 conduct
 of
 the
 clinical
 
study.
 To
 enhance
 the
 integrity
 of
 the 
study,
 the
 DMC
 may
 also
 formulate 
recommendations
 
related
 to
 the
 selection, 
recruitment,
 and
 retention
 of
 subjects,
 their
 management,
 improvement
 
of
 adherence
 to 
protocol-specified
 regimens
 and
 procedures
 for
 data
 management
 and
 quality
 
control. 
 
 
 
 
Recommendations
 
 
The
 DMC
 will
 be
 advisory
 to
 the
 sponsor.
 The
 DMC
 may
 provide
 recommendations
 for 
early
 
termination
 of
 the
 study.
 Review
 and
 consensus
 by
 the
 entire
 committee
 is 
required
 to
 
recommend
 that
 the
 study
 should
 be
 stopped. 
The
 DMC
 may
 also
 make
 recommendations
 related
 
to 
the
 selection,
 management
 and 
retention
 of
 subjects,
 improvement
 of
 adherence
 to
 protocol-
specified
 regimens,
 and 
procedures
 for
 data
 management
 and
 quality
 control. 
DMC
 Meetings 
All
 DMC
 meetings
 may
 be
 conducted
 either
 in
 person
 or
 by
 teleconference.
 
 There
 will
 be
 an
 initial
 
meeting
 prior
 to
 the
 start
 of
 the
 Pivotal
 Phase
 of
 the
 study.
 
 Additionally,
 the
 DMC
 will
 meet
 
approximately
 every
 6
 months
 to
 review
 study
 data.
 
 The
 first
 meeting
 must
 be
 within
 6
 months
 of
 
the
 first
 enrollment
 in
 the
 Pivotal
 Phase 
of
 the
 study.
 
 Reports
 will
 consist
 of
 data
 on
 study
 conduct
 
and
 aggregate
 adverse
 events
 review.
 
 Once 
the
 study
 follow-up
 is
 completed,
 the
 DMC
 will
 be
 
disbanded,
 with
 no
 need
 to
 review
 final
 results
 of
 the
 study. 

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11.2. Clinical Events Committee (CEC) 
An
 independent
 Clinical
 Events
 Committee
 (CEC)
 will
 review
 and
 adjudicate,
 at
 a
 minimum, 
all
 
procedure-
 and
 system-related
 adverse
 events, 
as
 well
 as
 all
 adverse
 events
 resulting
 in
 death.
 
  
 
The
 CEC
 will
 consist
 of
 a
 minimum
 of
 three
 (3)
 non-Medtronic
 employed
 physicians
 that
 are
 not
 
participating
 Investigators
 for
 the
 study,
 including
 a
 CEC
 chairperson.
  
Medtronic
 personnel
 may
 facilitate
 and
 participate
 in
 a
 CEC
 meeting
 but
 will
 be
 non-voting
 
members.
 
For
 adverse
 events
 and
 deaths
 reviewed
 by
 the
 CEC,
 Medtronic
 will
 provide
 the
 CEC
 with
 the
 
Investigator’s
 description
 and
 classification.
 The
 CEC
 is
 responsible
 for
 reviewing
 the
 
Investigator’s
 assessment
 and
 supportive
 documentation
 (when
 available),
 reviewing
 applicable
 
definitions,
 and
 determining
 final
 classifications
 for
 all
 adjudication
 parameters.
 Additionally,
 the
 
CEC
 will
 provide
 an
 adjudication
 of
 the
 death
 classification
 for
 all
 reported
 deaths
 including
 primary
 
cause
 of
 death
 and
 death
 classification. 
If
 the
 CEC
 disagrees
 with
 the
 Investigator’s
 classification
 of
 the
 event,
 the
 difference 
will
 be
 
provided
 to
 the
 Investigator.
 If
 the
 Investigator
 agrees
 with
 the
 CEC’s
 adjudication,
 the
 eCRF
 
documenting
 the
 event
 will
 be
 updated
 accordingly. 
If
 the
 Investigator
 does
 not
 agree
 with
 the
 CEC’s
 adjudication
 classification,
 both
 determinations
 
will
 be
 provided
 within
 the
 final
 report;
 however,
 the
 CEC’s
 adjudication
 will
 be
 used
 for
 data
 
analysis.
 The
 disagreement
 will
 also
 be
 included
 in
 reporting
 to
 IRB/REB/MECs
 and
 regulatory
 
authorities,
 if
 required. 
 
 

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12. Statistical Design and Methods 
This
 section
 includes
 a
 description
 of
 the
 statistical
 methods
 and
 analyses
 to
 be
 included 
in
 reports
 
that
 include
 analysis
 of
 endpoints.
 Any
 change
 to
 the
 data
 analysis
 methods
 described
 in
 the 
CIP
 
will
 require
 an
 amendment
 to
 the
 CIP
 only
 if
 it
 changes
 a
 principal
 feature
 of
 the
 CIP.
 Any
 other 
change
 to
 the
 data
 analysis
 methods
 described
 in
 the
 CIP,
 and
 the
 justification
 for
 making
 the
 
change, 
will
 be
 described
 in
 the
 clinical
 study
 report. 
 
Standard
 baseline
 and
 relevant
 medical
 history
 will
 be
 collected
 on
 the
 CRFs
 for
 all
 enrolled
 
subjects.
 Baseline
 variables
 to
 be
 summarized
 include,
 but
 are
 not
 limited
 to:
 age,
 sex,
 race 
(if
 
allowed
 by
 local
 law),
 and
 physical
 exam
 findings.
 
 
Additional
 exploratory
 analyses
 of
 the
 data
 may
 be
 conducted
 as
 deemed
 appropriate.  
 
Each
 arm
 (paroxysmal
 AF
 and
 persistent
 AF)
 of
 the
 Pivotal
 Phase
 of
 this
 study
 contains
 the
 
following
 cohorts,
 with
 each
 enrolled
 subject
 belonging
 to
 one-and-only-one
 of
 the
 cohorts:
 
•  Non-treated
 Cohort
 –
 Subjects
 enrolled
 in
 the
 study
 who
 exit
 prior
 to
 having 
the
 PFA
 
system
 multielectrode
 catheter
 inserted
 into
 vasculature.
 
•  Roll-in
 Cohort
 –
 roll-in
 subjects
 are
 defined
 in
 Section
 7.2.1.
 
•  Primary
 Analysis
 Cohort
 –
 Treated
 (those
 who
 have
 the
 PFA
 system
 multielectrode
 
catheter
 inserted
 into
 vasculature)
 subjects
 who
 are
 not
 part
 of
 the
 Roll-in
 Cohort. 
 
 
There
 is
 no
 intention
 to
 pool
 data
 from
 the
 Pilot
 Phase
 and
 the
 3
 Pivotal
 Phase
 cohorts. 
 
All
 will
 be
 
analyzed
 separately. 
 
 

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Analysis
 Methods 
The
 percentage
 of
 procedures 
with
 a
 PFA
 system-related
 or
 PFA 
procedure-related
 SAE
 will
 be
 
calculated
 as 
the
 number
 of
 procedures
 with
 at
 least
 one
 SAE
 meeting
 the
 endpoint
 definition 
divided
 by
 the 
number
 of
 PFA
 system
 ablation 
procedures.
 Each
 procedure
 will
 count,
 so
 subjects 
with
 repeat 
PFA
 system
 ablations
 will
 contribute
 more
 than
 once
 to
 the
 denominator.
 Exact
 
methods
 will
 be
 used
 to
 construct
 a
 95%
 confidence
 interval
 for
 the
 percentage
 of
 procedures
 with 
an
 SAE
 meeting
 the
 endpoint
 definition. 
 
Determination
 of
 Subjects/Data
 for
 Analysis 
All
 procedures
 in
 Pilot
 Phase 
subjects
 where
 the
 PFA
 system
 multielectrode
 catheter 
is 
inserted
 
into
 vasculature
 will
 be
 included.
  
 
 

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056-F275, v A Clinical Investigation Plan Template 
12.1.2.  Pilot Phase Effectiveness Objective 
Assess
 the
 acute
 procedural
 success
 of
 PVI
 ablation
 with
 the
 PFA
 system. 
Endpoint
 Definition 
Acute
 procedural
 failure
 is
 defined
 as: 
 
a. Inability
 to 
isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (assessed
 for
 entrance
 
block
 and,
 where
 assessable,
 exit
 block)
 during
 the
 index
 ablation
 procedure.
  
b. Ablation
 using 
a
 non-study
 device
 to
 isolate
 any
 pulmonary
 vein.
  
 
Acute
 procedural
 success
 is
 the
 opposite
 of
 acute
 procedural
 failure. 
 
Analysis
 Methods 
The 
percentage
 of
 procedures 
with
 acute
 procedural
 success
 will
 be
 calculated
 as 
the
 number
 of
 
procedures
 meeting
 the
 endpoint
 definition
 of
 acute
 procedural 
success
 divided
 by
 the 
number
 of
 
PFA
 system
 ablation 
procedures.
 Each
 procedure
 will
 count,
 so
 subjects
 with
 repeat 
PFA
 system
 
ablations
 will
 contribute
 more
 than
 once
 to
 the
 denominator.
 Exact
 methods
 will
 be
 used
 to
 
construct
 a
 95%
 confidence
 interval
 for
 the
 percentage
 of
 procedures
 with
 acute
 procedural
 
success.
 
 
Additionally,
 acute
 success
 at
 the
 pulmonary
 vein
 level
 will
 be
 calculated.
 
 Each 
accessible
 targeted
 
pulmonary
 vein
 will
 be
 classified
 as
 acute
 success
 or
 not.
 The
 percentage
 of
 total
 pulmonary
 veins
 
attempted
 with
 the
 PFA
 system 
will
 be
 calculated.
 
 Exact
 methods
 will
 be
 used
 to
 construct
 a
 95%
 
confidence
 interval. 
Determination
 of
 Subjects/Data
 for
 Analysis 
All
 procedures
 in
 Pilot
 Phase 
subjects
 where
 the
 PFA
 system
 multielectrode
 catheter 
is 
inserted
 
into
 vasculature
 will
 be
 included.
 
 
 
 
 

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12.2. Pivotal Phase 
12.2.1.  Planned Analyses 
The paroxysmal and persistent arms will be analyzed separately.  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 a
ll
 subjects
 
will
 be
 followed
 for
 12
 months,
 and
 a
 final
 report
 will
 be
 prepared
 for
 each
 arm. 
Unless
 specified,
 the
 objectives
 are
 identical
 for
 the
 paroxysmal
 and
 persistent
 arms
 of
 the
 study. 
Primary
 objective
 results
 by
 age,
 sex,
 race,
 and
 site
 will
 be
 provided
 in
 the
 final
 report.
  
 
 

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12.2.2.  Primary Safety Objective 
Demonstrate
 an
 acceptable
 safety
 profile
 of
 PVI
 ablation
 with
 the
 PFA
 system. 
Hypothesis
  
The
 following
 hypothesis
 will
 be
 tested
 in
 a
 one-sided
 test:
  
Ho:
 PS
 ≥
 13%
  
Ha:
 PS
 <
 13%
  
Where
 PS
 is
 the
 probability
 of
 a
 safety
 event
 through
 6
 months. 
 
Endpoint
 Definition
  
The
 primary
 safety
 endpoint
 definition,
 as
 follows,
 is
 identical
 for
 each
 arm
 (paroxysmal
 AF
 and
 
persistent
 AF)
 of
 the
 Pivotal
 Phase.
 
 
The
 following
 PFA
 system-related
 and
 ablation
 PFA
 procedure-related
 serious 
adverse
 events
 
(SAEs),
 as
 adjudicated
 by
 the
 Clinical
 Events
 Committee
 (CEC),
 will
 be
 considered
 a
 primary
 safety
 
event:
 
Within
 6
 months
 post-ablation: 
•  Pulmonary
 vein
 stenosis
 (>70%
 diameter
 reduction) 
•  Phrenic
 nerve
 injury/diaphragmatic
 paralysis
 (ongoing
 at
 6
 months) 
•  Atrioesophageal
 fistula
  
 
Within
 30 
days
 of
 ablation
 procedure: 
•  Cardiac
 tamponade/perforation
  
•  Cerebrovascular
 accident
  
•  Major
 bleeding
 requiring
 transfusion 
•  Myocardial
 infarction
  
•  Pericarditis
 requiring
 intervention 
•  Transient
 ischemic
 attack 
•  Vagal
 nerve
 injury
 resulting
 in
 esophageal
 dysmotility
 or
 gastroparesis
  
•  Vascular
 access
 complications
 requiring
 intervention
  
•  Death 
 
•  Any PFA system-related
 or
 PFA
 procedure-related cardiovascular and/or pulmonary
 
adverse
 event that prolongs or requires hospitalization for more than 48 hours (excluding
 
recurrent
 AF/AFL/AT)
  
Analysis
 Methods
  
The
 probability
 of
 a
 safety
 event
 at
 6
 months
 (183
 days)
 will
 be
 estimated
 using
 survival
 analysis, 
the
 Kaplan-Meier
 method.
 The
 standard
 error
 will
 be
 approximated
 using
 Greenwood's
 formula.
 A 
two-sided
 95%
 log-log
 confidence
 interval
 for
 the
 probability
 will
 be
 constructed.
  

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For
 every
 treated
 subject,
 day
 0
 is
 defined
 as
 the
 day
 of
 the
 index
 ablation
 procedure.
 For
 subjects 
with
 a
 safety
 event,
 the
 survival
 date
 will
 be
 set
 to
 the
 onset
 date
 of 
the
 safety
 event.
 For
 subjects 
without
 a
 safety
 event,
 those
 subjects
 will
 be
 censored
 at
 the
 last
 study
 contact
 date
 recorded
 on 
CRF
 which
 may
 include
 the
 last
 study
 visit,
 the
 exit
 date,
 or
 death
 date.
 If
 a
 subject
 without
 a
 safety 
event
 is
 lost
 to
 follow-up,
 the
 censoring
 date
 will
 be
 set
 to
 the
 last
 known
 study
 visit
 date.
  
 
Safety
 events
 related
 to
 a
 repeat
 ablation
 procedure
 with
 the
 PFA
 system
 will
 not
 be
 counted
 as
 
safety
 events
 against
 the
 primary
 safety
 objective.
 
 However,
 all
 repeat
 PVI
 ablations
 using
 the
 PFA
 
system
 and
 the
 safety
 events
 associated
 with
 them
 will
 be
 reported
 separately.
  
 
Performance
 Requirements
  
If
 the
 upper
 bound
 of
 the
 two-sided
 95%
 confidence
 interval
 at
 6
 months
 is
 less
 than
 the
 
performance
 goal
 of
 13%,
 the
 objective
 will 
be
 considered
 met.
  
 
Rationale
 for
 Performance
 Criteria
  
Figure
  4 and Table
 14 display safety rates in recent
 studies in paroxysmal AF and persistent AF 
patients.24,25,26,27,28,29,30,31,32 
Included are published literature where the search criteria include 
large
 
multi-centered studies where the therapy was the use of catheter ablation (RF ablation,
 
cryoablation,
 or
 visually
 guided
 laser
 balloon
 [VGLB]
 ablation)
 for
 a
 PVI-only
 approach
 for 
paroxysmal
 
AF
 or
 persistent
 AF.
 The
 summary
 includes
 study
 results
 published
 as
 manuscripts
 in
 peer
 reviewed
 
                                                           
 
24 
P100010/R017
 “STOP
 AF
 PAS
 Final
 Post-Approval
 Study
 Report”. 
25 
Kuck, K. H., Brugada, J., Fürnkranz, A., et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. 
New
 England
 Journal
 of
 Medicine 
374,
 2235-2245
 (2016). 
26 
Squara, F., Zhao, A., Marijon, E., et al. Comparison between radiofrequency with contact force-sensing and second-
generation
 cryoballoon
 for
 paroxysmal
 atrial
 fibrillation
 catheter
 ablation:
 a
 multicentre
 European
 evaluation.
 Europace 
17,
 
718-724
 (2015). 
27 
Schmidt, M., Dorwarth, U., Straube, F., et al. Cryoballoon in AF ablation: impact of PV ovality on AF recurrence. Int J 
Cardiol 
167,
 114-120
 (2013). 
28 
Providencia,
 R.,
 Defaye,
 P.,
 Lambiase,
 P.,
 et
 al.
 Results
 from
 a
 multicentre
 comparison
 of
 cryoballoon
 vs.
 radiofrequency
 
ablation
 for
 paroxysmal
 atrial
 fibrillation:
 is
 cryoablation
 more
 reproducible?
 Europace 
19,
 48-57
 (2017). 
29 
Dukkipati, S., Cuoco, F., Kutinsky, I., et al. Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: A 
Prospective, Multicenter, and Randomized Comparison to Standard Radiofrequency Ablation. Journal of the American 
College
 of
 Cardiology 
66,
 1350-1360
 (2015). 
30 
Boveda, S., Metzner, A., Nguyen, D., et al. Single-Procedure Outcomes and Quality-of-Life Improvement 12 Months 
Post-Cryoballoon Ablation in Persistent Atrial Fibrillation: Results From the Multicenter CRYO4PERSISTENT AF Trial. 
Journal
 of
 the
 American
 College
 of 
Cardiology,
 doi:10.1016/j.jacep.2018.07.007
 (2018). 
31 
Tondo, C., Iacopino, S., Pieragnoli, P., et al. Pulmonary Vein Isolation Cryoablation for Persistent and Long-Standing
 
Persistent
 Atrial
 Fibrillation
 Patients.
 Clinical
 Outcomes
 from
 Real
 Word
 Multicentric
 Observational
 Project.
 Heart
 Rhythm 
15,
 363-368,
 doi:10.1016/j.hrthm.2017.10.038
 (2017). 
32 
Aryana,
 A.,
 Baker,
 J.,
 Espinosa
 Ginic
 M.,
 et
 al.
 Posterior
 wall
 isolation
 using
 the
 cryoballoon
 in
 conjunction
 with
 pulmonary 
vein ablation is superior to pulmonary vein isolation alone in patients with persistent atrial fibrillation: A multicenter 
experience.
 Heart
 Rhythm 
15,
 1121-1129
 (2018). 

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056-F275, v A Clinical Investigation Plan Template 
Rationale
 for
 Timing
 of
 the
 Final
 Safety
 Analysis 
The
 PFA
 system
 is
 a
 novel
 catheter
 ablation
 technology,
 but
 analogous
 in
 procedural
 use
 to
 currently
 
approved catheter ablation systems for the treatment of AF. The major complications related to 
traditional catheter ablation systems will describe the safety profile of the PFA system. The 2017 
HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial 
Fibrillation
 acknowledges
 that
 “AF
 ablation
 is
 an
 invasive
 procedure
 that
 entails
 risks,
 most
 of
 which
 
are
 present
 during
 the
 acute
 procedural 
period.
 However,
 complications
 can
 also
 occur
 in
 the
 weeks
 
or months following ablation.” Symptoms and complications associated with AF ablation are 
stratified
 by
 those
 that
 occur
 within
 1
 month
 post-ablation
 and
 those
 that
 occur
 more
 than
 1
 month
 
post-ablation.3 To evaluate the safety profile of the PFA system, the primary safety events in this 
study align with the recognized AF ablation complications. Recognizing that most AF ablation 
complications
 present
 acutely,
 Medtronic
 proposes
 that
 the
 safety
 profile
 of
 the
 PFA
 system
 will
 be
 
established with 6-month follow-up data. The study will
 continue to collect,
 analyze and report all
 
adverse
 events
 for
 all
 subjects
 through
 12
 months
 follow-up.
 
  
 
Sample
 Size
 Calculation
  
A sample size of 138 treated subjects followed for 6 months affords 90% power based on the 
following
 assumptions:
  
 
•  6-month
 safety
 rate
 =
 5%
 (desired
 rate
 for
 new
 catheter
 ablation
 technology) 
•  OPC
 =
 13%
 at
 6
 months
  
•  Overall
 alpha
 =
 0.025,
 one-sided
  
•  One
 final
 analysis 
•  Binomial
 exact
 methods
  
 
The
 primary
 analysis
 will
 utilize
 Kaplan-Meier
 survival
 methods.
 
 Binomial
 exact
 methods
 were
 
utilized
 for
 sample
 size
 and
 power
 calculations,
 as
 with
 very
 low
 expected
 attrition,
 Kaplan-Meier
 
and
 binomial
 methods
 yield
 very
 similar
 results.
 
 
Determination
 of
 Subjects/Data
 for
 Analysis
  
All
 Primary
 Analysis
 Cohort
 subjects 
(only 
their
 index
 PFA
 procedure)
 will
 be
 included.
 
 
 

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12.2.3.  Primary Effectiveness Objective 
Objective 
 
Demonstrate
 an
 acceptable
 chronic
 effectiveness
 of
 PVI
 ablation
 with
 the
 PFA
 System,
 based
 on
 
freedom
 from
 treatment
 failure. 
 
 
 
Hypotheses
  
For
 the
 paroxysmal
 AF
 arm: 
Ho:
 PS
 ≤
 55% 
Ha:
 PS
 >
 55% 
For
 the
 persistent 
AF
 arm: 
Ho:
 PS
 ≤
 40%
 
Ha:
 PS
 >
 40%
 
Where
 PS
 is
 the
 probability
 of
 treatment
 success
 at
 12 
months.
 
  
Endpoint
 Definition
  
The definition of treatment success and failure differs slightly between the paroxysmal and 
persistent
 arms
 of
 the
 Pivotal
 Phase.
  
 
Primary
 Effectiveness
 Endpoint
 for
 Paroxysmal
 AF 
Treatment
 success
 is
 defined
 as
 freedom
 from
 treatment
 failure.
 The
 study
 requires 
24-hour
 
Holter
 monitoring
 at
 6
 and
 12
 months
 in
 addition
 to
 weekly
 and
 symptomatic
 patient
 activated
 
ambulatory
 monitoring 
transmissions
 from
 3
 through
 12
 months,
 and
 12-lead
 ECGs
 at
 all
 follow
 up
 
visits.
 Treatment
 failure
 is
 defined
 as
 any
 of
 the
 following
 components:
  
•  Acute
 procedural
 failure
 (see
 definition
 below) 
•  Documented
 AF/AT/AFL
 on
 Holter/patient
 activated
 ambulatory
 monitoring/12-lead
 ECG
 
after
 the
 90-day
 post-ablation
 blanking
 period
  
•  Minimum
 of
 30
 seconds
 on
 Holter/patient
 activated
 ambulatory
 monitoring 
or
 10
 seconds
 
on
 12-lead
 ECG
 recording 
•  Note:
 Documented
 occurrence
 and
 treatment
 of
 typical
 right-sided
 cavotricuspid
 isthmus
 
dependent
 atrial
 flutter
 is
 not
 considered
 a
 failure. 
•  Any
 subsequent
 AF
 surgery
 or
 ablation
 in
 the
 left
 atrium,
 except
 for
 repeat
 PVI
 ablations
 
using
 PFA
 within
 the 
90-day 
blanking
 period. 
•  Direct
 current
 cardioversion
 for
 atrial
 tachyarrhythmia
 recurrences
 after
 the
 90-day
 
blanking
 period. 
•  Class
 I
 or
 III
 antiarrhythmic
 drug
 (AAD)
 use
 after
 the
 90-day
 blanking
 period.
  
 

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Blanking
 period
 is
 defined
 as
 the
 first
 90
 days
 after
 the
 index
 ablation
 procedure.
 Recurrences
 of
 
atrial
 arrhythmias
 during
 the
 blanking
 period
 will
 not
 be
 counted
 in
 the
 determination
 of
 the
 first
 
clinical
 failure
 for
 the
 primary
 endpoint.
 Within
 the
 blanking
 period,
 recurrent
 arrhythmias
 can
 be
 
managed
 with
 antiarrhythmic
 drugs
 or
 cardioversions.
 Titration
 of
 Class
 I
 and
 III
 antiarrhythmic
 
medications
 are
 allowed
 during
 the
 blanking
 period. 
Acute
 procedural
 failure
 is
 defined
 as:
  
•  Inability
 to
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (minimally
 assessed
 for
 entrance
 
block
 and,
 where
 assessable,
 exit
 block)
 during
 the
 index
 procedure
  
•  Ablation
 using
 a
 non-study
 device
 to
 isolate
 any 
pulmonary
 vein 
 
Primary
 Effectiveness
 Endpoint
 for
 Persistent
 AF 
Treatment
 success
 is
 defined
 as
 freedom
 from
 treatment
 failure.
 The
 study
 requires 
24-hour
 
Holter
 monitoring
 at
 6
 and
 12
 months
 in
 addition
 to
 weekly
 and
 symptomatic
 patient
 activated
 
ambulatory
 monitoring 
transmissions
 from
 3
 through
 12
 months,
 and
 12-lead
 ECGs
 at
 all
 follow
 up
 
visits.
 Treatment
 failure
 is
 defined
 as
 any
 of
 the
 following
 components:
  
•  Acute
 procedural
 failure
 (see
 definition
 below) 
•  Documented
 AF/AT/AFL
 on
 Holter/patient
 activated
 ambulatory/12-lead
 ECG
 after
 the
 
90-day
 post-ablation
 blanking
 period
  
•  Minimum
 of
 30
 seconds
 on
 Holter/patient
 activated
 ambulatory 
or
 10
 seconds
 on
 12-lead 
ECG
 recording 
•  Note:
 Documented
 occurrence
 and
 treatment
 of
 typical
 right-sided
 cavotricuspid
 isthmus
 
dependent
 atrial
 flutter
 is
 not
 considered
 a
 failure. 
•  Any
 subsequent
 AF
 surgery
 or
 ablation
 in
 the
 left
 atrium,
 except
 for
 repeat
 PVI
 ablations
 
using
 PFA
 within
 the
 90-day
 blanking
 period. 
•  Direct
 current
 cardioversion
 for
 atrial
 tachyarrhythmia
 recurrences
 after
 the
 90-day
 
blanking
 period. 
•  Class
 I
 or
 III
 antiarrhythmic
 drug
 (AAD)
 dose
 increase
 from
 the
 historic
 maximum
 ineffective
 
dose
 (prior
 to
 the
 ablation
 procedure)
 or
 initiation
 of
 a
 new
 Class
 I
 or
 III
 AAD
 after
 the
 90-
day
 blanking
 period.
 Note:
 remaining
 on
 the
 same
 pre-ablation
 dose 
or
 decreased
 dose
 of
 a
 
previously
 failed
 or
 not
 tolerated
 Class
 I
 or
 III
 AAD
 after
 the
 90-day
 blanking
 is
 not
 
considered
 a
 failure.
  
 
Blanking
 period
 is
 defined
 as
 the
 first
 90
 days
 after
 the
 index
 ablation
 procedure.
 Recurrences
 of
 
atrial
 arrhythmias
 during
 the
 blanking
 period
 will
 not
 be
 counted
 in
 the
 determination
 of
 the
 first
 
clinical
 failure
 for
 the
 primary
 endpoint.
 Within
 the
 blanking
 period,
 recurrent
 arrhythmias
 can
 be
 
managed
 with
 antiarrhythmic
 drugs
 or
 cardioversions.
 Titration
 of
 Class
 I
 and
 III
 antiarrhythmic
 
medications
 are
 allowed
 during
 the
 blanking
 period. 

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056-F275, v A Clinical Investigation Plan Template 
Acute
 procedural
 failure
 is
 defined
 as:
  
•  Inability
 to
 isolate
 all
 accessible
 targeted
 pulmonary
 veins
 (minimally
 assessed
 for
 entrance
 
block
 and,
 where
 assessable,
 exit
 block)
 during
 the
 index
 procedure
  
•  Ablation
 using
 a
 non-study
 device
 to
 isolate
 any 
pulmonary
 vein 
 
Analysis
 Methods
  
The
 probability
 of
 a
 subject
 achieving
 effectiveness
 success
 at
 12
 months
 (365
 days)
 will
 be
 
estimated
 using
 survival
 analysis,
 the
 Kaplan-Meier
 method.
 The
 standard
 error
 will
 be
 
approximated
 using
 Greenwood's
 formula.
 A
 two-sided
 95%
 log-log
 confidence
 interval
 for
 the
 
probability
 will
 be
 constructed.
  
 
For
 every
 treated
 subject,
 day
 0
 is
 defined
 as
 the
 day
 of
 the
 index
 ablation
 procedure.
 For
 subjects
 
with
 treatment
 failure,
 the
 survival
 date
 will
 be
 set
 to
 the
 date
 of
 the
 treatment
 failure.
 For
 subjects
 
without
 treatment
 failure
 through
 12
 months,
 those
 subjects
 will
 be
 censored
 at
 the
 last
 study
 
contact
 date
 recorded
 on
 a
 CRF
 which
 may
 include
 the
 last
 study
 visit,
 the
 last
 weekly
 patient
 
activated
 ambulatory,
 the
 exit
 date,
 or
 death
 date.
 If
 a
 subject
 without
 a
 treatment
 failure
 is
 lost
 to
 
follow-up,
 the
 censoring
 date
 will
 be
 set
 to
 the
 last
 known
 study
 visit
 date.
  
 
For
 the
 component
 of
 the
 endpoint,
 documented
 AF/AT/AFL,
 if
 this
 documentation
 resulted
 from
 
rhythm
 monitoring
 occurring
 at
 the
 12-month
 visit
 within
 the
 12-month
 visit
 window,
 the
 date
 of
 
recurrence
 will
 be
 set
 to
 365
 days
 from
 the
 study
 ablation
 procedure
 so
 that
 these
 events
 will
 be
 
counted
 as
 treatment
 failures
 in
 the
 12-month
 Kaplan-Meier
 analysis. 
 
Sensitivity
 Analyses
  
A
 sensitivity
 analysis
 will
 be
 conducted
 to
 estimate
 the
 potential
 impact
 of
 subjects
 with
 less
 than
 
12
 months
 of
 follow-up
 at
 the
 final
 analysis.
 The
 mortality
 rate
 in
 this
 patient
 population
 is
 
anticipated
 to
 be
 low.
 The
 total
 assumed
 attrition
 rate
 through
 one
 year
 is
 5%.
 Because
 the
 
primary
 endpoint
 will
 be
 tested
 using
 survival
 methods,
 all
 treated
 subjects
 are
 included
 in
 the
 
primary
 analysis,
 and
 therefore
 no
 subjects
 will
 have
 complete
 missing
 data.
 For
 subjects
 that
 exit
 
early,
 a
 tipping
 point
 analysis
 will
 be
 conducted
 to
 estimate
 the
 potential
 impact
 of
 subjects
 with
 
less
 than
 12
 months
 of
 follow-up.
 These
 subjects
 will
 be
 defined
 as
 subjects
 with
 partial
 data.
 The
 
tipping
 point
 analysis
 methods
 will
 be
 as
 follows.
 For
 each
 subject
 with
 less
 than
 12
 months
 of
 
follow-up,
 each
 subject
 will
 be
 set
 to
 treatment
 failure
 (failure
 date
 set
 to
 date
 of
 study
 exit).
 The
 
12-month
 Kaplan-Meier
 estimate
 will
 be
 re-calculated
 with
 the
 earliest
 (closest
 to
 index
 ablation)
 
sequentially
 added
 to
 the
 Kaplan-Meier
 analysis,
 and
 the
 results
 presented
 in
 table
 format.
 The
 
tipping
 point
 will
 be
 defined
 as
 the
 number
 of
 additional
 failures
 in
 which
 the
 performance
 goal
 
(55%
 for
 paroxysmal
 and
 40%
 for
 persistent)
 is
 crossed
 by
 the
 lower
 95%
 confidence
 bound. 
 
Performance
 Requirements
  
If
 the
 lower
 bound
 of
 the
 confidence
 interval
 (coverage
 level
 determined
 by
 the
 alpha
 spending
 
function)
 is
 greater
 than
 the
 performance
 goal
 (55%
 for
 paroxysmal
 and
 40%
 for
 persistent),
 the
 
objective
 will
 be
 considered
 met. 
 
 

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056-F275, v A Clinical Investigation Plan Template 
Rationale
 for
 Performance
 Criteria
 (Paroxysmal) 
Traditionally, the choice of acceptable effectiveness performance criteria for paroxysmal AF with 
12-month follow-up data is selected based on the 2017 HRS/EHRA/ECAS Expert Consensus 
Statement
 on
 Catheter
 and
 Surgical
 Ablation
 of
 Atrial
 Fibrillation,
 which
 provides
 recommendations
 
for success rates in clinical trials. The recommendation for evaluating the effectiveness of a 
treatment
 for
 paroxysmal
 AF
 is
 as
 follows:
 “If
 minimum
 chronic
 success
 rate
 is
 selected
 as
 an
 objective
 
effectiveness
 endpoint
 for
 a
 clinical
 trial,
 we
 recommend
 that
 the
 minimum
 chronic
 acceptable
 success
 
rate for paroxysmal AF at 12-month follow-up is 50%.”3 Medtronic proposes a single-arm, non-
randomized
 paroxysmal
 AF
 study
 is
 appropriate
 with
 performance
 criteria
 that
 is
 established
 based
 
on effectiveness rates for currently approved ablation catheters (RF ablation, cryoablation, and 
VGLB ablation), in addition to the recommendation provided by the 2017 Expert Consensus 
Statement. 
 
Figure
 5 
and 
Table
 15 
display 
effectiveness
 rates
 observed
 in
 current
 clinical
 trials
 studying
 approved
 
catheter ablation technologies in paroxysmal AF patients. Included are published literature where 
the search criteria include publications of large multi-centered studies where the therapy was the 
use of catheter ablation (RF ablation, cryoablation, or VGLB ablation) for a PVI-only approach for 
paroxysmal AF. The summary includes study results published as manuscripts in peer reviewed 
medical
 journals.
 Varying
 rates
 in
 12-month
 effectiveness
 have
 been
 observed.
 Similarly,
 variations
 
in definitions of primary effectiveness and variations in arrhythmia monitoring have been utilized. 
 
The proposed PULSED AF study design has an aggressive definition of primary paroxysmal AF 
effectiveness
 (requiring
 acute
 success
 and
 disallowing
 AAD
 use
 and
 reablations)
 and
 a
 more
 rigorous
 
study
 design
 (requiring
 weekly
 patient
 activated
 ambulatory 
monitoring
 through
 12
 months).
 
  
 
To test a novel catheter ablation technology, under these study design requirements, an OPC of 
55% provides a reasonable margin to compare the PFA system against current approved ablation 
technologies.
 

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056-F275, v A Clinical Investigation Plan Template 
Rationale
 for
 Performance
 Criteria
 (Persistent) 
The choice of acceptable effectiveness performance criteria for persistent
 AF with 12-month
 
follow-up data is selected based on
 the 2017 HRS/EHRA/ECAS Expert Consensus Statement on 
Catheter and Surgical Ablation of Atrial Fibrillation, which provides recommendations for success 
rates in clinical trials.
  The recommendation for evaluating the effectiveness of a treatment for 
persistent AF is as follows: “If minimum chronic success rate is selected as an objective effectiveness 
endpoint for a clinical trial, we recommend that the minimum chronic acceptable success rate for 
persistent
 AF
 at
 12-month
 follow-up
 is
 40%.”3 
 
Additionally,
 there
 is
 mounting
 evidence
 in
 published
 literature
 on
 the
 use
 of
 catheter
 ablation
 in
 the
 
treatment of persistent AF. Figure
 6 and
 Table
 16 display a summary of published literature where 
the
 search
 criteria
 were
 publications
 of
 large
 multi-centered
 studies
 where
 the
 therapy
 was
 the
 use
 
of catheter ablation (RF ablation or
 cryoablation) for a PVI-only approach for persistent AF. The 
summary
 includes
 study
 results
 published
 as
 manuscripts
 in
 peer
 reviewed
 medical
 journals.
 Varying
 
rates in 12-month effectiveness have been observed. Similarly, variations in definitions of primary 
effectiveness and variations in arrhythmia monitoring have been utilized.  The PULSED AF study 
design
 has
 an
 aggressive
 definition
 of
 primary
 persistent
 AF
 effectiveness
 (requiring
 acute
 success;
 
and disallowing re-ablations, AAD dose increase from the historic maximum ineffective dose, or 
initiation of new AAD) and a more rigorous study design (requiring weekly patient activated 
ambulatory 
monitoring 
through
 12
 months).
 
  
 
To test a novel catheter ablation technology under these study design requirements, the Expert 
Consensus Statement recommended OPC
 of 40%
 provides a reasonable margin to compare the 
PFA
 system
 against
 ablation
 technologies
 currently
 used
 to
 treat
 persistent
 AF.
 

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056-F275, v A Clinical Investigation Plan Template 
Assumptions
 (Paroxysmal
 Arm) 
•  The
 overall
 alpha
 will
 be
 0.025,
 
 
 
•  Power=90% 
•  The
 number
 of
 Primary
 Analysis
 Cohort
 subjects
 enrolled
 per
 month
 will
 average
 5
 (1st 
month),
 7
 (2nd 
month),
 11,
 24,
 35,
 43,
 51,
 56,
 60,
 60,
 60…
 
  
•  Daily
 enrollments
 follow
 a
 Poisson
 distribution
 with
 an
 average
 of
 x/30,
 where
 x
 is
 the
 
average
 number
 of
 enrollments
 in
 that
 month.
 
 This
 allows
 multiple
 ablation
 procedures
 in
 a
 
day. 
•  50%
 of
 enrollments
 are
 persistent
 AF
 subjects,
 and
 the
 other
 50%
 are
 paroxysmal
 AF
 
subjects 
•  12-month
 effectiveness
 rate
 =
 68%
 (A
 weighted
 average
 12-month
 effectiveness
 was
 
calculated
 at
 the
 bottom
 of
 the 
Table
 15,
 resulting
 in
 an
 average
 effectiveness
 rate
 of
 
73.2%.
 Only
 three
 of
 the
 studies
 utilized
 weekly
 TTMs 
(similar
 to
 the
 weekly
 patient
 
activated
 ambulatory 
monitoring
 requirement),
 so
 due
 to
 the
 additional
 arrhythmia
 
monitoring
 and
 a
 more
 stringent
 endpoint
 definition
 in
 PULSED
 AF,
 the
 12-month
 
paroxysmal
 AF
 effectiveness
 point
 estimate
 for
 this
 study
 has
 been
 set
 to
 68%.)
 
•  6-month
 effectiveness
 rate
 =
 79%
 (based
 on
 past
 studies (
Table
 15),
 the
 6-month
 rate
 is
 
approximately
 11%
 higher
 than
 12-month
 rate) 
•  2%
 of
 patients
 will
 have
 an
 acute
 failure
 and
 these
 will
 occur
 on
 the
 first
 day
 post-ablation
 
procedure 
•  Chronic
 failures
 (AF
 recurrence)
 occur
 either
 in
 the
 3-6
 month
 period
 or
 in
 the
 6-12
 month
 
period,
 based
 on
 the
 assumed
 68%
 and
 79%
 numbers
 above. 
•  A
 patient
 with
 a
 chronic
 failure
 in
 the
 3-6
 month
 period
 has
 an
 equal
 chance
 of
 that
 failure
 
occurring
 any
 day
 between
 91
 and
 182
 days
 post-ablation
 procedure 
•  A
 patient
 with
 a
 chronic
 failure
 in
 the
 6-12
 month
 period
 has
 an
 equal
 chance
 of
 that
 failure
 
occurring
 any
 day
 between
 184
 and
 364
 days
 post-ablation
 procedure 
•  5%
 attrition
 from
 ablation
 (drop
 out)
 procedure
 to
 12
 months 
•  Attrition
 occurs
 uniformly
 from
 1-364
 days
 post-ablation
 procedure 
• 
 
 
 
 
 
Given
 the
 above
 assumptions,
 for
 the
 Paroxysmal
 AF
 arm
 of
 the
 study,
 a
 sample
 size
 of
 165 
Primary
 
Analysis
 Cohort
 subjects 
is
 required. 
 
To ensure proper characteristics of the study, especially alpha-level, the simulation program was 
rerun
 with
 all
 of
 the
 above
 assumptions
 (including
 the
 sample
 size
 of
 165
 subjects)
 the
 same,
 except
 
that the assumed 12-month effectiveness rate was set to the null hypothesis rate of 55% (and 6-
month effectiveness rate to 66%).  
 
 
 This
 meets
 the
 goal
 of
 having
 overall
 
alpha
 being
 less
 than
 2.5%. 

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Assumptions
 (Persistent Arm)
 
•  The
 overall
 alpha
 will
 be
 0.025,
 
 
 
•  Power=90% 
•  The
 number
 of
 Primary
 Analysis
 Cohort
 subjects
 enrolled
 per
 month
 will
 average
 5
 (1st 
month),
 7
 (2nd 
month),
 11,
 24,
 35,
 43,
 51,
 56,
 60,
 60,
 60…
 
  
•  Daily
 enrollments
 follow
 a
 Poisson
 distribution
 with
 an
 average
 of
 x/30,
 where
 x
 is
 the
 
average
 number
 of
 enrollments
 in
 that
 month.
 
 This
 allows
 multiple
 ablation
 procedures
 in
 a
 
day. 
•  50%
 of
 enrollments
 are
 persistent 
AF
 subjects,
 and
 the
 other
 50%
 are
 paroxysmal 
AF
 
subjects 
•  12-month
 effectiveness
 rate
 =
 54%
 (A
 weighted
 average
 12-month
 effectiveness
 was
 
calculated
 at
 the
 bottom
 of 
Table
 16,
 resulting
 in
 an
 average
 effectiveness
 rate
 of
 59.5%. 
Due
 to
 the
 additional
 arrhythmia
 monitoring
 and
 more
 stringent
 endpoint
 definition
 in
 
PULSED
 AF,
 the
 12-month
 persistent
 AF
 effectiveness
 point
 estimate
 for
 this
 study
 has
 
been
 set
 to
 54%.)
 
•  6-month
 effectiveness
 rate
 =
 72%
 (based
 on
 past
 studies (
Table
 16),
 the
 6-month
 rate
 is
 
approximately
 18%
 higher
 than
 12-month
 rate) 
•  2%
 of
 patients
 will
 have
 an
 acute
 failure
 and
 these
 will
 occur
 on
 the
 first
 day
 post-ablation
 
procedure 
•  Chronic
 failures
 (AF
 recurrence)
 occur
 either
 in
 the
 3-6
 month
 period
 or
 in
 the
 6-12
 month
 
period,
 based
 on
 the
 assumed
 54%
 and
 72%
 numbers
 above. 
•  A
 patient
 with
 a
 chronic
 failure
 in
 the
 3-6
 month
 period
 has
 an
 equal
 chance
 of
 that
 failure
 
occurring
 any
 day
 between
 91
 and
 182
 days
 post-ablation
 procedure 
•  A
 patient
 with
 a
 chronic
 failure
 in
 the
 6-12
 month
 period
 has
 an
 equal
 chance
 of
 that
 failure
 
occurring
 any
 day
 between
 184
 and
 364
 days
 post-ablation
 procedure 
•  5%
 attrition
 from
 ablation
 (drop
 out)
 procedure
 to
 12
 months 
•  Attrition
 occurs
 uniformly
 from
 1-364
 days
 post-ablation
 procedure 
 
 
 
 
 
 
Given the above assumptions, for the Persistent AF
 arm of the study, a sample size of 150 Primary
 
Analysis
 Cohort
 subjects 
is
 required. 
 
To ensure proper characteristics of the study, especially alpha-level, the simulation program was 
rerun
 with
 all
 of
 the
 above
 assumptions
 (including
 the
 sample
 size
 of
 150
 subjects)
 the
 same,
 except
 
that the assumed 12-month effectiveness rate was set to the null hypothesis rate of 40% (and 6-
month to 58%).  
 
  This meets the goal of having overall alpha 
being
 less
 than
 2.5%. 

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12.2.4.  Overall Study Sample Size Rationale 
The
 effectiveness
 sample
 sizes
 (165
 for
 Paroxysmal
 AF
 and
 150
 for
 Persistent
 AF)
 are
 higher
 than
 
the
 sample
 size
 of
 138
 for
 the
 safety
 objective.
 Therefore,
 a
 total
 of
 315
 Primary
 Analysis
 Cohort
 
subjects
 are
 needed
 to
 have
 adequate
 power.
 
 
Overall,
 up
 to
 475
 subjects
 will
 be
 enrolled
 to
 ensure
 there
 are
 20
 Pilot
 Phase
 subjects,
 up
 to
 80
 
Pivotal
 Phase
 roll-in
 subjects,
 and
 315
 Pivotal
 Phase
 primary
 analysis
 subjects
 treated
 with
 the
 PFA
 
system,
 and
 to
 account
 for
 subjects 
not
 treated
 prior
 to
 exit.
 
 
 
 

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12.3. Secondary Objective 
The
 secondary
 objective
 will
 be
 evaluated
 to
 gain
 additional
 information
 about
 the
 performance
 of
 
the
 PFA
 system. 
The 
secondary
 objective 
will
 be
 reported
 separately 
by
 paroxysmal
 AF
 and
 
persistent
 AF.
 
Within
 each
 arm,
 testing
 for
 the
 two
 QOL
 hypothesis
 tests 
will
 be
 performed
 if
 the
 primary
 
effectiveness
 and
 primary
 safety
 objectives
 are
 met.
 A
 Hochberg
 multiple
 testing
 procedure 
will
 be
 
utilized
 to
 maintain
 an
 overall
 type
 I
 error
 rate
 of
 0.025.
 
 
The
 Hochberg
 procedure
 is
 a
 stepwise
 procedure
 and
 will
 be
 implemented
 as
 follows: 
The
 two
 null 
hypotheses
 will
 be
 defined
 as
 H(1) (AFEQT)
 
and
 H(2)
 (EQ-5D).
 For
 each
 of
 the
 
hypotheses,
 p-values 
will
 be
 calculated
 and
 sorted
 p(1)
 <
 p(2).
 The
 decision
 rule
 to
 accept
 or
 reject
 
each 
hypothesis
 will
 follow
 the
 step-up
 algorithm,
 where
 α=0.025:
 
Step
 1:
 If
 p(2)
 ≥ 
α,
 accept
 H(2)
 and
 go
 to
 Step
 2,
 otherwise
 reject
 both 
hypotheses
 and
 stop 
Step
 2:
 If
 p(1)
 <
 α/2 
reject
 H(1);
 otherwise
 accept
 H(1)
 
12.3.1.  Secondary Objective: Quality of Life  
Assess changes
 in
 quality
 of
 life
 from 
baseline
 through
 12 
months 
after
 the
 index
 ablation
 
procedure 
 
This
 objective
 has
 two
 parts,
 the
 AFEQT
 questionnaire,
 and
 the
 EQ-5D
 questionnaire.
 
 
 

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12.3.1.1. Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
 
Hypothesis 
The
 following
 hypothesis
 will
 be
 tested: 
Ho:
 ∆AFEQT =
 0 
Ha:
 ∆AFEQT >
 0 
Where
 ∆AFEQT is
 the
 mean
 change
 in
 AFEQT
 score
 from
 baseline 
to
 12
 months.
 
  
 
Endpoint
 Definition 
The
 AFEQT
 questionnaire
 will
 be
 utilized
 for
 this
 objective.
 The
 questionnaire
 is
 an
 atrial
 fibrillation
 
specific
 health-related
 quality
 of
 life
 questionnaire
 to
 assess
 the
 impact
 of
 AF
 on
 a
 subject’s
 life.
 
 
The
 overall
 score
 ranges
 from
 0
 –
 100,
 with
 0
 corresponding
 to
 complete
 disability
 and
 100
 
corresponding 
to
 no
 disability. 
The
 endpoint
 for
 each
 subject
 is
 change
 in
 AFEQT
 score,
 which
 is
 the
 AFEQT
 score
 at
 12
 months
 
minus
 the
 AFEQT
 score
 at
 baseline. 
Analysis
 Methods 
The
 mean
 change
 in
 AFEQT
 score
 will
 be
 calculated,
 along
 with 
a
 two-sided
 95%
 confidence
 
interval. 
 
The
 hypothesis
 will
 be
 tested
 using
 the
 one-sample
 t-test. 
 
 
 The
 p
-value
 based
 on
 the
 final
 dataset
 will
 be
 compared
 to
 the
 Hochberg
 alpha
 level
 (Section 
12.3)
 to
 determine
 significance. 
Additionally,
 summary
 statistics
 (e.g.
 mean,
 SD)
 will
 be
 used
 to 
summarize
 the
 change
 in
 AFEQT
 
scores
 from
 baseline
 through
 12
 months,
 including
 values
 collected
 at
 6
 months. 
Performance
 criteria 
If
 the
 p-value
 from
 the
 one-sample
 t-test
 is
 less
 than
 the
 Hochberg-criteria
 alpha
 level,
 then
 the
 
objective
 will
 be
 considered
 met. 
Determination
 of
 Subjects/Data
 for
 Analysis 
Primary
 Analysis
 Cohort
 subjects
 who
 have
 completed
 baseline
 and
 12-month
 follow-up
 
questionnaires 
will
 be
 included. 

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Additional
 Analyses 
The
 AFEQT
 questionnaire
 has
 three
 subscale
 scores,
 Daily
 Activities
 Subscale,
 Treatment
 
Concern,
 and
 Treatment
 satisfaction.
 
 Each
 subscale
 ranges
 from
 0
 –
 100,
 where
 0
 corresponds
 to
 
low
 quality-of-life
 and
 100
 corresponds
 to
 high
 quality
 of
 life. 
 
An
 additional
 analysis
 will
 be
 
conducted
 to
 summarize
 these
 subscales
 through
 12
 months. 
Change
 in
 AFEQT
 subscale
 score
 is
 defined
 as
 12-month
 AFEQT
 subscale
 score
 minus
 baseline
 
AFEQT
 subscale
 score.
 
 A
 two-sided
 95%
 confidence
 interval
 will
 be
 calculated
 based
 on
 the
 t-
distribution. 
 
 
 
 

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12.3.1.2. EQ-5D Questionnaire 
Hypothesis 
The
 following 
hypothesis
 will
 be
 tested: 
Ho:
 ∆EQ-5D =
 0 
Ha:
 ∆EQ-5D >
 0 
Where
 ∆EQ-5D 
is
 the
 change
 in 
mean
 composite 
EQ-5D
 score
 from
 baseline 
to
 12
 months.
 
 
Endpoint
 Definition 
The
 Euroqol
 EQ-5D
 questionnaire 
(5L
 version) 
will
 be
 utilized
 for
 this
 objective.
 The
 EQ-5D
 
questionnaire
 is
 a
 standardized
 instrument
 for
 measuring
 generic
 health
 status.
 The
 EQ-5D
 has
 
two
 sections.
 The
 first
 section
 is
 a
 descriptive
 section
 where
 the
 subject
 checks
 a
 box
 by
 the
 most
 
appropriate
 statement.
 The
 second
 section
 is
 a
 visual
 analog
 scale. 
Composite
 scores
 will
 be
 
indexed
 against
 a
 US
 reference
 population.
 (Shaw,
 Johnson
 and
 Coons
 2004). 
The
 endpoint
 for
 each
 subject
 is
 change
 in
 EQ-5D
 composite
 score,
 which
 is
 the
 EQ-5D
 composite
 
score
 at
 12
 months 
minus
 the
 EQ-5D
 composite
 score
 at
 baseline. 
Analysis
 Methods 
The
 mean
 change
 in
 EQ-5D
 composite
 score
 and
 a 
two-sided
 95%
 confidence
 interval
 will
 be
 
calculated
 based
 on
 the
 t-distribution. 
 
 
 The
 p
-value
 based
 on
 the
 final
 dataset
 will
 be
 compared
 to
 the
 Hochberg
 alpha
 level
 (Section 
12.3)
 to
 determine
 significance. 
Summary
 statistics
 (e.g.
 mean,
 SD)
 will
 be
 used
 to
 summarize
 the
 change
 in
 EQ-5D
 composite
 
scores
 from
 baseline
 through
 12
 months,
 including
 values
 collected
 at
 6
 months. 
In
 addition,
 the
 
visual
 analog
 scale
 of
 the
 EQ-5D
 will
 be
 summarized
 through
 12
 months
 using
 summary
 statistics. 
Performance
 criteria 
If
 the
 p-value
 from
 the
 one-sample
 t-test
 is
 less
 than
 the
 Hochberg-criteria
 alpha
 level,
 then
 the
 
objective
 will
 be
 considered
 met. 
Determination
 of
 Subjects/Data
 for
 Analysis 
Primary
 Analysis
 Cohort
 subjects
 who
 have
 completed
 baseline
 and
 12-month
 follow-up
 
questionnaires
 will
 be
 included. 
 
 
 

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13. Ethics 
13.1. Statement(s) of Compliance  
The
 study
 will
 be
 conducted
 in
 compliance
 with
 international
 ethical
 and
 scientific
 quality
 
standards,
 known
 as
 good
 clinical
 practice
 (GCP).
 GCP
 includes
 review
 and
 approval
 by
 an
 
independent
 Ethics
 Board/Institutional
 Review
 Board
 (IRB)/Research
 Ethics
 Board
 (REB)/Medical 
Ethics
 Committee
 (MEC)/Head
 of
 Medical
 Institution
 (HOMI)/Human
 Research
 and
 Ethics
 
Committee
 (HREC) 
before
 initiating
 a
 study,
 continuing
 review
 of
 an
 ongoing
 study
 by
 an
 Ethics
 
Board,
 and
 obtaining
 and
 documenting
 the
 freely
 given
 informed
 consent
 of
 a
 subject
 before
 
initiating
 the
 study. 
The
 term
 Ethics
 Committee 
will
 henceforth
 be
 used
 collectively
 in
 reference
 to
 
an
 Institutional
 Review
 Board
 (IRB)/Medical
 Ethics 
Committee
 (MEC)/Human
 Research
 Ethics
 
Committee
 (HREC)/Research
 Ethics
 Board
 (REB)/Head
 of
 Medical
 Institution
 (HOMI)
 unless
 
otherwise
 stated.
 
The
 study
 was
 designed
 to
 reflect
 the
 GCP
 principles
 outlined
 in
 ISO
 14155:2011
 and
 other
 
international
 clinical
 requirements
 outlined
 below.
 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.
 In
 
accordance
 with
 ISO
 standard,
 the
 sponsor
 shall
 avoid
 improper
 influence
 on,
 or
 inducement
 of,
 
the
 subject,
 monitor,
 any
 Investigator(s)
 or
 other
 parties
 participating
 in
 or
 contributing
 to
 the
 
clinical
 investigation.
 
 All
 Investigators
 shall
 avoid
 improper
 influence
 on
 or
 inducement
 of
 the
 
subject,
 sponsor,
 monitor,
 other
 Investigator(s)
 or
 other
 parties
 participating
 in
 or
 contributing
 to
 
the
 clinical
 investigation.
 
 Adverse 
Event
 and
 Device
 Deficiency
 handling
 in
 this s
tudy
 is
 ISO 
14155:2011
 compliant
 for
 all 
participating
 geographies.
 
 
 
The
 study
 will
 be
 conducted
 according
 to
 federal,
 national
 and
 local
 laws,
 regulations,
 standards,
 
and
 requirements
 of
 the
 countries/geographies
 where
 the
 study
 is
 being
 conducted.
 
 For
 all
 
geographies,
 the
 principles
 of
 the
 Declaration
 of
 Helsinki
 have
 been
 implemented
 through
 the
 
patient
 informed
 consent
 (IC)
 process,
 Ethics
 Committee 
approval,
 study
 training,
 clinical
 trial
 
registration,
 preclinical
 testing,
 risk-benefit
 assessment
 and
 publication
 policy. 
 
 

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Ultimately,
 all
 sites
 in
 all
 geographies
 will
 follow
 and
 comply
 with: 
•  Principles
 of
 Declaration
 of
 Helsinki
 (including
 privacy
 and
 data
 protection
 laws),
 or
 the
 laws
 
and
 regulations
 of
 each
 participating
 country,
 whichever
 affords
 greater
 protection
 for
 the
 
study
 subjects 
•  21
 CFR
 Part
 11
 (Electronic
 Records,
 Electronic
 Signatures) 
•  21
 CFR
 Part
 54
 (Financial
 Disclosure
 by
 Clinical
 Investigators) 
•  The
 procedures
 described
 within
 this
 CIP 
•  Local
 Ethics
 Committee requirements
 
•  The
 Clinical
 Trial
 Agreement 
 
In
 addition
 to
 the
 regulatory
 requirements
 outlined
 above,
 the
 study
 will
 be
 conducted
 according
 to
 
federal,
 national
 and
 local
 laws,
 regulations,
 standards
 and
 requirements
 of
 the
 
countries/geographies
 where
 the
 study
 is
 being
 conducted. 
 
These
 include
 but
 are
 not
 limited
 to: 
•  In
 Australia,
 local
 laws
 will
 be
 complied
 with
 and
 below
 will
 be
 followed: 
 
o Declaration
 of
 Helsinki
 2013
 and
 ISO
 14155:2011
  
•  In
 Canada,
 the
 below
 will
 be
 followed: 
o Medical
 Devices
 Regulations,
 1998
 (SOR/98-282),
 59(1),
 59(2),
 60(1),
 and
 the
 
Canadian
 Regulatory
 Guidelines
 for
 Mandatory
 Medical
 Device
 Problem
 Reporting
 
for
 Medical
 Devices,
 2011.
  
•  In
 Europe,
 the
 study
 will
 be
 conducted
 in
 compliance
 with: 
o Declaration
 of
 Helsinki
 2013,
 the
 Competent
 Authority
 requirements,
 the
 Medical
 
Device
 Directive
 (MDD)
 93/42/EEC
 and
 ISO
 14155:2011
  
•  In
 Japan,
 the
 study
 will
 be
 conducted
 in
 compliance
 with:
 
 
o MHLW
 Ordinance
 No.
 36,
 2005
 and
 related
 laws
 and
 regulations 
•  In
 the
 United
 States,
 the
 study
 will
 be
 conducted
 under
 an
 FDA
 Investigational
 Device
 
Exemption
 (IDE)
 in
 compliance
 with
 US
 FDA
 21
 CFR
 Parts:
 
 
o 50:
 Protection
 of
 Human
 subjects,
 56:
 Institutional
 Review
 Boards
 and
 812:
 
Investigational
 Device
 Exemptions 
 
Any
 additional
 requirements
 imposed
 by
 an 
Ethics
 Committee 
or
 regulatory
 authority
 shall
 be
 
followed,
 if
 appropriate.
 All
 participating
 geographies
 will
 make
 study
 data
 available
 to
 the
 
regulatory
 body
 such
 as
 FDA,
 Health
 Canada
 or
 competent
 authority
 if
 the
 regulatory
 body
 deems
 
an
 onsite
 inspection
 necessary.
 
 The
 regulatory
 body
 will
 be
 able 
to
 inspect
 records
 at
 clinical
 study
 
sites
 around
 the
 world
 to
 resolve
 any
 uncertainties
 about
 whether
 the
 study
 was
 conducted
 in
 
accordance
 with
 good
 clinical
 practice. 
The
 study
 will
 be
 publicly
 registered
 prior
 to
 first
 enrollment
 in
 accordance
 with
 the
 2007
 Food
 and
 
Drug
 Administration
 Amendments
 Act
 (FDAAA)
 and
 Declaration
 of
 Helsinki
 on
 
http://clinicaltrials.gov
 (PL
 110-85,
 Section
 810(a)).
 In
 addition,
 the
 study
 may
 be
 registered
 in
 local
 
regulatory
 databases
 where
 required
 by
 local
 law. 

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Approval
 of 
the
 Clinical
 Investigation
 Plan
 (CIP)
 is
 required
 from
 the
 following
 groups
 prior
 to
 any
 
study
 procedures
 at
 a
 study
 site:
  
•  Medtronic
  
•  Principal
 Investigators
 (where
 required
 by
 local
 law) 
•  An
 independent
 Ethics
 Committee 
•  Geography-specific
 regulatory
 authorities
 (if
 regulatory
 approval
 is
 required) 
 
Similarly,
 approval
 of
 subsequent
 revisions
 to
 the
 CIP
 is
 required
 from
 the
 above-mentioned
 
groups 
prior
 to
 implementation
 of
 the
 revised
 CIP
 at
 the
 study
 sites. 
 
 

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14. Study Administration 
14.1. Monitoring  
It
 is
 the
 responsibility
 of
 Medtronic
 to
 ensure
 proper
 monitoring
 of
 this
 clinical
 study.
 
 Trained
 
Medtronic
 personnel
 or
 delegates
 appointed
 by
 Medtronic
 may
 perform
 study
 monitoring
 at
 the
 
study
 site 
in
 order
 to
 ensure
 that
 the 
study
 is
 conducted
 in
 accordance
 with
 the
 CIP,
 the
 Clinical
 
Trial
 Agreement,
 and
 applicable
 regulatory
 and
 local
 requirements.
 Medtronic,
 or
 delegates,
 must
 
therefore
 be
 allowed
 direct
 access
 to
 the
 subjects’
 case
 histories
 (clinic
 and
 hospital
 records,
 and
 
other
 source
 data/documentation)
 upon
 request
 as
 per
 the
 IC
 Form,
 Research
 Authorization
 
(where
 applicable)
 and
 Clinical
 Trial
 Agreement.
 The
 Principal
 Investigator
 should
 also
 be
 available
 
during
 monitoring
 visits. 
Frequency
 of
 monitoring
 visits
 may
 be 
based
 upon
 subject
 enrollment,
 duration
 of
 the
 study,
 study
 
compliance,
 number
 of
 adverse
 events,
 number
 of
 deviations,
 findings
 from
 previous
 monitoring
 
visits
 and
 any
 suspected
 inconsistency
 in
 data
 that
 requires
 investigation.
 Regulatory
 documents
 
may
 be
 reviewed
 at
 each
 study
 site.
 Monitoring
 for
 the
 study
 may
 include,
 but
 not
 limited
 to,
 site
 
qualification
 visits,
 site
 initiation
 visits,
 interim
 monitoring
 visits,
 and
 closeout
 visits,
 and
 will
 be
 
done
 in
 accordance
 to
 the
 study-specific
 monitoring
 plan. 
Monitoring
 visits
 may
 be
 conducted
 periodically
 to
 assess
 site 
study
 progress,
 the
 Investigator’s
 
adherence
 to
 the
 CIP,
 regulatory
 compliance
 including
 but
 not
 limited
 to
 Ethics
 Committee 
approval
 and
 review
 of
 the
 study,
 maintenance
 of
 records
 and
 reports,
 and
 review
 of
 source
 
documents
 against
 subject
 CRFs.
 Monitors
 review
 regulatory
 and
 study
 compliance 
of
 study
 sites 
by
 identifying
 findings
 of
 non-compliance
 and
 communicating
 those
 findings
 along
 with
 
recommendations
 for
 preventative/corrective
 actions
 to
 site 
personnel.
 
 Monitors
 may
 work
 with
 
study
 personnel
 to
 determine
 appropriate
 corrective
 action
 recommendations
 and
 to
 identify
 
trends
 within
 the
 study
 or
 at
 a
 particular
 site.
 
14.2. Data Management 
Data
 will
 be
 collected
 using
 an
 electronic
 data
 management
 system
 for
 clinical
 studies.
 
 eCRF
 data
 
will
 be
 stored
 in
 a
 secure,
 password-protected
 database
 which
 will
 be
 backed
 up
 nightly.
 
 Data
 will
 
be
 reviewed
 using
 programmed
 and
 manual
 data
 checks.
 
 Data
 queries
 will
 be
 made
 available
 to
 
sites
 for
 resolution.
 
  
Data
 collected
 by
 Holters,
 Patient
 Activated
 Ambulatory
 Monitors 
and
 ECGs
 will
 be
 managed
 and
 
over-read
 by
 a
 core
 lab.
 
 Final
 classification
 of
 recurrent
 AF/AT/AFL
 will
 be
 stored
 in
 the
 study
 
database. 

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Study
 management
 reports
 may
 be
 generated
 to
 assess
 data
 quality
 and
 study
 progress.
 
 At
 the
 
end
 of
 the
 study,
 the
 data
 will
 be
 frozen
 and
 will
 be
 retained
 per
 Medtronic
 standards
 and
 applicable
 
regulations.
 
All
 records
 and
 other
 information
 about
 subjects
 participating
 in
 the
 study
 will
 be
 treated
 as
 
confidential.
 Data
 will
 be
 transferred
 and
 processed
 by
 Medtronic
 or
 a
 third
 party
 designated
 by
 
Medtronic
 in
 a
 key
 coded
 form,
 unless
 it’s
 impossible
 to
 make
 it
 anonymous,
 for
 instance,
 where
 
the
 subject’s
 name
 cannot
 be
 removed
 from
 the
 data
 carrier,
 such
 as
 fluoroscopy
 images.
 
 In
 the
 
case
 that
 de-identifying
 is
 impossible
 or
 involves
 a
 disproportionate
 effort,
 files
 containing
 
personal
 data
 of
 subjects
 shall
 only
 be
 made
 accessible
 to
 authorized
 persons
 (secured
 role-based
 
access). 
Procedures
 in
 the
 CIP
 require
 source
 documentation.
 
 Source
 documentation
 will
 be
 maintained
 at
 
the
 study
 site.
 Source
 documents,
 which
 may
 include
 worksheets,
 quality
 of
 life
 questionnaires,
 
subject
 medical
 records,
 log 
files,
 must
 be
 created
 and
 maintained
 by
 the
 investigational
 site 
team.
  
The
 data
 reported
 on
 the
 eCRFs
 shall
 be
 derived
 from
 source
 documents
 and
 be
 consistent
 with
 
these
 source
 documents,
 and
 any
 discrepancies
 shall
 be
 explained
 in
 writing.
 
 The
 eCRF
 may
 be
 
considered
 source
 for
 the
 following
 data
 collection
 elements:
 
•  Database
 generated
 subject
 reference
 ID 
•  Esophageal
 temperature 
•  Investigator
 assessment
 of
 adverse
 event
 or
 death
 relatedness
 and
 severity 
•  Date
 site 
became
 aware
 of
 the
 adverse
 event,
 non-subject
 adverse
 event,
 device
 
deficiency
 or
 death 
•  Reason
 for
 study
 deviation 
•  Investigator’s
 assessment
 of
 conduction
 block 
 
When
 copies
 or
 printouts
 of
 the
 source
 documents
 are
 made,
 site 
personnel
 must
 ensure
 that
 all
 
copies
 or
 printouts
 of
 original
 source
 documents 
are
 certified
 copies 
(i.e.,
 signed
 and
 dated
 
including
 a
 statement
 of
 true
 reproduction).
 
The
 sponsor
 or
 a
 regulatory
 authority
 may
 audit
 or
 inspect
 the
 study
 site 
to
 evaluate
 the
 conduct
 
of
 the
 study.
 The
 clinical
 Investigator(s)/institution(s)
 shall
 allow
 study
 related
 monitoring,
 audits,
 
Ethics
 Committee 
review
 and
 regulatory
 inspection
 by
 providing
 direct
 access
 to
 source
 
data/documents. 
 
Copies
 of
 source
 documents
 will
 be
 requested
 to
 support
 event
 adjudication
 by
 the
 Clinical
 Events
 
Committee.
 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
 onto
 the
 
relevant
 CRF
 page. 

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14.3. Confidentiality 
All
 records
 and
 other
 information
 about
 subjects
 participating
 in
 the
 study
 will
 be
 treated
 as
 
confidential. 
See
 Section
 14.2 
for
 further
 information. 
14.4. Liability 
Australia: 
Medtronic
 Australasia
 Pty
 Ltd
 is
 an
 indirectly
 owned
 subsidiary
 of
 Medtronic,
 Inc.,
 which
 
maintains
 appropriate
 clinical
 study
 liability
 insurance
 coverage
 as
 required 
under
 applicable
 laws
 
and
 regulations
 and
 will
 comply
 with
 applicable
 local
 law
 and
 custom
 concerning 
specific
 insurance
 
coverage.
 If 
required,
 a
 Clinical
 Study
 insurance
 statement/certificate
 will
 be
 provided 
to
 the
 Ethics
 
Committee. 
 
Canada:
 Medtronic
 Canada
 ULC
 is
 an
 indirectly
 owned
 subsidiary
 of
 Medtronic,
 Inc.,
 which
 
maintains
 appropriate
 general
 liability
 insurance
 coverage
 as
 required
 under
 applicable
 laws
 and
 
regulations
 and
 will
 comply
 with
 applicable
 local
 law
 and
 custom
 concerning
 specific
 insurance
 
coverage.
 If
 required,
 a
 General
 Liability
 insurance
 statement/certificate
 will
 be
 provided
 to
 the
 
Ethics
 Committee. 
 
Europe:
 Medtronic
 Bakken
 Research
 Center
 B.V.
 is
 an
 indirectly
 owned
 subsidiary
 of
 Medtronic,
 
Inc.,
 which
 maintains
 appropriate
 clinical
 study
 liability
 insurance
 coverage
 as
 required
 under
 
applicable
 laws
 and
 regulations
 and
 will
 comply
 with
 applicable
 local
 law
 and
 custom
 concerning
 
specific
 insurance
 coverage.
 If
 required,
 a
 Clinical
 Trial
 insurance
 statement/certificate
 will
 be
 
provided
 to
 the
 Ethics
 Committee 
and/or
 Competent
 Authority
 (CA).
 
Japan:
 Medtronic
 Japan
 Co.
 Ltd.
 maintains
 appropriate
 clinical
 trial
 liability
 insurance
 coverage
 as
 
required
 under
 applicable
 laws
 and
 regulations.
 
 Documentation
 explaining
 compensation
 to
 the
 
subjects
 in
 the
 event
 of
 study-related
 injuries
 will
 be
 submitted
 to
 Ethics
 Board.
 
 Information
 
regarding
 insurance,
 warranty
 and
 compensation
 will
 be
 provided
 under
 separate
 cover. 
US:
 Medtronic,
 Inc.
 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
 Trial
 Insurance
 statement/certificate
 will
 be
 
provided
 to
 the
 IRB. 
 
The
 study
 is
 conducted
 in
 multiple
 countries;
 therefore,
 reimbursement
 and
 indemnification
 will
 be
 
addressed
 on
 a
 country
 specific
 basis
 in
 the
 study
 documents
 and
 site 
Clinical
 Trial
 Agreements. 
14.5. CIP Amendments 
Approval
 of
 subsequent
 revisions
 to
 the
 CIP
 is
 required
 at
 each
 study
 site 
from
 the
 following
 
groups
 prior
 to
 implementation
 of
 the
 revised
 CIP
 at
 the
 site:
 

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•  Medtronic 
•  Principal
 Investigators
 (where
 required
 by
 local
 law) 
•  Geography-specific
 regulatory
 authorities
 (if
 regulatory
 approval
 is
 required) 
•  An
 independent
 Ethics
 Committee 
 
If
 a
 CIP
 amendment
 occurs,
 site 
personnel
 will
 need
 to
 be
 re-trained
 as
 necessary,
 and
 will
 need
 to
 
submit
 any
 changes
 to
 their
 Ethics
 Committee 
as
 required
 by
 the
 committee.  
14.6. Record Retention and Reports 
Medtronic
 records
 and
 reports
 will
 be
 maintained
 in
 a
 password-protected
 document
 management
 
system,
 and
 paper
 documents
 (where
 applicable)
 will
 be
 stored
 in
 secured
 file
 cabinets
 at
 
Medtronic
 during
 the
 course
 of
 this
 study.
 After
 closure
 of
 the
 study
 Medtronic
 will
 archive
 records
 
and
 reports
 per
 Medtronic
 standards
 and
 applicable
 regulations.
 
14.6.1.  Investigator Records 
The
 Investigator,
 or
 in
 Japan,
 the
 record
 keeping
 manager
 at
 the
 study
 site,
 is
 responsible
 for
 the
 
preparation
 and
 retention
 of
 the
 records
 cited
 below.
 
 All
 of
 the
 below
 records,
 with
 the
 exception
 
of
 case
 history
 records
 and
 eCRFs,
 should
 be
 kept
 in
 the
 Investigator
 Site
 File
 (i.e.,
 the
 study
 binder
 
provided
 to
 the
 Investigator)
 or
 Subject
 Study
 Binder.
 
 CRFs
 must
 be
 maintained
 and
 signed
 
electronically
 within
 the
 electronic
 data
 capture
 system
 during
 the
 study.
 
  
The
 following
 records
 are
 subject
 to
 inspection
 and
 must
 be
 retained
 for
 a
 period
 of
 two
 years
 (or
 
longer
 as
 local
 law,
 regulations, 
or
 hospital
 administration
 requires)
 after
 the
 date
 on
 which
 the
 
investigation
 is
 terminated
 or
 the
 date
 that
 the
 records
 are
 no
 longer
 required
 for
 purposes
 of
 
supporting
 a
 pre-market
 approval
 application. 
•  All
 correspondence
 between
 the 
Ethics
 Committee,
 sponsor,
 monitor,
 local
 regulatory
 
agencies
 and
 the
 Investigator
 that
 pertains
 to
 the
 investigation,
 including
 required
 reports 
•  Subject’s
 case
 history
 records,
 including:
  
o IC
 Form
 signed
 and
 dated
 by
 subject
  
  In
 Europe
 and
 Japan,
 personally
 signed
 by
 subject
 and
 Investigator.
 
  
  In
 Japan,
 it
 is
 acceptable
 to
 retain
 only
 the
 signature
 page
 with
 the
 version
 
number
 of
 the
 IC
 Form.) 
o Observations
 of
 adverse
 events
 and
 device
 deficiencies 
o Medical
 history 
o Procedure
 and
 follow-up
 data 
o Documentation
 of
 the
 dates
 and
 rationale
 for
 any
 deviation
 from
 the 
CIP 
•  Reports
 of
 adverse
 events 

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•  Electronically
 signed
 and
 dated
 CRFs 
•  Blank
 case
 report
 forms
 (Australia
 and
 Europe
 only) 
•  Subject
 screening
 logs
 (if
 used)
 and
 subject
 identification
 logs 
•  List
 of
 investigation
 sites
 
•  Financial
 disclosure
 of
 Investigators 
•  Device
 Disposition
 Logs 
•  Shipping
 records
 of
 investigational
 devices 
•  Investigational
 device
 accountability
 logs 
•  All
 approved
 versions
 of
 the
 CIP,
 IC,
 and
 Investigator’s
 Brochure 
•  Signed
 and
 dated
 Clinical
 Trial
 Agreement
 and
 Investigator
 Statement 
•  Current
 signed
 and
 dated
 curriculum
 vitae
 of: 
o Investigators
 (all
 countries/geographies) 
o Key
 members
 of
 investigation
 site 
team
 (Australia
 and
 Europe
 only) 
•  Documentation
 of
 delegated
 tasks 
•  Ethics
 Committee 
approval
 documentation.
 Written
 information
 that
 the
 Investigator
 or
 
other
 study
 staff,
 when
 member
 of
 the
 Ethics
 Committee,
 did
 not
 participate
 in
 the
 
approval
 process.
 Approval
 documentation
 must
 include
 the
 Ethics
 Committee 
composition,
 in
 Europe
 and
 where
 required
 per
 local
 law.
  
•  Regulatory
 authority
 notification,
 correspondence
 and
 approval,
 where
 required
 per
 local
 
law 
•  Study
 training
 records
 for
 site 
staff 
•  Insurance
 certificates
 (where
 requested
 by
 the 
Ethics
 Committee
 or
 CA) 
•  Any
 other
 records
 that
 FDA
 or 
local
 regulatory
 agencies
 require
 to
 be
 maintained 
•  Final
 Study
 Report
 including
 the
 statistical
 analysis 
14.6.2.  Investigator Reports 
The
 Investigator
 is
 responsible
 for
 the
 preparation
 (review
 and
 signature)
 and
 submission
 to
 the
 
sponsor
 of
 all
 case
 report
 forms,
 adverse
 events,
 device
 deficiencies,
 deaths,
 and
 any
 deviations
 
from
 the
 CIP.
 
 If
 any
 action
 is
 taken
 by
 an
 Ethics
 Committee 
with
 respect
 to
 this
 clinical
 study,
 
copies
 of
 all
 pertinent
 documentation
 must
 be
 forwarded
 to
 Medtronic
 in
 a
 timely
 manner.
 Reports
 
are
 subject
 to
 inspection
 and
 to
 the
 retention
 requirements
 as
 described
 above
 for
 Investigator
 
records.
  
The
 Investigator 
shall
 prepare
 and
 submit
 in
 a
 complete,
 accurate
 and
 timely
 manner
 the
 reports
 
listed
 in
 this
 section 
and
 per
 local
 regulations.
 

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14.6.3.  Sponsor Records 
Medtronic
 shall
 maintain
 the
 following
 accurate,
 complete,
 and
 current
 records: 
•  All
 correspondence
 which
 pertains
 to
 the
 investigation 
•  Investigational
 Device
 Disposition
 Logs 
•  Signed
 Clinical 
Trial
 Agreements,
 financial
 disclosure
 of
 Investigators,
 and
 delegated
 task 
list 
 
•  Current
 signed
 and
 dated
 curriculum
 vitae
 of
  
o Investigators
 (all
 countries/geographies) 
o Key
 members
 of
 the
 investigation
 site 
team
 (Australia
 and
 Europe
 only) 
•  All
 approved
 versions
 of
 the
 IC
 Form,
 and
 other
 information
 provided
 to
 the
 subjects
 and
 
advertisements,
 including
 translations 
•  All
 approved
 versions
 of
 the
 Clinical
 Investigation
 Plan,
 study
 related
 reports,
 and
 
Investigator’s
 Brochure 
•  All
 case
 report
 forms
 and
 supporting
 documentation
 submitted
 by
 investigator,
 samples
 of
 
Informed
 Consent
 Forms,
 and
 other
 information
 provided
 to
 the
 subjects 
•  Copies
 of
 all
 Ethics
 Committee 
approval
 letters
 and
 relevant
 Ethics
 Committee 
correspondence
 and
 Ethics
 Committee 
voting
 list/roster/letter
 of
 assurance 
•  Names
 of
 the
 institutions
 in
 which
 the 
clinical
 study
 will
 be
 conducted 
•  Regulatory
 authorities
 correspondence,
 notification
 and
 approval
 as
 required
 by
 national
 
legislation 
•  Insurance
 certificates
 (where
 requested
 by
 the
 Ethics
 Committee) 
•  Shipping
 records
 of
 investigational
 devices 
•  Investigational
 device
 accountability
 logs 
•  Names/contact
 addresses
 of
 monitors 
•  Monitoring
 visit
 reports
 and
 follow-up
 letters 
•  Forms
 for
 reporting
 any
 adverse
 events
 and
 adverse
 device
 effects 
•  Statistical
 analyses
 and
 underlying
 supporting
 data 
•  Final
 report
 of
 the
 clinical 
investigation 
•  Study
 training
 records
 for
 site 
personnel
 and
 Medtronic
 personnel
 involved
 in
 the
 study 
•  Any
 other
 records
 that
 local
 regulatory
 agencies
 require
 to
 be
 maintained 
14.6.4.  Sponsor Reports 
Medtronic
 shall
 prepare
 and
 submit
 the
 following
 complete,
 accurate,
 and
 timely
 reports
 listed
 in
 
the
 tables
 below
 (by
 geography).
 
 In
 addition
 to
 the
 reports
 listed
 below,
 Medtronic
 shall,
 upon
 
request
 of
 reviewing
 Ethics
 Committee,
 regulatory
 agency
 or
 FDA,
 provide
 accurate,
 complete
 and
 
current
 information
 about
 any
 aspect
 of
 the
 investigation.
 Safety
 data
 reporting
 requirements
 are
 
listed
 in
 Section 
10.
 

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Medtronic
 records
 and
 reports
 will
 be
 maintained
 in
 a
 password-protected
 document
 management
 
system,
 and
 paper
 documents
 (where
 applicable)
 will
 be
 stored
 in
 stored
 in
 secured
 file
 cabinets
 at
 
Medtronic
 during
 the
 course
 of
 the
 study.
  
After
 closure
 of
 the 
study
 Medtronic
 will
 archive
 records
 and
 reports
 per
 Medtronic
 standards
 and
 
applicable
 regulations.
 
14.7. Publication and Use of Information 
Publications
 from
 the
 study
 will
 be
 handled
 according
 to
 Medtronic
 Global
 Standard
 Operating
 
Procedures
 and
 as
 indicated
 in
 the
 Clinical
 Trial
 Agreement. 
Publication
 Committee 
Medtronic
 may
 form
 the
 PULSED
 AF
 Publication
 Committee
 from
 the
 Steering
 Committee
 and/or
 
study
 Investigators.
 
 Medtronic
 personnel
 may
 serve
 as
 members
 of
 the
 committee.
 This
 
committee
 will
 manage
 study
 publications
 with
 the
 goal
 of
 publishing
 findings
 from
 the
 data.
 The
 
Publication
 Committee
 will
 develop
 the
 final
 Publication
 Plan
 as
 a
 separate
 document.
 
  
The
 Publication
 Committee’s
 role
 is
 to:
 1)
 manage
 elements
 addressed
 in
 the
 publication
 plan
 as
 
outlined
 in
 this
 section,
 2)
 develop
 the
 final
 Publication
 Plan
 under
 separate
 cover,
 3)
 execute
 the
 
Publication
 Plan,
 4)
 oversee
 the
 publication
 of
 primary,
 secondary
 and
 ancillary
 study
 results,
 5)
 
review
 and
 prioritize
 publication
 proposals,
 6)
 provide
 input
 on
 publication
 content,
 and
 7)
 
determine
 authorship.
 
 In
 addition,
 the
 committee
 will
 apply
 and
 reinforce
 the
 authorship
 guidelines
 
set
 forth
 in
 the
 Publication
 Plan.
 
  
Membership
 in
 the
 Publication
 Committee
 does
 not
 guarantee
 authorship.
 
 The
 committee
 will
 
meet
 as
 needed. 
Management
 of
 Primary,
 Secondary
 and
 Ancillary
 Publications 
The
 Publication
 Committee
 reviews,
 prioritizes,
 and
 manages
 all
 publications
 including
 primary,
 
secondary
 and
 ancillary
 publications.
 
 Primary
 and
 secondary
 publications
 are
 those
 that
 address
 
analyses
 of
 any
 or
 all
 primary
 objectives
 or
 secondary
 objectives,
 respectively,
 as
 specified
 in
 the
 
Clinical
 Investigation
 Plan.
  
An
 ancillary
 publication
 is
 any
 publication
 that
 does
 not
 address
 the
 study
 objectives
 identified
 in
 
the
 Clinical
 Investigation
 Plan.
 
 They
 include
 publications
 proposed
 and
 developed
 by
 other
 
Medtronic
 departments
 or
 entities,
 clinicians
 participating
 in
 this
 clinical
 study,
 and
 clinicians
 not
 
participating
 in
 this
 clinical
 study.
 
 The
 committee
 will
 work
 with
 Medtronic
 to
 ensure
 that
 requests
 
do
 not
 present
 conflicts
 with
 other
 proposals,
 are
 not
 duplicative,
 and
 to
 determine
 which
 ancillary
 
publication
 proposals,
 if
 any,
 will
 be
 supported.
 
  

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The
 committee
 may
 decide
 that
 no
 publications,
 including
 abstracts,
 will
 be
 published
 prior
 to
 the
 
end
 of
 the
 study
 or 
with
 individual
 site 
data.
 
 Requests
 for
 publications
 on
 study
 objectives
 utilizing
 
subset
 data
 (e.g.,
 regional)
 will
 be
 evaluated
 for
 scientific
 validity
 and
 the
 ability
 of
 Medtronic
 to
 
provide
 resources.
 
  
Criteria
 for
 Determining
 Authorship 
Publications
 will
 adhere
 to
 authorship
 criteria
 defined
 by
 the
 International
 Committee
 of
 Medical
 
Journal
 Editors
 (ICMJE,
 Uniform
 requirements
 for
 manuscripts
 submitted
 to
 biomedical
 journals,
 
www.icmje.org).
 
 Individual
 authorship
 criteria
 defined
 by
 the
 target
 journal
 or
 conference
 will
 be
 
followed
 when
 it
 differs
 from
 ICMJE
 criteria. 
Authors,
 including
 Medtronic
 personnel,
 must
 at
 a
 minimum
 meet
 all
 of
 the
 conditions
 below: 
•  Substantial
 contribution
 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
 
 
Decisions
 regarding
 authorship
 and
 contributor-ship
 will
 be
 made
 by
 the
 committee.
 The
 selected
 
authors
 will
 be
 responsible
 for
 drafting
 the
 publication.
 All
 selected
 authors
 must
 fulfill
 the
 
authorship
 conditions
 stated
 above
 to
 be
 listed
 as
 authors,
 and
 all
 contributors
 who
 fulfill
 the
 
conditions
 must
 be
 listed
 as
 authors. 
All
 Investigators
 not
 listed
 as
 co-authors
 will
 be
 acknowledged
 as
 the
 “Medtronic
 PULSED
 AF 
Study
 
Investigators”
 and
 will
 be
 individually
 listed
 according
 to
 the
 guidelines
 of
 the
 applicable
 scientific
 
journal
 when
 possible
 and
 affiliation.
 Any
 other
 contributors
 will
 be
 acknowledged
 by
 name
 with
 
their
 specific
 contribution
 indicated. 
Transparency 
Transparency
 of
 study
 results
 will
 be
 maintained
 by
 the
 following
 means: 
•  A
 final
 report,
 describing
 the
 results
 of
 all
 objectives
 and
 analysis,
 will
 be
 distributed
 to
 all
 
Investigators,
 Ethics
 Committees
 and
 Regulatory
 Authorities
 of
 participating
 countries
 
when
 required
 by
 local
 law 
•  Registering
 and
 posting
 the
 study
 results
 on
 public
 registries
 (e.g.,
 ClinicalTrials.gov,
 UMIN) 
based
 on
 the
 posting
 rules
 stipulated,
 as
 required
 by
 local
 law 
 
•  Submitting
 for
 publication
 the
 primary
 study
 results
 after
 the
 study
 ends
  

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•  Disclosing
 conflicts
 of
 interest
 (e.g.,
 financial)
 of
 the
 co-authors
 of
 publications
 according
 
to
 the
 policies
 set
 forth
 by
 the
 corresponding
 journals
 and
 conferences
  
•  Making
 an
 individual
 site’s
 study
 data
 accessible
 to
 the
 corresponding
 Investigator
 after
 the
 
completion
 of
 the
 study,
 if
 requested 
14.8. Investigator / Site Selection 
The
 role
 of
 the
 Principal
 Investigator
 is
 to
 implement
 and
 manage
 the
 day-to-day
 conduct
 of
 the
 
clinical
 investigation
 as
 well
 as
 ensure
 data
 integrity
 and
 the
 rights,
 safety
 and
 well-being
 of
 the
 
subjects
 involved
 in
 the
 clinical
 investigation. 
The
 minimum
 required
 criteria
 for
 a
 Principal
 Investigator
 and
 proposed
 investigational
 center
 are
 
listed
 below: 
•  Principal
 investigator
 has
 an
 MD
 degree,
 or
 equivalent,
 with
 a
 Fellowship
 in
 
Electrophysiology
 and
 a
 minimum
 of
 2
 years
 of
 experience
 treating
 atrial
 fibrillation
 in
 
patients
 using
 endocardial
 techniques. 
•  Principal
 Investigator
 must
 participate
 in
 a
 Medtronic
 physician
 engagement
 event
 with
 
hands
 on
 use
 of
 the
 Pulsed
 Field
 Ablation
 System,
 prior
 to
 enrolling
 a
 subject. 
•  Principal
 Investigator
 has
 adequate
 time
 and
 resources
 to
 conduct
 the
 study
 throughout
 
the
 duration
 of
 the
 study,
 including,
 as
 applicable,
 facilities,
 and
 qualified
 staff. 
•  Principal
 Investigator
 has
 access
 to
 an
 adequate
 number
 of
 subjects
 in
 the
 study
 specific
 
patient
 population
 to
 enroll
 1-2
 subjects
 per
 month. 
•  Principal
 Investigator
 has
 the
 ability
 to
 comply
 with
 the
 Clinical
 Investigation
 Plan,
 and
 
applicable
 REB/EC/IRB
 and
 regulatory
 requirements. 
•  Principal
 Investigator
 is
 not
 debarred,
 disqualified
 or
 working
 under
 sanctions. 
14.9. Site Activation 
During
 the
 activation
 process
 (prior
 to
 subject
 enrollment),
 Medtronic
 will
 train
 site 
personnel
 on
 
the 
CIP,
 relevant
 standards
 and
 regulations,
 informed 
consent,
 and
 on
 data
 collection
 and
 
reporting
 tools.
 If 
new
 members
 join
 the
 study
 site 
team,
 they
 will
 receive
 training
 on
 the
 applicable
 
clinical
 study 
requirements
 relevant
 to
 their
 role
 before
 contributing
 to
 the
 clinical
 study. 
Prior
 to
 performing
 study
 related
 activities,
 all
 local
 regulatory
 requirements
 shall
 be
 fulfilled,
 
including, 
but
 not
 limited
 to
 the
 following: 
•  Ethics
 Committee 
approval
 (and
 membership
 roster/voting
 list)
 of
 the
 current
 version
 of
 
the
 CIP,
 Informed
 Consent
 Form,
 subject
 facing
 materials,
 Investigator 
Brochure
 as
 
required
 by
 local
 laws
 and
 other
 materials,
 as
 necessary. 
•  Regulatory
 authority
 approval
 or
 notification
 (as
 required
 per
 local
 law) 
•  Fully
 executed
 Clinical
 Trial
 Agreement
 (CTA)
 and
 Investigator
 Statement
 where
 applicable 
•  Financial
 Disclosure
 of
 Investigators 

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•  Curriculum
 Vitae
 (CV)
 of
 Investigators
 and
 key
 members
 of
 the
 investigation
 site 
team
 (as 
required
 by
 local
 law)
 (in
 Australia
 and
 Europe,
 CVs
 are
 required
 for
 the
 Principal
 
Investigator
 and
 all
 site
 personnel
 who
 have
 been
 delegated
 tasks) 
•  Documentation
 of
 delegated
 tasks 
•  Documentation
 of
 study
 training 
(including
 CIP,
 IB
 if
 available,
 informed
 consent
 process,
 
data
 collection
 tools,
 regulations
 and
 product
 training) 
 
Documentation
 of
 delegated
 tasks
 must
 be
 completed
 prior
 to
 any
 person
 other
 than
 the
 Principal 
Investigator
 performing
 study
 activities. 
Additional
 requirements
 imposed
 by
 the
 Ethics
 Committee 
and
 regulatory
 authority
 shall
 be
 
followed. 
Medtronic
 contracts
 with
 participating
 institutions/investigators
 through
 a
 Clinical
 Trial
 
Agreement
 that
 defines
 the
 scope
 and
 responsibilities
 and
 associated
 compensation
 related
 to
 
carrying
 out
 the
 obligations
 under
 a
 clinical
 study
 sponsored
 by
 Medtronic. 
In
 addition,
 all
 participating
 site 
staff
 must
 be
 trained
 on
 the
 current
 version
 of
 the
 CIP
 and
 must
 be 
delegated
 by
 the
 Principal
 Investigator
 to
 perform
 study
 related
 activities. 
Medtronic
 will
 provide
 each
 study
 site 
with
 documentation
 of
 study
 site/Investigator
 readiness
 in
 
the 
form
 of
 a
 site 
readiness
 letter;
 this
 letter
 must
 be
 received
 prior
 to
 subject
 enrollment. 
Additional 
site 
personnel
 included
 after
 the
 initial
 activation
 will
 be
 notified
 when
 all
 requirements
 
have
 been 
completed. 
14.10. Suspension or Early Termination 
14.10.1. Early Termination or Suspension 
Early
 termination
 is
 the
 closure
 of
 a
 clinical
 study
 that
 occurs
 prior
 to
 meeting
 defined
 endpoints.
 
This
 is
 possible
 for
 the
 whole
 study
 or
 a
 single
 site.
 
 Suspension
 is
 a
 temporary
 postponement
 of
 
study
 activities
 related
 to
 enrollment.
 
 This
 is
 possible
 for
 the
 whole
 study
 or
 a
 single
 site.
 
 If
 
suspension
 is
 lifted,
 the
 Investigator
 shall
 assess
 whether
 or
 not
 to
 continue
 the
 clinical
 study
 at
 
their
 site.
 
14.10.2. Study-wide Termination or Suspension 
Possible
 reasons
 for
 considering
 study
 termination
 or
 suspension
 of
 the
 study
 include
 but
 are
 not
 
limited
 to: 

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•  Adverse
 events
 associated
 with
 the
 system
 or
 product
 under
 investigation
 which
 might
 
endanger
 the
 safety
 or 
welfare
 of
 the
 subject 
•  Observed/suspected
 performance
 different
 from
 the
 product’s
 design
 intent 
•  Decision
 by
 Medtronic
 or
 regulatory
 body
 (where
 the
 study
 is
 operating
 under
 regulatory
 
body
 authority)
  
•  Technical
 issues
 during
 the
 manufacturing
 process 
14.10.3. Investigator/Center Termination or Suspension 
Possible
 reasons
 for
 clinical
 Investigator
 or
 center/site 
termination
 or
 suspension
 include
 but
 are
 
not
 limited
 to: 
•  Failure
 to
 obtain
 Ethics
 Committee 
annual
 renewal
 of
 the
 study 
•  Persistent
 non-compliance
 to
 the
 Clinical
 Investigation
 Plan
 (e.g.
 failure
 to
 adhere
 to
 
inclusion/exclusion
 criteria,
 failure
 to
 follow
 subjects
 per
 visit
 schedule)
  
•  Lack
 of
 enrollment 
•  Noncompliance
 to
 regulations
 and
 the
 terms
 of
 the
 Clinical
 Trial
 Agreement
 (e.g.
 failure
 to
 
submit
 data
 in
 a
 timely
 manner,
 failure
 to
 resolve
 data
 queries
 and
 monitoring
 findings
 in
 a
 
timely
 manner)
  
•  Ethics
 Committee 
suspension
 of
 the
 site 
•  Fraud
 or
 fraudulent
 misconduct
 is
 discovered
 (as
 defined
 by
 local
 law
 and
 regulations)
  
•  Investigator
 request
 (e.g.
 no
 longer
 able
 to
 support
 the
 study) 
14.10.4. Procedures for Termination or Suspension 
14.10.4.1.  
Medtronic-Initiated and Regulatory Authority-Initiated 
•  Medtronic
 will
 promptly
 inform
 the
 clinical
 Investigators,
 or
 in
 Japan
 the
 HOMI,
 of
 the
 
termination
 or
 suspension
 and
 the
 reasons
 and
 inform
 the
 regulatory
 authority(ies)
 where
 
required. 
•  In
 the
 case
 of
 study
 termination
 or
 suspension
 for
 reasons
 other
 than
 a
 temporary
 Ethics
 
Committee 
approval
 lapse,
 the
 Investigator
 will
 promptly
 inform
 the
 Ethics
 Committee.
 
 In
 
Japan,
 the
 HOMI
 will
 promptly
 inform
 the
 Investigator
 and
 Ethics
 Board. 
•  In
 the
 case
 of
 study
 termination,
 the
 Investigator
 must
 inform
 the
 subjects
 and
 may
 inform
 
the
 personal 
physician
 of
 the
 subjects
 to
 ensure
 appropriate
 care
 and
 follow-up
 is
 provided 
•  In
 the
 case
 of
 a
 study
 suspension,
 subject
 enrollment
 must
 stop
 until
 the
 suspension
 is
 
lifted
 by
 Medtronic. 
•  In
 the
 case
 of
 a
 study
 suspension,
 enrolled
 subjects
 should
 continue
 to
 be
 followed
 out
 of
 
consideration
 of
 their
 safety,
 rights
 and
 welfare. 

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14.10.4.2.  
Investigator-Initiated 
•  The
 Investigator
 will
 inform
 Medtronic
 and
 provide
 a
 detailed
 written
 explanation
 of
 the
 
termination
 or
 suspension.
 
 In
 Japan,
 the
 Investigator
 will
 promptly
 inform
 the
 HOMI
 and
 
the
 HOMI
 will
 inform
 Medtronic
 in
 writing. 
•  The
 Investigator
 will
 promptly
 inform
 the
 institution
 (where
 required
 per
 regulatory
 
requirements).
 
•  The
 Investigator
 will
 promptly
 inform
 the
 Ethics
 Committee.
 
•  The
 Investigator
 will
 promptly
 inform
 the
 regulatory
 authorities
 (where
 required
 per
 
regulatory
 requirements). 
•  The
 Investigator
 will
 promptly
 inform
 the
 subjects
 and/or
 the
 personal
 physician
 of
 the
 
subjects
 to
 ensure
 appropriate
 care
 and
 follow-up
 is
 provided. 
•  In
 the
 case
 of
 a
 study
 suspension,
 subjects
 enrolled
 should
 continue
 to
 be
 followed
 out
 of
 
consideration
 of
 their
 safety,
 rights
 and
 welfare. 
 
14.10.4.3.  
Ethics Committee-Initiated 
•  The
 Investigator,
 or
 in
 Japan
 the
 HOMI,
 will
 inform
 Medtronic
 and
 provide
 a
 detailed
 written
 
explanation
 of
 the
 termination
 or
 suspension
 within
 5
 business
 days.
 
 In
 Japan,
 HOMI
 will
 
also
 inform
 the
 Investigator. 
•  Subject
 enrollment
 must
 stop
 until
 the
 suspension
 is
 lifted. 
•  Subjects
 already
 enrolled
 should
 continue
 to
 be
 followed
 in
 accordance
 with
 Ethics
 
Committee 
policy
 or
 its
 determination
 if
 an
 overriding
 safety
 concern
 or
 ethical
 issue
 is
 
involved. 
•  The
 Investigator
 will
 inform
 his/her
 institution
 (where
 required
 per
 local
 requirements). 
•  The
 Investigator
 will
 promptly
 inform
 the
 subjects
 and/or
 the
 personal
 physician
 of
 the
 
subjects,
 with
 the
 rationale
 for
 the
 study
 termination
 or
 suspension. 
•  The
 Investigator
 will
 promptly
 inform
 the
 regulatory
 authorities
 (where
 required
 per
 
regulatory
 requirements). 
 
 

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15. References 
1. Calkins
 H,
 et
 al.,
 2017
 HRS/EHRA/ECAS/APHRS/SOLAECE
 Expert
 Consensus
 Statement
 
on
 Catheter
 and
 Surgical
 Ablation
 of
 Atrial
 Fibrillation,
 Heart
 Rhythm
 (2017),
 
doi:10.10106/j.hrthm.2017.05.012. 
2. Chugh,
 S.
 S.,
 et
 al.
 Worldwide
 epidemiology
 of
 atrial
 fibrillation:
 a
 Global
 Burden
 of
 Disease
 
2010
 Study.
 Circulation
 129,
 837-847,
 doi:10.1161/circulationaha.113.005119
 (2014). 
3. Naccarelli,
 G.
 V.,
 Varker,
 H.,
 Lin,
 J.
 &
 Schulman,
 K.
 L.
 Increasing
 prevalence
 of
 atrial
 
fibrillation
 and
 flutter
 in
 the
 United
 States.
 The
 American
 journal
 of
 cardiology
 104,
 1534-
1539,
 doi:10.1016/j.amjcard.2009.07.022
 (2009). 
4. Zoni-Berisso
 M,
 et
 al.
 Epidemiology
 of
 atrial
 fibrillation:
 European
 perspective.
 Clinical
 
Epidemiology.
 2014;6:213-220.
 doi:10.2147/CLEP.S47385. 
5. Wolf
 P,
 et
 al.
 Atrial
 fibrillation
 as
 an
 independent
 risk
 factor
 for
 stroke:
 the
 Framingham
 
Study.
 Stroke.
 1991;22(8):983-988. 
6. Ghanbari 
H,
 et
 al.
 Mortality
 and
 cerebrovascular
 events
 after
 radiofrequency
 catheter
 
ablation
 of
 atrial
 fibrillation.
 Heart
 Rhythm.
 2014;11:1503-1511. 
7. Calkins
 H,
 et
 al.
 2012
 HRS/EHRA/ECAS
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 
Surgical
 Ablation
 of
 Atrial
 Fibrillation:
 Recommendations
 for
 Patient
 Selection,
 Procedural
 
Techniques,
 Patient
 Management
 and
 Follow-up,
 Definitions,
 Endpoints,
 and
 Research
 Trial
 
Design.
 Heart
 Rhythm
 2012;9:632-696. 
8. January
 C,
 Wann
 L,
 Alpert
 J,
 Calkins
 H,
 et
 al.
 2014
 AHA/ACC/HRS
 guideline
 for
 the
 
management
 of
 patients
 with
 atrial
 fibrillation:
 a
 report
 of
 the
 American
 College
 of
 
Cardiology/American
 Heart
 Association
 Task
 Force
 on
 Practice
 Guidelines
 and
 the
 Heart
 
Rhythm
 Society.
 J
 Am
 Coll
 Cardiol. 
2014. 
9. Raviele,
 et
 al.
 Venice
 Chart
 International
 consensus
 Document
 on
 Atrial
 Fibrillation:
 2011
 
Update.
 J
 Cardiovasc
 Electrophysiol,
 2012;23:890-923. 
10. Jais
 P,
 et
 al.
 Stepwise
 Catheter
 Ablation
 of
 Chronic
 Atrial
 Fibrillation:
 Importance
 of
 
Discrete
 Anatomic
 Sites
 for
 Termination.
 J
 Cardiovasc
 Electrophysiol.
 2006;17:
 S28-S36,
 
Suppl.
 3. 
11. Dong
 JZ,
 Sang
 CH,
 Yu
 RH,
 et
 al.
 Prospective
 randomized
 comparison
 between
 a
 fixed
 
“2C3L”
 approach
 vs.
 stepwise
 approach
 for
 catheter
 ablation
 of
 persistent
 atrial
 fibrillation.
 
Europace.
 doi:10.1093/europace/euv067.
  
12. Wynn
 GJ,
 Panikker
 S,
 Morgan
 M,
 et
 al.
 Effect
 of
 linear
 ablation
 in
 substrate-based
 AF:
 
Results
 of
 the
 substrate
 modification
 with
 ablation
 and
 antiarrhythmic
 drugs
 in
 non-
permanent
 atrial
 fibrillation
 trial.
 Heart
 Rhythm.
 2015;12:1715. 
13. Verma
 A,
 Jiang
 CY,
 Betts
 TR,
 et
 al,
 STAR
 AF
 II
 Investigators.
 Approaches
 to
 Catheter
 
Ablation
 for
 Persistent
 Atrial
 Fibrillation.
 N
 Engl
 J
 Med.
 2015;372:1812-1822. 
14. Scott
 P,
 Silberbauer
 J,
 Murgatroyd
 F.
 The
 impact
 of
 adjunctive
 complex
 fractionated
 atrial
 
electrograms
 ablation
 and
 linear
 lesions
 on
 outcomes
 in
 persistent
 atrial
 fibrillation:
 a
 meta-
analysis.
 Europace
 2016;
 18,
 359-367. 
15. Calkins
 H,
 et
 al.
 HRS/EHRA/ECAS
 Expert
 Consensus
 Statement
 on
 Catheter
 and
 Surgical
 
Ablation
 of
 Atrial
 Fibrillation:
 Recommendations
 for
 personnel,
 Policy,
 Procedures
 and
 
Follow-Up.
 Europace.
 2007;9(6):335-379. 

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16. Avitall,
 B.
 et
 al.
 The
 safety
 and
 efficacy
 of
 multiple
 consecutive
 cryo
 lesions
 in
 canine
 
pulmonary
 veins-left
 atrial
 junction.
 Heart
 rhythm
 1,
 203-209,
 
doi:10.1016/j.hrthm.2004.03.058
 (2004).
  
17. Dinerman,
 J.
 L.,
 Berger,
 R.
 D.
 &
 Calkins,
 H.
 Temperature
 monitoring
 during
 radiofrequency
 
ablation.
 Journal
 of
 cardiovascular
 electrophysiology
 7,
 163-173
 (1996).
 
 
18. Harrison,
 L.
 et
 al.
 Cryosurgical
 ablation
 of
 the
 A-V
 node-His
 bundle:
 a
 new
 method
 for
 
producing
 A-V
 block.
 Circulation
 55,
 463-470
 (1977). 
19. Georgiopoulos,
 G.,
 Tsiachris,
 D.
 &
 Manolis,
 A.
 S.
 Cryoballoon
 ablation
 of
 atrial
 fibrillation:
 a
 
practical
 and
 effective
 approach.
 Clinical
 cardiology
 40,
 333-342,
 doi:10.1002/clc.22653
 
(2017). 
20. Stewart,
 Mark
 T.,
 et
 al.
 "Intracardiac
 pulsed
 field
 ablation:
 proof
 of
 feasibility
 in
 a
 chronic
 
porcine
 model."
 Heart
 rhythm.
 16.5
 (2019):
 754-764. 
21. Howard,
 Brian
 T.,
 et
 al.
 "Pulsed
 Field
 Ablation
 Reduces
 Pulmonary
 Vein
 Stenosis
 Risk:
 An
 
Advanced
 Model
 for
 Assessment
 of
 PV
 Stenosis."
 Circulation
 138.Suppl_1
 (2018):
 A16516-
A16516. 
22. Verma,
 A.,
 et
 al.
 "Pulsed
 field
 ablation-feasibility,
 safety
 and
 comparison
 to
 radiofrequency."
 
EUROPEAN
 HEART
 JOURNAL.
 Vol.
 39.
 GREAT
 CLARENDON
 ST,
 OXFORD
 OX2
 6DP,
 
ENGLAND:
 OXFORD
 UNIV
 PRESS,
 2018. 
23. Attanasio,
 P.
 et
 al.
 Pain
 Reactions
 during
 Pulmonary
 Vein
 Isolation
 under
 Deep
 Sedation:
 
Cryothermal 
versus
 Radiofrequency
 Ablation.
 Pacing
 and
 clinical
 electrophysiology:
 PACE
 
39,
 452-457,
 doi:10.1111/pace.12840
 (2016). 
24. P100010/R017
 “STOP
 AF
 PAS
 Final
 Post-Approval
 Study
 Report”. 
25. Kuck,
 K.
 H.,
 Brugada,
 J.,
 Fürnkranz,
 A.,
 et
 al.
 Cryoballoon
 or
 Radiofrequency
 Ablation
 for
 
Paroxysmal
 Atrial
 Fibrillation.
 New
 England
 Journal
 of
 Medicine 
374,
 2235-2245
 (2016). 
26. Squara,
 F.,
 Zhao,
 A.,
 Marijon,
 E.,
 et
 al.
 Comparison
 between
 radiofrequency
 with
 contact
 
force-sensing
 and
 second-generation
 cryoballoon
 for
 paroxysmal
 atrial
 fibrillation
 catheter
 
ablation:
 a
 multicentre
 European
 evaluation.
 Europace 
17,
 718-724
 (2015). 
27. Schmidt,
 M.,
 Dorwarth,
 U.,
 Straube,
 F.,
 et
 al.
 Cryoballoon
 in
 AF
 ablation:
 impact
 of
 PV
 ovality
 
on
 AF
 recurrence.
 Int
 J
 Cardiol 
167,
 114-120
 (2013). 
28. Providencia,
 R.,
 Defaye,
 P.,
 Lambiase,
 P.,
 et
 al.
 Results
 from
 a
 multicentre
 comparison
 of
 
cryoballoon
 vs.
 radiofrequency
 ablation
 for
 paroxysmal
 atrial
 fibrillation:
 is
 cryoablation
 
more
 reproducible?
 Europace 
19,
 48-57
 (2017). 
29. Dukkipati,
 S.,
 Cuoco,
 F.,
 Kutinsky,
 I.,
 et
 al.
 Pulmonary
 Vein
 Isolation
 Using
 the
 Visually
 
Guided
 Laser
 Balloon:
 A
 Prospective,
 Multicenter,
 and
 Randomized
 Comparison
 to
 
Standard
 Radiofrequency
 Ablation.
 Journal
 of
 the
 American
 College
 of
 Cardiology 
66,
 1350-
1360
 (2015). 
30. Boveda,
 S.,
 Metzner,
 A.,
 Nguyen,
 D.,
 et
 al.
 Single-Procedure
 Outcomes
 and
 Quality-of-Life
 
Improvement
 12
 Months
 Post-Cryoballoon
 Ablation
 in
 Persistent
 Atrial
 Fibrillation:
 Results
 
From
 the
 Multicenter
 CRYO4PERSISTENT
 AF
 Trial.
 Journal
 of
 the
 American
 College
 of
 
Cardiology,
 doi:10.1016/j.jacep.2018.07.007
 (2018). 
31. Tondo,
 C.,
 Iacopino,
 S.,
 Pieragnoli,
 P.,
 et
 al.
 Pulmonary
 Vein
 Isolation
 Cryoablation
 for
 
Persistent
 and
 Long-Standing
 Persistent
 Atrial
 Fibrillation
 Patients.
 Clinical
 Outcomes
 from
 
Real
 Word
 Multicentric
 Observational
 Project.
 Heart
 Rhythm 
15,
 363-368,
 
doi:10.1016/j.hrthm.2017.10.038
 (2017). 

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056-F275, v A Clinical Investigation Plan Template 
32. Aryana,
 A.,
 Baker,
 J.,
 Espinosa
 Ginic
 M.,
 et
 al.
 Posterior
 wall
 isolation
 using
 the
 cryoballoon
 in
 
conjunction
 with
 pulmonary
 vein
 ablation
 is
 superior
 to
 pulmonary
 vein
 isolation
 alone
 in
 
patients
 with
 persistent
 atrial
 fibrillation:
 A
 multicenter
 experience.
 Heart
 Rhythm 
15,
 1121-
1129
 (2018). 
33. Deneke
 T
 et
 al.
 Silent
 cerebral
 events/lesions
 to
 AF
 ablation.
 J
 Cardiovasc
 Electrophysiol,
 
2015;
 26:
 455-463. 
34. Di
 Biase,
 Luigi,
 et
 al.
 "Does
 periprocedural
 anticoagulation
 management
 of
 atrial
 fibrillation
 
affect
 the
 prevalence
 of
 silent
 thromboembolic
 lesion
 detected
 by
 diffusion
 cerebral
 
magnetic
 resonance
 imaging
 in
 patients
 undergoing
 radiofrequency
 atrial
 fibrillation
 
ablation
 with
 open
 irrigated
 catheters?
 Results
 from
 a
 prospective
 multicenter
 
study." 
Heart
 Rhythm 
11.5
 (2014):
 791-798. 
35. Neumann,
 Thomas,
 et
 al.
 "MEDAFI-Trial
 (Micro-embolization
 during
 ablation
 of
 atrial
 
fibrillation):
 comparison
 of
 pulmonary
 vein
 isolation
 using
 cryoballoon
 technique
 vs.
 
radiofrequency
 energy." 
Europace 
13.1
 (2010):
 37-44. 
36. Gaita,
 Fiorenzo,
 et
 al.
 "Incidence
 of
 silent
 cerebral
 thromboembolic
 lesions
 after
 atrial
 
fibrillation
 ablation
 may
 change
 according
 to
 technology
 used:
 comparison
 of
 irrigated
 
radiofrequency,
 multipolar
 nonirrigated
 catheter
 and
 cryoballoon." 
Journal
 of
 cardiovascular
 
electrophysiology 
22.9
 (2011):
 961-968. 
37. Siklódy,
 Claudia
 Herrera,
 et
 al.
 "Incidence
 of
 asymptomatic
 intracranial
 embolic
 events
 after
 
pulmonary
 vein
 isolation:
 comparison
 of
 different
 atrial
 fibrillation
 ablation
 technologies
 in
 a
 
multicenter
 study." 
Journal
 of
 the
 American
 College
 of
 Cardiology 
58.7
 (2011):
 681-688. 
38. Nakamura,
 Tomofumi,
 et
 al.
 "Incidence
 of
 silent
 cerebral
 infarctions
 after
 catheter
 ablation
 
of
 atrial
 fibrillation
 utilizing
 the
 second-generation
 cryoballoon." 
Ep
 Europace 
19.10
 (2016):
 
1681-1688. 
39. Tokuda,
 Michifumi,
 et
 al.
 "Effect
 of
 air
 removal
 with
 extracorporeal
 balloon
 inflation
 on
 
incidence
 of
 asymptomatic
 cerebral
 embolism
 during
 cryoballoon
 ablation
 of
 atrial
 
fibrillation." 
Heart
 rhythm 
14.9
 (2017):
 1291-1296. 
40. Miyazaki,
 Shinsuke,
 et
 al.
 "Thromboembolic
 risks
 of
 the
 procedural
 process
 in
 second-
generation
 cryoballoon
 ablation
 procedures:
 analysis
 from
 real-time
 transcranial
 Doppler
 
monitoring." 
Circulation:
 Arrhythmia
 and
 Electrophysiology10.12
 (2017):
 e005612. 
41. Nakamura,
 Kohki,
 et
 al.
 "Postablation
 cerebral
 embolisms
 in
 balloon‐based
 atrial
 fibrillation
 
ablation
 with
 periprocedural
 direct
 oral
 anticoagulants:
 A
 comparison
 between
 cryoballoon
 
and
 HotBalloon
 ablation." 
Journal
 of
 cardiovascular
 electrophysiology 
30.1
 (2019):
 39-46. 
42. Miyazaki,
 Shinsuke,
 et
 al.
 "Silent
 cerebral
 events/lesions
 after
 second-generation
 
cryoballoon
 ablation:
 How
 can
 we
 reduce
 the
 risk
 of
 silent
 strokes?." 
Heart
 rhythm 
16.1
 
(2019):
 41-48. 
43. Gaita,
 Fiorenzo,
 et
 al.
 "Radiofrequency
 catheter
 ablation
 of
 atrial
 fibrillation:
 a
 cause
 of
 
silent
 thromboembolism?
 Magnetic
 resonance
 imaging
 assessment
 of
 cerebral
 
thromboembolism
 in
 patients
 undergoing
 ablation
 of
 atrial
 fibrillation." 
Circulation 
122.17
 
(2010):
 1667-1673. 
44. Doi,
 Atsushi,
 et
 al.
 "Incidence
 and
 predictors
 of
 silent
 cerebral
 thromboembolic
 lesions
 after
 
catheter
 ablation
 for
 atrial
 fibrillation
 in
 patients
 treated
 with
 direct
 oral
 
anticoagulants." 
Heart
 and
 Vessels 
32.10
 (2017):
 1227-1235. 

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45. Neuzil,
 et
 al.
 Electrical
 reconnection
 after
 pulmonary
 vein
 isolation
 is
 contingent
 on
 contact
 
force
 during
 initial
 treatment:
 results
 from
 the
 EFFICAS
 I
 study.
 Circ
 Arrhythm
 
Electrophysiol.
 (2):327-33. 
46. Kautzner
 J,
 et
 al.
 EFFICAS
 II:
 optimization
 of
 catheter
 contact
 force
 improves
 outcome
 of
 
pulmonary
 vein
 isolation
 for
 paroxysmal
 atrial
 fibrillation.
 Europace.
 2015;
 2015
 
Aug;17(8):1229-1235. 
47. Ahmed,
 et
 al.
 The
 permanency
 of
 pulmonary
 vein
 isolation
 using
 a
 balloon
 cryoablation
 
catheter.
 J
 Cardiovasc
 Electrophysiol.
 2010;21(7):731-737. 
48. Williems,
 et
 al.
 Persistence
 of
 pulmonary
 vein
 isolation
 after
 robotic
 remotenavigated
 
ablation
 for
 atrial
 fibrillation
 and
 its
 relation
 to
 clinical
 outcome.
 J
 Cardiovasc
 Electrophysiol.
 
2010;
 21(10):1079-1084. 
49. Reddy
 VY,
 et
 al.
 Durability
 of
 Pulmonary
 Vein
 Isolation
 with
 Cryoballoon
 Ablation:
 Results
 
from
 the
 Sustained
 PV
 Isolation
 with
 Arctic
 Front
 Advance
 (SUPIR)
 Study.
 J
 Cardiovasc
 
Electrophysiol.
 2015
 May;26(5):493-500. 
50. Kuck
 KR,et
 al.
 Impact
 of
 Complete
 Versus
 Incomplete
 Circumferential
 Lines
 Around
 the
 
Pulmonary
 Veins
 During
 Catheter
 Ablation
 of
 Paroxysmal
 Atrial
 Fibrillation
 Results
 From
 
the
 Gap-Atrial
 Fibrillation–German
 Atrial
 Fibrillation
 Competence
 Network
 1
 Trial.
 Circ
 
Arrhythm
 Electrophysiol.
 2016;
 9e003337. 
51. Medicare
 Physician/Supplier
 Procedure
 Summary
 data.
 Available
 at:
 
https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-
Reports/Physician-Supplier-Procedure-Summary/index.html 
 
 
 

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16. Appendices  
 
Appendix
 A:
 Study-Specific
 Requirements
 by
 Country 
Regulations
 for
 the
 conduct
 of
 clinical
 trials
 vary
 by
 country.
 Study-specific
 requirements 
in
 each
 
country 
not
 outlined
 in
 the
 Clinical
 Investigational
 Plan 
will
 be
 provided
 under
 separate
 cover.
 
 
 
 

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Perforation
 of
 the
 heart
 or
 other
 
organs
 during
 transseptal
 
puncture
 or
 other
 procedures 
Creation
 of
 a
 dissection
 or
 tear
 in 
myocardial
 tissue
 or
 other
 
non-cardiac
 tissues
 during
 the
 ablation
 procedure
 that
 
compromises
 hemodynamic
 stability 
Cardiac
 tamponade 
Pressure
 on
 the
 heart
 as
 a
 result
 of
 a
 significant
 pericardial
 
effusion 
Chest
 discomfort 
Includes
 a
 range
 of
 feeling
 from
 sharp
 stabbing
 to
 dull
 ache
 in
 
the
 chest 
Cough 
Rapid
 expulsion
 of
 air
 from
 the
 lungs 
Embolism 
Introduction
 of
 air,
 formation
 and
 dislodgement
 of
 a
 blood
 
clot
 (thrombus)
 or
 dislodgement
 of
 cholesterol/plaque
 within
 
the
 blood
 vessel,
 which
 travels
 downstream
 into
 small
 
vessels,
 blocking
 blood
 flow
 and
 causing
 temporary
 or
 
permanent
 damage
 to
 organs
 distal
 to
 blockage.
 Emboli
 are
 
known
 to
 cause
 myocardial
 infarction,
 transient
 ischemic
 
attack,
 stroke/cardiovascular
 accident,
 blurred
 vision,
 visual
 
changes,
 paralysis,
 paresis,
 or
 kidney
 damage,
 peripheral
 
ischemia
 and
 may
 ultimately
 lead
 to
 incapacitation
 or
 death.
 
Symptomatic
 and
 non-symptomatic. 
Catheter
 entrapment
 in
 cardiac
 
structures
 requiring
 intervention 
 
Tangling
 of
 the
 catheter
 with 
heart
 tissues
 which
 requires
 
invasive
 intervention,
 including
 surgical
 repair 
Cerebrovascular
 accident
 (CVA)  Blockage
 of
 blood
 flow,
 or
 rupture
 of
 an
 artery,
 to
 the
 brain
 
which
 causes
 sudden
 death
 of
 brain
 cells 
Transient
 ischemic
 attack
 (TIA)  New
 focal
 neurological
 deficit
 with
 rapid
 symptom
 resolution
 
(usually
 1
 to
 2
 hours),
 no
 more
 than
 24
 hours 
Collateral
 damage
 to
 the
 
conduction
 system
 or
 coronary
 
vasculature 
Coronary
 artery
 injury
 due
 to
 occlusion
 or
 stenosis
 of
 the 
coronary
 arteries
 that
 may
 require
 balloon
 dilation,
 
nitroglycerin
 use,
 or
 stenting.
 Prolonged
 injury
 may
 lead
 to 
myocardial
 infarction. 
Collateral
 damage
 to
 the
 conduction
 system
 includes
 
unintended
 damage
 to
 the
 cardiac
 conduction
 system
 (e.g.,
 
atrioventricular
 node
 or
 sinus
 node).
 
Death 
Complication
 or
 deterioration
 of
 health
 ultimately
 leading
 to
 a
 
patient’s
 death 
Esophageal
 damage
 (including
 
atrial
 esophageal
 fistula) 
Damage
 to
 the
 esophagus,
 including
 ulcer
 and
 
atrioesophageal
 fistula
 (an
 abnormal
 passageway
 between
 
the
 heart 
and
 esophagus) 
Hemoptysis 
Coughing
 up
 blood
 or
 blood-stained
 mucus 
Hypotension/
 hypertension  
Low/high
 blood
 pressure 
Infections 
Invasion
 and
 multiplication
 of
 microorganisms
 (e.g.
 bacteria,
 
virus)
 not
 normally
 present
 within
 the
 body 
Myocardial
 infarction
 or
 ischemia  Blockage
 of
 blood
 flow
 to
 the
 heart
 muscle
 (i.e.
 heart 
attack) 

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Nerve
 injury
 or
 nerve
 damage
 
(e.g.
 phrenic
 nerve
 injury) 
Phrenic
 Nerve
 Injury:
 Absent
 phrenic
 nerve
 function
 as
 
assessed
 by
 diaphragmatic
 fluoroscopy/sniff
 test. 
Vagal
 Nerve
 Injury:
 an
 injury
 to
 the
 vagal
 nerve
 that
 results
 in
 
esophageal
 dysmotility
 or
 gastroparesis 
Obstruction,
 perforation,
 
damage,
 or
 spasm
 of
 the
 vascular
 
system
 including
 the
 coronary
 
circulation
 system 
Collateral
 damage
 to
 the
 vascular
 system
 includes
 
unintended
 damage
 to
 the
 peripheral
 vascular
 system
 (ex:
 
superior
 vena
 cava). 
Pericarditis
 or
 endocarditis  
Inflammation
 of
 the
 sac-like
 tissue
 that
 surrounds
 the
 heart,
 
or
 vegetative
 growth
 inside
 the
 heart. 
Pleural
 effusion
  
Collection
 of
 extra
 fluid
 around
 the
 lungs 
Pericardial
 effusion 
Fluid
 collecting
 in
 the
 pericardial
 sac
 that
 surrounds
 the
 heart 
Pneumonia 
Lung
 infection
 that
 inflames
 air
 sacs
 in
 one
 or
 both
 lungs 
Pneumothorax 
Collapsed
 lung 
Pulmonary
 vein
 stenosis  
Shrinkage
 of
 one
 or
 more
 pulmonary
 veins
 that
 carry
 blood
 
from
 the
 lungs
 to
 the
 left
 atrium
 of
 the
 heart. 
Radiation
 injury
 or
 damage
 and
 
late
 malignancy 
Delayed
 effect
 of
 the
 radiation
 received
 by
 the
 patients,
 
including
 acute
 and
 subacute
 skin
 injury,
 malignancy,
 and
 
genetic
 abnormalities. 
Respiratory
 depression  
Suppression
 of
 normal
 breathing
 ability. 
Sore
 throat 
Pain
 in
 throat 
Unintended
 complete
 or
 
incomplete
 atrioventricular
 node
 
(AV-Node)
 or
 sinus
 node
 block
 or
 
damage 
AV
 block
 has
 been
 defined
 by
 the
 occurrence
 of
 a
 complete
 
AV
 block
 lasting
 ≥3
 s
 during
 either
 catheter
 manipulation
 or
 
the
 administration
 of
 RF
 pulses.
  
Sinus
 node
 dysfunction:
 abnormality
 of
 cardiac
 impulse
 
formation
 that
 may
 be
 caused
 by
 pacemaking
 dysfunction
 of
 
the
 SA
 node,
 which
 may
 manifest
 on
 an
 electrocardiogram
 as:
 
sinus
 bradycardia,
 sinus
 arrest
 or
 exit
 block,
 combinations
 of
 
sino-atrial
 and
 atrioventricular
 nodal
 conduction
 
disturbances,
 atrial
 tachyarrhythmias,
 with
 symptoms
 of:
 
syncope,
 pre-syncope,
 palpitations,
 or
 dizziness. 
Valvular
 insufficiency
 or
 damage  Damage
 to
 heart
 valve
 (e.g.
 tricuspid,
 mitral),
 including
 
backward
 flow
 of
 blood
 through
 the
 valve 
Vasovagal
 reaction 
Reflex
 of
 the
 involuntary
 nervous
 system
 that
 causes
 the
 
heart
 to
 slow
 down
 and
 blood
 pressure
 drops;
 may
 result
 in
 
fainting 
 
 
 
 

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months
 or
 longer
 following
 ablation
 will
 be
 considered
 against
 
the
 primary
 safety
 endpoint. 
Pulmonary
 vein
 stenosis  
Reduction
 of
 the
 diameter
 of
 a
 PV
 or
 PV
 branch.
 PV
 stenosis
 
can
 be
 categorized
 as
 mild
 <50%,
 moderate
 50%–70%,
 and
 
severe
 ≥70%
 reduction
 in
 the
 diameter
 of
 the
 PV
 or
 PV
 
branch.
 A
 severe
 PV
 stenosis
 will
 be
 considered
 against
 the
 
primary
 safety
 endpoint. 
Transient
 ischemic
 attack  
New
 focal
 neurological
 deficit
 with
 rapid
 symptom
 resolution
 
(usually
 1
 to
 2
 hours),
 no
 more
 than
 24
 hours.
 Confirmed
 by
 
neurology 
assessment
 and/or
 radiographic
 confirmation. 
Vagal
 nerve
 injury
 resulting
 in
 
esophageal
 dysmotility
 or
 
gastroparesis
  
Injury
 to
 the
 vagal
 nerve
 that
 results
 in
 esophageal
 
dysmotility
 or
 gastroparesis
 (i.e.
 delayed
 gastric
 emptying) 
that
 prolongs
 hospitalization,
 requires 
hospitalization,
 or
 
results
 in
 ongoing
 symptoms
 for
 more
 than
 30
 days
 following
 
the 
ablation
 procedure 
Vascular
 access
 complications
 
requiring
 intervention
  
Development
 of
 a
 hematoma
 (excluding
 minor
 hematomas
 
not
 requiring
 surgical
 treatment),
 AV
 fistula
 or
 
pseudoaneurysm
 that
 requires
 intervention,
 prolongs
 the
 
hospital
 stay,
 or
 requires
 hospital
 admission. 
Any
 PFA
 system-related
 or
 PFA
 
procedure-related
 cardiovascular
 
and/or 
pulmonary
 adverse
 event
 
that
 prolongs
 or
 requires
 
hospitalization
 for
 more
 than
 48
 
hours
 (excluding
 recurrent
 
AF/AFL/AT)
  
Any
 PFA
 system-related
 or
 PFA
 procedure-related
 
cardiovascular
 and/or 
pulmonary
 adverse
 event
 that
 
prolongs
 or
 requires
 hospitalization
 for
 more
 than
 48 
hours.
 
Because
 early
 recurrences
 of
 AF/AFL/AT
 are
 to
 be
 expected
 
following
 AF
 ablation,
 recurrent
 AF/AFL/AT
 within
 90
 days 
that
 requires
 or 
prolongs
 a
 patient’s
 hospitalization
 will 
not
 be
 
considered
 against
 the
 primary
 safety
 endpoint. 
 
 
 
 

PULSED AF Clinical Investigation Plan  
 
 
MDT16027
 
Version
 2.0,  24-OCT-2019
  
Page
 168
 of
 171 
 
 
 
Medtronic Con
Medtronic Controlled Information
trolled Information 
 
 
056-F275, v A Clinical Investigation Plan Template 
Appendix
 E:
 Instructions
 For
 Use 
Always
 reference
 the
 current
 version
 of
 the
 Instructions
 For
 Use
 document
 as
 provided
 by
 
Medtronic
 under
 separate
 cover. 
 
Appendix
 F:
 Data
 Collection
 Elements
 (Case
 Report
 Forms) 
Draft
 CRFs
 for
 the
 study
 will
 be
 provided
 under
 separate
 cover.
 Final
 CRFs
 will
 be
 provided
 to
 sites
 
via
 the
 electronic
 data
 management
 system
 after
 the
 site 
has
 fulfilled
 all
 requirements
 for
 database
 
access. 
 
Appendix
 G:
 Informed
 Consent
 Template 
The
 Informed
 Consent
 Template
 will
 be
 distributed
 under
 separate
 cover. 
 
Appendix
 H:
 Participating
 Investigators
 and
 Institutions 
A
 final
 list
 of
 participating
 Investigators
 and
 institutions
 has
 not
 been
 finalized
 prior
 to
 
development
 of
 the
 Clinical
 Investigation
 Plan
 and
 will
 be
 distributed
 under
 separate
 cover.
 
 
Appendix
 I:
 IRB/REB/EC
 List 
A
 final
 IRB/REB/EC
 list
 has
 not
 been
 finalized
 prior
 to
 development
 of
 the
 Clinical
 Investigation 
Plan
 and
 will
 be
 distributed
 under
 separate
 cover 
if
 required
 or
 upon
 request.
 
 
Appendix
 J:
 Pre-Clinical
 Testing 
A
 summary
 of
 results
 from
 pre-clinical
 testing 
with
 the
 PFA
 system
 is
 provided
 in
 the
 Investigator’s
 
Brochure
 under
 separate
 cover.
 
 
 
 

PULSED AF Clinical Investigation Plan  
 
 
MDT16027
 
Version
 2.0,  24-OCT-2019
  
Page
 169
 of
 171 
 
 
 
Medtronic Con
Medtronic Controlled Information
trolled Information 
 
 
056-F275, v A Clinical Investigation Plan Template 
Appendix
 K:
 Centers
 for 
Medicare
 and
 Medicaid
 Services
 (CMS)
 IDE 
Study
 
Criteria 
Applicability
 of
 PFA
 to
 the
 Medicare
 Population 
There
 is
 a
 high
 prevalence
 of
 atrial
 fibrillation
 in
 the
 Medicare
 population
 as
 evidenced
 by
 the
 most
 
recently
 available
 claims
 data
 for
 pulmonary
 vein
 isolation
 (PVI)
 ablation
 procedures.
 According
 to
 
Medicare
 Physician/Supplier
 Procedure
 Summary
 data51,
 there
 were
 41,906
 PVI
 ablation
 
procedures
 performed
 on
 Medicare
 beneficiaries
 in
 CY2017.
  
Although
 study
 participation
 will
 be
 open
 to
 patients
 between
 the
 ages
 of
 18-80,
 it
 is
 anticipated
 
that
 approximately
 50%
 of
 the
 patients
 enrolled
 will
 be
 age
 65+.
 This
 enrollment
 pattern
 mirrors
 
the
 age
 distribution
 of
 the
 general
 population
 of
 patients
 with
 atrial
 fibrillation
 (AF)1,2,3,4 
and
 
therefore
 results
 from
 this
 trial
 may
 be
 both
 relevant
 and
 generalizable
 to
 the
 Medicare
 beneficiary
 
population. 
 
 
                                                           
 
51 
Medicare Physician/Supplier Procedure Summary data. Available at: https://www.cms.gov/Research-Statistics-Data-
and-Systems/Statistics-Trends-and-Reports/Physician-Supplier-Procedure-Summary/index.html  

PULSED AF Clinical Investigation Plan  
 
 
MDT16027
 
Version
 2.0,  24-OCT-2019
  
Page
 171
 of
 171 
 
 
 
Medtronic Con
Medtronic Controlled Information
trolled Information 
 
 
056-F275, v A Clinical Investigation Plan Template 
2.0 
•  Sections
 10
 and
 12.2.2:
 updated
 
language
 throughout
 to
 require
 
collection
 of
 all
 adverse
 events;
 
removed
 definition
 of
 “cardiovascular
 
related”
 AE
 and
 instructions
 for
 
Investigator
 to
 classify
 cardiovascular
 
relatedness
 for
 AEs. 
 
 
 
 
 
 
•  Section
 13:
 updated
 to
 remove
 the
 
language
 claiming
 an
 exception
 to
 the
 
ISO14155:2011
 requirement
 to
 collect
 
all
 adverse
 events.
  
Jeff
 Cerkvenik,
 Distinguished
 
Statistician 
Josh
 Treadway,
 Clinical
 
Research
 Specialist