Treatment of Persistent Atrial Fibrillation With the Sphere-9 Mapping and Ablation Catheter and the Affera Mapping and Ablation System
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Medtronic Cardiac Ablation Solutions

 
 
TREATMENT OF PERSISTENT ATRIAL FIBRILLATION WITH  
THE SPHERE-9 MAPPING AND ABLATION CATHETER AND  
THE AFFERA MAPPING AND ABLATION SYSTEM 
 
CLINICAL INVESTIGATION PLAN 
 
 
Clinical Investigation Plan 
CP-00009 
Version and Date 
Revision G 
03 June, 2022 
Investigational Device 
Sphere-9™ Mapping and Ablation Catheter with the Affera 
Mapping and Ablation System 
Description 
Prospective, multicenter, randomized interventional study to 
evaluate the safety and effectiveness of the Sphere-9 Mapping 
and Ablation Catheter with the Affera Mapping and Ablation 
System for the treatment of symptomatic persistent atrial 
fibrillation (PerAF) refractory or intolerant to drugs using 
radiofrequency (RF) and pulsed field (PF) ablation 
Sponsor and 
Investigational Device 
Manufacturer 
Affera, Inc. 
320 Nevada St, Suite 401 
Newton, MA 02460 
USA 
 
 
 
 
 
DISCLOSURE STATEMENT 
This document contains information that is confidential and proprietary to Affera, Inc. This 
information is being provided to you solely for the purpose of evaluating or conducting a clinical 
study for Affera. You may disclose the contents of this document only to study personnel under 
your supervision who need to know the contents for this purpose and to your Institutional 
Review Board (IRB) or Ethics Committee (EC). Otherwise, the contents of this document may 
not be disclosed without the prior authorization from Affera. The foregoing shall not apply to 
disclosure required by governmental regulations or laws. Any supplemental information that may 
be added to this document also is confidential and proprietary to Affera and must be kept in 
confidence in the same manner as the contents of this document. 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 2 of 86 
INVESTIGATOR AGREEMENT 
 
I have read this Clinical Investigation Plan and agree to adhere to the requirements. I will 
provide copies of this Clinical Investigation Plan and all pertinent information to all site 
personnel involved in this study. I will discuss this material with them and ensure they are fully 
informed regarding the investigational device and the conduct of the study. 
 
I agree to conduct the study as outlined in the Clinical Investigation Plan, in accordance with the 
signed clinical study agreement, and according to the ethical principles stated in the latest 
version of the Declaration of Helsinki (2013), the applicable guidelines for good clinical 
practices, 21 CFR parts 11, 50, 54, 56, and 812, ISO 14155:2011 (Clinical Investigation of 
Medical Devices for Human Subjects – Good Clinical Practice), or the applicable local and 
international regulations, whichever provides the greater protection of the individual.  
 
I agree to actively enroll subjects into the study. I agree to provide all information requested in 
the Case Report Forms provided to me by the Sponsor in a manner to assure completeness, 
legibility, and accuracy.  
 
I agree that all information provided to me by the Sponsor, including pre-clinical data, protocols, 
Case Report Forms, and any verbal and written information, will be kept strictly confidential and 
confined to the clinical personnel involved in conducting the study. It is recognized that this 
information may be relayed in confidence to the Institutional Review Board (IRB) or Ethics 
Committee (EC).  
 
I will not provide protocols, reports, or information about the study or its progress to anyone who 
is not involved in the study other than the Sponsor, the IRB/EC, and relevant regulatory 
authorities. Any such submission will indicate that the material is confidential. 
 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Investigator’s Name (print) 
 
 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 3 of 86 
TABLE OF CONTENTS 
1 
CLINICAL INVESTIGATION SUMMARY ......................................................................................8 
2 
ABBREVIATIONS ....................................................................................................................15 
3 
INTRODUCTION ......................................................................................................................16 
3.1 
Background ............................................................................................................16 
3.1.1 
Atrial Fibrillation ......................................................................................16 
3.1.2 
Demographic Profile of Atrial Fibrillation Patients .................................16 
3.1.3 
Ablation of Atrial Fibrillation ..................................................................16 
3.1.4 
Safety of AF Ablation ..............................................................................17 
3.1.5 
Clinical Outcomes of AF Ablation ...........................................................18 
3.2 
Rationale for Clinical Investigation .......................................................................18 
4 
INVESTIGATIONAL DEVICE INFORMATION .............................................................................20 
4.1 
Intended Use ..........................................................................................................20 
 
 
5 
CONTROL DEVICE INFORMATION ...........................................................................................24 
5.1 
Indications for Use .................................................................................................24 
6 
STUDY OBJECTIVES ...............................................................................................................25 
6.1 
Primary Study Objectives ......................................................................................25 
 
 
7 
STUDY ENDPOINTS ................................................................................................................26 
7.1 
Primary Safety Endpoint ........................................................................................26 
7.2 
Primary Effectiveness Endpoint ............................................................................26 
7.3 
Secondary Endpoints .............................................................................................28 
 
 
8 
STUDY DESIGN ......................................................................................................................30 
8.1 
Population ..............................................................................................................30 
8.2 
Clinical Sites ..........................................................................................................30 
8.3 
Study Duration .......................................................................................................30 
8.4 
Inclusion Criteria ...................................................................................................30 
8.5 
Exclusion Criteria ..................................................................................................30 
8.6 
Roll-In Phase ..........................................................................................................32 
 
 
8.8 
Subject Accountability ...........................................................................................32 
8.8.1 
Screening Failure ......................................................................................32 
8.8.2 
Excluded Subjects ....................................................................................32 
8.8.3 
Discontinued Subjects ..............................................................................33 
8.8.4 
Treated Subjects .......................................................................................33 
8.8.5 
Withdrawal and Lost to Follow-Up ..........................................................33 
8.8.6 
Completed Subjects ..................................................................................33 
9 
STUDY PROCEDURES..............................................................................................................34 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 4 of 86 
9.1 
Patient Screening ...................................................................................................34 
9.2 
Informed Consent...................................................................................................34 
9.3 
Roll-In ....................................................................................................................34 
9.4 
Randomization .......................................................................................................35 
9.5 
Pre-Procedure/Baseline Assessments ....................................................................35 
9.6 
Anticoagulation ......................................................................................................36 
9.6.1 
Systemic Anticoagulation Prior to Ablation ............................................36 
9.6.2 
Intraprocedural Anticoagulation ...............................................................36 
9.6.3 
Early Postprocedural Anticoagulation ......................................................36 
9.7 
Thrombus Screening ..............................................................................................36 
9.8 
Ablation Procedure ................................................................................................37 
9.8.1 
Pulmonary Vein Isolation .........................................................................38 
9.8.2 
Additional Ablation ..................................................................................38 
9.8.3 
Data Collection .........................................................................................39 
9.8.4 
Investigational Device Use .......................................................................39 
9.8.5 
Control Device Use ..................................................................................40 
 
 
9.10 
Repeat Ablation .....................................................................................................43 
9.11 
Antiarrhythmic Drugs (AADs) ..............................................................................43 
9.12 
Transtelephonic Monitoring (TTM) ......................................................................43 
9.13 
Holter Monitoring (HM) ........................................................................................44 
9.14 
12-Lead ECG Recordings ......................................................................................44 
9.15 
Follow-Up Visits ....................................................................................................44 
9.15.1 Pre-Discharge Visit ..................................................................................44 
9.15.2 Day 10 Telephone Call (7-13 days) .........................................................45 
9.15.3 Day 30 Office/Hybrid Visit (14-42 days) .................................................45 
9.15.4 Day 75 Telephone Call (60-90 days) .......................................................46 
9.15.5 Day 90 Office/Telehealth Visit (76-104 days) .........................................46 
9.15.6 Day 180 Office/Telehealth Visit (150-210 days) .....................................46 
9.15.7 Day 360 Office/Telehealth Visit (330-390 days) .....................................47 
9.15.8 Unscheduled Visits ...................................................................................47 
10 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ......................................................................51 
10.1 
Definitions..............................................................................................................51 
10.1.1 Adverse Events .........................................................................................51 
10.1.2 Serious Adverse Events ............................................................................51 
10.1.3 Adverse Device Effects ............................................................................51 
10.1.4 Device Deficiency ....................................................................................52 
10.2 
Assessment of Adverse Events ..............................................................................52 
10.3 
Reporting Requirements ........................................................................................54 
11 
STATISTICAL METHODS .........................................................................................................60 
11.1 
Primary Analyses ...................................................................................................60 
11.1.1 Poolability across Sites .............................................................................61 
11.1.2 Sensitivity Analysis ..................................................................................61 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 5 of 86 
11.1.3 Subgroup Analyses ...................................................................................62 
11.1.4 Sample Size ..............................................................................................62 
11.2 
Secondary Analyses ...............................................................................................62 
11.3 
Additional Analyses ...............................................................................................63 
 
 
12 
RISK ANALYSIS ......................................................................................................................65 
12.1 
Potential Benefits ...................................................................................................65 
12.2 
Potential Risks .......................................................................................................65 
12.3 
Minimization of Risks............................................................................................68 
13 
STUDY CONDUCT ...................................................................................................................69 
13.1 
Ethics......................................................................................................................69 
13.2 
Institutional Review Board / Ethics Committee ....................................................69 
13.3 
US FDA and Local Competent Authority .............................................................69 
13.4 
Informed Consent...................................................................................................69 
13.5 
Confidentiality and Data Protection.......................................................................70 
13.6 
Insurance ................................................................................................................70 
13.7 
Data Quality Assurance .........................................................................................71 
13.7.1 Site Selection ............................................................................................71 
13.7.2 Training ....................................................................................................71 
13.7.3 Site Initiation ............................................................................................71 
13.7.4 Case Report Forms ...................................................................................71 
13.7.5 Documentation .........................................................................................72 
13.7.6 Data Monitoring .......................................................................................72 
13.7.7 Device Accountability ..............................................................................73 
13.7.8 Data Management .....................................................................................73 
13.7.9 Core Labs .................................................................................................73 
13.8 
Protocol Deviations ................................................................................................74 
13.9 
Study Audits...........................................................................................................74 
13.10 
Record Keeping .....................................................................................................75 
13.10.1 Data Retention ..........................................................................................76 
13.11 
Reports ...................................................................................................................76 
13.11.1 Investigator Reports .................................................................................76 
13.11.2 Publication ................................................................................................77 
14 
STUDY OVERSIGHT ................................................................................................................78 
14.1 
Study Advisory Committee....................................................................................78 
14.2 
Investigator Responsibilities ..................................................................................78 
14.3 
Sponsor Responsibilities ........................................................................................78 
14.4 
Data and Safety Monitoring Board ........................................................................79 
14.5 
Clinical Events Committee ....................................................................................79 
14.6 
Protocol Amendments ............................................................................................80 
14.7 
Suspension or Discontinuation of the Study ..........................................................80 
15 
REFERENCES ..........................................................................................................................81 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 7 of 86 
TABLE OF TABLES 
Table 1. Affera Mapping System components. ............................................................................ 21 
Table 2. Affera Ablation System components. ............................................................................. 22 
Table 3. Recommended RF ablation settings for Sphere-9 Catheter. ........................................... 40 
Table 4. Recommended PF ablation settings for Sphere-9 Catheter. ........................................... 40 
Table 5. Recommended RF ablation settings for THERMOCOOL SMARTTOUCH SF® 
catheter. ........................................................................................................... 41 
Table 6. Schedule of evaluations and visits. ................................................................................. 48 
 
Table 8. Adverse event severity definitions. ................................................................................. 53 
Table 9. Adverse event expectedness definitions. ........................................................................ 53 
Table 10. Adverse event relationship to the device or procedure definitions. .............................. 54 
Table 11. Adverse event reporting timelines. ............................................................................... 54 
Table 12. Anticipated adverse events. .......................................................................................... 56 
Table 13. Primary adverse event definitions................................................................................. 58 
Table 14. Subject cohorts for statistical analysis. ......................................................................... 60 
 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 15 of 86 
2 
ABBREVIATIONS 
 
AAD 
Antiarrhythmic Drug 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
CA 
Competent Authority 
CHF 
Congestive Heart Failure 
CPK 
Creatinine Phosphokinase 
CRF 
Case Report Form 
CS 
Clinically Significant 
CT 
Computed Tomography 
CVA 
Cerebrovascular Accident 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Ejection Fraction 
GCP 
Good Clinical Practices 
HM 
Holter Monitor 
ICD 
Implantable Cardioverter-Defibrillator 
ICE 
Intracardiac Echocardiography 
IRB 
Institutional Review Board 
LV 
Left Ventricular 
MI 
Myocardial Infarction 
MoCA 
Montreal Cognitive Assessment 
NCS 
Not Clinically Significant 
NIM 
Non-Inferiority Margin 
NOAC 
Non-Vitamin K Oral Anticoagulant 
PerAF 
Persistent Atrial Fibrillation 
PF 
Pulsed Field 
PHI 
Protected Health Information 
PRBCs 
Packed Red Blood Cells 
PV 
Pulmonary Vein 
PVI 
Pulmonary Vein Isolation 
QOL 
Quality of Life 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SCE 
Silent Cerebral Event 
SCL 
Silent Cerebral Lesion 
SOP 
Standard Operating Procedure 
TEE 
Transesophageal Echocardiogram 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiogram 
TTM 
Transtelephonic Monitoring 
UADE 
Unanticipated Adverse Device Effect 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 16 of 86 
3 
INTRODUCTION 
 
3.1 
BACKGROUND 
 
3.1.1 
ATRIAL FIBRILLATION 
Atrial fibrillation (AF) is a supraventricular tachycardia that manifests as a rapid, irregular atrial 
rhythm with no clearly defined P-wave on the electrocardiogram. AF that terminates within 
seven days is defined as paroxysmal, while AF lasting longer than seven days is defined as 
persistent. Long-standing persistent AF is defined as continuous AF persisting for longer than 12 
months [1].  
 
AF carries significant risks. AF leads to dramatically increased risk of stroke and mortality, 
particularly among patients with persistent forms of AF. Furthermore, AF is often symptomatic, 
leading to fatigue and reduced quality of life (QOL); however, it carries similar risks with or 
without symptoms [1].  
 
3.1.2 
DEMOGRAPHIC PROFILE OF ATRIAL FIBRILLATION PATIENTS 
AF affects an estimated 37 million people worldwide [2]. The lifetime risk of developing AF 
after age 40 was 26% and 23% for men and women, respectively, in the Framingham Heart 
Study [3]. AF incidence rises rapidly with advancing age, and approximately one-fourth of adults 
diagnosed with AF are at least 80 years old [3, 4]. AF incidence is higher among whites than 
among African Americans [5].  
 
Awareness of atrial fibrillation is poor [6], and disparities in awareness and treatment of AF have 
been identified. Factors identified as being associated with lack of awareness of AF have 
included race, lower education, rural location, lower number of general practitioner visits, and 
lower cognition [7, 8].  
 
In the PRECEPT and STOP Persistent AF studies for catheter ablation to treat persistent AF 
(PerAF), the mean age was approximately 65 years, with a standard deviation of 9 years. 
Approximately 70% of treated subjects in each study were male. Less than 10% of subjects 
treated in each study were non-white, and less than 2% were Black or African American [9, 10]. 
 
3.1.3 
ABLATION OF ATRIAL FIBRILLATION 
Thermal ablation using radiofrequency (RF) energy has become a widely accepted treatment for 
many tachyarrhythmias and is considered first-line therapy in some cases [11, 1]. The success 
rate of RF catheter ablation for treating atrial fibrillation has been found to be superior to that of 
antiarrhythmic drugs. For example, the RAAFT-2 trial found that catheter ablation led to a 55% 
recurrence rate for atrial fibrillation or atrial tachycardia at 2 years follow-up compared to 72% 
recurrence using antiarrhythmic drugs [1]. Similarly, recurrence of AF, atrial flutter, or atrial 
tachycardia in the CABANA trial favored catheter ablation over drug therapy with a hazard ratio 
of 0.53, and analysis based on treatment received suggests a benefit from ablation in terms of 
death and hospitalization [12]. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 17 of 86 
Catheter ablation is considered a reasonable treatment (Class IIa) for the treatment of 
symptomatic persistent AF refractory or intolerant to antiarrhythmic drugs. Two ablation 
catheters have been approved for treatment of drug-refractory persistent AF: the 
THERMOCOOL SMARTTOUCH® SF Catheter, which is a focal RF ablation catheter; and the 
Arctic Front Advance™ Cardiac Cryoablation Catheter. Electrical isolation of all pulmonary 
veins (PVs) is recommended (Class I) as part of all AF ablation procedures. However, PV 
reconnection is common, and repeat ablation is often necessary [1, 13].  
 
Catheter ablation of AF is often accomplished by delivering focal RF energy in a point-by-point 
fashion to create circles (e.g. to isolate PVs) and/or lines (e.g. to block an arrhythmogenic 
channel). RF energy delivery through an electrode at the tip of an ablation catheter causes 
resistive heating in tissue, which, along with conductive heating, leads to thermal ablation of 
cardiac tissue. Features such as saline irrigation and temperature feedback can help to avoid the 
formation of thrombus and char due to blood heating during RF delivery [1].  
 
Pulsed field (PF) ablation, also known as irreversible electroporation, relies on the application of 
non-thermal electrical pulses to form pores in the cell membranes of target tissue resulting in 
tissue apoptosis or necrosis. Recently published preclinical and clinical research suggests that PF 
ablation may be as effective as RF ablation while reducing risks associated with RF ablation 
such as damage to collateral structures [14, 15, 16, 17]. 
 
In the recent PRECEPT pivotal IDE study of the THERMOCOOL SMARTTOUCH® SF 
catheter for treatment of persistent AF (NCT02817776), only PV isolation was required; linear 
ablation lines including left atrial roof line, mitral isthmus line, left atrial floor line, and 
cavotricuspid isthmus line were only required to treat documented macro-reentrant atrial 
tachycardias. Results of the PRECEPT study showed that a left atrial roof line was delivered in 
just under half (48.6%) of the per-protocol group, and a cavotricuspid isthmus line was delivered 
in just over one-third (35.2%) of the per protocol group. A left inferior PV mitral line and other 
linear lesions were each delivered in less than 10% of patients in the per-protocol group (7.8% 
and 8.9%, respectively) [9]. 
 
3.1.4 
SAFETY OF AF ABLATION 
A review of data from the Nationwide Inpatient Sample between 2000 and 2010 found an overall 
incidence of complications of 6.3%, with a trend of increasing complications over that period 
[18]. A 2010 questionnaire-based survey of centers performing catheter ablation for atrial 
fibrillation reported a major complication rate of 4.5% [19]. A 2017 analysis of prospective data 
from the ESC-EHRA Atrial Fibrillation Ablation Long-Term Registry reported procedure-
related complications in 7.8% [20]. In the recent PRECEPT pivotal IDE study of the 
THERMOCOOL SMARTTOUCH® SF catheter for treatment of persistent AF (NCT02817776), 
which used a similar primary safety endpoint to this protocol, the rate of the primary safety 
endpoint was 4.7% [21]. The PRECEPT study used an objective performance criterion (OPC) of 
16%, based on an expected safety event rate of 8% and an 8% region of indifference, for 
analyzing the primary safety endpoint [22].  
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 18 of 86 
Pivotal IDE studies of focal catheter ablation for paroxysmal AF have also used similar primary 
safety endpoints. The DIAMOND-AF pivotal IDE study of the DiamondTemp ablation system 
for treatment of paroxysmal AF (NCT03334630) reported a primary safety event in 3.3% of 
subjects treated with the investigational device and in 6.6% of subjects treated with the control 
device (TactiCath™ Quartz) [23]. The SMART-SF study (NCT02359890), which evaluated the 
THERMOCOOL SMARTTOUCH® SF catheter for the treatment of paroxysmal AF, reported a 
primary adverse event in 2.6% of subjects (95% CI 0.7-6.5%). However, the SMART-SF study 
only evaluated early safety and acute effectiveness, so the chronic effectiveness of the treatments 
was not reported [24]. An OPC of 14% was used for analysis of the primary safety endpoint in 
SMART-SF [25]. The SMART-AF (NCT01385202) study was a pivotal IDE evaluating the 
THERMOCOOL SMARTTOUCH® catheter for treatment of paroxysmal AF, with primary 
safety and effectiveness endpoints similar to this protocol. The incidence of primary adverse 
events in SMART-AF was 9.9% (95% CI 5.8-15.6%) [26]. The OPC used for SMART-AF was 
not reported [27] but was presumably higher than the upper confidence bound of 15.6% based on 
the study’s success. 
 
3.1.5 
CLINICAL OUTCOMES OF AF ABLATION 
In a 2018 systematic literature review, single-procedure clinical success in treating persistent AF 
was estimated at 47% (95% CI 40-54%) across 18 cohorts between 2010 and 2015. Single-
procedure clinical success in treating any AF with pulmonary vein isolation (PVI) plus linear 
ablation was estimated at 44% (95% CI 36-53%) across 10 cohorts over the same time period. 
Overall, this review found declining clinical success for AF ablation between 2001 and 2015 [28, 
28]. The 2017 HRS consensus on AF ablation recommended a minimum acceptable success rate 
for treatment of persistent AF of 40% [1]. Subsequent single-arm pivotal IDE studies, including 
the PRECEPT study, used this minimum rate as an objective performance criterion for primary 
effectiveness. In the recent PRECEPT pivotal IDE study of the THERMOCOOL 
SMARTTOUCH® SF catheter for treatment of persistent AF (NCT02817776), primary 
effectiveness success was 59.3% through the end of the nine-month effectiveness evaluation 
period [21]. However, in contrast to this protocol, PRECEPT used a 6-month blanking and 
therapy consolidation period, and repeat ablation was allowed during that period (which occurred 
in 5.7%) [29].  
 
3.2 
RATIONALE FOR CLINICAL INVESTIGATION 
Catheter ablation is the most widely used curative treatment for cardiac arrhythmia. However, 
the reliable application of durable ablation lesions remains an unmet need [1, 13, 30]. Despite 
recent advances in catheter ablation technology, conduction gaps remain in a substantial minority 
of ablation lines in the left atrium [31]. Gaps between lesions may lead to electrical reconnection 
in the heart and the recurrence of the treated arrhythmia, requiring repeated treatment, or may 
create new arrhythmia circuits that may be more symptomatic [11].  
 
Contiguity of linear lesions depends on factors such as lesion size and placement [1]. Delivery of 
focal ablation lesions with a wider surface area may reduce the likelihood of gaps by increasing 
the probability of overlap between adjacent ablations in point-by-point ablation. An ablation 
electrode with stable tissue engagement may improve the predictability and reliability of lesion 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 19 of 86 
placement. Temperature feedback from the tissue surface may provide improved feedback for 
RF energy titration and for delivery of contiguous sets of lesions. For these reasons, ablation 
through a large, focal ablation electrode may improve lesion contiguity. Furthermore, given 
research suggesting similar or better performance and reduced risks associated with damage to 
collateral structures, PF may prove to be an appropriate adjunct to RF for cardiac ablation, 
particularly in regions of the heart in which the risk of collateral damage with RF ablation is 
high.  
 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 24 of 86 
5 
CONTROL DEVICE INFORMATION 
 
5.1 
INDICATIONS FOR USE 
The THERMOCOOL SMARTTOUCH® SF Catheter is indicated for the treatment of drug 
refractory recurrent symptomatic paroxysmal atrial fibrillation (AF) and for drug refractory 
recurrent symptomatic persistent AF (continuous AF > 7 days but < 1 year), refractory or 
intolerant to at least 1 Class I or III AAD, when used with the CARTO® 3 System. 
 
The intended use of the CARTO® 3 System is catheter-based cardiac electrophysiological (EP) 
procedures. The CARTO® 3 System provides information about the electrical activity of the 
heart and about catheter location during the procedure. The system can be used on patients who 
are eligible for a conventional electrophysiological procedure. The system has no special 
contraindications. 
 
The use of the SMARTABLATE™ RF Generator and all accessories is indicated in combination 
with compatible therapeutic catheters for use in conventional intracardiac RF ablation 
procedures. 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 26 of 86 
7 
STUDY ENDPOINTS 
 
7.1 
PRIMARY SAFETY ENDPOINT 
The primary safety endpoint is the incidence of the following device- or procedure-related 
serious adverse events (SAEs) following the index ablation procedure: 
Within 7 days: 
• Death 
• Myocardial infarction 
• Phrenic nerve paralysis 
• Transient ischemic attack (TIA) 
• Stroke/cerebrovascular accident (CVA) 
• Thromboembolism 
• Major vascular access complications / bleeding 
• Heart block 
• Gastroparesis 
• Severe pericarditis 
• Hospitalization (initial and prolonged) due to cardiovascular or pulmonary AE‡ 
Within 30 days: 
• Cardiac tamponade / perforation 
Within 90 days: 
• Atrio-esophageal fistula 
Within 180 days: 
• Pulmonary vein stenosis 
‡ Excludes hospitalization due to AF/AFL/AT recurrence 
 
Definitions related to Primary Aes are provided in Table 13. Adverse events occurring during or 
after a repeat ablation procedure will not be considered Primary Aes (see Section 9.10). 
 
As discussed in Section 3.1.4, an objective performance criterion (OPC) of 16% was used for the 
primary safety endpoint in the PRECEPT study of the THERMOCOOL SMARTTOUCH® SF 
catheter for treatment of persistent AF (NCT02817776) based on an expected rate of 8% with an 
8% region of indifference [22]. The reported rate of the primary safety endpoint in that study was 
4.7% [21]. Other recent studies of RF ablation for the treatment of AF (paroxysmal or persistent) 
have reported primary adverse event rates as high as 9.9% [26]. For this study, a non-inferiority 
margin (NIM) of 8% between the investigational group and the control group will be used for the 
primary analysis of the Primary Safety Endpoint. 
 
7.2 
PRIMARY EFFECTIVENESS ENDPOINT 
The primary effectiveness endpoint is freedom from documented recurrence of AF, atrial 
tachycardia (AT), or atrial flutter (AFL) based on electrocardiographic data through 12-month 
follow-up and excluding a 90-day blanking period. The following are considered primary 
effectiveness endpoint failures: 
• Inability to isolate all targeted pulmonary veins during the index procedure. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 27 of 86 
• Ablation using devices other than the assigned study device for any left atrial ablation 
during the index procedure. (The assigned study device is the Sphere-9 Catheter for the 
investigational arm and the THERMOCOOL SMARTTOUCH SF for the control arm.) 
• Any repeat ablation, surgical ablation, or arrhythmia surgery for treatment of recurrent 
AF/AT/AFL after the index procedure. 
• Documented AF/AT/AFL recurrence after the 90-day blanking period. 
• Class I or III AAD dose increase from the historic maximum ineffective dose (prior to the 
index procedure) or initiation of a new Class I or III AAD for treatment of AF/AT/AFL 
after the 90-day blanking period. 
• DC cardioversion for AF/AT/AFL after the 90-day blanking period. 
 
A documented recurrence of AF/AT/AFL based on electrocardiographic data is (a) an episode ≥ 
30 seconds in duration documented by ECG, TTM, or Holter monitor or (b) an episode covering 
an entire 12-lead ECG recording lasting at least 10 seconds. 
 
The blanking period is the first 90 days after the index ablation procedure. The effectiveness 
evaluation period will be from Day 91 through Day 360. 
 
Failure to complete the ablation procedure due to failure of non-study equipment (e.g., 
fluoroscopy, intracardiac echocardiography, or electrophysiology recording system) during the 
index procedure will not be considered a primary effectiveness endpoint failure. If the procedure 
cannot be completed due to failure of non-study equipment, the subject will be discontinued as 
described in Section 8.8. 
 
Use of multiple devices of the assigned type during the ablation procedure (e.g., due to device 
deficiency) is not a primary effectiveness endpoint failure. Failure to isolate a pulmonary vein 
that was not targeted for isolation (e.g., due to unusual anatomy) is not a primary effectiveness 
endpoint failure. 
 
The historical maximum ineffective dose for an AAD is the highest dose administered for AF 
that was ineffective in controlling AF or produced intolerable side effects prior to the ablation 
procedure. For amiodarone only, the maintenance dose is considered as the historic maximum 
ineffective dose. A new AAD is an AAD that the subject has never taken for AF prior to the 
ablation procedure. 
 
During the blanking period, use of a new or previously failed AAD is not a primary effectiveness 
endpoint failure, regardless of dose. 
 
Use of any new Class I or III AAD (as defined above) for treatment of AF/AT/AFL recurrence 
during the effectiveness evaluation period will be considered a primary effectiveness endpoint 
failure. Use of any previously failed Class I or III AAD at a dose greater than the historic 
maximum ineffective dose (as defined above) for treatment of AF/AT/AFL recurrence during the 
effectiveness evaluation period will be considered a primary effectiveness endpoint failure. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 30 of 86 
8 
STUDY DESIGN 
This is a prospective, multicenter, randomized clinical evaluation of the Sphere-9 Mapping and 
Ablation Catheter with the Affera Mapping and Ablation System. Subjects will be randomly 
assigned 1:1 to receive treatment with either the Sphere-9 Mapping and Ablation Catheter and 
the Affera Mapping and Ablation System (investigational device) or the THERMOCOOL 
SMARTTOUCH® SF Catheter (control device). Subjects will be blinded to treatment 
assignment. 
 
8.1 
POPULATION 
The study population is patients with symptomatic persistent atrial fibrillation (PerAF) refractory 
or intolerant to drugs and planned for catheter ablation. 
 
8.2 
CLINICAL SITES 
Subjects will be enrolled at up to 35 sites in the United States (US), Canada, Europe, Australia, 
and/or Israel, with up to approximately 50% of subjects enrolled outside the US. 
 
8.3 
STUDY DURATION 
The total duration of the clinical investigation is anticipated to be between 24 and 42 months. 
The enrollment phase is expected to take between 12 and 30 months from enrollment of the first 
subject. 
 
8.4 
INCLUSION CRITERIA 
Subjects must meet all of the following criteria to be included in the study: 
1. Symptomatic PerAF documented by 
• (1) a physician’s note indicating symptoms consistent with AF sustained longer than 7 
days but less than 12 months; 
AND either 
• (2a) a 24-hour Holter documenting continuous AF within the past year 
OR 
• (2b) two electrocardiograms (from any form of rhythm monitoring, including consumer 
devices) taken at least 7 days apart within the past year, each showing continuous AF. 
2. Failure or intolerance of at least one Class I or III anti-arrhythmic drug (AAD). 
3. Suitable candidate for catheter ablation. 
4. Adults aged 18 – 80 years. 
5. Willing and able to comply with all baseline and follow-up evaluations for the full length 
of the study. 
6. Willing and able to provide informed consent. 
 
8.5 
EXCLUSION CRITERIA 
Subjects will not be eligible for the study if any of the following criteria are met: 
1. Continuous AF lasting for 12 months or longer. 
2. AF secondary to electrolyte imbalance, thyroid disease, acute alcohol intoxication, or 
other reversible or non-cardiac cause. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 31 of 86 
3. Previous left atrial ablation or surgical procedure (including septal closure or left atrial 
appendage closure). 
4. Valvular cardiac surgical/percutaneous procedure (e.g., ventriculotomy, atriotomy, and 
valve repair or replacement and presence of a prosthetic valve). 
5. Any carotid stenting or endarterectomy. 
6. Any cardiac procedure (surgical or percutaneous) or percutaneous coronary intervention 
within the 90 days prior to the initial procedure. 
7. Coronary artery bypass graft (CABG) procedure within the 6 months prior to the initial 
procedure. 
8. Awaiting cardiac transplantation or other cardiac surgery within the 12 months following 
the initial ablation procedure. 
9. Presence of a permanent pacemaker, biventricular pacemaker, or any type of implantable 
cardiac defibrillator (with or without biventricular pacing function). 
10. Documented thromboembolic event (stroke or transient ischemic attack) within 6 months 
(180 days) prior to the initial ablation procedure. 
11. Documented left atrial thrombus on imaging. 
12. History of blood clotting or bleeding abnormalities. 
13. Any condition contraindicating chronic anticoagulation. 
14. Myocardial infarction (MI) within the 3 months (90 days) prior to the initial procedure. 
15. Body mass index >40 kg/m2. 
16. Left atrial diameter >55 mm (anterioposterior). 
17. Diagnosed atrial myxoma. 
18. Left ventricular ejection fraction (EF) < 35%. 
19. Uncontrolled heart failure or NYHA Class III or IV heart failure. 
20. Rheumatic heart disease. 
21. Hypertrophic cardiomyopathy. 
22. Unstable angina. 
23. Moderate to severe mitral valve stenosis. 
24. Severe mitral regurgitation (regurgitant volume ≥ 60 mL/beat, regurgitant fraction ≥ 
50%, and/or effective regurgitant orifice area ≥ 0.40cm2). 
25. Primary pulmonary hypertension. 
26. Significant restrictive or obstructive pulmonary disease or chronic respiratory condition. 
27. Renal failure requiring dialysis. 
28. History of severe Gastroesophageal Reflux Disease (GERD) requiring surgical and/or 
mechanical intervention. 
29. Acute illness, active systemic infection, or sepsis. 
30. Contraindication to both computed tomography and magnetic resonance angiography 
31. Significant congenital anomaly or medical problem that, in the opinion of the 
investigator, would preclude enrollment in this study or compliance with follow-up 
requirements or would impact the scientific soundness of the clinical study results. 
32. Any woman known to be pregnant or breastfeeding, or any woman of childbearing 
potential who is not on a reliable form of birth regulation method or abstinence. 
33. Current or anticipated participation in any other clinical study of a drug, device, or 
biologic during the duration of the study not pre-approved by the Sponsor. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 33 of 86 
 
8.8.3 
DISCONTINUED SUBJECTS 
Discontinued subjects are those who are enrolled in the study, meet all eligibility criteria, and 
undergo a procedure in which the assigned study device is introduced into the heart, but no 
ablation energy is delivered. Subjects may be discontinued due to non-investigational equipment 
failure or based on intra-operative findings (e.g., if only non-study arrhythmias are present or if 
PVI is contraindicated due to a finding during the procedure). Discontinued subjects will count 
against the maximum study enrollment. Discontinued subjects will be followed through the Day 
30 visit to evaluate safety and will be included in evaluation of study endpoints. Discontinued 
subjects may not be re-enrolled. 
 
8.8.4 
TREATED SUBJECTS 
Treated subjects are those who are enrolled in the study, undergo the index ablation procedure, 
and are treated with a study device (i.e., ablation energy is delivered). Treated subjects will count 
toward the maximum study enrollment. Treated subjects will be followed through the Day 360 
visit and will be included in evaluation of study endpoints. 
 
8.8.5 
WITHDRAWAL AND LOST TO FOLLOW-UP 
While study withdrawal is discouraged, any subject may voluntarily withdraw from the study at 
any time, for any reason, without prejudice. If a subject withdraws from the study, the reason for 
withdrawal will be documented. The Sponsor must be notified of subject withdrawal within five 
(5) working days.  
 
Subjects will be considered lost to follow-up if contact with the subject is lost after three (3) 
documented attempts to contact the subject including two (2) documented phone calls and one 
(1) written attempt by registered mail.  
 
The investigator will make every effort to collect information about subjects who withdraw or 
are lost to follow-up. Withdrawal should be treated as an unscheduled office visit as described in 
Section 9.15.8. No additional data may be collected after a subject has been withdrawn. 
However, data collected up to the point of subject withdrawal may be used. 
 
8.8.6 
COMPLETED SUBJECTS 
Completed subjects are enrolled subjects who have not been excluded, discontinued, withdrawn, 
or lost to follow-up and have completed the final study visit.  
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 34 of 86 
9 
STUDY PROCEDURES 
The schedule of study evaluations and visits is summarized in Table 6. Study procedures are 
illustrated in the flowchart in Figure 3. Details are provided below. 
 
9.1 
PATIENT SCREENING 
Patients ≥18 years with symptomatic PerAF refractory or intolerant to drugs who are planned for 
catheter ablation should be screened for study eligibility. Subjects who have provided informed 
consent but do not satisfy eligibility criteria will conclude their participation in the study and will 
not undergo treatment with the investigational device but may receive standard of care treatment 
outside of this study.  
 
The Sponsor intends to enroll patients reflecting, as well as possible, the demographics of the 
study population. Similar to the recent PRECEPT and STOP Persistent AF trials for catheter 
ablation to treat PerAF, the Sponsor expects to enroll roughly 70% males and 30% females [9, 
10].  
 
9.2 
INFORMED CONSENT 
The investigator or a designated member of the research team will obtain written informed 
consent prior to any procedures that are specific to the investigation and fall outside of the 
standard of care, including any testing required to confirm eligibility for enrollment. The 
informed consent form must have approval from the site’s IRB/EC prior to consenting patients 
for the study. 
 
The investigator or designee will document the process of obtaining informed consent in the 
patient’s source documents. The potential benefits and risks of participation will be explained to 
the patient. The patient will be provided a copy of the informed consent for review and will be 
given ample opportunity to review and ask questions. If the patient agrees to participate, both the 
patient and the investigator will sign the informed consent, and the patient will be recorded on an 
enrollment log. Failure to obtain informed consent renders the patient ineligible for participation. 
 
Adverse events will be collected from the time informed consent is provided until the subject 
exits the study. 
 
9.3 
ROLL-IN 
Each site will be permitted to use the investigational device in up to two non-randomized Roll-In 
subjects to allow investigators to become acquainted with the features of the investigational 
device. All Roll-In subjects will be treated with the investigational device. Subjects must be 
prospectively identified as Roll-In subjects during enrollment. Designation of a subject as a Roll-
In subject is not permitted after randomization has been completed for the subject. 
 
Roll-In procedures are not required prior to randomizing subjects at a site. Roll-In procedures are 
recommended to allow investigators not familiar with the investigational device to gain 
experience with the investigational device. Until the site has completed two Roll-In procedures, 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 37 of 86 
the subject does not meet the study eligibility criteria and may not undergo the index ablation 
procedure.  
 
9.8 
ABLATION PROCEDURE 
The goal of the index ablation procedure is isolation of all PVs as demonstrated by entrance 
block. Starting with transseptal puncture, the ablation procedure may only be performed by 
authorized investigators. 
 
Photos, video, and/or audio recordings of the procedure may be taken during the ablation 
procedure for future training purposes.  
 
The following sequence is recommended for the ablation procedure: 
• Esophagus temperature probe placement 
• Diagnostic catheter placement (e.g., in the coronary sinus) 
• Thrombus screening (if ICE is used) 
• Initial heparin bolus 
• Confirmation of target ACT, with monitoring minimally at 30-minute intervals thereafter 
• Transseptal puncture 
• Aspiration and flushing of transseptal sheath(s) 
• Introduction of catheter(s) into the left atrium 
• High-density mapping of the left atrium 
• Phrenic nerve pacing 
• PV isolation 
• Mapping and ablation of additional atrial tachycardias 
• Confirmation of PV isolation after waiting period 
• Confirmation of block across linear lesions 
• Screening for phrenic nerve injury 
Additional details are provided below. 
 
A single or double transseptal puncture may be performed at the discretion of the investigator. A 
constant heparinized drip is recommended for all long sheaths with access to the left atrium. 
 
If an esophagus temperature probe is used, it is recommended that the probe be placed prior to 
administration of a heparin bolus. Thrombus screening is required prior to introduction of the 
ablation catheter and prior to any cardioversion. The target ACT should be maintained while the 
ablation catheter is in the body. If the ACT drops below the target during the ablation procedure, 
the ablation procedure may continue while additional heparin is administered. 
 
Cardioversion may be used to restore sinus rhythm at the discretion of the investigator.  
 
At the end of the procedure, phrenic nerve function must be assessed by either (a) direct pacing 
of the phrenic nerve or (b) observation of diaphragm motion on fluoroscopy during spontaneous 
breathing. If new phrenic nerve injury is observed or suspected based on assessment at the end of 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 38 of 86 
the ablation procedure, a sniff test or inhalation-exhalation fluoroscopy will be performed prior 
to discharge. 
 
9.8.1 
PULMONARY VEIN ISOLATION 
See Sections 9.8.4 and 9.8.5 for specific requirements and recommendations regarding ablation 
with the investigational device and the control device.  
 
High-density mapping of the left atrium with the assigned mapping system (i.e., the Affera 
Mapping System or the CARTO® 3 System) is required prior to pulmonary vein isolation. Prior 
to any RF delivery near the right superior PV (RSPV) ostium, pacing maneuvers must be used to 
evaluate phrenic nerve location. 
 
Wide antral circumferential ablation (WACA, i.e., adjacent ablation lesions encircling ipsilateral 
veins 1 – 2 cm outside of the vein ostium) must be used to encircle and isolate all targeted PVs.  
 
Entrance block will be confirmed in each targeted PV (a) after a 20-minute waiting period from 
the last ablation delivery for that PV or, as part of routine practice at experienced centers with 
prior approval from the Sponsor, (b) during provocative testing with adenosine or isoproterenol. 
It is recommended that entrance block be confirmed using a circular or multi-spline catheter or, 
for subjects treated with the investigational device, the Sphere-9 Catheter (see section 9.8.4). 
According to the 2017 HRS consensus on AF ablation, “Entrance block of the left PVs should be 
assessed during distal coronary sinus or left atrial appendage pacing in order to distinguish far-
field atrial potentials from PV potentials.” [1] 
 
Failure to isolate all targeted PVs will be considered a primary effectiveness endpoint failure. 
Ablation using devices other than the assigned study device to isolate a targeted PV will also be 
considered a primary effectiveness endpoint failure. Failure to isolate a PV that was not targeted 
for isolation (e.g., due to unusual anatomy) is not a primary effectiveness endpoint failure. 
 
9.8.2 
ADDITIONAL ABLATION 
See Section 9.8.4 and 9.8.5 for specific requirements and recommendations regarding ablation 
with the investigational device and the control device. 
 
Any ablation beyond PVI for treating AF, if required, should be performed with the assigned 
study catheter if possible. Any AF ablation not completed with the assigned study catheter must 
be documented. Ablation using devices other than the assigned study device for any left atrial 
ablation during the index procedure will be considered a Primary Effectiveness Endpoint failure. 
 
The following linear ablations are only required in order to treat documented macroreentrant 
tachycardias: 
• Linear lesions between the tricuspid annulus and the inferior vena cava (cavotricuspid 
isthmus line) 
• Linear lesions between the left and right PVs (roof line and/or posterior line), optionally 
including homogenization of the posterior wall of the left atrium 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 39 of 86 
• Linear lesions between the mitral annulus and the left PVs (mitral isthmus line), with 
ablation permitted in the apposing coronary sinus. 
Cavotricuspid isthmus linear ablation is required in cases with documented typical right atrial 
flutter either prior to or during the procedure. Empirical atrial linear ablation is discouraged.  
 
Additional ablation beyond these lesion sets (e.g., ablation at sites of fractionated electrograms) 
is not permitted unless the target is shown to be a critical isthmus or focal source in an organized 
atrial tachycardia (e.g., atypical atrial flutter).  
 
Delivery of ablation lesions that are not part of routine clinical practice is not recommended. 
Bidirectional conduction block across each ablation line must be confirmed with mapping and/or 
pacing as appropriate. 
 
9.8.3 
DATA COLLECTION 
Data collected during the procedure will include the following: 
• Adverse events 
• Cardiac medications 
• Device deficiencies 
• Rhythm(s) prior to and during the ablation procedure 
• Rhythm at the end of the ablation procedure 
• Devices used for mapping and/or verification 
• Lesion sets applied 
• Method(s) of confirming each lesion set 
• Use of RF and/or PF for each lesion set/group 
• Device(s) used for each lesion set/group 
• Total number of RF and PF deliveries 
• Total RF and PF delivery time 
• Total fluid infused from mapping and ablation catheters 
• Total fluoroscopy time 
• Time(s) of catheter introduction and removal 
• Ablation data (electronic or paper records) captured by the mapping system, ablation 
system, and/or EP recording system 
 
After the ablation procedure, an investigator involved in performing the procedure will evaluate 
electroanatomical mapping performance. Scoring of electroanatomical mapping will be on a 
scale from 1 – 5, with 1 representing a strongly negative response, 5 representing a strongly 
positive response, and 3 being neutral or just acceptable. 
 
9.8.4 
INVESTIGATIONAL DEVICE USE 
For subjects randomized to receive treatment with the investigational device, the following 
devices are required to be used in the ablation procedure for mapping and ablation: 
• Sphere-9 Mapping and Ablation Catheter 
• Affera Mapping System, including the HexaMAP Catheter Interface Unit (CIU) 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 43 of 86 
 
 
9.10 REPEAT ABLATION 
Repeat ablation for treatment of recurrent AF/AT/AFL at any time after the index ablation 
procedure will be considered a primary effectiveness failure. Any repeat ablation must be more 
than 30 days after the index ablation procedure. It is strongly recommended that any repeat 
ablation be more than 90 days after the index procedure. Repeat ablation using the 
investigational device is not permitted. 
 
If a repeat ablation procedure is performed: 
• Diagnostic evaluation related to adverse events (e.g., chest CT or MRI for subjects with 
symptoms suggestive of PV stenosis) should be completed prior to a repeat ablation 
procedure. 
• See Section 9.6 for anticoagulation requirements. 
• Thrombus screening must be repeated according to Section 9.7. 
• A pregnancy test must be repeated for women of childbearing potential. 
• Assessments will include medical history as well as cardiac medications and 
anticoagulation 
• The schedule of follow-up visits will not reset.  
 
9.11 ANTIARRHYTHMIC DRUGS (AADS) 
See Section 7.2 for definitions of AAD use related to the Primary Effectiveness Endpoint.  
 
During the 90-day blanking period, subjects may receive new AADs or previously failed Class I 
or III AADs without affecting their primary effectiveness classification. It is recommended that a 
Class I or III AAD be selected according to the ACC/AHA/ESC 2014 Guidelines for the 
Management of Patients with AF [42]. Initiation, re-initiation, or up-titration of amiodarone is 
not recommended post ablation. In addition, it is recommended to discontinue use of Class I or 
III AADs used for treating AF/AT/AFL by the end of the 90-day blanking period. 
 
During the effectiveness evaluation period (Day 91 through Day 360): 
• Continuation or initiation of any new Class I or III AAD for treating AF/AT/AFL 
recurrence will be considered a primary effectiveness endpoint failure. 
• Use of any previously failed Class I or III AAD at a dose greater than the historic 
maximum ineffective dose for treating AF/AT/AFL recurrence will be considered a 
primary effectiveness endpoint failure.  
Use of a previously failed AAD at or below the historical maximum ineffective dose during the 
effectiveness evaluation period is not a primary effectiveness endpoint failure.  
 
9.12 TRANSTELEPHONIC MONITORING (TTM) 
A transtelephonic monitor (TTM, or other event monitoring device) will be provided to each 
subject prior to the end of the 90-day blanking period. Subjects will be instructed to transmit 
recordings at least monthly and when AF-related symptoms occur. Subjects will use the 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 44 of 86 
monitoring device to report symptoms at the time of transmission. Missed TTM recordings will 
not be considered a protocol deviation. 
 
TTM recordings will be analyzed by a core laboratory. Episodes of atrial tachyarrhythmia 
(AF/AFL/AT) recorded on TTM within the effectiveness evaluation period and lasting longer 
than 30 seconds will be reviewed by the investigator at the Day 180 and Day 360 visits. 
Symptomatic and asymptomatic recurrences will be identified by the core laboratory. The 
number of TTM recordings will be documented. 
 
9.13 HOLTER MONITORING (HM) 
Prior to the Day 180 and Day 360 visits, each subject will have a 24-hour Holter Monitor (HM). 
HM recordings will be analyzed by a core laboratory. Episodes of atrial tachyarrhythmia 
(AF/AFL/AT) recorded on HM within the effectiveness evaluation period and lasting longer than 
30 seconds will be reviewed by the investigator at the Day 180 and Day 360 visits.  
 
9.14 12-LEAD ECG RECORDINGS 
12-lead ECG will be recorded as part of any in-person visits at Day 30, Day 90, Day 180, and/or 
Day 360, as well as any unscheduled visit (if possible). 12-lead ECG recordings during the 
effectiveness evaluation period will be analyzed by a core laboratory to identify episodes of atrial 
tachyarrhythmia (AF/AFL/AT) (a) lasting longer than 30 seconds or (b) covering an entire 
recording lasting at least 10 seconds. 
 
9.15 FOLLOW-UP VISITS 
A Pre-Discharge Visit will be conducted prior to hospital discharge after ablation. Telephone 
follow-up will be conducted at Day 10 (7-13 days) to assess medications and adverse events. 
Follow-up visits are at 1 month (Day 30, 14-42 days), 3 months (Day 90, 76-104 days), 6 months 
(Day 180, 150-210 days), and 12 months (Day 360, 330-390 days). The Day 30 visit may be 
either an in-person visit or a “hybrid” visit as described in section 9.15.3. Unless an office visit is 
needed to assess adverse events or as part of the Neurological Assessment Sub-Study, office 
visits at Day 90, Day 180, and Day 360 may be conducted as telehealth visits, with transmission 
of TTM recordings in lieu of 12-lead ECG. Additional telephone follow-up will be conducted at 
75 days (Day 75, 60-90 days) unless the Day 90 office visit occurs within 90 days of the ablation 
procedure.  
 
A post-approval study with subject follow-up for up to 5 years may be requested by the U.S. 
Food and Drug Administration (FDA) or other regulatory body as a condition of approval of the 
investigational device. As a result, follow-up visits including medical history, arrhythmia history, 
and adverse events may extend for up to 5 years. 
 
The follow-up schedule will not reset if the subject undergoes a repeat ablation procedure. 
 
9.15.1 
PRE-DISCHARGE VISIT 
Prior to hospital discharge after ablation, assessments will include the following: 
• Physical exam, including cardiovascular/pulmonary examination 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 47 of 86 
• Adverse events 
• PV anatomy imaging (Chest CT or MRI) is required if the subject has symptoms 
suggestive of PV stenosis. 
 
9.15.7 
DAY 360 OFFICE/TELEHEALTH VISIT (330-390 DAYS) 
Subjects will be provided with a Holter Monitor prior to the Day 360 visit. Results of Holter 
Monitor and TTM will be reviewed at the Day 360 visit. 
 
Unless an office visit is needed to assess adverse events, the Day 360 visit may optionally be 
conducted as a telehealth visit with transmission of TTM recordings during the visit. The Day 
360 visit will include the following assessments: 
• QOL assessment using the Atrial Fibrillation Effect on Quality of Life (AFEQT) 
Questionnaire and the SF-12v2 Health Survey. These assessments should be completed 
before the other assessments during this visit. 
• 12-lead ECG (if office visit) or TTM transmission (if telehealth visit) 
• Medical history 
• Arrhythmia history (TTM, HM, etc.) and symptoms 
• Cardiac medications and anticoagulation 
• Adverse events 
• PV anatomy imaging (chest CT or MRI) is required if the subject has symptoms 
suggestive of PV stenosis. 
• If there was new phrenic nerve injury during the index ablation procedure that was 
unresolved at the Pre-Discharge Visit and the Day 30 Visit, a sniff test or inhalation-
exhalation fluoroscopy is required at the Day 360 visit. 
Prior to unblinding, the subject will be asked to guess which study arm he/she was assigned to. 
 
9.15.8 
UNSCHEDULED VISITS 
An unscheduled visit is any unplanned cardiovascular-related visit with the study site that occurs 
outside of protocol-driven visits, including early study exit. Unscheduled visits will include the 
following assessments: 
• Medical history 
• Arrhythmia history 
• Cardiac medications and anticoagulation 
• Adverse events 
• PV anatomy imaging (chest CT or MRI) is required if the subject has symptoms 
suggestive of PV stenosis. 
The following assessments should be performed if possible: 
• Physical exam 
• 12-lead ECG 
 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
Affera, Inc. 
CONFIDENTIAL 
Page 49 of 86 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 51 of 86 
10 ADVERSE EVENTS AND DEVICE DEFICIENCIES 
 
10.1 DEFINITIONS 
 
10.1.1 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. This definition includes 
events related to the investigational device or the control device. This definition includes events 
related to the ablation procedure. For users or other persons, this definition is restricted to events 
related to the investigational medical device. 
 
Conditions or diseases that are chronic but stable should not be recorded as an AE. For example, 
recurrence of AF or of a pre-existing atrial flutter (AFL) or atrial tachycardia (AT) and 
associated treatment (including repeat ablation or pharmacological or electrical cardioversion) 
are considered progression of pre-existing disease and do not meet the definition of an AE. 
Changes in a chronic condition or disease that are consistent with natural disease progression are 
not considered Aes, but these medical conditions should be adequately documented in the 
subject’s medical history. An underlying disease or pre-existing condition will not be reported as 
an AE unless it significantly worsens in severity or frequency in a manner that is not attributed to 
natural progression. 
 
10.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is an adverse event that: 
• Led to death 
• Led to serious deterioration in the health of the subject, that either resulted in: 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or body function, or 
o In-patient or prolonged hospitalization (> 24 hours), or 
o Medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or body function, or 
o Chronic disease 
• Led to fetal distress, fetal death, or a congenital abnormality or birth defect 
Hospitalization for a pre-existing condition or for a procedure that is required as part of this 
study, without a serious deterioration in health, is not an SAE. 
 
10.1.3 
ADVERSE DEVICE EFFECTS 
An adverse device effect (ADE) is an AE related to the use of an investigational medical device. 
This definition includes AEs resulting from insufficient or inadequate instructions for use, 
deployment, installation, or operation, or any malfunction of the device. This definition includes 
any event resulting from use error or from intentional misuse of the investigational device. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 52 of 86 
A serious adverse device effect (SADE) is an ADE that that resulted in any of the consequences 
characteristic of a SAE. 
 
An unanticipated serious adverse device effect (USADE) is an SADE which by its nature, 
incidence, severity, or outcome has not been identified in the current risk assessment. An 
anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity, or outcome has been identified in the risk analysis report. 
 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
10.1.4 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and inadequate labeling. 
 
10.2 ASSESSMENT OF ADVERSE EVENTS 
For the purposes of this study, the following AEs will be collected from the time informed 
consent is provided until the subject exits the study: 
• All device or procedure related AEs, including AEs related to either the investigational or 
control device, and including possible relationship to the device or procedure 
• All cardiovascular related AEs 
• All SAEs, regardless of relationship to the device or procedure 
Adverse events will be recorded, reported, and followed regardless of which device 
(investigational or control) was used to treat the subject. 
 
AEs will be reported to the Sponsor using an electronic case report form (eCRF). The following 
information should be obtained for each AE: 
• A description of the event including diagnosis based on signs, symptoms, and other 
supporting data 
• Date of onset 
• Date of awareness of the site 
• Action taken including treatment 
• Outcome including date of resolution 
• Severity (see Table 8) 
• Seriousness 
• Expectedness (see Table 9) 
• Relationship to the device or procedure (see Table 10) 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 55 of 86 
• Anesthesia related nausea / vomiting for up to 24 hours 
• Low-grade fever (less than 100°F or 37.8°C) for up to 48 hours 
• Mild to moderate bruising / ecchymosis or pain in the groin area for up to 168 hours 
• Sleep problems for up to 72 hours 
• Back pain (related to laying on the procedure table) for up to 72 hours 
Minor pericarditis limited to pleuritic chest discomfort with or without pericardial rub and ECG 
changes is generally not considered an AE in the context of AF ablation and is not reportable. A 
trace, trivial, or minor pericardial effusion that does not require intervention is generally not 
considered an AE as is not reportable unless it requires extended hospitalization [1, 21]. 
 
All device deficiencies related to the investigational device must be reported to the Sponsor 
through a Device Deficiency eCRF immediately upon awareness and no later than 72 hours after 
site awareness. Device deficiencies related to the control device will be reported according to the 
standard complaint handling procedure at the site. 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 56 of 86 
Table 12. Anticipated adverse events. 
• Acute respiratory distress syndrome  
• Air embolism 
• Allergic reaction, including anaphylaxis 
• Anemia 
• Anesthesia reaction, including nausea 
• Aneurysm 
• Angina / chest pain / discomfort 
• Apnea – sedation induced 
• Arrhythmia, including palpitations, 
bradycardia, tachycardia, proarrhythmia, and 
ECG changes 
• Arteriovenous fistula 
• Aspiration pneumonia 
• Asthmatic attack 
• Atelectasis 
• Atrial fibrillation 
• Atypical atrial flutter 
• Bleeding complications 
• Bronchial injury 
• Bruise at puncture site 
• Cardiac perforation 
• Cardiac thromboembolism 
• Cardiac or respiratory arrest 
• Catheter entrapment 
• Cerebrovascular accident (CVA) / stroke 
• Complete heart block, temporary or 
permanent 
• Conduction block 
• Congestive heart failure (CHF), or 
exacerbation of existing CHF due to fluid 
overload 
• Coronary artery dissection 
• Coronary artery spasm 
• Coronary artery thrombosis / occlusion 
• Damage to ICD or implantable pacemaker 
• Death 
• Deep vein thrombosis 
• Diaphragmatic paralysis 
• Dislodgement of ICD or permanent pacing 
leads 
• Disseminated intravascular coagulation 
• Dyspnea / shortness of breath 
• Endocarditis 
• Esophageal ulceration / erythema 
• Exacerbation of pre-existing arrhythmia 
• Myocardial infarction 
• Epistaxis, pharyngitis, or soft palate injury 
due to esophageal temperature probe 
• Nausea 
• Neck, back, or groin pain 
• Neurological disorders including tremor, poor 
coordination, and headache 
• Obstruction / perforation / damage to the 
vascular system 
• Pericardial effusion, with or without 
tamponade 
• Pericarditis 
• Peripheral embolus or thromboembolism 
• Peripheral nerve injury 
• Persistent atrial septal defect 
• Phlebitis 
• Phrenic nerve damage 
• Pleural effusion 
• Pneumonia 
• Pneumothorax 
• Pseudoaneurysm 
• Pulmonary edema 
• Pulmonary embolism 
• Pulmonary hemorrhage 
• Pulmonary hypertension 
• Pulmonary toxicity 
• Pulmonary vein damage / dissection 
• Pulmonary vein thrombus 
• Pulmonary vein stenosis 
• Radiation injury to skin, muscle, and/or organ 
• Radiation-related cancers 
• Renal failure 
• Respiratory depression / failure 
• Retroperitoneal hematoma 
• Rhabdomyolysis 
• Seizure 
• Sepsis 
• Skin burns 
• Skin discoloration 
• Skin irritation or rash 
• Severe PV stenosis or complete occlusion  
• Stiff left atrial syndrome 
• Syncope / dizziness / fainting 
• Tamponade 
• Temperature elevation 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 57 of 86 
• Expressive aphasia 
• Fatigue 
• Gastric reflux 
• Gastroparesis / gastric hypomotility 
• Headache 
• Heart failure 
• Hemoptysis 
• Hemorrhage 
• Hematoma (local) / ecchymosis 
• Hemothorax 
• Hypotension 
• Hypoxia 
• Increased creatinine phosphokinase (CPK) 
level 
• Infection, localized or systemic 
• Injury to skin, muscle, connective tissue due 
to body position or electrical cardioversion 
• Laceration 
• Leakage of air or blood into the lungs or other 
organs due to perforation 
• Left atrial-esophageal fistula 
• Liver toxicity 
• Major bleeding, requiring surgery or 
transfusion 
• Temporary AV, sinus node, or other heart 
block/damage 
• Thrombocytopenia 
• Thromboembolism 
• Thrombosis 
• Thyroid disorders 
• Transient extremity numbness 
• Transient ischemic attack (TIA) 
• Unintended complete or incomplete AV, sinus 
node, or other heart block/damage 
• Urinary retention 
• Urinary tract injury or infection related to the 
urinary catheter 
• Valvular damage / insufficiency 
• Vascular bleeding / local hematomas / 
ecchymosis 
• Vasovagal reactions 
• Vessel wall damage 
• Vision changes / abnormal vision 
• Volume overload 
• Vomiting 
• Worsening obstructive, restrictive, or other 
pulmonary disease 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 61 of 86 
The Primary Safety Analysis will be performed at a one-sided Type I error rate of α = 0.05 using 
the Farrington-Manning method. If the upper 95% confidence bound is less than 0.08, the study 
will be considered to have demonstrated safety of the investigational device.  
 
Primary Effectiveness Analysis 
The null hypothesis (H0) is that the true rate of Primary Effectiveness Endpoint success (no 
failures through Day 360) for the investigational device (PI) is less than or equal to the true rate 
for the control device (PC) minus the NIM of 0.15. The alternative hypothesis (HA) is that the 
success rate for the investigational arm (PI) is greater than the success rate for the control device 
(PC) minus the NIM of 0.15. 
 
H0: PI ≤ PC – 0.15 
HA: PI > PC – 0.15 
 
The Primary Effectiveness Analysis will be performed at a one-sided Type I error rate of α = 
0.025 using the Farrington-Manning method. If the lower 97.5% confidence bound is greater 
than −0.15, the study will be considered to have demonstrated effectiveness of the investigational 
device.  
 
11.1.1 
POOLABILITY ACROSS SITES 
Data from different sites are expected to be poolable based on (i) consistent site selection criteria 
based on the Sponsor’s standard operating procedures (SOPs), (ii) the use of a consistent clinical 
investigation plan with well-defined inclusion/exclusion criteria, and (iii) site monitoring to 
ensure compliance. To minimize the influence of any individual site, each site should not enroll 
more than 20% of the total enrollment. 
 
A regression approach will be used to evaluate homogeneity of treatment effect (Primary Safety 
and Primary Effectiveness) across sites using the PAC. This will use a logistic regression model 
with fixed terms for randomized treatment group, site, and the interaction of treatment group and 
site. If necessary, Firth’s adjustment will be used to handle sparse data. If heterogeneity across 
sites is found to be potentially significant (p < 0.1), additional analyses will be conducted to 
investigate sources of the apparent differences across sites. If data from different sites are not 
found to be poolable, a random-effects model will be fit to examine the impact of site 
heterogeneity on the primary endpoints.  
 
11.1.2 
SENSITIVITY ANALYSIS 
Multiple imputation of the primary effectiveness endpoint will be employed to address missing 
data. This will be based on a fully conditional specification logistic regression approach with 100 
imputed data sets. Imputation will be performed separately by treatment group. The imputation 
model will include the following covariates: age, sex, and LA size. Details will be provided in 
the statistical analysis plan. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 62 of 86 
Tipping point analyses will also be conducted where the hazard of failure for those with missing 
outcomes are increased (and decreased) to explore the impact of potential missing not at random 
on the primary effectiveness analysis. 
 
Reasons for missing data within the follow-up period will be reported. TTM compliance will be 
calculated for each subject in the PAC as the number of TTM recordings during a given period 
divided by the expected number of TTM recordings during that period. Expected transmissions 
will be estimated based on a 7-day week and a 31-day month. 
 
11.1.3 
SUBGROUP ANALYSES 
Subgroup analyses will be performed to evaluate the primary safety and effectiveness endpoints 
within subgroups of subjects. Subgroup analysis will be based on at least the following 
demographic and baseline variables: 
• Age 
• Sex 
• LA size 
 
The primary endpoints will be assessed separately within each patient subgroup.  
  
11.1.4 
SAMPLE SIZE 
A sample size of 350 evaluable subjects is planned for the PAC. Power calculations were 
performed using the Farrington-Manning method [44]. A sample size of 350 subjects in the PAC 
(175 in each arm) provides 82.2% power for Primary Effectiveness and 84.0% power for 
Primary Safety in the Primary Analysis.  
 
To ensure that investigators have adequate experience with the investigational device, each site 
will be permitted to use the investigational device in up to two enrolled non-randomized subjects 
(Roll-In Cohort). Subjects in the Roll-In Cohort will be analyzed separately from the PAC.  
 
It is estimated that the attrition rate will be approximately 15%, leading to a planned randomized 
total of 410 subjects. The maximum number of Roll-In subjects will be 70. As a result, an overall 
maximum of 480 subjects will be enrolled in the study. 
 
 
11.2 SECONDARY ANALYSES 
If the Primary Analysis demonstrates safety and effectiveness of the investigational device, 
Secondary Analyses will be performed to test the following secondary hypotheses using the 
PAC: 
 
1. Total Energy Application Time Superiority: The null hypothesis (H0) is that the mean 
total energy application time during the ablation procedure for the investigational device 
(µETI) is greater than or equal to the mean time for the control device (µETC). The 
alternative hypothesis (HA) is that the mean total energy application time for the 
investigational device is less. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 64 of 86 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 65 of 86 
12 RISK ANALYSIS 
 
12.1 POTENTIAL BENEFITS 
Available clinical data for the Sphere-9 Catheter and the Affera Mapping and Ablation System 
[32, 33, 34] suggest the following potential benefits of the investigational device: 
• Improved durability of ablation lesions 
• Reduced procedural and energy delivery time 
• Safety benefits associated with PF ablation including reduced risk of thermal injury to the 
esophagus 
There may be other benefits that are unforeseen at this time. 
 
12.2 POTENTIAL RISKS 
Risks to subjects enrolled in this investigation include all risks currently associated with 
percutaneous electrophysiology procedures and RF catheter ablation procedures, which are well 
understood [1, 22, 36]. A brief summary of published complication rates can be found in Section 
3.1.4. Anticipated adverse events are listed in Table 12, and some more common adverse events 
are listed in Section 10.3. Serious adverse events (SAEs) have also been reported for the 
PRECEPT pivotal IDE study of the THERMOCOOL SMARTTOUCH® SF catheter for 
treatment of persistent AF (NCT02817776) [21]. Specific risks are described in more detail 
below based on published literature and study results for catheter ablation for AF. 
 
Some pain and/or ecchymosis at the groin access sites is common. The incidence of major 
vascular access complications has been reported between 0.2% and 1.5%. Access site 
complications can include hemorrhage or hematoma at the groin access sites after the ablation 
procedure [1]. The results of the PRECEPT study included hemorrhage reported as an SAE in 
0.6% [21]. Access site complications can also include AV fistula or pseudoaneurysm. Ultrasound 
should be performed if AV fistula or pseudoaneurysm is suspected [1]. 
 
The ablation procedure may cause cardiac perforation leading to pericardial effusion and 
potentially tamponade. The incidence of tamponade has been reported between 0.2% to 5% [1]. 
Tamponade was reported as an SAE in 1.4% in the PRECEPT study [21]. Cardiac tamponade 
has been reported as the most frequent cause or periprocedural death [45]. Echocardiography 
should be performed if tamponade or significant pericardial effusion is suspected [1].  
 
The reported incidence of cardiac valve damage is low (≤0.5%) [1, 20, 18]. Cardiac valve 
damage can be caused by catheter entrapment and should be confirmed with echocardiography 
when suspected [1].  
 
The reported incidence of PV stenosis is less than 1%. PV stenosis can potentially lead to chest 
pain, shortness of breath, coughing, hemoptysis, or other pneumonia-like symptoms. There is 
also a risk of pulmonary hemorrhage, which has been reported in cases of pulmonary venous 
occlusion [46]. Chest CT or MR imaging should be performed if PV stenosis is suspected [1].  
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 66 of 86 
The reported incidence of coronary artery stenosis or occlusion is low (less than 0.1%) [1]; 
however, the incidence of myocardial infarction has been reported up to 0.4% in the literature 
[18], and myocardial infarction was reported as an SAE in 0.6% in the PRECEPT study [21]. 
 
There is a small risk of cardiac arrest (less than 0.1%) [1]. Heart block was reported as an SAE in 
approximately 0.6% in both the PRECEPT study and the SMART-AF study of the 
THERMOCOOL SMARTTOUCH® catheter for treatment of symptomatic paroxysmal AF 
(NCT01385202) [21, 26]. Arrhythmias are common after the ablation procedure [26] and may 
include atrial or ventricular fibrillation, tachycardia or bradycardia, possibly requiring 
cardioversion or pacemaker implantation.  
 
Hypotension has been reported in previous studies of RF ablation for paroxysmal AF in up to 
1.2% of subjects, and syncope has been reported at a similar rate [26, 23]. Unexplained 
hypotension should be evaluated promptly with echocardiography to rule out pericardial effusion 
or cardiac tamponade [1].  
 
The incidence of death reported in the literature is 0.1% to 0.4% [1]. Two subject deaths (0.5%) 
were reported in the PRECEPT study [21]. 
 
Pleuritic chest pain with or without a “trace” pericardial effusion due to pericarditis is very 
common after catheter ablation for AF [1]. There is also a risk of pulmonary edema (1.4% 
reported as SAEs in the PRECEPT study) [21] or pneumothorax (reported between 0.1% to 0.4% 
in the literature) [20, 18]. There may be a risk of bronchial injury, particularly when ablating 
near the superior pulmonary veins [47, 48]. 
 
RF ablation near the posterior wall of the left atrium may cause esophagus injury, in rare cases 
leading to atrio-esophageal fistula, which is often fatal [1]. While esophageal injury is relatively 
common (15%) [49]; the incidence of atrio-esophageal fistula has been reported between 0.02% - 
0.11% [1], with 0.2% reported in one single-center study [50]. When ablating near the esophagus 
with the control device in this study, reduced RF power is recommended to reduce the risk of 
thermal injury [1]. When ablating with the investigational device, only PF energy delivery is 
permitted on the posterior wall of the left atrium. PF ablation has not been shown to injure the 
esophagus [16]. 
 
RF ablation near the phrenic nerve can lead to temporary or permanent injury (diaphragmatic 
paralysis). The incidence of permanent phrenic nerve paralysis has been reported between 0% 
and 0.4 [1]. Diaphragmatic paralysis was reported as an SAE in one subject (0.3%) in the 
PRECEPT study [21]. Pacing maneuvers should be used to evaluate the location of the right 
phrenic nerve prior to any RF ablation near the right superior PV [1].  
 
RF ablation on the posterior wall of the left atrium can injure the vagal nerves, which can lead to 
pyloric spasm and gastric hypomotility (gastroparesis). Gastric hypomotility has been reported 
with an incidence of up to 17%, and asymptomatic functional impairment has been reported in 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 67 of 86 
up to 74% of patients. The risk can be reduced using the same techniques used to avoid 
esophageal injury [1], which are described above.  
 
There is a risk of thromboembolism or air embolism leading to stroke or transient ischemic 
attack, asymptomatic cerebral emboli, or occlusion of other vessels (e.g., deep vein thrombosis 
or pulmonary embolism). The incidence of stroke or transient ischemic attack has been reported 
between 0% and 2%, and air embolism has been reported with an incidence less than 1% [1]. 
One stroke (0.3%) and two pulmonary embolisms (0.6%) were reported in the PRECEPT study 
[29].  
 
Asymptomatic cerebral ischemia is often observed on cerebral MRI following catheter ablation 
for atrial fibrillation but has not been linked to decline in neurocognitive function [1]. A 2015 
review defined a silent cerebral event (SCE) as an “acute new MRI-detected brain lesion typical 
to cerebral ischemia in a patient without clinically apparent neurological deficit”, which is 
detected based on new DWI hyperintensity with corresponding ADC reduction. A silent cerebral 
lesion (SCL) is an SCE with corresponding FLAIR hyperintensity. This 2015 review found 
reported incidence of SCE following RF catheter ablation for AF (paroxysmal or persistent) 
between 6.8% and 24%, with reported incidence of SCL between 7.4% and 8.3% [51]. 
Publications since that time have reported widely varying incidence of post-ablation 
asymptomatic cerebral ischemia. A 2020 report of 285 AF patients undergoing catheter ablation 
with either RF or cryoballoon, targeting only PVI, found SCE in 23% [41]. Another 2020 report 
of 55 AF patients undergoing RF catheter ablation, including PVI and optional substrate 
ablation, found SCE in 42 – 67% depending on MRI parameters [52]. Meanwhile, a 2019 report 
of 97 paroxysmal AF patients undergoing ablation with a novel gold-tip RF ablation catheter 
found ischemia in 9.3%, which the authors called SCL but defined as being independent of 
FLAIR [40].  
 
The risk of thromboembolism can be reduced by careful attention to anticoagulation before, 
during, and after the ablation procedure [1]. Continuous, uninterrupted anticoagulation is 
required in this study before, during, and after the ablation procedure, and the target activated 
clotting time (ACT) must be maintained while the ablation catheter is in the body. 
 
Air embolism is most often caused by introduction of air through the transseptal sheath, 
including during catheter exchanges or associated with long apnea. Sheaths with access to the 
left atrium should be carefully managed according to the catheter instructions for use and 
training in order to minimize this risk. However, air embolism can also be caused by atrio-
esophageal fistula, which should be excluded if air embolism occurs post-procedure [1].   
 
Nausea or lightheadedness/fainting is common in procedures involving anesthesia. The subject 
may have an allergic reaction to anesthesia, sedatives, contrast dye, heparin, protamine, or other 
agents administered during the ablation procedure.  
 
There is also a small risk of radiation injury, potentially increasing the lifetime risk of fatal 
malignancy (estimated at ≤0.1% for 60 minutes of fluoroscopy) [53]. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 68 of 86 
 
While PF ablation may potentially reduce risks associated with RF catheter ablation such as 
damage to the phrenic nerves, vagal nerves, and esophagus, theoretical risks of PF ablation 
include arrhythmia induction, transient phrenic nerve injury, and asymptomatic cerebral emboli 
due to microbubble formation [15, 17]. 
 
The assessments included in this investigation are considered standard of care at the participating 
sites. Additional follow-up required as part of this investigation is not expected to increase risk to 
subjects.  
 
12.3 MINIMIZATION OF RISKS 
Risk analysis of the investigational device has been conducted in accordance with ISO 14971. 
Mitigating steps to address hazardous situations, use errors, and potential device malfunctions 
have been implemented to reduce the risks as low as possible. Risk mitigations have been 
confirmed in nonclinical bench, laboratory, and animal testing. 
 
This investigation plan has been designed to minimize risk to participating subjects in several 
ways: 
• Eligibility criteria have been designed to exclude subjects who may be at increased risk 
for complications from – or who are less likely to benefit from – catheter ablation for 
PerAF. 
• Subjects will be screened to ensure compliance with inclusion and exclusion criteria.  
• Investigators and sites will be selected for participation based on demonstrated 
experience with similar mapping and ablation procedures using the control device for the 
treatment of PerAF, and personnel will be trained on the use of the investigational 
devices prior to participation.  
• Ablation settings available on the Affera Ablation System will be limited based on data 
obtained from animal and clinical studies. 
• Affera personnel will be present for ablation procedures involving the investigational 
device and will monitor the use of the investigational device. 
• Data monitoring will be conducted regularly to identify and address protocol deviations.  
• A Data and Safety Monitoring Board will review data from the clinical investigation on 
an ongoing basis and advise the Sponsor regarding the safety and well-being of subjects 
any changes to the risk-benefit analysis. 
The degree of risk to each subject relative to potential benefits of participation in the 
investigation should be evaluated by a qualified physician. 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 69 of 86 
13 STUDY CONDUCT 
 
13.1 ETHICS 
This investigation will be conducted in compliance with this clinical investigation plan, the 
signed clinical study agreement, the ethical principles stated in the latest version of the 
Declaration of Helsinki, 21 CFR Parts 11, 50, 54, 56, and 812, ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice), EU 2017/745 
(Medical Device Regulations), and applicable local and international regulations in order to 
provide the greatest protection for the subject. Any deviations from this investigation plan that 
may affect the safety and welfare of study participants will be immediately reported to the 
Sponsor and to the Institutional Review Board (IRB) or Ethics Committee (EC) per each site’s 
guidelines. Additional requirements imposed by the local IRB/EC or regulatory authority will be 
followed where appropriate. 
 
13.2 INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE 
Prior to the initiation of the study, the clinical investigation plan and the patient informed consent 
form will be submitted to the Institutional Review Board (IRB) or Ethic Committee (EC) for 
approval. By signing the clinical study agreement, the investigator is assuring that an IRB/EC 
will be responsible for initial and continuing review of the proposed clinical study. 
 
A copy of the IRB/EC approval letter for the protocol, the informed consent, and the protocol 
signature page must be submitted to the Sponsor or its designee prior to subject enrollment. The 
approval letter must refer to the specific protocol and the informed consent form. Any 
investigator who is also a member of the IRB/EC is not to participate in the protocol approval 
decision. This non-participation must be noted in the approval letter. The study site must 
maintain an accurate and complete record of all reports, documents, and other submissions made 
to the IRB/EC concerning this protocol. 
 
The investigator must report any withdrawal of IRB/EC approval to the Sponsor or its designee 
within five (5) working days. 
 
13.3 US FDA AND LOCAL COMPETENT AUTHORITY 
The study will be reviewed by the US FDA and other applicable regulatory authority as needed. 
The Sponsor or its designee is responsible for obtaining regulatory approval for the study. No 
subjects may be enrolled at a study site until written notification of the relevant local regulatory 
approval has been given by the Sponsor.  
 
13.4 INFORMED CONSENT 
It is the responsibility of the investigator to obtain informed consent from a subject prior to 
participation in this study. One original informed consent form is to be retained by the study site, 
and a signed copy is to be given to the subject. The informed consent process must be 
documented in the subject’s source/medical record. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 70 of 86 
Any changes made to the informed consent must first be approved by the Sponsor or its 
designee. After approval by the Sponsor or its designee, the informed consent must be submitted 
to and approved by the reviewing IRB/EC. The informed consent form may be translated as 
appropriate. 
 
If new information becomes available that can significantly affect a subject’s future health and 
medical care, the information will be provided to the subjects in written form. The Sponsor is 
responsible for producing the written information and providing it to investigators who will 
provide it to the subjects. If applicable, all affected subjects will be asked to confirm their 
continued, informed consent in writing.  
 
Any failure to obtain informed consent prior to use of the investigational device will be reported 
to the Sponsor and the reviewing IRB/EC within five (5) working days after the use. 
 
13.5 CONFIDENTIALITY AND DATA PROTECTION 
All information concerning the subjects in the study will be considered confidential by the 
Sponsor. Only authorized Sponsor representatives, the participating IRB/EC, local government 
authorities, or the FDA will have access to this information. All data used in analysis and 
reporting of this investigation will be performed using pseudonymized (key coded) data unless it 
is impossible to do so or involves disproportionate effort (e.g., if the subject’s name is included 
as part of an image). Subjects will be identified on electronic case report forms (eCRFs) using a 
unique identifier (code). Any information that is obtained in connection with this study that can 
be identified with the subjects will remain confidential and will be made accessible only to 
authorized persons. Any data that may be published in scientific journals will not reveal the 
identity of the study participants. 
 
All Sponsor representatives conducting this investigation in the US will have undergone training 
for HIPAA regulations and will comply with HIPAA including Protected Health Information 
(PHI), contact with subjects, medical records, copying of data. Patient informed consent will 
include authorization for access to PHI by Sponsor representatives and reflect applicable local 
regulations (e.g., GDPR in the European Union) as appropriate. 
 
The investigator acknowledges that any and all information acquired from the Sponsor or its 
designee or developed or acquired in connection with the study are strictly confidential. The 
investigator will not disclose any confidential information to any third party nor use confidential 
information for any purpose without first obtaining the consent of Sponsor in writing. Such 
consent shall be deemed to have been given for disclosure to any person for whom the 
investigator is responsible at his/her center, but only so far as required for the purposes of the 
study, and, in the case of disclosures to staff, only if such staff are bound by obligations of 
confidentiality no less strict than those set out herein. 
 
13.6 INSURANCE 
The Sponsor will provide proof of appropriate insurance coverage for this clinical investigation 
as required by applicable local laws. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 71 of 86 
 
13.7 DATA QUALITY ASSURANCE 
 
13.7.1 
SITE SELECTION 
Potential investigational sites will be evaluated according to the Sponsor’s SOPs to ensure that 
each site has appropriate facilities and personnel to conduct the study in compliance with the 
investigational plan. Investigator and site selection criteria will include demonstrated experience 
with similar mapping and ablation procedures using the control device for the treatment of 
PerAF. 
 
13.7.2 
TRAINING 
Prior to initiating enrollment at an investigational site, Sponsor representatives will provide 
appropriate device and protocol training in accordance with the documented study training plan. 
Investigators performing ablation procedures will be trained on the use of the Sphere-9 Catheter 
and the Affera Mapping and Ablation System. Site personnel training will include the clinical 
investigation plan, inclusion/exclusion criteria, case report forms (eCRFs), follow-up schedules, 
and regulatory requirements. In some cases, training of additional site staff may be performed by 
site staff who have been trained by Sponsor representatives.  
 
13.7.3 
SITE INITIATION 
Prior to performing study related activities, requirements including but not limited to the 
following must be completed: 
• IRB/EC approval 
• Regulatory authority approval as required by local law 
• Signed clinical study agreement and Investigator Agreement 
• Financial disclosure forms 
• Curriculum vitae (CV) for each investigator, lab director (if applicable), and any 
dedicated clinical research staff 
• Documentation of delegated tasks 
• Documented training, including investigational device training for all investigators 
performing ablation procedures and protocol training for all site staff performing study 
procedures 
 
13.7.4 
CASE REPORT FORMS 
Electronic case report forms (eCRFs) will be used for this investigation, which are part of an 
Electronic Data Capture (EDC) system that meets 21 CFR Part 11 requirements. 
 
Good Clinical Practice Guidelines require that Investigators maintain information in the study 
subject’s medical records that corroborate data collected on the eCRFs. In order to comply with 
these regulatory requirements, the following information should be maintained: 
• Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol entry criteria. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 72 of 86 
• Dated and signed notes on the day of entry into the study including the study investigator, 
study name, subject number assigned and a statement that consent was obtained. 
• Dated and signed notes from each study subject visit with reference to the eCRFs for 
further information, if appropriate (for specific results of procedures and exams). 
• Information related to adverse events. 
• Study subject’s condition upon completion of or withdrawal from the study. 
• Discharge summaries/procedure reports. 
 
The investigator is responsible for the accuracy and completeness of eCRFs. The investigator 
will electronically sign the eCRF to verify that he or she has reviewed the eCRF and attests to the 
validity of the entered data. eCRFs will be completed by the investigator within 14 days from the 
corresponding visit or bimonthly. Queries regarding eCRF entries must be answered within 14 
days. 
 
13.7.5 
DOCUMENTATION 
Data entered into eCRFs will be based on source documentation. Source documents are a 
subject’s original documents, data, or records from before and during the study, related to the 
medical treatment and history of the patient, and from which study data are obtained. Source 
documents may include, for example, the subject’s medical records, hospital charts, clinic charts, 
questionnaires, study files, and results of diagnostic tests such as laboratory tests, 
electrocardiograms, and imaging. If no standard source document exists to capture data required 
by the eCRF, a worksheet may be developed to record this data. Worksheets signed and dated by 
the investigator may serve as source documents. Data recorded by the mapping and ablation 
system during the ablation procedure may be transferred to the EDC system by site staff, and the 
EDC data will be considered the source. The eCRF may be considered the source document if no 
relevant source data exist (e.g., investigator classification of adverse events, date of awareness, 
reasons for study deviations, or patient ID). 
 
13.7.6 
DATA MONITORING 
Sponsor representatives will periodically conduct monitoring, both in person and via telephone, 
written, and/or electronic communication, to ensure compliance with the investigation plan and 
applicable regulations and guidelines. A study specific monitoring plan will be developed to 
ensure compliance with the protocol and with applicable regulatory requirements. Monitoring 
visits may include, but will not be limited to, site qualification visits, site initiation visits, interim 
monitoring visits, and close-out visits.  
 
Data monitoring activities may include, but will not be limited to: 
• Ensuring compliance with the study protocol 
• Verification of IRB/EC and regulatory approval 
• Review of eCRFs for completeness and accuracy, including verification of eCRFs against 
source documentation 
• Verification of study logs including training, screening, enrollment, and device 
accountability 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 73 of 86 
• Verification of informed consent for enrolled subjects 
• Queries and identification of corrective actions to resolve issues 
The investigator agrees to provide access for these monitoring activities and to assist Sponsor 
representatives as needed during monitoring visits. The investigator also agrees to provide access 
to regulatory agencies if requested. Data monitoring will comply with local privacy regulations. 
 
13.7.7 
DEVICE ACCOUNTABILITY 
The Sponsor will maintain documentation of all investigational devices shipped to the site. 
Investigational device labels will include the text “Investigational device” in a prominent 
location. 
 
The investigator or a designee will maintain documentation of receipt, use, and return of all 
investigational devices (by lot or serial number) in a device accountability log until the 
conclusion of the study. Investigational devices are to be used only in accordance with this 
clinical investigation plan and under supervision of the investigator or a duly designated person. 
It is the investigator’s responsibility to ensure that all investigational devices are kept in a secure 
location, with access limited to individuals authorized by the investigator. 
 
All Sphere-9 Catheters (used and unused) and Affera Mapping and Ablation Systems will be 
returned to the Sponsor. The Catheter Extension Cable should also be returned to the Sponsor if 
possible. Returned single-use devices should be labeled with the subject identification number, 
date of use, and indication of any device deficiency or adverse event as appropriate. Used 
devices must be decontaminated per hospital policy prior to return. Tracking information will be 
retained by the site for shipped devices. Specific instructions for returning investigational 
devices will be provided to the sites by the Sponsor. 
 
13.7.8 
DATA MANAGEMENT 
Data will be collected using an Electronic Data Capture (EDC) system for clinical studies. eCRF 
data will be stored in a secure database with password-protected access and will be backed up on 
a regular schedule. Data validation will include programmed and manual data checks. 
 
13.7.9 
CORE LABS 
12-lead ECG, TTM, and Holter Monitor recordings during the effectiveness evaluation period 
will be sent to a core lab for analysis. All events will be analyzed for symptomatic or 
asymptomatic arrhythmia recurrence according to the definitions in this protocol. Evaluations of 
arrhythmia recurrence will be reviewed by a qualified physician. In case of disagreement 
between the core lab and the investigator regarding the rhythm analysis, a third-party cardiologist 
will review the recording to make a final rhythm determination. 
 
Cerebral MR images will be transmitted to a core lab for analysis. Images will be analyzed for 
ischemia according to the definitions in this protocol. Evaluations will be reviewed by a qualified 
physician. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 74 of 86 
Any PV anatomy images (chest CT or MRI) collected in patients who experience symptoms 
suggestive of PV stenosis will be transmitted to a core lab for analysis. Images will be analyzed 
to assess PV stenosis according to the definitions in this protocol. Evaluations will be reviewed 
by a qualified physician. 
 
13.8 PROTOCOL DEVIATIONS 
A protocol deviation is a failure to comply with the requirements specified within this clinical 
study protocol. An investigator is not allowed to deviate from the protocol without prior approval 
by the Sponsor. Protocol deviations that affect subjects’ rights, safety, or well-being or the 
scientific integrity of the clinical investigation require prior review and documented approval 
from the IRB/EC. In the US, these protocol deviations require prior approval from the FDA.  
 
Under emergency circumstances, deviations from the clinical investigation plan to protect the 
life, rights, safety or well-being of human subjects may proceed without prior approval of the 
Sponsor and the IRB/EC. These deviations will be reported to the Sponsor and the IRB/EC as 
soon as possible after site awareness. In the US, emergency protocol deviations to protect the life 
or physical well-being of a subject must be reported to the local IRB/EC within 5 working days 
after the emergency occurred. Emergency protocol deviations must be reported to regulatory 
bodies as required by local regulations. 
 
Deviations must be documented on the appropriate Protocol Deviation eCRF. If a Clinical 
Monitor becomes aware that an Investigator is not complying with the signed Investigator’s 
Agreement, the Investigational Plan, the requirements of ISO 14155:2011 or other applicable 
regulations, or any conditions of approval imposed by the reviewing EC, the Sponsor or designee 
will discuss with the site corrective and preventive actions for avoiding future deviations, 
including repeat training as deemed necessary.  
 
Repeated serious protocol deviations will be closely monitored. If excessive deviations or a 
failure to reduce deviations is noted, the Sponsor reserves the right to suspend study enrollment 
or terminate the site from the study until a sufficient system is in place at the site to reduce 
further deviations. If disqualified, site is required to return all investigational devices unless this 
action would jeopardize the rights, safety, or welfare of a subject. The decision to resume study 
enrollment and treatment at a site will be made by the Sponsor in coordination with the 
investigator. 
 
Protocol deviations will be analyzed by the Sponsor for impact to the overall integrity of the 
study. 
 
13.9 STUDY AUDITS 
Audits of the study may be conducted by the Sponsor, regulatory agencies, or a third party 
designated by the Sponsor to evaluate compliance with the protocol, Investigator Agreement, and 
written procedures. These audits may cover all involved parties, systems, and facilities 
supporting the conduct of the study and are independent of, and separate from, routine 
monitoring functions. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 75 of 86 
 
In the event that an Investigator is contacted by a regulatory agency regarding this study, the 
Investigator will notify the Sponsor or its designee immediately. The Investigator and research 
coordinator must be available to respond to reasonable requests and queries made during the 
inspection process. The Investigator must provide the Sponsor or designee with copies of all 
correspondence that may affect review of the current study. The Sponsor may provide needed 
assistance in responding to regulatory audits. 
 
13.10 RECORD KEEPING 
Records to be maintained by the investigator include: 
• Clinical investigation plan and amendments 
• Signed clinical study agreement 
• IRB/EC approval letters including informed consent form 
• IRB/EC membership 
• Curriculum vitae for each investigator, lab director (if applicable), and any dedicated 
clinical research staff 
• Investigator’s medical license 
• Study logs including: 
o Study personnel/delegation log 
o Training log 
o Screening log 
o Enrollment log 
o Site visit/monitoring log 
o Device accountability log 
• Subject records including: 
o Informed consent 
o eCRFs (stored electronically) 
o Source documentation to support eCRFs 
o Procedure reports, procedure nursing notes, and results of interventional 
procedures while enrolled in the study 
o Record of any complications, AES, and device problems/malfunctions, with 
supporting documentation 
o Records pertaining to subject deaths throughout the course of the study (including 
death records, death certificate, and autopsy report, if performed) 
• Lab certification and lab test normal ranges 
• Study correspondence 
• Site training records 
• Protocol deviations (if applicable) 
• Financial disclosure forms 
• Study reports including final report and periodic reports required by the IRB/EC 
• Copy of all IRB/EC approved subject-related materials and/or study advertising materials 
• Investigator Brochure, if required by local regulations 
• Insurance certificate, if required by local regulations 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 77 of 86 
13.11.2 PUBLICATION 
Affera is committed to the publication and dissemination of study results regardless of outcomes. 
This study will be registered at www.clinicaltrials.gov before enrollment begins.  
 
Upon the prior written consent of Sponsor, investigators shall have the right to publish papers 
related to the Study as outlined in the clinical study agreement. Any publication or presentation 
of study results will acknowledge the financial support of the Sponsor. 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 78 of 86 
14 STUDY OVERSIGHT 
 
14.1 STUDY ADVISORY COMMITTEE 
A Study Advisory Committee will be established that will be responsible for: 
• Review of the clinical investigation plan 
• Ensuring investigator compliance with the investigation plan 
• Advising investigators regarding the investigational devices, ablation procedure, roll-in 
procedures, and medical concerns 
• Advising the Sponsor regarding medical concerns identified during the study 
• Review and interpretation of study results 
• Providing strategy and consultation regarding publication of study results 
 
14.2 INVESTIGATOR RESPONSIBILITIES 
The clinical investigators will be responsible for: 
• Obtaining approval (and renewals as appropriate) from the IRB/EC for the institution at 
which procedures will be performed 
• Providing the Sponsor with the following prior to enrollment: 
o IRB/EC approval letters 
o Informed consent form approved by the IRB/EC 
o Signed clinical study agreement 
o Signed financial disclosure form 
o Curriculum vitae for each investigator 
• Maintaining accurate and complete logs including study personnel/delegation and 
training, subject screening and enrollment, and site visit/monitoring 
• Completing training, and ensuring training of research personnel, prior to enrollment 
• Supervising research personnel 
• Assuring that all subjects enrolled in the study conform to the subject selection criteria. 
• Obtaining informed consent (including HIPAA language as appropriate) from all subjects 
before enrollment as described in 9.2.  
• Maintaining accurate records of receipt, use, and return of investigational devices as 
described in 13.7.7 
• Performing the study procedures according to this investigation plan 
• Completing eCRFs accurately, and reviewing and signing eCRFs, as described in 13.7.4 
• Maintaining sufficient source data to support eCRFs 
• Making every effort to maintain contact with all enrolled subjects as described in 8.8 
• Retaining study records as described in this protocol 
• Preparing a final report and periodic reports required by the IRB/EC 
 
14.3 SPONSOR RESPONSIBILITIES 
The Sponsor will be responsible for: 
• Ensuring adherence to Sponsor responsibilities under 21 CFR 812 and ISO 14155:2011 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 79 of 86 
• Preparing study documents including the clinical investigation plan, eCRFs, study logs, 
and a draft informed consent form 
• Obtaining IDE approval from FDA and communicating with FDA 
• Preparing and obtaining approval for IDE supplements as necessary 
• Informing investigators of their responsibilities 
• Informing investigators of any new information about the study that may affect the 
health, safety, or welfare of subjects or may influence their decision to participate in the 
study 
• Site initiation assessments and approvals 
• Training of investigators and site research personnel 
• Providing investigational devices to the site 
• Data monitoring 
• Data management 
• Providing resources for statistical analysis and study report writing necessary to complete 
reporting of study results 
 
14.4 DATA AND SAFETY MONITORING BOARD 
The study will utilize a Data and Safety Monitoring Board (DSMB) including a statistician and 
three (3) individuals with relevant experience who are not participating investigators in this 
study. The DSMB will meet at regular intervals to review data from this clinical investigation 
and advise the Sponsor regarding the safety and well-being of subjects, any changes to the risk-
benefit analysis, and the scientific validity of the study results. 
 
If the DSMB determines the study should be suspended, discontinued, or otherwise modified 
because of safety concerns, the DSMB will prepare formal written recommendations to the 
Sponsor to consider final action. The Sponsor will notify the FDA and other regulatory 
authorities, as appropriate, of any such recommendation. Moreover, any safety concerns that the 
DSMB identifies will be verbally communicated to both the Sponsor and investigators as soon as 
possible, prior to written documentation. 
 
A charter for the DSMB will be established that will include: 
• Description of responsibilities 
• Identification of members, including qualifications 
• Declaration of possible conflicts of interest 
• Frequency and format of meetings 
• Description of communication procedures, including data flow 
 
14.5 CLINICAL EVENTS COMMITTEE 
The study will utilize an independent Clinical Events Committee (CEC) including three (3) 
physicians who are not participating investigators in this study. The CEC will meet at frequent 
intervals to adjudicate endpoint-related adverse events, classify adverse events according to 
severity and association with the device or procedure, and adjudicate death classifications 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 80 of 86 
(including primary cause and cardiac classification). The CEC may request additional 
information and assessments from the investigator to support adjudication. 
 
A charter for the CEC will be established that will include: 
• Description of responsibilities 
• Identification of members, including qualifications 
• Declaration of possible conflicts of interest 
• Frequency and format of meetings 
• Description of communication procedures, including data flow 
 
14.6 PROTOCOL AMENDMENTS 
The Sponsor will document any modifications to the protocol in the form of a written 
amendment and obtain IRB/EC approval. Substantial changes may also require approval from 
the FDA and/or Competent Authority prior to implementation.  
 
14.7 SUSPENSION OR DISCONTINUATION OF THE STUDY 
The Sponsor has the right to suspend or discontinue the study at any or all investigational sites 
for any safety, ethical, or administrative reason at any time. The Sponsor may stop inclusion of 
subjects at a specific site if no subjects have been enrolled for a period of three (3) months or if 
the site or investigators meet the criteria for disqualification described in Section 13.8.  
 
An investigator or IRB/EC may discontinue participation or withdraw approval for the study, 
respectively, with suitable written notice to the Sponsor, the IRB/EC, and regulatory authorities 
as appropriate. If an investigator discontinues participation in the study, the investigator’s 
responsibilities will be transferred to another investigator if possible. If an investigator’s 
participation in the study ends for any reason, the investigator is required to return all documents 
and investigational devices to the Sponsor unless this action would jeopardize the rights, safety, 
or welfare of a subject. 
 
In case of suspension or discontinuation, enrolled subjects who have already undergone 
treatment with the investigational devices will continue to be followed according to the 
investigation plan if possible. Plans for continued follow-up will be provided by the Sponsor. 
 
 
 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 81 of 86 
15 REFERENCES 
 
[1]  H. Calkins, G. Hindricks, R. Cappato, Y. Kim, E. Saad, L. Aguinaga, J. Akar, V. Badhwar, 
J. Brugada, J. Camm and P. Chen, "2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert 
consensus statement on catheter and surgical ablation of atrial fibrillation," Heart Rhythm, 
vol. 14, no. 10, pp. e275-e444, 2017.  
[2]  G. Lippi, F. Sanchis-Gomar and G. Cervellin, "Global epidemiology of atrial fibrillation: 
An increasing epidemic and public health challenge," International Journal of Stroke, vol. 
16, no. 2, pp. 217-21, 2021.  
[3]  D. M. Lloyd-Jones, T. J. Wang, E. P. Leip, M. G. Larson, D. Levy, R. S. Vasan, R. B. 
D'Agostino, J. M. Massaro, A. Beiser, P. A. Wolf and E. J. Benjamin, "Lifetime Risk for 
Development of Atrial Fibrillation: The Framingham Heart Study," Circulation, vol. 110, 
no. 9, pp. 1042-6, 2004.  
[4]  A. S. Go, E. M. Hylek, K. A. Phillips, Y. Chang, L. E. Henault, J. V. Selby and D. E. 
Singer, "Prevalence of Diagnosed Atrial Fibrillation in Adults," Journal of the American 
Medical Association, vol. 285, no. 18, pp. 2370-5, 2001.  
[5]  A. Alonso, S. K. Agarwal, E. Z. Soliman, M. Ambrose, A. M. Chamberlain, R. J. Prineas 
and A. R. Folsom, "Incidence of atrial fibrillation in whites and African-Americans: the 
Atherosclerosis Risk in Communities (ARIC) Study," American Heart Journal, vol. 158, 
no. 1, pp. 111-7, 2009.  
[6]  A. M. Wendelboe, G. E. Raskob, P. Angchaisuksiri, A. N. Blanco, H. Büller, H. Ddungu, J. 
D. Dvorak, B. J. Hunt, E. M. Hylek, A. Kakkar, S. V. Konstantinides, M. McCumber, C. 
McLintock, T. Urano and J. I. Weitz, "Global public awareness about atrial fibrillation," 
Research and practice in thrombosis and haemostasis, vol. 2, no. 1, pp. 49-57, 2018.  
[7]  J. F. Meschia, P. Merrill, E. Z. Soliman, V. J. Howard, K. M. Barrett, N. A. Zakai, D. 
Kleindorfer, M. Safford and G. Howard, "Racial Disparities in Awareness and Treatment 
of Atrial Fibrillation: The REasons for Geographic and Racial Differences in Stroke 
(REGARDS) Study," Stroke, vol. 41, no. 4, pp. 581-7, 2010.  
[8]  J. Frewen, C. Finucane, H. Cronin, C. Rice, P. M. Kearney, J. Harbison and R. A. Kenny, 
"Factors that influence awareness and treatment of atrial fibrillation in older adults," QJM: 
An International Journal of Medicine, vol. 106, no. 5, pp. 415-24, 2013.  
[9]  Biosense Webster, Inc, "P030031/S100 Summary of Safety and Effectiveness Data 
(SSED)," 30 September 2020. [Online]. Available: 
http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030031S100B.pdf. [Accessed 11 October 
2021]. 
[10] Medtronic Inc., "P100010/S098 Summary of Safety and Effectiveness Data (SSED)," 23 
June 2020. [Online]. Available: 
http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100010S098B.pdf. [Accessed 12 
October 2021]. 
[11] R. L. Page, J. A. Joglar, M. A. Caldwell, H. Calkins, J. B. Conti, B. J. Deal, N. M. Estes 
III, M. E. Field, Z. D. Goldberger, S. C. Hamill and J. H. Indik, "2015 ACC/AHA/HRS 
guideline for the management of adult patients with supraventricular tachycardia: a report 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 82 of 86 
of the American College of Cardiology/American Heart Association Task Force on 
Clinical Practice Guidelines and the Heart Rhythm Society," Heart Rhythm, vol. 13, no. 4, 
pp. e136-e221, 2016.  
[12] D. L. Packer, D. B. Mark, R. A. Robb, K. H. Monahan, T. D. Bahnson, J. E. Poole, P. A. 
Noseworthy, Y. D. Rosenberg, N. Jeffries, B. Mitchell, G. C. Flaker, E. Pokushalov, A. 
Romanov, T. J. Bunch, G. Noelker, A. Ardashev, A. Revishvili, D. J. Wilber, R. Cappato, 
K. H. Kuck, G. Hindricks, D. W. Davies, P. R. Kowey, G. V. Naccarelli, J. A. Reiffel, J. P. 
Piccini, A. P. Silverstein, H. R. Al-Khalidi and K. L. Lee, "Effect of Catheter Ablation vs 
Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among 
Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial," Journal of 
the American Medical Association, vol. 321, no. 13, pp. 1261-74, 2019.  
[13] D. Callans, E. Gerstenfeld, S. Dixit, E. Zado, M. Vanderhoff, J. REN and F. Marchlinski, 
"Efficacy of repeat pulmonary vein isolation procedures in patients with recurrent atrial 
fibrillation," Journal of cardiovascular electrophysiology, vol. 15, no. 9, pp. 1050-1055, 
2004.  
[14] V. Y. Reddy, P. Neuzil, J. S. Koruth, J. Petru, M. Funosako, H. Cochet, L. Sediva, M. 
Chovanec, S. R. Dukkipati and P. Jais, "Pulsed field ablation for pulmonary vein isolation 
in atrial fibrillation," Journal of the American College of Cardiology, vol. 74, no. 3, pp. 
315-26, 2019.  
[15] F. H. Wittkampf, R. van Es and K. Neven, "Electroporation and its Relevance for Cardiac 
Catheter Ablation," Journal of the American College of Cardiology: Clinical 
Electrophysiology, vol. 4, no. 11, pp. 1481-2, 2018.  
[16] E. Maor, A. Sugrue, C. Witt, V. R. Vaidya, C. V. DeSimone, S. J. Asirvatham and S. Kapa, 
"Pulsed electric fields for cardiac ablation and beyond: A state-of-the-art review," Heart 
Rhythm, vol. 16, no. 7, pp. 1112-20, 2019.  
[17] D. E. Haines and C. J. Bradley, "The Promise of Pulsed Field Ablation," EP Lab Digest, 
vol. 19, no. 12, 2019.  
[18] A. Deshmukh, N. J. Patel, S. Pant, N. Shah, A. Chothani, K. Mehta, P. Grover, V. Singh, S. 
Vallurupalli, G. T. Savani, A. Badheka, T. Tuliani, K. Dabhadkar, G. Dibu, Y. M. Reddy, 
A. Sewani, M. Kowalski, R. Mitrani, H. Paydak and J. F. Viles-Gonzalez, "In-hospital 
complications associated with catheter ablation of atrial fibrillation in the United States 
between 2000 and 2010: analysis of 93,801 procedures," Circulation, vol. 128, no. 19, pp. 
2104-12, 2013.  
[19] R. Cappato, H. Calkins, S.-A. Chen, W. Davies, Y. Iesaka, J. Kalman, Y.-H. Kim, G. 
Klein, A. Natale, D. Packer, A. Skanes, F. Ambrogi and E. Biganzoli, "Updated Worldwide 
Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial 
Fibrillation," Circulation: Arrhythmia and Electrophysiology, vol. 3, no. 1, pp. 32-8, 2010.  
[20] E. Arbelo, J. Brugada, C. Blomstrom-Lundqvist, C. Laroche, J. Kautzner, E. Pokushalov, 
P. Raatikainen, M. Efremidis, G. Hindricks, A. Barrera, A. Maggioni, L. Tavazzi and N. 
Dagres, "Contemporary management of patients undergoing atrial fibrillation ablation: in-
hospital and 1-year follow-up findings from the ESC-EHRA atrial fibrillation ablation 
long-term registry," European Heart Journal, vol. 38, no. 17, pp. 1303-16, 2017.  

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 83 of 86 
[21] "Safety and Effectiveness of STSF Catheter Evaluated for Treating Symptomatic Persistent 
Atrial Fibrillation (PsAF) (PRECEPT)," U.S. National Library of Medicine, 12 January 
2021. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT02817776. [Accessed 1 
April 2021]. 
[22] Biosense Webster, Inc., "Prospective Review of the Safety and Effectiveness of the 
THERMOCOOL SMARTTOUCH® SF Catheter Evaluated for Treating Symptomatic 
PersistenT AF (PRECEPT)," 1 May 2018. [Online]. Available: 
https://clinicaltrials.gov/ProvidedDocs/76/NCT02817776/Prot_000.pdf. [Accessed 3 May 
2021]. 
[23] "DiamondTemp™ Ablation System for the Treatment of Paroxysmal Atrial Fibrillation 
(DIAMOND-AF)," U.S. National Library of Medicine, 3 January 2021. [Online]. 
Available: https://clinicaltrials.gov/ct2/show/NCT03334630. [Accessed 1 April 2021]. 
[24] "SMART-SF Radiofrequency Ablation Safety Study," U.S. National Library of Medicine, 
20 August 2018. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT02359890. 
[Accessed 1 April 2021]. 
[25] L. A. Chinitz, D. P. Melby, F. E. Marchlinski, C. Delaughter, R. S. Fishel, G. Monir, A. M. 
Patel, D. N. Gibson, C. A. Athill, L. M. Boo, R. Stagg and A. Natale, "Safety and 
efficiency of porous-tip contact-force catheter for drug-refractory symptomatic paroxysmal 
atrial fibrillation ablation: results from the SMART SF trial," EP Europace, vol. 20, pp. 
392-400, 2018.  
[26] "THERMOCOOL® SMARTTOUCH™ Catheter for the Treatment of Symptomatic 
Paroxysmal Atrial Fibrillation," U.S. National Library of Medicine, 26 January 2015. 
[Online]. Available: https://clinicaltrials.gov/ct2/show/NCT01385202. [Accessed 1 April 
2021]. 
[27] A. Natale, V. Y. Reddy, G. Monir, D. J. Wilber, B. D. Lindsay, H. T. McElderry, C. 
Kantipudi, M. C. Mansour, D. P. Melby, D. L. Packer, H. Nakagawa, B. Zhang, R. B. 
Stagg, L. M. Boo and F. E. Marchlinski, "Paroxysmal AF Catheter Ablation With a 
Contact Force Sensing Catheter Results of the Prospective, Multicenter SMART-AF Trial," 
Journal of the American College of Cardiology, vol. 64, no. 7, pp. 647-56, 2014.  
[28] J. A. Clarnette, A. G. Brooks, R. Mahajan, A. D. Elliott, D. J. Twomey, R. K. Pathak, S. 
Kumar, D. A. Munawar, G. D. Young, J. M. Kalman, D. H. Lau and P. Sanders, 
"Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a 
systematic review and meta-analysis," EP Europace, vol. 20, no. FI_3, pp. f366-76, 2018.  
[29] M. Mansour, H. Calkins, J. Osorio, S. J. Pollak, D. Melby, F. E. Marchlinski, C. A. Athill, 
C. Delaughter, A. M. Patel, P. J. Gentlesk, B. DeVille, L. Macle, K. A. Ellenbogen, S. R. 
Dukkipati, V. Y. Reddy and A. Natale, "Persistent Atrial Fibrillation Ablation With 
Contact Force–Sensing Catheter: The Prospective Multicenter PRECEPT Trial," JACC: 
Clinical Electrophysiology, vol. 6, no. 8, 2020.  
[30] M. Rodgers, C. McKenna, S. Palmer, D. Chambers, S. Van Hout, S. Golder, C. Pepper, D. 
Todd and N. Woolacott, "Curative catheter ablation in atrial fibrillation and typical atrial 
flutter: systematic review and economic evaluation," NIHR Journals Library, 2008. 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 84 of 86 
[31] J. Kautzner, P. Neuzil, H. Lambert, P. Peichl, J. Petru, R. Chihak, J. Skoda, D. Wichterle, 
E. Wissner, A. Yulzari and K. H. Kuck, "EFFICAS II: optimization of catheter contact 
force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation," EP 
Europace, vol. 17, no. 8, pp. 1229-35, 2015.  
[32] E. Anter, P. Neuzil, G. Rackauskas, P. Peichl, A. Aidietis, J. Kautzner, H. Nakagawa, W. 
M. Jackman, A. Natale and V. Y. Reddy, "A Lattice-Tip Temperature-Controlled 
Radiofrequency Ablation Catheter for Wide Thermal Lesions: First-in-Human Experience 
with Atrial Fibrillation," JACC: Clinical Electrophysiology, 2020.  
[33] V. Y. Reddy, P. Neuzil, P. Peichl, G. Rackauska, E. Anter, J. Petru, M. Funasako, K. 
Minami, A. Aidietis, G. Marinskis, A. Natale, H. Nakagawa, W. M. Jackman and J. 
Kautzner, "A Lattice-Tip Temperature-Controlled Radiofrequency Ablation Catheter: 
Durability of Pulmonary Vein Isolation and Linear Lesion Block," JACC: Clinical 
Electrophysiology, 2020.  
[34] V. Y. Reddy, E. Anter, G. Rackauskas, P. Peichl, J. S. Koruth, J. Petru, M. Funasako, K. 
Minami, A. Natale, P. Jais, H. Nakagawa, G. Marinskis, A. Aidietis, J. Kautzner and P. 
Neuzil, "A Lattice-Tip Focal Ablation Catheter that Toggles Between Radiofrequency and 
Pulsed Field Energy to Treat Atrial Fibrillation: A First-in-Human Trial," Circulation: 
Arrythmia and Electrophysiology, 2020.  
[35] C. T. January, L. S. Wann, H. Calkins, M. E. Field, L. Y. Chen, K. L. Furie, J. E. Cigarroa, 
P. A. Heidenreich, J. C. Cleveland, K. T. Murray, P. T. Ellinor, J. B. Shea, M. D. 
Ezekowitz, C. M. Tracy and C. W. Yancy, "2019 AHA/ACC/HRS focused update of the 
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a 
report of the ACC/AHA Task Force on Clinical Practice Guidelines and the HRS," Journal 
of the American College of Cardiology, vol. 71, no. 1, pp. 104-32, 2019.  
[36] G. Hindricks, T. Potpara, N. Dagres, E. Arbelo, J. J. Bax, C. Blomström-Lundqvist, G. 
Boriani, M. Castella, G.-A. Dan, P. E. Dilaveris, L. Fauchier, G. Filippatos, J. M. Kalman 
and M. La Meir, "2020 ESC Guidelines for the diagnosis and management of atrial 
fibrillation developed in collaboration with the European Association for Cardio-Thoracic 
Surgery (EACTS)," European Heart Journal, vol. 42, no. 5, pp. 373-498, 2021.  
[37] F. Gaita, D. Caponi, M. Pianelli, M. Scaglione, E. Toso, F. Cesarani, C. Boffano, G. 
Gandini, M. C. Valentini, R. De Ponti, F. Halimi and J. F. Leclercq, "Radiofrequency 
Catheter Ablation of Atrial Fibrillation: A Cause of Silent Thromboembolism?," 
Circulation, vol. 122, no. 17, pp. 1667-73, 2010.  
[38] M. Grimaldi, V. Swarup, B. DeVille, J. Sussman, P. Jais, F. Gaita, M. Duytschaever, G. A. 
Ng, E. Daoud, D. Lakkireddy, R. Horton, A. Wickliffe, C. Ellis and L. Geller, "Importance 
of anticoagulation and postablation silent cerebral lesions: Subanalyses of REVOLUTION 
and reMARQable studies," Pacing and Clinical Electrophysiology, vol. 40, no. 12, pp. 
1432-9, 2017.  
[39] S. Miyazaki, T. Watanabe, T. Kajiyama, J. Iwasawa, S. Ichijo, H. Nakamura, H. Taniguchi, 
K. Hirao and Y. Iesaka, "Thromboembolic Risks of the Procedural Process in Second-
Generation Cryoballoon Ablation Procedures," Circulation: Arrhythmia and 
Electrophysiology, vol. 10, no. 12, p. e005612, 2017.  

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 85 of 86 
[40] B. Schmidt, G. Szeplaki, B. Merkely, J. Kautzner, V. van Driel, F. Bourier, M. Kuniss, A. 
Bulava, G. Nolker, M. Khan, T. Lewalter, N. Klein, B. Wenzel, J. Chun and D. Shah, 
"Silent cerebral lesions and cognitive function after pulmonary vein isolation with an 
irrigated gold‐tip catheter: REDUCE-TE Pilot study," Journal of Cardiovascular 
Electrophysiology, vol. 30, no. 6, pp. 877-85, 2019.  
[41] M. Harada, Y. Motoike, Y. Nomura, A. Nishimura, M. Koshikawa, K. Murayama, Y. 
Ohno, E. Watanabe, Y. Ozaki and H. Izawa, "Factors Associated with Silent Cerebral 
Events During Atrial Fibrillation Ablation in Patients on Uninterrupted Oral 
Anticoagulation," Journal of Cardiovascular Electrophysiology, vol. 31, no. 11, pp. 2889-
97, 2020.  
[42] C. T. January, L. S. Wann, J. S. Alpert, H. Calkins, J. E. Cigarroa, J. B. Conti, P. T. Ellinor, 
M. D. Ezekowitz, M. E. Field, K. T. Murray and R. L. Sacco, "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," Journal of the American College of Cardiology, vol. 64, no. 
21, pp. e1-76, 2014.  
[43] Medtronic, Inc., "STOP Persistent AF Clinical Investigation Plan," 1 December 2017. 
[Online]. Available: 
https://clinicaltrials.gov/ProvidedDocs/41/NCT03012841/Prot_003.pdf. [Accessed 3 May 
2021]. 
[44] C. P. Farrington and G. Manning, "Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non‐zero risk difference or non‐unity relative risk," 
Statistics in Medicine, vol. 9, no. 12, pp. 1447-54, 1990.  
[45] R. Cappato, H. Calkins, S.-A. Chen, W. Davies, Y. Iesaka, J. Kalman, Y.-H. Kim, G. 
Klein, A. Natale, D. Packer and A. Skanes, "Prevalence and Causes of Fatal Outcome in 
Catheter Ablation of Atrial Fibrillation," Journal of the American College of Cardiology, 
vol. 53, no. 19, pp. 1798-803, 2009.  
[46] M. Hayashi, T. Minezawa, K. Imaizumi, Y. Sobue, E. Watanabe, Y. Ozaki and M. 
Okazawa, "Pulmonary Hemorrhage due to Pulmonary Venous Occlusion after 
Radiofrequency Catheter Ablation for Atrial Fibrillation," Respiration, vol. 86, no. 3, pp. 
252-3, 2013.  
[47] Y.-G. Li, M. Yang, Y. Li, Q. Wang, L. Yi and J. Sun, "Spatial relationship between left 
atrial roof or superior pulmonary veins and bronchi or pulmonary arteries by dual-source 
computed tomography: implication for preventing injury of bronchi and pulmonary arteries 
during atrial fibrillation ablation," EP Europace, vol. 13, no. 6, pp. 809-14, 2011.  
[48] A. Sparks, J. Kozinn, A. Wimmer and J. R. Stewart, "Distal Left Main Bronchial Injury 
after Catheter Ablation for Atrial Fibrillation: Report of Two Cases," Clinics in Surgery, 
vol. 2, pp. 1-3, 2017.  
[49] B. Yarlagadda, T. Deneke, M. Turagam, T. Dar, S. Paleti, V. Parikh, L. DiBiase, P. 
Halfbass, P. Santangeli, S. Mahapatra, J. Cheng, A. Russo, J. Edgerton, M. Mansour, J. 
Ruskin, S. Dukkipati, D. Wilber, V. Reddy, D. Packer, A. Natale and D. Lakkireddy, 
"Temporal relationships between esophageal injury type and progression in patients 

 
Treatment of Persistent Atrial Fibrillation with the Sphere-9 Mapping 
and Ablation Catheter and the Affera Mapping and Ablation System 
CP-00009 
Revision: G 
 
Affera, Inc. 
CONFIDENTIAL 
Page 86 of 86 
undergoing atrial fibrillation catheter ablation," Heart Rhythm, vol. 16, no. 2, pp. 204-12, 
2019.  
[50] N. Dagres, G. Hindricks, H. Kottkamp, P. Sommer, T. Gaspar, K. Bode, A. Arya, D. 
Husser, L. S. Rallidis, D. T. Kremastinos and C. Piorkowski, "Complications of Atrial 
Fibrillation Ablation in a High‐Volume Center in 1,000 Procedures: Still Cause for 
Concern?," Journal of Cardiovascular Electrophysiology, vol. 20, no. 9, pp. 1014-9, 2009.  
[51] T. Deneke, P. Jais, M. Scaglione, R. Schmitt, L. Di Biase, G. Christopoulos, A. Schade, A. 
Mügge, M. Bansmann, K. Nentwich, P. Müller, J. Krug, M. Roos, P. Halbfass, A. Natale, 
F. Gaita and D. Haines, "Silent Cerebral Events/Lesions Related to Atrial Fibrillation 
Ablation: A Clinical Review," Journal of Cardiovascular Electrophysiology, vol. 26, no. 4, 
pp. 455-63, 2015.  
[52] Y. Yu, X. Wang, X. Li, X. Zhou, S. Liao, W. Yang, J. Yu, F. Zhang, W. Ju, H. Chen, G. 
Yang, M. Li, K. Gu, L. Tang, Y. Xu, J. Y.-S. Chan, P. Kojodjojo, K. Cao, J. Fan, B. Yang 
and M. Chen, "Higher Incidence of Asymptomatic Cerebral Emboli After Atrial 
Fibrillation Ablation Found With High-Resolution Diffusion-Weighted Magnetic 
Resonance Imaging," Circulation: Arryhthmia and Electrophysiology, vol. 13, no. 1, p. 
e007548, 2020.  
[53] L. Lickfett, M. Mahesh, C. Vasamreddy, D. Bradley, V. Jayam, Z. Eldadah, T. Dickfeld, D. 
Kearney, D. Dalal, B. Lüderitz, R. Berger and H. Calkins, "Radiation Exposure During 
Catheter Ablation of Atrial Fibrillation," Circulation, vol. 110, no. 19, pp. 3003-10, 2004.