Randomized Evaluation of Redo Ablation Procedures of Atrial Fibrillation With Focal Impulse and Rotor Modulation Guided Procedures (REDO-FIRM)
Phase: NA
Conditions: Persistent Atrial Fibrillation, Paroxysmal Atrial Fibrillation
Sponsor: Abbott Medical Devices



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13 STUDY MANAGEMENT ................................................................................................................................ 37 
13.1 
IRB/IEC OR COMPETENT AUTHORITY APPROVAL ........................................................................... 37 
13.2 
MONITORING ..................................................................................................................................................... 37 
13.3 
STUDY AUDITS ................................................................................................................................................... 37 
13.4 
PROTOCOL DEVIATIONS ............................................................................................................................... 37 
13.5 
DATA MONITORING COMMITTEE ............................................................................................................. 38 
14 DEVICE ACCOUNTABILITY ......................................................................................................................... 39 
15 PROTECTION OF HUMAN SUBJECTS ...................................................................................................... 39 
15.1 
STATEMENT OF COMPLIANCE ................................................................................................................... 39 
15.2 
INFORMED CONSENT ..................................................................................................................................... 39 
16 STATISTICAL CONSIDERATIONS ............................................................................................................. 40 
16.1 
GENERAL ANALYSIS PRINCIPLES ............................................................................................................. 40 
16.2 
STUDY ENDPOINTS ................................................................................................................................................ 40 
16.3 
POWER AND SAMPLE SIZE ESTIMATION ............................................................................................... 42 
17 PUBLICATION POLICY ................................................................................................................................. 44 
 
 

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1 
PROTOCOL SIGNATURE PAGE 
Protocol: Redo‐FIRM 
 
 
Confidentiality 
I understand that the following is considered confidential: study protocol, study case 
report forms, study‐related documentation including correspondence with the study 
sponsor, all pre‐publication data derived from the study, and technical information 
that has not been previously made public.  
 
I understand that the contents of this Protocol may not be used in any other clinical 
study and may not be disclosed to any other person or entity without the prior 
written permission of the Sponsor. The foregoing shall not apply to disclosure 
required by law or regulation, for example submission to an Ethics Committee; 
however, I will give prompt notice to the Sponsor of any such disclosure. 
Compliance with EC and Protocol Requirements 
I have read and agree to conduct this clinical study in accordance with the design and 
specific provisions of this protocol; modifications to the study or protocol are 
acceptable only with a mutually agreed upon protocol amendment. I agree to await 
approval for the protocol and informed consent from the governing EC or equivalent 
review board, and from the local Ministry of Health (if required) if my site is located 
outside the United States, before initiating the study. I agree to obtain informed 
consent from subjects prior to performance of study‐specific screening assessments 
or enrollment in the study. I agree to collect and record data as required by this 
protocol and case report forms, to prepare annual, final and adverse effect reports as 
required by this protocol, and to maintain study documentation for the period of time 
required.   
 
Site Number:  
Printed Name of Investigator: 
Signature of Investigator: 
Date of Signature:  
 
 
 

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2 
ABBREVIATIONS and DEFINITIONS 
 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
AF 
Atrial fibrillation 
 
AFEQT 
Atrial Fibrillation Effect on Quality of Life questionnaire 
ASD 
Atrial septal defect 
AT 
Atrial tachycardia 
CABG 
Coronary artery bypass graft (surgery) 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CEC 
Clinical Event Committee 
CFAE 
Complex fractionated atrial electrograms 
CHADS2 
Scoring system in determining stroke risk for those with AF  
 
CIED 
Cardiac implanted electronic device 
CRA 
Clinical Research Associate 
e‐CRF 
Electronic Case Report Form 
CT 
Computed tomography 
CTI 
Cavotriscuspid isthmus 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotrophin 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQL 
Health Related Quality of Life, a subscale of the UFS‐QOL 
ICE 
Intracardiac echocardiography 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
LAA 
Left atrial appendage 
LMWH 
Low‐molecular‐weight heparin 
LV 
Left ventricle 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
NYHA 
New York Heart Association 
PVI 
Pulmonary vein isolation 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TEE 
Transesophageal echocardiogram 
TTE 
Transthoracic echocardiogram 
TIA 
Transient ischemic attack 
UADE 
Unanticipated Adverse Device Effect 
 

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3 
PROTOCOL SYNOPSIS 
Sponsor: Abbott Electrophysiology (Topera, Inc.)
Protocol Title: Randomized Evaluation of Redo Ablation Procedures of Atrial Fibrillation 
with Focal Impulse and Rotor Modulation Guided Procedures (REDO‐FIRM) 
Planned Study Centers: Up to 30 centers in Europe and North America
Primary Objective: 
Evaluate the safety and effectiveness of FIRM‐guided procedures in conventional repeat 
(“redo”) RF ablation for the treatment of paroxysmal and persistent atrial fibrillation. 
Secondary/Additional Objectives: 
 
Evaluate the acute effectiveness of FIRM‐guided procedures in eliminating the source of 
arrhythmia. 
 
Quality of life outcomes. 
 
Paroxysmal and persistent AF outcomes. 
 
Post‐ablation inducibility. 
 
Health economic outcomes. 
Study Design:  
This is a prospective, multicenter, randomized study to assess the safety and effectiveness of 
FIRM‐guided procedures in conventional “redo” RF ablation for the treatment of persistent 
and paroxysmal atrial fibrillation. 
Sample Size:  
A total of 268 subjects will be enrolled and equally (1:1) randomized. 
Randomization:  
FIRM + PVI vs. PVI+ (after confirming PVI reconnection by Lasso). 
Ablation Procedure: 
 
FIRM + (Re‐) PVI vs (Re‐)PVI+ 
 
Optional ablation: 
 
FIRM group: prophylactic ablation* of the RA‐Isthmus line and any inherent 
arrhythmia that is found to have focal firing during procedure.  
 
Control group: ablation of any arrhythmia that is found to have focal firing 
during procedure/that is provoked. The following prophylactic ablation* may 
be performed:  
 
RA‐isthmus line 
 
Non PV‐trigger (if provoked) 
 
Caval vein isolation 
 
No LA appendage isolation.  
 
*Prophylactic ablation should be performed for all study subjects if it is the standard of 
practice of the Investigator. 
Study Assessments & Follow‐Up: 
 
Patient informed consent 
 
Screening/Baseline 

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Follow‐Up Assessments: 
 
10 days post procedure for safety assessment. 
 
6 weeks post procedure prior to blanking period exit.  
 
3, 6, and 12 months with 7 days of continuous monitoring within 1‐2 weeks of each 
follow‐up visit. 
Blanking period is 8 weeks post‐procedure. Cardioversion may be done around week 6 to 
have patients exit blanking period. 
Amiodarone discontinuation: 4‐6 weeks prior to procedure; 4‐6 weeks post‐procedure or 
follow standard practice. 
Antiarrhythmic drug, Class IC: Discontinue after 5 half‐lives. 
Inclusion Criteria: 
Subjects are required to meet the following inclusion criteria: 
1. Male or female 18 – 80 years of age. 
2. Has at least one (1) episode of spontaneous persistent or paroxysmal atrial fibrillation 
documented by rhythm strip/ECG following the most recent ablation. 
3. Had one (1) previous AF ablation after January 01, 2013, but NOT within the last 3 
months. 
4. Oral anticoagulation required with either Novel Oral Anticoagulant (NOAC) or Warfarin 
(in the case of Warfarin, therapeutic INR ≥ 2.0 for at least three weeks prior to 
randomization) for those subjects who meet two or more of the following criteria:  
a. Age 65 years or older 
b. Diabetes 
c. Coronary artery disease (CAD) 
d. Congestive heart failure 
e. Hypertension with systolic>165 mm Hg 
5. Willingness and able to remain on anti‐coagulation therapy for a minimum of 3 months 
post procedure for all subjects and at least 12 months post procedure if the patient is on 
anti‐coagulation pre‐procedure or has CHADS2 score ≥ 2 (or CHADs‐Vasc score >1). 
6. Left atrial diameter < 6.0 cm via transthoracic echo or transesophageal echo; or <6.5 cm 
via CT or MRI up to 6 months pre‐procedure with documented image of largest 
dimension, or intra‐procedural ICE or atrial angiogram if CT/MRI not available. 
7. Willingness, ability and commitment to participate in baseline and follow‐up evaluations 
without participation in another clinical trial which may confound the results of this 
study, unless approved by the Sponsor. 
8. Informed consent in writing from patient. 

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Exclusion Criteria: 
Subjects must NOT meet any of the following exclusion criteria:  
1. Presence of structural heart disease of clinical significance including: 
a. Coronary artery disease with either: 
o Coronary artery bypass surgery (CABG) within the last six months, 
or 
o Stable/unstable angina or ongoing myocardial ischemia 
b. Congenital heart disease where either the underlying abnormality or its 
correction prohibits or increases the risk of ablation. 
2. NYHA Class IV. 
3. Ejection fraction < 35% (within previous 6 months). 
4. Previous AF ablation within the last 3 months. 
5. ASD closure device, LAA closure device, prosthetic mitral or tricuspid valve, or 
permanent pacemaker. 
6. History of myocardial infarction (MI) within the past three (3) months. 
7. Contraindication to Heparin and Warfarin/other novel oral anticoagulants (e.g. 
dabigatran, rivaroxaban, apixaban). 
8. Diagnosed atrial myxoma. 
9. Any concomitant arrhythmia or therapy that could interfere with the interpretation 
of the results from this study. 
10. Untreatable allergy to contrast media. 
11. Severe electrolyte abnormalities at time of the ablation procedure or atrial 
fibrillation secondary to electrolyte imbalance, thyroid disease, or reversible non‐
cardiac cause. 
12. Atrial fibrillation from a reversible cause (e.g., surgery, hyperthyroidism, 
pericarditis). 
13. History of pulmonary embolus within one year of enrollment. 
14. Acute pulmonary edema. 
15. Atrial clot/thrombus on imaging such as on a trans‐esophageal echocardiogram 
(TEE) performed within 72 hours of the procedure if deemed appropriate by 
investigator. 
16. Any history of a cerebrovascular disease (including stroke or TIA) within the past 6 
months. 
17. Any anticipation of cardiac transplantation or other cardiac surgery within the next 
12 months. 
18. Significant pulmonary disease, (e.g. restrictive pulmonary disease, constrictive or 
chronic obstructive pulmonary disease) or any other disease or malfunction of the 
lungs or respiratory system that produces severe chronic symptoms and 
significantly increases risk to sedation or anesthesia. 
19. Acute illness or active systemic infection or sepsis. 
20. Any history of blood clotting abnormalities or bleeding abnormalities. 
21. Life expectancy of less than 12 months. 
22. Any Intramural thrombus, tumor, or other abnormality that precludes catheter 
introduction or safe manipulation. 

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23. Women known to be pregnant.
Safety Assessments: 
Safety shall be evaluated both acute (in hospital) and long term: 
 
Freedom from serious adverse events related to the procedure within 10 days of the 
procedure. 
 
Freedom from procedure‐related serious adverse events (including from any repeat 
procedures required) within one year of the procedure. 
 
Effectiveness Assessments: 
 
Acute Effectiveness 
The acute success of FIRM‐guided procedure is defined as elimination of the source of 
arrhythmia identified by FIRMap as indicated by: 
1. No evidence of the source on FIRMap immediately post‐procedure, OR 
2. Reduction of electrogram amplitude to <0.2mV in region designated by FIRMap. 
 
 
Long‐term Effectiveness 
The long‐term effectiveness of FIRM‐guided procedures versus conventional ablation 
shall be defined as:  
 
1. Freedom from atrial fibrillation (AF), atrial tachycardia (AT), or atrial flutter (AFL) 
recurrence at 3‐12 months post procedure. 
 
Freedom from AF/AT/AFL recurrence is defined as no documented episodes > 30 
seconds with conventional non‐invasive 7‐day monitoring. In the case of a cardiac 
implanted electronic device (CIED), freedom from AF/AT /AFL recurrence is defined 
as no documented episodes > 30 seconds in a 1‐week window of the follow‐up visits, 
in addition to any symptomatic episodes with documented episode > 30 seconds.  AT 
recurrence does not include episodes of CTI (cavotricuspid isthmus) dependent 
flutter. 

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4 
BACKGROUND AND RATIONALE 
 
Atrial fibrillation (AF) is the most common sustained arrhythmia in man, and 
has an increasing population prevalence over time. Treatment is aimed at 
stroke prevention on the one hand, and amelioration of symptoms 
(palpitations, lightheadedness, dyspnea, fatigue) due to the arrhythmia. 
Medical therapy often fails to render a satisfactory response for the latter, 
prompting the search for alternative therapies. Surgical and, in the last 15 
years, catheter ablation techniques have been devised to try to prevent 
episodes from starting. Groundbreaking work by Haïssaguerre1 showed that 
premature discharges or rapid repeated firing from the pulmonary veins (PVs) 
could trigger AF episodes and that electrical isolation of the PVs could 
potentially cure the patient of AF. PV isolation currently is a painstaking 
process consisting of delivering radiofrequency energy in the left atrium to 
isolate these veins. Such procedures take 3‐5 hrs. to complete depending on 
the complexity of the individual case, and a majority of patients require a 2nd 
or even 3rd procedure to achieve acceptable antiarrhythmic results. Despite 
considerable investigative effort, the exact pathophysiology of how PV triggers 
initiate and or maintain episodes of AF has been elusive.  
 
Recently, Narayan et al2 have developed an algorithm that has been licensed 
for use with a novel mapping technology (RhythmView, Abbott 
Electrophysiology (Topera, Inc.), Menlo Park, CA) for analyzing atrial 
recordings during human AF, finding that >95% of cases demonstrate either a 
rapidly spinning rotor (small circuit) or very rapid focal impulse formation. 
Furthermore, they have shown that catheter ablation at these relatively 
circumscribed areas can significantly affect AF, either by substantial slowing of 
the rate or termination (to an atrial tachycardia or sinus rhythm). In the 
CONFIRM (CONventional vs Focal Impulse and Rotor Modulation) trial, 
patients were treated with either conventional mapping and ablation (largely 
PV isolation or PVI) vs ablation of rotors or sites of focal impulse formation as 
designated by the mapping algorithm, followed by conventional ablation (PVI). 
The authors found much higher acute and long‐term efficacy when focal 
impulse and rotor modulation (FIRM procedure) was used (82.4 vs 44% 
freedom from AF at 24 months post procedure). Although CONFIRM was a 
controlled study, a randomized evaluation would be warranted. 
 
                                            
1 Haïssaguerre M, Jaïs P, Shah DC et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary 
veins. N Engl J Med 1998; 339: 659–66. 
2 Narayan,S.M., D.E. Krummen, P. Clopton, K. Shivkumar and  J.M. Miller. Direct Or Coincidental Elimination of Stable Rotors or 
Focal Sources May Explain Successful Atrial Fibrillation Ablation: On‐Treatment Analysis of the CONFIRM (CONventional 
ablation for AF with or without Focal Impulse and Rotor Modulation) Trial. Journal of the American College of Cardiology 
(2013) 62:138‐147. 

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Redo‐FIRM is a prospective, multicenter, randomized, controlled study to 
assess the safety and effectiveness of FIRM procedures followed by ablation 
including PVI versus a standard conventional procedure including PVI for the 
redo‐treatment of persistent or paroxysmal atrial fibrillation after 1 failed 
preview PVI.   
 
4.1 
RATIONALE 
According to the American Heart Association, atrial fibrillation affects 
approximately 2 million Americans.  Atrial fibrillation may reduce cardiac 
performance and may result in thrombus formation in the left atrium and 
thromboembolic events, such as stroke. Approximately 15% of all strokes 
occur in people with atrial fibrillation.  Ablation of atrial fibrillation that 
specifically targets approximately 2‐3 mm outside of the pulmonary vein is 
currently a standard of care treatment in subjects with symptomatic atrial 
fibrillation who have failed drug therapy.  Unfortunately, this procedure is time 
consuming, creates substantial damage in the left atrium due to the number of 
lesions required, and has mixed success with the best outcomes being 50‐70% 
freedom from symptoms at 1 year post ablation.  Also, as with any invasive 
procedure, patient complications may heighten with increased time and 
additional radiation exposure. 
 
One of the major issues with the current procedure is the lack of knowledge 
about the critical regions of the heart that have the source rhythms causing 
and sustaining AF.  Some very new technology developed based upon work 
done under NIH support at the University of California San Diego has shown 
promise in diagnosing these key source rhythms.  Ablation to target these 
sources, called Focal Impulse and Rotor Modulation (FIRM) guided procedure, 
shows promise but need to be evaluated further. 
  
4.2 
HYPOTHESIS 
Focal Impulse and Rotor Modulation (FIRM) guided procedures will eliminate 
the source of clinical arrhythmias in subjects with clinical indications for 
repeat AF ablation procedures. 
 

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5 
STUDY OBJECTIVES 
The primary objective is to evaluate the safety and effectiveness of FIRM‐
guided procedures in conventional repeat ablation for the treatment of 
persistent or paroxysmal atrial fibrillation (AF). 
 
The secondary objectives are: 1) to evaluate the acute success of FIRM‐guided 
procedure in eliminating the source of arrhythmias, and 2) to evaluate quality 
of life outcomes. 
6 
STUDY DESIGN  
The study is designed as a prospective, multicenter, randomized, study to 
assess the safety and effectiveness of FIRM‐guided repeat RF ablation 
procedure including PVI versus a standard PVI procedure for the treatment of 
persistent and paroxysmal atrial fibrillation.   
 
6.1 
SAMPLE SIZE 
Up to 268 subjects at up to 30 investigative sites will be enrolled and equally 
(1:1) randomized between a cohort undergoing conventional RF ablation, vs. a 
cohort undergoing FIRM‐guided conventional RF ablation. Additionally, 
ablation of any atrial tachycardias (AT) and/or the cavotricuspid isthmus may 
be performed in those subjects with documented AT/atrial flutter. 
 
6.2 
STUDY DURATION 
Overall study duration (first subject enrolled through last subject exit) will be 
comprised of approximately 18 months of enrollment period, 1 month per 
subject for screening and baseline measurements, and 12 months per subject 
for follow‐up, for a total study duration of up to 31 months.   Study duration for 
an individual subject, once consented, will be up to 1 month for screening 
(including baseline measurements) and 12 months for follow up after 
treatment for a total duration of approximately 13 months. 
 

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7 
ENDPOINTS 
 
7.1 PRIMARY EFFECTIVENESS ENDPOINTS 
Effectiveness endpoints are defined in the table below. 
 
 
Table 1 – Primary Effectiveness Endpoints 
Endpoint 
Definition
Long term success 
The long‐term effectiveness of FIRM‐guided procedures versus 
conventional ablation shall be defined as:  
 
Freedom from atrial fibrillation AF/AT/AFL recurrence at 3 
‐12 months post procedure.  
 
Freedom from AF/AT/AFL recurrence is defined as no 
documented episodes > 30 seconds with conventional non‐
invasive 7‐day monitoring. In the case of a cardiac implanted 
electronic device (CIED), freedom from AF/AT/AFL recurrence 
is defined as no documented episodes > 30 seconds in a 1‐week 
window at the follow‐up visits, in addition to any symptomatic 
episodes with documented episode > 30 seconds.  AT 
recurrence does not include episodes of CTI (cavotricuspid 
isthmus) dependent flutter. 
 
 
 
7.2 
PRIMARY SAFETY ENDPOINTS 
Safety shall be evaluated both acute (in hospital) and long term, as defined in the 
table below.  
 
Table 2 – Primary Safety Endpoints 
Endpoint 
Description
Acute success
Freedom from serious adverse events related to the procedure 
within 10 days of the procedure. 
Long‐term success 
Freedom from procedure‐related serious adverse events 
(including those related to repeat procedures) within one year 
of the initial procedure. 
 
7.3 
SECONDARY ENDPOINTS  
Secondary endpoints are defined in Table 3 below. This study will also collect data 
relating to the health economics of the FIRM‐guided procedure to conduct 
additional evaluations if primary endpoints are met. 
 

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Table 3 – Secondary Endpoints 
Endpoint 
Definition
Acute Effectiveness 
The acute success of FIRM‐guided procedure is defined as 
elimination of the source of arrhythmia identified by FIRMap 
as indicated by: 
1. No evidence of the source on FIRMap immediately post‐
procedure, OR 
2. Reduction of electrogram amplitude to <0.2mV in region 
designated by FIRMap. 
 
Table 4 – Additional Evaluations 
Parameter 
Definition
Total RF ablation time 
Total RF ablation time as measured by total time of ablation 
lesion applications, from first ablation lesion to end of last 
lesion, will be documented.  These values will be compared 
between the FIRM‐guided and conventional ablation groups. 
If ablation for AT/atrial flutter is pursued, this ablation time 
will be documented separately 
Repeat procedure and 
hospitalization 
Any descriptive information regarding repeat procedures and 
re‐hospitalizations will be compared between groups  
Cumulative long‐term 
freedom from AF 
Cumulative long‐term freedom from AF will be assessed at 12 
months after the initial AF procedure but will permit results 
of repeat ablation 
Early Recurrence of 
AF/AT 
Recurrences of sustained AF/AT in the first 8 weeks
(blanking period). 
Change in Atrial Function 
Change in left atrial size and pulmonary vein inflow Doppler 
on echocardiogram (when available) 
Change in Ventricular 
Function 
Change in left ventricular ejection fraction and parameters of 
diastolic dysfunction (when available) 
Quality of Life 
Impact on quality of life, using patient‐reported outcome 
instruments (EQ‐5D and AFEQT), within treatment groups 
(change from pre‐procedure to post‐procedure follow‐up 
time points) and between treatment groups.  Analysis will be 
performed if primary endpoints are met. 
Economic Analysis 
Cost‐effectiveness analysis based on clinical and patient‐
reported outcomes and resource utilization.  Analysis will be 
performed if primary endpoints are met.  
 
 

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8 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF 
SUBJECTS 
8.1 
SELECTION CRITERIA 
The criteria listed below shall be used to determine if a participant is eligible for entry 
into the study. A subject must meet ALL of the study inclusion criteria and NONE of 
the study exclusion criteria in order to be considered eligible for participation. 
 
A. 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria: 
1. Male or female 18 – 80 years of age. 
2. Has at least one (1) episode of spontaneous persistent or paroxysmal atrial 
fibrillation documented by rhythm strip/ECG following the most recent ablation. 
3. Had one (1) previous AF ablation after January 01, 2013, but NOT within the last 
3 months. Detailed documentation of the previous ablation strategy is required. 
4. Oral anticoagulation required with either Novel Oral Anticoagulant (NOAC) or 
Warfarin (in the case of Warfarin, therapeutic INR ≥ 2.0 for at least three weeks 
prior to randomization) for those subjects who meet two or more of the 
following criteria:  
a. Age 65 years or older 
b. Diabetes 
c. Coronary artery disease (CAD) 
d. Congestive heart failure 
e. Hypertension with systolic>165 mm Hg 
5. Willingness and able to remain on anti‐coagulation therapy for a minimum of 3 
months post procedure for all subjects and at least 12 months post procedure if 
the subject is on anti‐coagulation pre‐procedure or has CHADS2 score ≥ 2 (or 
CHADs‐Vasc score >1). 
6. Left atrial diameter < 6.0 cm via transthoracic echo; or <6.5 cm via CT or MRI up 
to 6 months pre‐procedure with documented image of largest dimension, or 
intra‐procedural ICE or atrial angiogram if CT/MRI not available. 
7. Willingness, ability and commitment to participate in baseline and follow‐up 
evaluations without participation in another clinical trial which may confound 
the results of this study, unless approved by the Sponsor. 
8. Signed informed consent. 
B. 
Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria:  
1. Presence of structural heart disease of clinical significance including: 
a. Coronary artery disease with either: 
o Coronary artery bypass surgery (CABG) within the last six 
months, or 
o Stable/unstable angina or ongoing myocardial ischemia 
b. Congenital heart disease where either the underlying abnormality or its 
correction prohibits or increases the risk of ablation. 
2. NYHA Class IV. 

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3. Ejection fraction < 35% (within previous 6 months). 
4. Previous AF ablation within the last 3 months. 
5. ASD closure device, LAA closure device, prosthetic mitral or tricuspid valve, or 
permanent pacemaker. 
6. History of myocardial infarction (MI) within the past three (3) months. 
7. Contraindication to Heparin and Warfarin/other novel oral anticoagulants (e.g. 
dabigatran, rivaroxaban, apixaban). 
8. Diagnosed atrial myxoma. 
9. Any concomitant arrhythmia or therapy that could interfere with the 
interpretation of the results from this study. 
10. Untreatable allergy to contrast media. 
11. Severe electrolyte abnormalities at time of the ablation procedure or atrial 
fibrillation secondary to electrolyte imbalance, thyroid disease, or reversible 
non‐cardiac cause. 
12. Atrial fibrillation from a reversible cause (e.g., surgery, hyperthyroidism, 
pericarditis). 
13. History of pulmonary embolus within one year of enrollment. 
14. Acute pulmonary edema. 
15. Atrial clot/thrombus on imaging such as on a trans‐esophageal echocardiogram 
(TEE) performed within 72 hours of the procedure if deemed appropriate by 
investigator. 
16. Any history of a cerebrovascular disease (including stroke or TIA) within the 
past 6 months. 
17. Any anticipation of cardiac transplantation or other cardiac surgery within the 
next 12 months. 
18. Significant pulmonary disease, (e.g. restrictive pulmonary disease, constrictive 
or chronic obstructive pulmonary disease) or any other disease or malfunction 
of the lungs or respiratory system that produces severe chronic symptoms and 
significantly increases risk to sedation or anesthesia. 
19. Acute illness or active systemic infection or sepsis. 
20. Any history of blood clotting abnormalities or bleeding abnormalities. 
21. Life expectancy of less than 12 months. 
22. Any Intramural thrombus, tumor, or other abnormality that precludes catheter 
introduction or safe manipulation. 
23. Women known to be pregnant. 
8.2 
INFORMED CONSENT  
The investigator will obtain written informed consent from the subject using the 
IRB/EC‐approved consent form prior to initiation of any study‐specific assessments 
or procedures. Consent is documented by the dated signatures of the subject the 
person conducting the consent discussion, and the investigator.  Written informed 
consent must be obtained from a potential subject no more than 90 days prior to 
performing the study procedure.  
 

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8.3 
MOMENT OF ENROLLMENT 
 
The subject will be considered “enrolled” in the study after the subject has signed 
the study informed consent form, completed all baseline assessments, and 
randomized to a study treatment group. Randomization will occur on the day of the 
procedure.  
 
Optional sub‐study cohort enrollment: If the patient is disqualified on the day of 
the procedure because PV reconnection cannot be confirmed, the patient cannot be 
randomized / enrolled in the study. However, if AF can be sustained the patient may 
undergo FIRM‐guided ablation and enroll in the sub‐study cohort. The patient will 
be required to comply to all protocol follow‐up requirements. See Section 10.2b. 
 
8.4 
SUBJECT DISCONTINUATION OR WITHDRAWAL 
The investigator should instruct the subject regarding the importance of complying 
with the data collection and follow‐up visit requirements. Poor subject adherence 
may result in the sponsor discontinuing the subject from the study.   
Subjects may be involuntarily removed from the study for failure to adhere to the 
protocol, failure to attend follow‐up visits, or due to safety reasons. In such cases, 
the investigator shall arrange for an exit visit and complete a study exit case report 
form for the subject.  
Subjects may voluntarily withdraw from the study at any time without reason. The 
investigator shall make an effort to obtain an exit visit but cannot insist on the visit 
if the subject does not wish to come in.   The investigator shall complete a study exit 
case report form with as much information as is available at the time of withdrawal.   
A subject may be withdrawn after screening and before receiving the study 
treatment if, at the investigator’s discretion, he or she has developed a general 
health condition that would increase risks from study treatment. 
 
8.5 
CONTACT FOR FOLLOW‐UP AND LOSS TO FOLLOW‐UP 
 
Subjects who miss a study visit should be contacted immediately by the 
Investigational Site to determine the reason for the missed visit and to reschedule 
the visit as soon as possible to meet the study visit window. If the subject cannot be 
located after 3 attempts through a variety of communication modes (phone, email, 
letter), then the subject will be considered lost to follow‐up. The investigational sites 
should collect contact information (home phone, cell phone, fax, email, home 
address, etc.) from the subject in order to minimize loss to follow‐up. All attempts to 
contact the subjects will be documented and retained in the subject study record. 
 

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9 
INVESTIGATOR SELECTION 
9.1 
INVESTIGATIVE SITES 
A. 
Up to 30 investigational sites in Europe and North America will participate in 
this study 
B. 
To qualify for participation, the study investigator will have completed the 
following: 
o Undergone the standard training provided by Abbott EP/Topera, Inc. in 
the use of the RhythmView® system and analysis of FIRM maps 
produced by the system.  
o Participated in 5 FIRM‐guided procedures prior to enrolling any 
subjects in the study.  
 
9.2 
EQUIPMENT REQUIREMENT 
A. 
In order to participate in this study, the site must also have the following 
equipment available: 
o 64‐pole mapping catheter (Topera FIRMap Catheter) and appropriate 
analyzer to acquire full chamber data (RA or LA) per Topera 
RhythmView system requirements. 
o Topera RhythmView 3D electrophysiologic mapping system. 
o Optionally, 3‐D electroanatomic mapping system (CARTO, Biosense 
Webster, Velocity or Nav‐X, St Jude Medical) compatible with FIRMap 
for documentation of lesions relative to recordings from mapping 
catheter. 
9.3 
INVESTIGATOR DISCONTINUATION 
 
Prior to participation in the study, all investigators must sign the Protocol Signature 
Page which outlines the investigator’s obligations in the study. The sponsor may 
elect to discontinue, or suspend, the investigator’s participation in the study due to 
poor study compliance, lack of compliance with applicable regulations or IRB/EC 
requirements, or insufficient recruitment of study subjects. 
 
10 
 STUDY FLOW AND VISIT SCHEDULE 
The study will be conducted in three phases listed below and depicted in  
Figure 1. 
  
1. Screening & Baseline 
2. Study procedure through discharge 
3. Follow‐up periods 
 
Each of these phases is discussed separately below, following Table 5 – Schedule of 
Assessments.  
  
 

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Figure 1: Study Flow Chart 
 
 
 

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10.1 SCREENING AND BASELINE 
A. Screening 
Patients at the investigational sites with persistent or paroxysmal AF will be asked 
about their interest in study participation. For those patients who express an 
interest to participate, the inclusion/exclusion criteria will be reviewed against 
existing medical history and the results of any standard clinical work‐up to assess 
preliminary eligibility.  Potential patients who do not meet entrance criteria may, as 
appropriate, repeat screening evaluations at a later time for possible enrollment 
into the study. 
 
B. Baseline Assessment 
If the patient is not excluded based on existing medical history and standard clinical 
work‐up, the patient will be asked to provide informed consent to participate in the 
study.  Baseline assessments include the following as shown in Table 5 – Schedule of 
Assessments.  
 
 
Determine study eligibility based on the requirements specified in the 
inclusion / exclusion criteria. 
 
Medical history, including any hospitalizations or emergency room 
visits for episodes of all cardiac arrhythmias within six months of 
screening, all anti‐arrhythmic drugs (AADs) and other cardiac 
medications. 
 
Reported incidence of at least 1 episode of persistent or paroxysmal 
atrial fibrillation (AF) documented by rhythm strip/ECG following the 
most recent ablation.. 
 
Treatments administered for atrial fibrillation in the six months prior to 
enrollment, e.g., pharmacologic treatments and non‐pharmacologic 
interventions.  Medications should include dose and duration. 
 
Documentation of therapeutic International Normalization Ratio (INR) 
for three weeks prior to the procedure (if applicable per Inclusion 
Criteria) in cases of subjects taking Warfarin. 
 
NYHA and ERHA class assessment. 
 
Current cardiac rhythm. 
 
Largest dimension left atrial diameter measured from transthoracic 
echo, cardiac CT or cardiac MR within the last 6 months with image 
documentation.  Intracardiac echocardiographic measurement at the 
time of the procedure can alternatively be used to document this. 
 
Ejection fraction (EF) measured within the last 6 months or from the 
pre‐procedure TEE or TTE. 
 
When clinically indicated, TEE will be performed prior to the ablation 
procedure. If any evidence of left atrial thrombus is discovered, then the 
ablation procedure will not be performed at that time.  The patient may 
be either excluded from the study or maintained on oral anticoagulation 
for an additional period of at least 6 weeks and re‐tested (TEE repeated) 
for thrombi. 

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 
12‐Lead ECG within 72 hours of study procedure. 
 
Cardiac medications currently prescribed for the subject’s daily medical 
therapy. 
 
Pre‐ procedure Laboratory values per standard practice.  
 
Neurological Exam (if clinically indicated) if symptoms suggestive of 
neurologic disease, and is to be performed by the neurology medical 
staff.  
 
Prior to the procedure, subjects fitting the investigator’s standard 
criteria for anticoagulation will have been orally anti‐coagulated (in case 
of Warfarin, with therapeutic INR (≥2.0) for at least three weeks prior to 
randomization, or they may be placed on therapeutic doses of 
subcutaneous low‐molecular‐weight heparin (LMWH)).  As dictated by 
center clinical practice, oral anti‐coagulation will be discontinued and 
either subcutaneous LMWH or IV heparin will be substituted at 
therapeutic doses until the time of the procedure.  At the investigator’s 
discretion, dabigatran, rivaroxaban or apixaban will be withheld for 24 
hours prior to the procedure. 
 
Amiodarone to be discontinued 4 weeks prior to procedure. 
 
Antiarrhythmic drug, Class IC: Discontinue after 5 half‐lives. 
 
EQ‐5D and AFEQT Quality of Life surveys.  
 
Pregnancy test to be performed for women of child bearing potential 
 
Each site will maintain a screening log noting the reasons for screening failures. 
10.2 STUDY PROCEDURE 
The individual center and investigator should define the ablation strategy  for the 
conventional redo‐procedures of the Control group prior to participation in the trial. 
 
 
Ablation guidelines (optional): 
 
FIRM group: prophylactic ablation* may be performed for the RA‐Isthmus 
line and for any inherent arrhythmia that is found to have focal firing during 
the procedure.  
 
 
Control group: additional ablation may be performed for any arrhythmia 
that is found to have focal firing during procedure. The following prophylactic 
ablation* may be performed:  
 
RA‐isthmus line 
 
Non PV‐trigger (if provoked) 
 
Caval vein isolation 
*Prophylactic ablation should be performed for all study subjects if it is 
determined to be the standard of practice of the Investigator. 
 
 
LA appendage isolation are not permitted.  
 
A. 
Pre‐procedure Preparation 
Just prior to and/or during the procedure, a glycoprotein IIb/IIIa inhibitor or other 
platelet inhibitor may be administered if it is standard practice.  The insertion of the 

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FIRMap catheter or performing transseptal puncture, whichever comes first, will be 
followed immediately by an IV heparin bolus, followed by repeated heparin 
administration, adjusted as necessary to achieve and maintain an ACT above 300 
seconds. 
B. 
Intra‐procedure  
Subject randomization will be performed during the procedure after the following 
criteria are met. See Figure 2. 
1) 
AF is sustained for at least 5 minutes uninterrupted.  
2) 
Confirmation of PV reconnection.  
 
IMPORTANT:  
 
If AF cannot be sustained and PV reconnection cannot be confirmed, the 
patient is disqualified and cannot be randomized / enrolled in the study. The 
patient will undergo conventional AF ablation at the discretion of the 
investigator.  
 
If the patient is in sinus rhythm and one or more of his/her veins are not 
isolated, it is acceptable to isolate the vein(s) before induction of AF.  AF must 
still be sustained for 5 minutes before the patient can be randomized. If AF 
cannot be sustained after re‐isolation of veins, the patient will be excluded 
from study before randomization. 
 
Optional sub‐cohort enrollment: If AF can be sustained but PV 
reconnection cannot be confirmed, the patient is disqualified and cannot not 
be randomized / enrolled in the study. However, the patient may undergo 
FIRM‐guided ablation and enroll in the sub‐study cohort. The patient will be 
required to comply to all protocol follow‐up requirements. 
 
Figure 2. 
 
 
 
 
 

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Table 6 – Intra‐Procedure Guidelines 
During the procedure, the following steps should be taken. 
Parameter 
Description
Vascular access 
Under sterile technique, the right and/or left femoral veins may be 
cannulated via Seldinger, or percutaneous approach.  Other vascular access 
also may be obtained based upon physician judgment.   
1. Induction of 
sustained AF 
 
2. Induction of 
non PV‐
Triggers (if 
standard care 
includes 
ablation of 
extra‐
pulmonary 
foci) 
Burst pacing at 200 ms for 5 s from the RA and twice from the CS.
 
 
A non‐PV trigger is defined as a PAC that triggers either sustained or non‐
sustained AF or atrial tachyarrhythmia (AT).  Repetitive PACs that do not 
result in sustained or non‐sustained AF/AT are not considered non‐PV 
triggers.  Reproducible AF/AT initiation is required for non‐PV triggers to 
allow for accurate mapping of the region of origin outside the PVs with 
multi polar catheters with or without 3D mapping systems. 
 
Non‐PV triggers will be induced as follows: 
 
1. Isoproterenol infusion (starting at 2 mcg and incrementing up to 20 
mcg per standard laboratory protocol).  Per standard laboratory 
protocol, another sympathomimetic agent (e.g., IV norepinephrine or 
epinephrine) may be substituted for isoproterenol. 
2. Cardioversion of spontaneous AF or AF induced by left or right atrial 
rapid pacing.  AF and the subsequent cardioversion may be induced/ 
performed during infusion of isoproterenol so as to maximize the 
possibility of inducing AF triggers. 
 
As part of the trigger protocol, multiple cardioversions may be necessary 
whenever AF is induced (spontaneously or with isoproterenol infusion / 
burst pacing) with the endpoint of mapping the trigger beat(s) leading to 
post‐cardioversion early AF recurrence. In case of early AF recurrence, the 
beat initiating AF will be considered a trigger and will be analyzed for site of 
origin using the mapping techniques described in the definition. 
PV reconnection 
Look for PV reconnection (at least one vein) with Lasso catheter.
Randomization 
The patient will be randomized once PV reconnection is confirmed and AF 
is sustained > 5 minutes.  
Reference catheter 
placement 
Reference catheters (including 64‐pole FIRMap catheter(s)) may be 
inserted and placed within the heart to record signals as clinically required 
at the discretion of the physician. 
Access to left atrium 
Access to the left atrium should be according to the institution’s standard 
practice. 
Anticoagulation 
Upon insertion of 64‐pole FIRMap catheter or transseptal puncture 
(whichever comes first), an IV heparin bolus should be administered, 
followed by repeated heparin administration, adjusted as necessary to 
achieve and maintain an ACT above 300 sec.  ACT will be monitored every 
10 minutes following initial heparin delivery until the target value is 
achieved and subsequently checked at least every thirty minutes during the 
procedure. 

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Catheter placement 
Catheters may be inserted and used according to the institution’s standard 
practice. 
Source arrhythmia 
diagnosis 
After obtaining at least 1 minute of continuous electrograms from the 64‐
pole FIRMap catheter either simultaneously or sequentially in the right and 
left atria, these electrogram data will be transferred to the Topera 
RhythmView® system.  This will then produce FIRMap displays which will 
be interpreted by the operator to determine which locations have focal or 
rotor rhythms that could be sources of the AF.  
3‐D Electroanatomic 
Mapping 
3‐D electroanatomic maps may be created using CARTO or Nav‐X systems 
for documentation of anatomy and ablation lesion locations. 
FIRM‐guided 
procedure 
Under fluoroscopic guidance, a cardiac ablation catheter is passed to the 
location(s) identified as AF source rhythms (rotors or focal impulses).   
Conventional 
Ablation 
In the conventional arm of the study, data will be recorded regarding any 
additional ablation such as that performed per local routine for AF (e.g. 
additional trigger elimination).   
Additional ablation 
for other 
arrhythmias (non‐
AF) 
Additional ablation for other arrhythmias will be noted for atrial 
tachycardia (AT) and/or right cavo‐tricuspid isthmus ablation in the event 
that the patient has documented AT/atrial flutter prior to or during the 
procedure. 
Vascular access 
sheath removal 
The vascular access sheaths will be removed when the ACT reaches a 
clinically acceptable level.   
Voltage mapping 
Perform voltage mapping is strongly recommended. 
 
The following precautions should be taken per standard of practice: 
 
Typically, in order to reduce the risk of introducing air emboli through a trans‐
septal sheath into the left atrium, the following precautions are taken: 
o Aspiration or spontaneous bleed back from the trans‐septal sheath 
side‐port may be performed after each catheter withdrawal;  
o Trans‐septal catheter insertion and withdrawal will always be 
performed slowly; 
o Unnecessary catheter exchanges may be avoided; 
o The time any trans‐septal sheath is through the septum may be 
minimized; and 
o The time multiple sheaths cross the septum may be minimized. 
 
Just prior to ablation, at each ablation site in the posterior LA or RA, pacing at 
high output (>15 mA) from the ablation catheter tip or fluoroscopic 
visualization of diaphragmatic movement may be used to assess whether the 
phrenic nerve is in proximity to the ablation zone.  These data will be 
documented and used to guide ablation at each site. 
 
Esophageal temperature monitoring during ablation in the posterior LA, per 
local standard of care, may also be considered. 
 

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C. 
Intra‐procedure Measurements   
Table 7. 
Data 
Description
Fluoroscopy times 
To be recorded:
Total fluoroscopy time 
 The total fluoroscopy time for the procedure (a.k.a., “pedal 
down” time) 
Ablation fluoroscopy time 
 The time between the first ablation catheter insertion to last 
ablation catheter removal from the left atrium. 
Total RF ablation 
time 
Total RF ablation time as measured by total time of ablation 
lesion applications, from first ablation lesion to end of last lesion, 
will be documented.  These values will be noted in both the 
FIRM‐guided and conventional ablation groups. 
If ablation for AT/atrial flutter is pursued, this ablation time will 
be documented separately 
Total procedure 
time 
Total procedure time defined as: time from insertion of first 
sheaths for vascular access to removal of catheters. 
Medication 
administration 
Cardiac medications administered during the procedure 
including drug name, dosage, and indication and will be 
recorded. 
Devices and 
equipment 
Devices and equipment used during the procedure including 
access devices, diagnostic and ablation catheters, and mapping 
equipment type will be recorded. 
 
D. 
Post‐procedure & Discharge Requirements 
The measurements and evaluations that will occur at post‐procedure are provided 
below. 
 
Post‐ablation and following recovery from anesthesia, subjects will be 
monitored until stable.   
 
Once the sheaths have been removed and hemostasis has been 
achieved, heparin or LMWH will be restarted along with oral 
anticoagulation (warfarin or novel oral anticoagulants (e.g. dabigatran, 
rivaroxaban, apixaban)). 
 
The platelet inhibitor (if administered during the procedure) and 
heparin or LMWH will be continued until the INR exceeds 2.0 (in the 
case of warfarin use for longer‐term oral anticoagulation). 
 
Oral anti‐coagulation will continue for at least three months after the 
procedure.  Subjects who were on oral anticoagulation pre‐procedure 
will be maintained on anticoagulation for the duration of the study. 
 
Note:  Oral Glycoprotein IIb/IIIa Inhibitors use is discouraged during the 
follow‐up period. 

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 
Resolution Period 
Following ablation treatment, subjects will undergo 8‐week “resolution” period 
(aka “blanking period”) where medical therapy may be optimized and where 
any of the procedurally‐derived arrhythmias that commonly follow ablation 
procedures may resolve.  Cardioversion may be done around week 6 to have 
patients exit blanking period. 
Note:  During the 8‐week resolution period, medications may be adjusted as 
medically indicated, and as indicated in above section.  Any clinically indicated 
changes must be documented along with the reason for change. 
 
Anti‐arrhythmic Medications 
Amiodarone must be discontinued 4‐6 weeks prior to ablation and may be re‐
administered after ablation by the discretion of the investigator. 
Antiarrhythmic drug, Class IC:  must be discontinued (5 half‐lives.)  prior to 
ablation and can be re‐administered after ablation by the discretion of the 
investigator. 
 
Recurrence of AF 
If re‐ablation for AF is necessary after documentation of the recurrent 
arrhythmia has occurred, the patient will be considered a primary efficacy 
study failure but still followed up for AF burden.   
A. 
Day 10 Follow‐up ( 2 days) 
(Phone Call or visit at investigator’s discretion)  
 
Subjects will be asked if they have experienced any untoward medical 
occurrences since the study procedure. If so, these events will be recorded on 
the Adverse Event form.  
 
Symptom and rhythm assessment. 
B. 
Six‐Week Follow‐up ( 1 week) 
The following assessments/procedures will be performed: 
 
Diagnostic 12-lead ECG 
 
EQ-5D and AFEQT Quality of Life surveys 
 
Symptom and rhythm assessment  
 
Concomitant anti-arrhythmic medications 
 
Adverse event documentation 
 In case of atrial fibrillation electric cardioversion within 4 weeks 
C. 
Three‐Month Follow‐up ( 1 week) 
The following assessments/procedures will be performed: 
 
Diagnostic 12-lead ECG 
 
7-day continuous ECG monitor or CIED interrogation 
 
EQ-5D and AFEQT Quality of Life surveys 
 
Symptom and rhythm assessment  

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 
Concomitant anti-arrhythmic medications 
 Adverse event documentation 
D. 
Six‐Month Follow‐up ( 2 weeks) 
The following assessments/procedures will be performed: 
 
Diagnostic 12-lead ECG 
 
7-day continuous ECG monitor or CIED interrogation 
 
Echocardiography, if clinically indicated 
 
EQ-5D and AFEQT Quality of Life surveys 
 
Symptom and rhythm assessment  
 
Concomitant anti-arrhythmic medications 
 
Adverse event documentation 
E. 
Twelve‐Month Follow‐up ( 4 weeks) 
The following assessments/procedures will be performed: 
 
Diagnostic 12-lead ECG 
 
7-day continuous ECG monitor or CIED interrogation 
 
EQ-5D and AFEQT Quality of Life surveys 
 
Symptom and rhythm assessment  
 
Concomitant anti-arrhythmic medications 
 
Adverse event documentation 
F. 
Unscheduled Follow‐up Visit 
The following assessments/procedures will be performed, if possible: 
 
Diagnostic 12-lead ECG 
 
7-day continuous ECG monitor or CIED interrogation by the discretion of the 
operator  
 
EQ-5D and AFEQT Quality of Life surveys 
 
Symptom and rhythm assessment  
 
Concomitant anti-arrhythmic medications 
 
Adverse Event documentation 
 
 

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11 ADVERSE EVENTS 
At enrollment, time of procedure, and at each post‐procedure visit the subject 
will be evaluated for any complications or adverse event. The Investigator will 
be required to provide the Sponsor with any information concerning any 
findings that suggest any adverse events/complications pertinent to the 
investigation. All AEs occurring during the study will be recorded on the 
appropriate e‐CRFs. 
 
Subjects will be carefully monitored during the study for possible AEs.  Any AE 
observed will be fully investigated by the Investigator and classified in line with 
the definitions below. All adverse events will be followed until resolution or until 
the Investigator judges the outcome to be chronic or stable.  
11.1 DEFINITIONS 
Adverse events will be reported and classified by the Investigator using the 
specific signs, symptoms or abnormal laboratory values, or medical diagnosis if 
no signs, symptoms or abnormal laboratory values can be identified. The 
Investigator will classify the adverse events based on the definitions as follows 
(EN ISO/FDIS 14155:2010): 
 Adverse Event (AE) ‐ Any untoward medical occurrence, unintended disease 
or injury or any untoward clinical signs (including an abnormal laboratory 
finding) in subjects, users or other persons whether or not related to the 
investigational 
medical 
device. 
 
 NOTE 1: This includes events related to the procedures involved. 
NOTE 2: For users or other persons this is restricted to events related to the 
investigational medical device. 
 Adverse Device Effect (ADE) – Adverse Event related to the use of a medical 
device. This includes: 
o Any adverse event resulting from insufficiencies or inadequacies in 
the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the medical device. 
o Any event that is a result of a use error or intentional misuse. 
 Serious Adverse Event (SAE) ‐ Adverse Event that 
o Led to death 
o Led to a serious deterioration in the health of the subject that either: 
 resulted in a life‐threatening illness or injury*, or 
 resulted in a permanent impairment of a body structure or a 
body function, or 
 required in‐patient hospitalization or prolongation of existing 
hospitalization, or 

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 resulted in medical or surgical intervention to prevent life 
threatening illness or injury or permanent impairment to a 
body structure or a body function**. 
o Led to fetal distress, fetal death or congenital abnormality or birth 
defect 
 
NOTE 1:  
* In this context, the term refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does NOT refer to an 
event that might have caused death if it were more severe. 
** For example, if the occurrence of a “catheter insertion site hematoma” or 
an “AV fistula” requires a blood transfusion and/or surgical repair, it should 
be considered a serious adverse event. 
NOTE 2:  
 
Pre‐planned hospitalizations for pre‐existing condition, or a procedure 
required by the protocol, without a serious deterioration in health, is 
not considered to be a serious adverse event. For example, repeat 
ablation for recurrence of AF would not be considered an SAE. 
 
Emergency room visits that do not result in hospitalization (i.e., an 
overnight stay) should be evaluated for one of the other serious 
outcomes to determine if they qualify as SAEs. 
  Serious Adverse Device Effect (SADE) – Adverse device effect that has 
resulted in any of the consequences characteristic of a serious adverse event.  
 Unanticipated Adverse Device Effect (UADE) ‐ Serious adverse device 
effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report.   
 
11.2 ADVERSE EVENT EVALUATION AND REPORTING 
 AE Reporting 
Conditions or diseases which are pre‐existing and chronic should not be 
recorded as adverse events.  Changes in a chronic condition or disease that are 
consistent with natural disease progression are NOT considered adverse events.  
Pre‐existing conditions or diseases should be documented as part of the 
subject’s medical history. 
 
Elective or pre‐planned treatments for atrial fibrillation (e.g. scheduled re‐
ablation or cardioversion) which are part of the subject’s scheduled treatment 
plan should not be considered adverse events.  However, any events related to a 
procedure (including re‐do procedures) or the patient’s underlying atrial 
fibrillation which were not expected or indicate a worsening of condition should 
be reported as adverse events.  (example: procedure‐related perforation or 
cardiac tamponade). 
 

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Every effort should be made to report the underlying condition or unifying 
diagnosis for the event.  The adverse event should be recorded in standard 
medical terminology rather than the subject’s own words when possible.  Signs 
and symptoms that are considered unrelated to an encountered condition or 
disease should be recorded as individual adverse events (e.g. if congestive heart 
failure and severe headache are observed at the same time, each event should be 
recorded as an individual adverse event).  In contrast, adverse events that occur 
secondary to other events (e.g. sequelae), if clearly identifiable, should be 
identified by the primary cause (example: bradycardia → dizziness → fainting; 
the primary adverse event is bradycardia). 
 Relatedness 
The investigator will assess each adverse event for its relationship to the study 
device, and whether it was anticipated in the protocol.  The determination of the 
level of relatedness of the adverse event to the study device or procedure will be 
made according to the definitions below  
o Device Related: The adverse event was directly and clearly related to 
the device or procedure  
o Not Device Related 
o Unknown 
 
Adverse events that are serious and/or unanticipated will be reviewed 
immediately by the Abbott EP (Topera) Medical Monitor and will also be 
reviewed during quarterly DSMB meeting. 
 SAE Reporting 
All serious adverse events (SA(D)Es) should be phoned / faxed / e‐mailed to 
Abbott EP (Topera, Inc.) within 24 hours of learning of an event.  The following 
information will be collected and recorded as appropriate. 
 
Nature of adverse event 
 
Date of onset of adverse event 
 
Date of resolution of adverse event, if applicable  
 
Statement as to why it is considered unanticipated, if applicable 
 
Statement as to why it is considered serious, if applicable 
 
Statement as to the degree to which it is considered device related, 
and why 
 
Results of any diagnostic tests that were performed 
 
Description of any treatment administered 
 

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It is the responsibility of each Investigator to report all Serious Adverse Events 
and/or Serious Adverse Device Effects to the IRB/EC, according to national 
regulations and IRB/EC requirements.  
 
Abbott EP (Topera Inc.) will assure that the Authorized Representative will 
report all Serious Adverse Events to the Competent Authorities in accordance 
with European Medical Devices directives and all applicable national 
regulations. 
 
Any protocol modifications deemed necessary by this review will be reported to 
the IRB/EC and, for sites located outside of Europe, to the applicable Ministry of 
Health.  
 
11.3 ANTICIPATED ADVERSE EVENTS 
Table 9 – Anticipated Adverse Events 
Description 
Description 
Discomfort due to insertion/removal of vascular sheaths 
beyond what is normally observed 
Ventricular arrhythmia 
requiring defibrillation 
Hemorrhage and/or hematoma at sheath insertion 
requiring evacuation or transfusion  
Cardiac tamponade due to 
perforation 
Extremity weakness, swelling, and/or pain 
Discomfort and/or damage to the skin, muscles, or 
nerves due to remaining in a supine position for an 
extended period of time. 
Nerve injury (diaphragmatic 
paralysis, pyloric spasm, 
gastric hypomotility) 
Complete AV block  
Air embolism 
Nausea /vomiting 
Allergic reaction 
Headache different from baseline
Endocarditis 
Hypertension >180 mm Hg systolic (repeated measures)
Esophageal‐atria fistula
Hypotension <80 mm Hg systolic (repeated measures)
Hemothorax 
Brief “black out” periods 
Pericarditis 
Shortness of breath/Dyspnea
Pseudo aneurysm 
Feeling of chest pain, skipped beats, and/or rapid heart 
rate different from baseline 
Pulmonary vein stenosis
Damage to skin from prolonged exposure to x‐rays
Radiation injury 
New arrhythmias (not previously documented)
Renal failure form IV contrast
Arterial injury requiring intervention
Respiratory failure 
Thromboembolism 
Stroke/TIA 
Local/systemic infection 
Valvular damage 
Pneumothorax 
Pleural effusion 
AV fistula 
Pulmonary edema 
Thrombophlebitis 
Anemia requiring transfusion
Pulmonary embolism 
Vasovagal reaction 
Myocardial infarction 
New pericardial effusion >1 cm

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Discomfort and/or damage to the skin, muscles, or 
nerves due to percutaneous access in excess of usual  
Death (must be reported 
within the regulation of 
serious adverse events) 
Left heart access via trans‐septal puncture has known 
potential adverse events of: cardiac perforation, cardiac 
tamponade, and embolic events*.   
* Literature reviews have demonstrated that the risk of such events are <1%. Mullins, 
Charles E. “Trans‐septal left heart catheterization: Experience with a new technique in 
520 pediatric and adult subjects.”  Pediatric Cardiology, v. 4, pgs. 239‐246 (1983). 
 
11.4 DEVICE DEFICIENCIES AND MALFUNCTIONS 
Investigators must report all possible device deficiencies, malfunctions or near 
incidents associated with the device, per institutional standard practice and 
regulations.  This includes unexpected outcomes or device deficiencies that 
might have led to a serious adverse event if a) suitable action had not been taken 
or b) intervention had not been made or c) if circumstances had been less 
fortunate. 
 Definitions 
o Device deficiency ‐ inadequacy of a medical device related to its 
identity, quality, durability, reliability, safety or performance, such as 
malfunction, misuse or use error and inadequate labeling (EN 
ISO/FDIS 14155:2010). 
o Malfunction ‐ failure of an investigational medical device to perform 
in accordance with its intended purpose when used in accordance 
with the instructions for use or protocol (EN ISO/FDIS 14155:2010).  
 
 

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12 INVESTIGATOR REQUIREMENTS 
12.1 PROTOCOL ADHERENCE 
Each Investigator must adhere to the protocol as detailed in this document and agree 
that the Sponsor must approve any change to the protocol before seeking approval 
from the IRB/EC or CA. Each Investigator will be responsible for enrolling only those 
subjects who have met all of the protocol inclusion criteria and none of the exclusion 
criteria. 
12.2 ELECTRONIC CASE REPORT FORMS AND DATA CAPTURE SYSTEM 
Data collection will involve the use of the Electronic Data Capture (EDC) system, to 
which only authorized personnel will have access. Electronic case report forms 
(eCRFs) will be used to capture study data in an EDC system. Entering of eCRFs should 
be handled in accordance with instructions from the Sponsor or Sponsor 
representative. All eCRFs must be completed by qualified study center personnel. 
Each Investigator is responsible for ensuring that accurate data are entered into the 
EDC system in a timely manner. 
 
The Investigator or designee will be responsible for reviewing eCRFs, resolving data 
queries generated by the Sponsor via the system, providing missing or corrected data, 
approving all changes performed on the subject data, and endorsing these data within 
the EDC system. This approval method will include applying an electronic signature, 
a uniquely assigned user name, and a password that together will represent a 
traditional handwritten signature. 
 
Queries may be issued electronically to the study site and answered electronically by 
that site’s personnel. The identifying information (assigned user name, date, and 
time) for both the originator of the query and the originator of the data change (if 
applicable) will be collected. 
12.3 SOURCE DOCUMENT MAINTENANCE 
Source documents may include, but are not limited to, study progress notes, study‐ or 
subject‐specific e‐mail correspondence, computer printouts, laboratory data, and 
recorded data from automated instruments. The original signed ICF for each 
participating subject shall be filed with records kept by the Investigator. All 
documents produced in this study will be maintained by the Investigator and made 
available for inspection by the Sponsor or Sponsor representative and applicable 
regulatory authorities. 
12.4 STUDY MONITORING REQUIREMENTS 
The Sponsor or Sponsor representative will conduct site visits to inspect study data, 
subjects’ medical records, and eCRFs in accordance with current ICH E6 Good Clinical 
Practice (GCP) guidelines, and the respective United States or foreign regulations and 
guidelines, as applicable. The Sponsor or Sponsor representative will also be able to 
review query status remotely, which may warrant additional communication with the 
Investigator and the study site’s personnel. The Investigator will make available to 
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study‐related documents. The Investigator will allow the Sponsor or Sponsor 
representative and applicable regulatory authorities to inspect facilities and records 
relevant to this study. 
 
12.5 STUDY COMPLETION 
The Sponsor requires the following data and materials before a study can be 
considered complete or terminated, including, but not limited to: 
 
o Laboratory findings, clinical data, and all special test results from screening 
through FU 
o eCRFs properly completed by appropriate study personnel and signed and 
dated by the Investigator within the EDC system. This approval method will 
include applying an electronic signature, a uniquely assigned user name, and 
a password that together will represent a traditional handwritten signature. 
o Copies of complete device accountability records, if applicable  
o Copies of all IRB/IEC or CA approvals and acknowledgements 
o 
A summary of the study prepared by the Investigator (an IRB/IEC or CA 
summary letter is acceptable) 
 
 

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13 STUDY MANAGEMENT 
Study management will occur in accordance with ISO 14155, (Clinical investigation 
of medical devices for human subjects – Good clinical practices), the Declaration of 
Helsinki, the applicable national regulations and Institutional research policies and 
procedures. Several key components of study management are discussed separately 
below. 
 
13.1 IRB/IEC OR COMPETENT AUTHORITY APPROVAL 
The IRB/IEC or CA must approve the protocol or amended protocol (if applicable) 
and the corresponding ICF before the study may be initiated; any recruiting materials 
before use; and subsequent amended protocols and corresponding ICFs before 
instituting amendment‐specified changes to the study, unless required for subject 
safety.  
 
The Investigator is responsible for informing the IRB/IEC or CA of any changes made 
to the protocol, and to advise the IRB/IEC or CA, at least once a year, about the 
progress of the study. The Investigator (or Sponsor, if applicable) is also responsible 
for notifying the IRB/IEC or CA of any significant AEs that occur during the study 
according to local IRB/IEC or CA requirements. 
 
 
Study Registration 
The study will be registered with www.clinicaltrials.gov in accordance with the 
Declaration of Helsinki. 
 
13.2 MONITORING  
The study will be monitored periodically at each enrolling site per the study 
monitoring plan for the purposes of 
 
o Verifying compliance to the protocol and applicable regulations, 
o Verifying case report form data to original entries in source files,  
o Abbott EP (Topera) employees or representatives will monitor the study 
according to company standard operating procedures. 
 
13.3 STUDY AUDITS 
The Sponsor and representatives of regulatory health authorities are permitted to 
inspect the study documents (protocol, case report forms, study‐related medical 
records, study correspondence with EC and sponsor, etc.). In addition to ongoing 
monitoring of the study, GCP audits by the Sponsor or its representatives are also 
permitted. All attempts will be made to preserve subject 
  
 
13.4 PROTOCOL DEVIATIONS 

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A protocol deviation is defined as any event where the clinical investigator or site 
personnel did not conduct the study according to the protocol.  
 
Investigators can only initiate deviations from the protocol where necessary to 
protect the life or physical wellbeing of a subject, i.e., in an emergency.  Protocol 
deviations shall be reported to the Sponsor regardless of whether medically 
justifiable, pre‐approved by the Sponsor, or taken to protect the subject in an 
emergency.  Subject‐specific deviations will be reported on the eCRF.  Non‐subject 
specific deviations, (e.g., unauthorized use of a study device by a physician who has 
not signed an investigator agreement, etc.), will also need to be reported to the 
Sponsor.  All deviations, regardless of major / minor or pre‐approved, will be 
reported on the eCRF.  Investigators will also adhere to procedures for reporting 
study deviations to their IRB/EC in accordance with their specific IRB/EC reporting 
policies and procedures.  
 
Regulations require that investigators maintain accurate, complete and current 
records, including documents showing the dates of and reasons for each deviation 
from the protocol.  
 
o Definitions 
For reporting purposes, the Sponsor classifies study deviations as major or 
minor: 
 
 
Major deviation:  Any deviation from subject inclusion and 
exclusion criteria; subject informed consent procedures (e.g. 
failure to obtain informed consent or failure to obtain informed 
consent prior to study entry); randomization errors; failure to 
report SAE’s, unanticipated adverse device effects, and deaths 
within applicable regulatory timeframes; device accountability 
issues (e.g. missing or lost investigational product); or device 
misuse / unauthorized device use. 
 
 
Minor deviation:  Deviation from a protocol requirement such as 
incomplete/ inadequate subject testing procedures, non‐
compliance with medication regimens, follow‐ups performed 
outside specified time windows, etc. 
 
The Sponsor will continuously monitor site compliance.  The site will receive 
a list of site‐specific study deviations on an annual basis as part of the 
Annual Progress Report and as part of the Final Report upon completion of 
the study. 
 
13.5 DATA MONITORING COMMITTEE 
A Data Monitoring Committee [DMC] will provide ongoing independent review of 
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scientific merit of the trials.  The DMC consists of at least three voting members, 
with relevant expertise.  The DMC members are not directly related to the study. 
 
14 DEVICE ACCOUNTABILITY 
The investigator shall maintain adequate records of the receipt and disposition 
of all devices per local institutional procedure and regulations.  
 
15 PROTECTION OF HUMAN SUBJECTS 
15.1 STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the current ICH E6 GCP, the ethical 
principles of the Declaration of Helsinki, current FDA GCP guidelines, and any 
additional national or IRB/IEC or CA‐required procedures, whichever represents 
the greater protection for the individual. 
 
15.2 INFORMED CONSENT 
This study will be conducted in compliance with current ICH E6 GCP pertaining to 
informed consent, the current CFR (Title 21, Parts 50). To participate in the study, 
the subject must sign and date the ICF after having been informed about the nature 
and purpose of the study, participation and termination conditions, risks, and 
benefits, before initiation of any study‐related procedures. A copy of the signed ICF 
must be provided to the subject. If applicable, the ICF will be provided in certified 
translation for non‐English‐speaking subjects. Signed ICFs must remain in the 
subjects’ study files and be available for verification by the Sponsor or Sponsor 
representative at any time. 
 
 

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16 STATISTICAL CONSIDERATIONS 
16.1 GENERAL ANALYSIS PRINCIPLES 
All primary endpoint analyses will be conducted under the principle of “Intention‐To‐
Treat” (ITT), where each subject randomized to a treatment group who has met all 
inclusion/exclusion criteria and had a mapping and/or ablation catheter inserted 
shall be considered part of the ITT group.  As a secondary exploratory analysis, a “Per 
Protocol” (PP) analysis may be performed with a subgroup of the ITT group who have 
no major protocol deviations reported, and have achieved their 12‐month visit 
(endpoint). 
 
16.2 Study Endpoints 
A. 
Long‐Term Effectiveness (Primary effectiveness endpoint) 
 
Single Repeat Procedure Freedom from AF/AT/AFL recurrence* in the period from 3 
to 12 months after the initial AF ablation procedure. 
 
Freedom from AF/AT/AFL recurrence is defined as no documented episodes > 30 
seconds with conventional non‐invasive 7‐day continuous monitoring.  In the case of a 
cardiac implanted electronic device (CIED), freedom from AF/AT/AFL recurrence is 
defined as no documented episodes > 30 in a 1‐week window at the follow‐up visits, 
in addition to any symptomatic episodes with documented episode > 30 seconds.  AT 
recurrence does not include episodes of CTI (cavotricuspid isthmus) dependent 
flutter. 
 
The statistical hypothesis for this endpoint is operationalized as follows: 
 
HO: pE = pC 
HA: pE  pC 
 = .05 (two‐tailed) 
 
Where: 
 
pE = the proportion of “successes” in the FIRM arm 
pC = the proportion of “successes” in the conventional ablation control arm 
 
The proportion of successes in each treatment arm shall be evaluated relative to their 
respective primary endpoint using both Chi‐Square (Binomial, 1df) and by Kaplan‐
Meier survival estimation. Each evaluation will include 95% confidence intervals. 
B. 
Acute Effectiveness (Secondary effectiveness endpoint) 
 
The acute success of FIRM‐guided procedure is defined as elimination of the source of 
arrhythmias identified by FIRMap as indicated by;  
 
1. 
No evidence of the source on FIRMap immediately post‐procedure, OR  

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2. 
Reduction of electrogram amplitude to <0.2mV in region designated by 
FIRMap  
 
The proportion of successes in each arm will be calculated as follows: 
 
n
N  
 
Where: 
 
n = the total count of “successful” subjects in the arm in question 
N = the total count of subjects for that arm in the ITT group 
 
The statistical hypothesis for this endpoint is operationalized as follows: 
 
HO: pE = pC 
HA: pE  pC 
 = .05 (two‐tailed) 
 
Where: 
 
pE = the proportion of “successes” in the FIRM arm 
pC = the proportion of “successes” in the conventional ablation control arm 
 
This endpoint will be evaluated using a Chi‐Square test of independence, the 
proportions assumed to be binomial for each group. 
C. 
Acute Safety (Primary safety endpoint) 
 
The acute safety success of either treatment arm is defined as freedom from serious 
adverse events related to the procedure within ten (10) days of the index procedure. 
The proportion of successes in each arm will be calculated as follows: 
 
n
N  
 
Where: 
 
n = the total count of subjects presenting freedom from serious adverse events related 
to the procedure within ten (10) days of the index procedure. 
N = the total count of subjects in that arm in the ITT group 
 
The statistical hypothesis for this endpoint is operationalized as follows: 
 
HO: pE = pC 
HA: pE  pC 
 = .05 (two‐tailed) 
 

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Where: 
 
pE = the proportion of “successes” in the FIRM arm 
pC = the proportion of “successes” in the conventional ablation control arm 
 
This endpoint will be evaluated using a Chi‐Square test of independence, the 
proportions assumed to be binomial for each group. 
D. 
Long‐Term Safety (Primary safety endpoint) 
 
Long‐term safety is defined as freedom from procedure‐related serious adverse 
events (SAEs) (including those related to repeat procedures) within one year of the 
initial procedure. 
 
The statistical hypothesis for this endpoint is operationalized as follows: 
 
HO: pE = pC 
HA: pE  pC 
 = .05 (two‐tailed) 
 
Where: 
 
pE = the proportion of subjects free from serious adverse events related to the 
procedure (including from any repeat procedures required) within one year of the 
index procedure in the FIRM arm 
 
pC = the proportion of subjects free from serious adverse events related to the 
procedure (including from any repeat procedures required) within one year of the 
index procedure in the conventional ablation control arm 
 
The proportion of events in each treatment arm shall be evaluated relative to their 
respective primary endpoint using both Chi‐Square (Binomial, 1df) and by Kaplan‐
Meier survival estimation. Each evaluation will include 95% confidence intervals. 
 
16.3 POWER AND SAMPLE SIZE ESTIMATION 
 
 
 
 
 
 
 
 

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17 PUBLICATION POLICY 
The data generated in this clinical study are the exclusive property of the Sponsor and 
are 
 As the study Sponsor, Abbott retains the first right to disclose the 
results of the Study through a publication or any other public disclosure.  A 
Publication Steering Committee (PSC) may be formulated to oversee the publication 
process. The PSC may include Principal Investigator(s), members of the Steering 
Committee, investigators and other individuals who have expertise in the area and 
employees of Abbott. All manuscripts and abstracts will be reviewed and approved 
by the PSC and/or Abbott.  Authorship on the primary publication of the results from 
this study will be based on contributions to study design, enrollment, data analysis, 
and interpretation of results.