Renal Nerve Denervation in Patients With Hypertension and Paroxysmal and Persistent Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation, Hypertension
Sponsor: Medtronic Vascular

 
 
 
Symplicity AF Clinical Investigation Plan 
Version 18.0 
19Aug2020 
 
NCT02064764 

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Symplicity AF 
 
Clinical Investigation Plan 
Version 18 
19AUG2020 
 
 
 
 
 
 
Regional Sponsors and Contacts 
United States 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
 
Europe, Middle East, Africa 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
(+31)-43-35-66-566 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................... 2 
CORE LABS ..................................................................................................................... 5 
COMMITTEES .................................................................................................................. 6 
1. 
INTRODUCTION ..................................................................................................... 7 
1.1 
Study purpose ........................................................................................................ 7 
1.2 
Study description ................................................................................................... 7 
2. 
BACKGROUND AND JUSTIFICATION .................................................................. 8 
3. 
SYSTEM DESCRIPTION AND INTENDED USE ................................................... 11 
3.1 
Symplicity Spyral Renal Denervation System .................................................... 12 
3.2 
Reveal LINQ ICM System ..................................................................................... 13 
3.3 
Additional system components .......................................................................... 13 
4. 
REGULATORY COMPLIANCE .............................................................................. 14 
5. 
METHODOLOGY .................................................................................................. 15 
5.1 
Study objectives................................................................................................... 15 
5.2 
Subject selection criteria ..................................................................................... 15 
5.3 
Minimization of bias ............................................................................................. 17 
6. 
STUDY PROCEDURES ......................................................................................... 17 
6.1 
Investigator/center selection criteria .................................................................. 17 
6.2 
Center activation .................................................................................................. 18 
6.3 
Equipment requirements ..................................................................................... 18 
6.4 
Role of the sponsor representative during study procedures and follow up 
visits 19 
6.5 
Data collection ..................................................................................................... 19 
6.6 
Patient informed consent process ...................................................................... 23 
6.7 
Medications .......................................................................................................... 24 
6.8 
Enrollment and baseline ...................................................................................... 25 
6.9 
Randomization ..................................................................................................... 26 
6.10 
Pulmonary vein isolation procedure .......................................................... 27 
6.11 
Peri – procedural anticoagulation ............................................................... 28 
6.12 
Renal angiography ....................................................................................... 28 
6.13 
Renal artery denervation procedure ........................................................... 29 
6.14 
LINQ insertion .............................................................................................. 29 
6.15 
Device deficiencies ...................................................................................... 30 
6.16 
Hospital discharge ....................................................................................... 30 

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6.17 
Scheduled follow-up visit windows ............................................................ 30 
6.18 
Scheduled in-office follow-up visits ........................................................... 31 
6.19 
Unscheduled follow-up visits ...................................................................... 33 
6.20 
System modification for Reveal LINQ ........................................................ 33 
6.21 
Permissible repeat ablation ........................................................................ 33 
6.22 
Repeat renal artery denervations................................................................ 34 
6.23 
Recurrence of atrial fibrillation ................................................................... 34 
6.24 
Study exit ...................................................................................................... 34 
7. 
INVESTIGATIONAL DEVICE STORAGE, HANDLING AND TRACEABILITY ....... 35 
7.1 
Symplicity Spyral Renal Denervation System .................................................... 35 
7.2 
Arctic Front Advance and Freezor MAX Cardiac Cryoablation Catheters ....... 36 
7.3 
Final product disposition .................................................................................... 36 
8. 
STUDY DEVIATIONS ............................................................................................. 37 
9. 
ADVERSE EVENTS AND DEVICE DEFICIENCIES .............................................. 37 
9.1 
Adverse event and device deficiency definitions .............................................. 38 
9.2 
Adverse event and device deficiency assessment .......................................... 41 
9.3 
Market-released reporting requirements ............................................................ 42 
9.4 
Adverse event and reporting requirements ....................................................... 42 
9.5 
Subject death ....................................................................................................... 44 
9.6 
CEC review ........................................................................................................... 45 
9.7 
Adverse event classification ............................................................................... 45 
10. 
RISK ANALYSIS .................................................................................................... 47 
10.1 
Risk minimization ........................................................................................ 50 
10.2 
Potential benefits ......................................................................................... 51 
11. 
PLANNED STUDY CLOSURE, EARLY TERMINATION OF STUDY OR STUDY 
SUSPENSION ....................................................................................................... 51 
11.1 
Planned study closure ................................................................................. 51 
11.2 
Early termination or suspension ................................................................. 51 
11.3 
Procedures for termination or suspension ................................................ 52 
12. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................. 53 
12.1 
Sample size determination .......................................................................... 53 
12.2 
General considerations ............................................................................... 53 
12.3 
Primary safety objective .............................................................................. 54 
12.4 
Primary effectiveness objective .................................................................. 57 
12.5 
Secondary objective .................................................................................... 59 

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12.6 
Ancillary objectives ..................................................................................... 60 
12.7 
Subgroup analysis ....................................................................................... 60 
12.8 
Interim analysis ............................................................................................ 60 
12.9 
Pooling of study centers for analysis ......................................................... 61 
12.10 
Missing data ................................................................................................. 61 
13. 
DATA AND QUALITY MANAGEMENT .................................................................. 62 
14. 
WARRANTY/INSURANCE INFORMATION ........................................................... 62 
15. 
MONITORING........................................................................................................ 62 
15.1 
Monitoring visits .......................................................................................... 63 
16. 
REQUIRED RECORDS AND REPORTS ............................................................... 63 
16.1 
Investigator records .................................................................................... 63 
16.2 
Investigator reports ..................................................................................... 64 
16.3 
Sponsor records .......................................................................................... 65 
16.4 
Sponsor reports ........................................................................................... 66 
APPENDIX A: DRAFT DATA COLLECTION ELEMENTS ............................................... 68 
APPENDIX B: PRELIMINARY PUBLICATION PLAN ..................................................... 69 
APPENDIX C: DATA MONITORING COMMITTEE ......................................................... 71 
APPENDIX D: INFORMED CONSENT TEMPLATES ..................................................... 72 
APPENDIX E: PARTICIPATING INVESTIGATORS, INSTITUTIONS AND IRB/MECS .... 73 
APPENDIX F: LABELING .............................................................................................. 74 
APPENDIX G: BLOOD PRESSURE MEASUREMENT PROCEDURES ........................ 75 
APPENDIX H: BIBLIOGRAPHY AND PRECLINICAL AND CLINICAL INVESTIGATIONS
 .............................................................................................................................. 77 
APPENDIX I: MODIFICATIONS TO THE CLINICAL INVESTIGATION PLAN ................ 78 
 

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SPONSOR CONTACT INFORMATION 
Medtronic contact information is provided below. This information is subject to change 
during the course of the clinical study. Periodic updates to study contact information will 
be sent to the centers as needed. 
 
Table 1: Study sponsor contact information 
 
Study sponsors and contacts 
Worldwide Clinical study leader 
 Europe, Middle East, Africa (EMEA) 
Marina Ostanniy, Pr. Clinical Research Specialist 
Anita van Wijlick MSc, Sr. Clinical Research Specialist 
Direct Phone: +17635269751 
Direct Phone: +31 (0)6 22592645 
 
anita.wijlick@medtronic.com 
marina.ostanniy@medtronic.com 
 
 Monitoring contact 
Worldwide Monitoring leader 
 
Beth A. Ornell, MS, Clinical Monitoring Manager 
Direct Phone: +1 763-280-2332 
beth.a.ornell@medtronic.com 
 
 
CORE LABS 
Table 2: Study Core Labs 
Core Lab 
Contact information  
 Purpose  
 
VasCore 
One Bowdoin Square 10th Floor 
Boston, MA 02114 
Phone: 617-726-5552 
Assessment of Renal Duplex 
Ultrasound (RDUS) 
Beth Israel Deaconess 
Medical Center 
375 Longwood Avenue, 3rd Floor 
Boston, MA 02215 
Phone: 617-667-7000 
Assessment of renal angiogram for 
renal stenosis 
Intelemage/ 
Medidata 
700 W. Pete Rose Way 
Cincinnati, OH 45203 
Phone: 973-659-6780 
Study specific image uploading and 
viewing platform 
 
 
 
 
 
 
 
 
 
 
 
 

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COMMITTEES 
Table 3: Committee contact information 
 
Committee Member 
Contact information  
 Purpose  
 
Steering Committee 
Larry Chinitz, MD 
Principal Investigator 
New York University, Langone Medical 
Center 
333 East 30th Street 
New York, NY 10016 
Provide consultation on therapy 
and product usage throughout the 
lifecycle of the clinical study. 
Clinical Events Committee 
(CEC) 
Provided under separate cover, if requested. 
Provide unbiased review of 
adverse events and adjudicate all 
death and endpoint events. 
Data Monitoring 
Committee (DMC) 
Provided under separate cover, if requested. 
Provide unbiased review of safety 
data and provide 
recommendations for study 
continuation or termination. 

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1. INTRODUCTION 
1.1 Study purpose 
Medtronic, Inc. is sponsoring the Symplicity AF study, a prospective, 
randomized, multi-center clinical study. This is an investigational, feasibility 
study in the United States; the study is a post-market interventional study in 
Europe. The purpose of this clinical study is to evaluate the feasibility of 
performing both renal artery denervation and pulmonary vein isolation on the 
same patient with the intent of characterizing both safety and effectiveness in a 
paroxysmal and persistent atrial fibrillation (AF) population with hypertension. 
To assess safety, a primary objective will measure the occurrence of a 
composite safety endpoint and, to assess effectiveness, a primary objective will 
measure freedom of chronic treatment failure through a minimum of six months 
of follow-up. The Arctic Front Advance™ Cardiac Cryoablation system and 
Symplicity™ Spyral Renal Denervation system (Symplicity Spyral™ Multi-
Electrode Renal Denervation Catheter and the Symplicity G3™ Renal 
Denervation RF Generator, hereafter referred to as the Symplicity Spyral 
Catheter and Symplicity G3 Generator) will be used in the study. Both are 
commercially available in Europe. The Arctic Front Advance Cardiac 
Cryoablation system is commercially available in the United States; however, is 
not approved for the treatment of persistent AF with an AF episode duration of6 
months and longer; therefore, it is considered investigational in this specific 
persistent AF patient population. The components of the Symplicity Spyral 
Renal Denervation System are investigational in the United States. 
This study has been designed to support the following proposed Indication for 
Use should Medtronic choose to study this further: 
Renal denervation with the Symplicity System increases the success rate and 
augments the benefits of pulmonary vein isolation with the Arctic Front Advance 
System in patients with symptomatic drug refractory paroxysmal and persistent 
AF and uncontrolled hypertension for the prevention of AF recurrence. 
 
1.2 Study description 
The study is expected to be conducted at up to 12 centers located in The 
United States and up to three centers in Europe. Up to 245 subjects will be 
enrolled in the study to ensure there are 70 randomized subjects. The number 
of enrollments permitted relative to the number of subjects to be randomized is 
high since it is expected that a fair number of subjects will not meet all 
screening criteria (rigorous blood pressure monitoring and renal anatomy) once 
consented. Center randomization will be capped at 50% (35) of the total 
randomized subjects. 
Randomized study subjects will be followed for a minimum of six months, and 
then every six months thereafter until official study closure as determined by 
Medtronic and/or regulatory authority, whichever occurs first. Accordingly, the 
expected total study duration is approximately fifty-seven months, representing 
approximately fifty-one months of enrollment and six months of subject follow-up 
after the last patient has undergone the study procedure. 
Interim analyses of the primary effectiveness objective will take place and if 
data are deemed to sufficiently characterize this study objective by the sponsor 

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at one of these analyses, enrollment may be stopped. 
 
2. BACKGROUND AND JUSTIFICATION 
Hypertension1 and AF2 share many commonalities in demographics, prevalence, and 
disease implications. These two diseases often co-exist and are each responsible for 
considerable deleterious changes in morbidity and mortality.3 By relative risk score 
evaluation, the risk of developing AF in hypertensive patients is modest (relative risk 
score = 1.4 to 2.1) when compared to other more serious cardiac conditions, such as 
heart failure (relative risk score = 6.1 to 17.5) and valvular heart disease (relative risk 
score = 2.2 to 8.3).4 Yet, due to the much higher prevalence of hypertension in the 
general population, hypertension accounts for more actual cases of AF than 
compared to any other risk factor.5 Approximately 25% of the United States 
population has high blood pressure1, which makes it the primary risk factor for AF 
development in North America.3,6 Currently hypertension is the most prevalent and 
independent risk factor for developing AF, but it also is potentially the most modifiable 
risk factor for halting the development of AF.2,7 
On its own hypertension is associated with several long-term maladaptive cardiac 
adjustments, including: left ventricular cardiac hypertrophy, left atrial enlargement, 
slowing of left and right atrial conduction velocity, and impaired ventricular filling.4 
Nonetheless, these structural and physiological changes in the hypertensive heart 
also predispose and start the cardiac abnormalities which also help to initiate AF. This 
link between hypertension and AF is seen with demographic incidence rates. The 
annual incidence of AF is approximately 19.2 per 1,000 person-years;7  however, 
when examined in the subset of preexisting hypertensive patients, the incidence of AF 
is about 94 per 1,000 person-years.8 Follow-up cohort studies demonstrated that 
hypertension was present in approximately 50% of all North American patients with 
AF3,6 and that hypertension was shown to be causative to AF in about 15% of the 
patients.2 
Recently, a series of studies have demonstrated that pharmaceutical therapies guided 
at reducing hypertension have also reduced atrial fibrillation incidence in patients with 
hypertension, heart failure, and myocardial infarction. In particular, pharmaceutical 
blockage of the renin-angiotensin system (by either angiotensin-converting enzyme 
(ACE) inhibitors or angiotensin II receptor antagonists) proved to be the most effective 
in reducing the incidence of AF.9,10,11,12 Animal studies confirmed that the duration of 
AF was decreased when treated with ACE inhibitors and concluded that the renin- 
angiotensin pathway played a critical role in arrhythmogenic atrial remodeling.13 
More recently, therapeutic renal denervation, which is the deliberate disruption of the 
nerves connecting the kidneys with the central nervous system, has been shown to 
be an effective means of reducing elevated sympathetic nervous system (SNS) 
activity, which is a common and key factor in disease states such as hypertension, 
heart failure and atrial fibrillation. Renal denervation modulates the SNS activity by 1) 
reducing the sympathetic control of renal function (renin release, sodium excretion 
and renal blood flow) and 2) removing the renal afferent sympathetic contribution to 
central blood pressure elevation. 
 
Renal denervation was developed as a potential treatment for hypertension based on 
prior surgical studies demonstrating reduction in blood pressure with surgical disruption 
of thoracoabdominal sympathetic nerves and surgical nephrectomy in renal failure 
patients.  Renal denervation is believed to interrupt efferent sympathetic nerves 

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impacting renal function as well as afferent nerves impacting feedback to the brain and 
thus systemic sympathetic tone. A series of early feasibility clinical studies 
demonstrated impact on hypertension as well as other associated disease processes 
where increased systemic sympathetic tone is believed to be involved, such as heart 
failure, renal dysfunction, diabetes, and cardiac arrhythmias. Following the 
SYMPLICITY HTN-3 study, which raised concerns about incomplete denervation with 
the Symplicity renal denervation system and lack of adequate control in some prior 
studies, two recent feasibility studies of renal denervation using the Symplicity Spyral 
renal denervation system and catheter have successfully addressed these issues and 
demonstrated the ability of this system to reduce blood pressure both in the absence 
and in the presence of antihypertensive drugs. Each of these studies reported on 80 
subjects with combined systolic and diastolic hypertension (office systolic blood 
pressure between 150 and less than 180 mmHg; diastolic office pressure of 90 mmHg 
or above, and 24-hour mean systolic pressure between 140 and less than 170 mmHg). 
The OFF-MED study enrolled subjects who had either not been treated with 
antihypertensive drugs or had these drugs discontinued for a period of time before 
randomization. The ON-MED study enrolled subjects prescribed 1, 2, or 3, 
antihypertensive medications.   
 
The SPYRAL OFF-MED study14 demonstrated 3-month reductions in both office 
systolic blood pressure reduction (-7.7-mm Hg; P = .016) and mean 24-hour systolic 
pressure (-5.5 mmHg (p=0.04). There were no major safety events in either arm.  
Significant reductions were also observed between groups for multiple parameters 
including office diastolic blood pressure and 24-hr mean diastolic blood pressure. This 
trial provided biological proof of principle for the efficacy of catheter-based renal 
denervation to reduce blood pressure in patients with hypertension not treated with 
antihypertensive medications, addressing the limitations identified from the prior 
SYMPLICITY HTN-3 study. 
The SPYRAL ON-MED study15 demonstrated 6-month placebo subtracted reductions in 
both office systolic pressure (-6.8 mmHg; p=0.02) and mean 24-hour systolic pressure 
(-7.4; -p=0.005) in the presence of commonly used antihypertensive medications.  
Significant reductions were also observed between groups for multiple parameters 
including office diastolic blood pressure, 24-hr mean diastolic blood pressure, daytime 
systolic blood pressure and nighttime systolic blood pressure. Examination of the 
circadian 24-hr blood pressure normalized to waking time indicated that blood pressure 
reductions were consistent throughout the day and night including the high-risk 
“morning surge” period. Thus, the effects of renal denervation may provide additional 
clinical benefit during the high-risk period unlike drug therapy. The extent of blood 
pressure reduction grew during follow up, raising the possibility that further reduction 
may be seen with more prolonged follow-up. No major adverse events out to 6 months 
were reported.   
 
In order to test the hypothesis in the SPYRAL PIVOTAL - SPYRAL HTN-OFF MED 
study that renal denervation decreases blood pressure and is safe when studied in the 
absence of antihypertensive medications, study subjects were randomized to the 
Denervation or Control group in a 1:1 fashion. In addition to subjects being blinded to 
their randomization assignment, site personnel involved in the measurement of office 
blood pressure were also blinded to study subjects’ randomization assignment through 
the primary endpoint to prevent potential bias of results. Subjects were studied in the 
absence of antihypertensive medications to assess the impact of renal denervation on 

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systolic blood pressure in the absence of medication.  
 
Study enrollment was stopped for efficacy after the first interim analysis in February 
2020. Data from the initial 80 patients with 3 months follow up from the SPYRAL HTN-
OFF MED study was combined with data from the initial 251 patients with 3 months 
follow up from the SPYRAL PIVOTAL-SPYRAL HTN-OFF MED study and was 
presented at ACC World Congress of Cardiology in March 2020.  Concurrently, an 
article presenting the data was published in the Lancet.  A brief summary of the 
SPYRAL PIVOTAL-SPYRAL HTN-OFF MED data is provided below.  
 
The primary endpoint, change in 24-h blood pressure at 3 months, was compared 
between groups. Drug surveillance was done to ensure patient compliance with 
absence of antihypertensive medication. The primary analysis was done in the 
intention-to-treat population. Safety events were assessed to 3 months.  
 
From June 25, 2015, to Oct 15, 2019, 1519 patients were enrolled, of whom 1188 were 
excluded because they did not meet inclusion criteria. 166 were randomly assigned to 
renal denervation and 165 to the sham procedure (80 were included in the pilot and 251 
in Pivotal). 
 
There were no major safety events reported at 1 month. There was one major safety 
event in each treatment group up to 3 months (one admission to hospital for 
hypertensive crisis or emergency in the renal denervation group and one new stroke in 
the sham procedure group), and neither was attributed to the device or trial procedures. 
 
For the primary efficacy endpoint of changes from baseline in 24-h systolic blood 
pressure at 3 months, there was a significant difference between the renal denervation 
and sham procedure groups. This endpoint was met with a posterior probability of 
superiority greater than 0.999 and a treatment difference of -3.9 mm Hg (95% BCI -6.2 
to -1.6). For the secondary efficacy endpoint of difference in 3-month changes in office 
systolic blood pressure between the two groups, the difference was significant and the 
endpoint was met (difference -6.5 mm Hg (95% BCI -9.6 to -3.5), with posterior 
probability of superiority of more than 0.999. The blood pressure changes analysed 
using the prespecified ANCOVA-adjusted frequentist analysis of the overall population 
show similar changes in blood pressure to Bayesian results. 
 
A small pilot study in hypertensive patients with paroxysmal and persistent AF 
demonstrated the benefits of concomitant AF ablation and renal denervation (RDN) 
ablation.16   When patients were given both simultaneous AF and RDN ablation, 69% 
of the subjects were AF-free at twelve-month post-ablation follow-up examination. 
This was compared to 29% of subjects that remained AF-free during the same study 
when they were only administered an AF ablation. The 40% difference in success rate 
was attributed to the differential success that is achieved when hypertension is 
controlled through sympathetic modulation and no longer adversely contributing to the 
disease progression of AF; in addition, direct effects on the atria following renal 
denervation are possible.  
 
Until very recently, the treatment of AF had been focused on maintenance and 
regulation of rate, rhythm, and anti-coagulation. The current therapies largely ignore 
the underlying disease process including the sympathetic nervous system’s 
involvement into the development of hypertension and structural heart disease which 

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can lead to the development of AF through atrial remodeling and subsequent 
maladaptive changes in atrial electrical conduction. Aggressive treatment of 
hypertension may reverse structural heart changes, reduce thromboembolic events, 
and retard/prevent AF. Patients with both paroxysmal and persistent AF are included 
in this study to better understand the treatment effect of renal artery denervation in 
combination with cryoablation along the AF disease continuum. In addition, this study 
will gather feasibility outcomes data on the use of the Arctic Front Advance and Arctic 
Front Advance Pro Cardiac Cryoablation Catheter for pulmonary vein isolation in the 
persistent AF population. In June 2020,  FDA granted approval of Arctic Front 
Advance, Arctic Front Pro and Freezor MAX with the Persistent AF expanded 
indication for the treatment of drug refractory recurrent symptomatic paroxysmal and 
persistent atrial fibrillation (episode duration less than 6 months). 
 
 
3. SYSTEM DESCRIPTION AND INTENDED USE 
The study will be conducted using the components described in the table below (and 
future commercially released generations). Instructions for use of the devices used in 
this study are provided in their respective manuals. In Europe, centers will utilize the 
commercially available Symplicity Spyral Renal Denervation System, Arctic Front 
Advance Cardiac Cryoablation System and Reveal LINQTM Insertable Cardiac 
Monitor System within intended use. 
 
Table 4: System component information 
 
Component  
 
Model Number 
Investigational / Market-
released 
 
Manufacturer 
Symplicity SpyralTM multi-
electrode renal 
denervation catheter 
(Symplicity SpyralTM 
catheter) and Symplicity 
G3TM renal denervation 
RF Generator (Symplicity 
G3TM generator) 
IDERDN016 or IDEHTNRDN016  
(Symplicity Spyral catheter) 
IDERDN017 or IDEHTNRDN017  
(Symplicity G3 generator) 
US: Investigational 
 
 
 
Medtronic, Inc. 
RDN016  
(Symplicity Spyral catheter) 
RDN017 
(Symplicity G3 generator) 
Europe: Market-released 
 
Arctic Front Advance 
Cardiac Cryoablation 
System 
2AF234 
US: Market-released for 
treatment of paroxysmal AF 
and persistent AF with an 
episode duration less than 6 
months. 
Investigational for treatment of 
persistent AF with an episode 
duration over 6 months 
US: Investigational for 
treatment of persistent AF with 
an AF episode duration 6 
months or greater. 
Medtronic 
CryoCath LP 
 
2AF284 
 
 
 
AFAPRO23 
AFAPRO28 
 
 

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2AF233 
Europe: Market-released 
 
2AF283 
 
AFAPRO23 
 
 
 
AFAPRO28 
 
 
Reveal LINQ™ Insertable 
Cardiac Monitor (ICM) 
System 
LNQ11 (Reveal LINQ ICM, 
Incision/Insertion Tool) 
2090 (Medtronic Programmer) 
9538 or PA96000 (Patient Assistant) 
24950/24951/24952 (MyCareLink 
Patient Monitor) 
US: Market-released  
Europe:  Market-released 
Medtronic, Inc. 
 
 
 
3.1 Symplicity Spyral Renal Denervation 
System 
The system consists of the following: 
• 
Symplicity Spyral™ Multi-Electrode Renal Denervation Catheter 
• 
Symplicity G3™ Renal Denervation RF Generator 
• 
Symplicity RF Generator Component, Foot Switch 
• 
Symplicity RF Generator Component, Power Cord 
 
The Symplicity Spyral Renal Denervation System is intended for use of 
delivering low-level radiofrequency (RF) energy through the wall of the renal 
artery to denervate the human kidney. 
In Europe, the commercially available product is indicated for the treatment of 
uncontrolled hypertension. 
This system will be considered investigational in the United States for the 
duration of the clinical study.Arctic Front Advance Cardiac Cryoablation System 
The system consists of the following: 
• 
Arctic Front Advance Cardiac Cryoablation Catheter in two balloon sizes 
(23mm and 28mm) 
• 
Arctic Front Advance Pro Cardiac Cryoablation Catheter 
• 
Manual Retraction Kit 
• 
The Freezor MAX Cardiac Cryoablation Catheter in two curves (55mm and 
66mm) 
• 
Medtronic CryoCath® CryoConsole 
 
Approved indication in the US: The Arctic Front Advance/Arctic Front Advance Pro 
Cardiac Cryoablation Catheters are indicated for the treatment of drug refractory 
recurrent symptomatic paroxysmal atrial fibrillation or persistent AF with an AF episode 
duration less than 6 months. 
 
Approved indication in Europe: The Arctic Front Advance/Arctic Front Advance Pro 
Cardiac Cryoablation Catheters are indicated for the treatment of patients with atrial 
fibrillation. 
 
Approved indication in the US: The Freezor MAX Cardiac Cryoablation Catheter is 
used as an adjunctive device in the endocardial treatment of paroxysmal atrial 

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fibrillation in conjunction with Arctic Front Advance/Arctic Front Advance Pro Cardiac 
Cryoablation Catheter for the following uses: 
• 
gap cryoablation to complete electrical isolation of the pulmonary veins 
• 
cryoablation of focal trigger sites, and 
• 
creation of atrial flutter line between the inferior vena cava and the tricuspid 
valve 
 
Approved indication in Europe: The Freezor MAX Cardiac Cryoablation Catheter is 
intended for use in treatment of cardiac arrhythmias. 
 
This system is considered investigational for use in the persistent AF population with an 
episode duration over 6 months in the United States. 
 
3.2 Reveal LINQ ICM System 
The system consists of the following: 
• 
Reveal LINQ ICM 
• 
Incision Tool 
• 
Insertion Tool 
• 
Medtronic CareLink Model 2090 programmer or CareLink Encore Model 
22901 programmer 
• 
MyCareLink® Home Monitor 
• 
Reveal Patient Assistant 
 
Approved indication in the US: The Reveal LINQ ICM is an implantable patient- 
activated and automatically-activated monitoring system that records subcutaneous 
ECG and is indicated in the following cases:  
• 
Patients with clinical syndromes or situations at increased risk of cardiac 
arrhythmias 
• 
Patients who experience transient symptoms such as dizziness, palpitation, 
syncope, and chest pain that may suggest a cardiac arrhythmia 
 
Approved indication in Europe: The Reveal LINQ Insertable Cardiac Monitor is an 
implantable patient-activated and automatically-activated monitoring system that 
records subcutaneous ECG and is indicated in the following cases: 
• 
Patients with clinical syndromes or situations at increased risk of cardiac 
arrhythmias 
• 
Patients who experience transient symptoms that may suggest a cardiac 
arrhythmia  
 
This device will be used to identify recurrent AF which is further described in Section 
12: Statistical methods and data analysis. 
The AF detection algorithm looks at incoherence patterns in a series of RR intervals 
over a period of 2 minutes to detect AF. 
 
3.3 Additional system components 

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Additional components that may be used include Medtronic FlexCath™ sheaths and 
Medtronic Achieve™ and Achieve Advance™ mapping catheters. Medtronic may 
incorporate additional components into this clinical study as they receive appropriate 
license or regulatory approval and are released commercially by Medtronic. 
 
4. REGULATORY COMPLIANCE 
The Symplicity AF clinical study is an Investigational Device Exemption (IDE) study 
in the United States and a post-market interventional study in Europe. This clinical 
study is required to be in compliance with the CIP, Clinical Trial Agreement (CTA) 
and applicable regulations. 
This study will be conducted in compliance with ethical and scientific quality 
standards, known as good clinical practice (GCP). GCP includes review and approval 
by an independent Institutional Review Board (IRB)/Medical Ethics Committee (MEC) 
before initiating a study, continuing review of an ongoing study by an IRB/MEC and 
obtaining and documenting the freely given informed consent of a subject before 
initiating the study. 
 
The study will be conducted according to federal, national and local laws, regulations, 
standards, and requirements of the countries/geographies where the study is being 
conducted. For all geographies, the principles of the Declaration of Helsinki have been 
implemented through the patient informed consent (PIC) process, Ethics 
Board/IRB/MEC approval, study training, clinical trial registration, preclinical testing, 
risk-benefit assessment and publication policy. 
 
Ultimately, all centers in all geographies will follow and comply with: 
• Principles of Declaration of Helsinki (including privacy and data protection laws), or 
the laws and regulations of each participating country, whichever affords greater 
protection for the study subjects 
• 21 CFR Part 11 (Electronic Records, Electronic Signatures) 
• 21 CFR Part 54 (Financial Disclosure by Clinical Investigators) 
• The procedures described with in this CIP 
• Local Ethics Board requirements 
 
In addition to the regulatory requirements outlined above, the study will be conducted in 
compliance with relevant local laws. These include but are not limited to: 
• In the United States, US FDA 21 CFR Parts 
• 
50: Protection of Human subjects 
• 
56: Institutional Review Boards  
• 
812: Investigational Device Exemptions 
• In Europe, Declaration of Helsinki 2013 and the local laws 
 
All participating geographies will make study data available to the regulatory body such 
as FDA or competent authority if the regulatory body deems an onsite inspection 
necessary. The regulatory body will be able to inspect records at clinical centers around 
the world to resolve any uncertainties about whether the study was conducted in 
accordance with good clinical practice. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 
Food and Drug Administration Amendments Act (FDAAA) and Declaration of Helsinki 
on http://clinicaltrials.gov. 

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Approval of the CIP, CIP revisions or CIP amendments is required from the following 
groups prior to any study procedures at a study center: Medtronic, FDA, regulatory 
body, Principal Investigators (where required by law), and an IRB/MEC at each study 
center. 
Similarly, approval of subsequent revisions to the CIP is required at each study 
center from the above-mentioned groups prior to implementation of the revised CIP 
at the center. 
 
5. METHODOLOGY 
5.1 Study objectives 
There are two primary objectives, one secondary objective, and six ancillary 
objectives for this study. The primary safety objective compares the rate of 
safety composite events between subjects randomized to receive both 
pulmonary vein isolation and renal artery denervation within one procedure 
compared to subjects randomized to receive pulmonary vein isolation alone. 
The primary effectiveness objective compares the proportion of subjects in 
each study arm that are free from a chronic treatment failure through all follow-
up. Further details about study objectives can be found in Section 12. 
 
5.2 Subject selection criteria 
Subjects will be screened to ensure they meet all the inclusion and none of the 
exclusion criteria. IRB/MEC and Medtronic approval of the Symplicity AF CIP 
and Informed Consent Form must be obtained prior to enrolling subjects in the 
study. 
Enrollment of the subject must occur prior to any study procedures take place. 
5.2.1 Inclusion criteria 
• 
Drug refractory recurrent symptomatic paroxysmal or persistent atrial 
fibrillation 
o Drug refractory is defined as: failed (drug is ineffective, or patient is 
intolerant) at least one Class I or III anti-arrhythmic drug 
o If the subject has persistent atrial fibrillation it must have been 
diagnosed within the last two years from the date of consent with a left 
atrial volume index ≤ 40 ml/m2 within the last year from the date of 
consent 
• 
Office-based systolic blood pressure > 140 mm Hg based on average of three 
blood pressure readings despite treatment with 1 or more antihypertensive 
medication(s). The subject should be on a stable antihypertensive drug 
regimen with no changes for a minimum of 2 weeks prior to enrollment and the 
antihypertensive drug regimen is not expected to change for at least 6 months, 
as determined by the subject’s referring cardiologist and/or the investigator. 
• 
Age 18 years to 80 years old 
• 
Willing to give informed consent and agree to all study procedures, and is 
competent and willing to provide written, informed consent to participate in this 
clinical study 
• 
Willing and able to be remotely monitored through the Medtronic 
CareLink® Network 
 

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5.2.2 Exclusion criteria 
• 
Active systemic infection 
• 
Cryoglobulinemia 
• 
One or more pulmonary vein stents 
• 
Type I Diabetes 
• 
NYHA Class IV heart failure with in the past 6 months 
• 
Renal artery anatomy that is ineligible for treatment including: 
o Lacks at least one renal artery for each kidney with ≥3 mm and ≤ 8 mm 
diameter and minimum treatable length per the Spyral Instructions for 
Use prior to a significant arterial branch (NOTE: All renal arteries with ≥3 
mm and ≤ 8 mm diameter with minimum treatable length per the Spyral 
Instructions for Use shall be treated, including dual renal arteries 
meeting these morphologic criteria.) 
o Renal artery stenosis (>50%) or renal artery aneurysm in either 
renal artery 
o A history of prior renal artery intervention including balloon 
angioplasty or stenting 
o Renal artery which contain calcification which does not allow at 
least four radio frequency ablations to be delivered 
o Diffuse fibromuscular dysplasia (FMD) or FMD which does not allow at 
least four radio frequency ablations to be delivered; FMD defined as 
visible beading of the artery on angiography 
o Unilateral kidney 
• 
Estimated Glomerular Filtration Rate (eGFR) of <30 mL/min/1.73m2 
• 
Primary pulmonary hypertension 
• 
Pheochromocytoma, Cushing’s Disease, coarctation of the aorta, untreated 
hyperthyroidism, primary hyperparathyroidism or hyperaldosteronism (Note: 
treated hyperthyroidism is permissible) 
• 
Myocardial infarction, unstable angina pectoris, syncope, PCI/PTCA, or 
coronary artery stenting within 3 months prior to signing the consent form, or 
has widespread atherosclerosis with documented intravascular thrombosis or 
unstable plaques 
• 
Cerebrovascular accident or TIA within 1 month prior to signing the consent 
form 
• 
Prior ablation for atrial fibrillation in the left atrium 
• 
Presence of a permanent pacemaker, biventricular pacemaker, atrial 
defibrillator or any type of implantable cardiac defibrillator (with or without 
biventricular pacing function) 
• 
Cardiac valve stenosis for which a significant reduction of blood pressure is 
contraindicated 
• 
A condition that would prohibit or interfere with ability to obtain an accurate blood 
pressure measurement using the protocol-specified automatic blood pressure 
monitor (e.g., arm diameter too large for the cuff) 
• 
Serious medical condition, which may adversely affect the safety and/or 
effectiveness of the participant or the trial (e.g., patients with clinically 
significant peripheral vascular disease, abdominal aortic aneurysm, 
bleeding disorders such as thrombocytopenia, hemophilia, or significant 
anemia) 

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• 
Pregnant, nursing or planning to be pregnant. [Female participants of 
childbearing potential must have a negative serum or urine human 
chorionic gonadotropin (hCG) pregnancy test prior to angiography] 
• 
Known history of drug use or alcohol dependency, lacks the ability to 
comprehend or follow instructions, or would be unlikely or unable to comply 
with study follow-up requirements 
• 
Previous organ transplant 
• 
Currently enrolled or plans to participate in a potentially confounding drug or 
device trial during the course of this study. Co-enrollment in concurrent 
studies is allowed when documented pre-approval is obtained from the 
Medtronic study manager. 
 
5.3 Minimization of bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential 
sources of bias. Methods incorporated in the study design to minimize potential bias 
include (but are not limited to): 
• 
Subjects will undergo a rigorous screening to confirm eligibility for 
enrollment with defined inclusion/exclusion criteria prior to enrollment 
• 
All centers will use the same version of the CIP and Case Report Form 
(CRFs) 
• 
Data collection requirements and study procedures will be standardized for all 
centers 
• 
All investigational center personnel and Medtronic personnel will be 
trained on their respective aspects of the study using standardized 
training materials 
• 
All investigational center personnel will be trained on and required to 
follow the CIP 
• 
An independent CEC will be utilized to regularly review and 
adjudicate reported adverse events and deaths 
• 
An independent DMC will be utilized to safeguard the interests of 
study subjects and monitor the overall conduct of the study. 
In summary, potential sources of bias that may be encountered in this clinical 
study have been considered and minimized by careful study design. 
 
6. STUDY PROCEDURES 
6.1 Investigator/center selection criteria 
An Investigator/center may be included in this investigation if they meet the 
following criteria: 
• 
Principal Investigator is credentialed in catheter ablation and femoral 
arterial cannulation in a hospital with an interventional vascular 
specialist who is credentialed in renal artery interventions.  The 
vascular specialist is to be immediately on-call during the renal 
denervation procedure to assist as needed in renal artery cannulation, 
catheter manipulation within the renal artery, and managing any 
vascular adverse events such as renal artery perforation or dissection. 

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• 
Principal investigator has experience using the Arctic Front®/ 
Arctic Front Advance/Arctic Front Advance Pro Cardiac 
Cryoablation Catheter system in at least 10 cases. 
• 
Center has a Medtronic CryoCath CryoConsole installed at the 
facility (Generation 5 console). 
• 
Willingness to perform both pulmonary vein isolation ablation with the 
Arctic Front Advance/Arctic Front Advance Pro Cardiac Cryoablation 
Catheter system and renal artery denervation with the Symplicity 
Spyral Catheter and Symplicity G3 Generator during the same case. 
• 
Principal investigator has access to an adequate number of 
potential subjects. 
• 
Sufficient experienced staff and equipment (e.g. study coordinator, 
renal duplex ultrasound, renal angiography, and trans-thoracic 
echocardiogram (TTE)) to execute and maintain protocol compliance. 
 
6.2 Center activation 
During the activation process (prior to subject enrollment), Medtronic will train 
center personnel on the CIP, relevant standards and regulations, informed 
consent, data collection and reporting tools. If new members join the 
investigational center team, they will receive training on the applicable clinical 
study requirements relevant to their role before contributing to the clinical study. 
Prior to performing study related activities, all local regulatory requirements 
shall be fulfilled, including, but not limited to the following: 
• 
Medtronic and IRB/MEC approval (and membership roster/voting list, as 
required by local law) of the current version of the CIP and Informed Consent 
Form, subject facing materials, Report of Prior Investigation as required by 
local laws and other materials, as necessary 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Fully executed Clinical Trial Agreement (CTA) 
• 
Investigator Curriculum Vitae (CV) 
• 
Delegation of center personnel responsibilities 
• 
Documentation of study training 
• 
Financial Disclosure 
 
In addition, all participating center staff must be trained on the current version of the 
CIP and must be delegated by the principal investigator to perform study related 
activities. 
 
Additional requirements imposed by the IRB/MEC and regulatory authority shall be 
followed. 
Medtronic will provide each study center with written documentation of study 
center/investigator readiness, this letter must be received prior to subject enrollment. 
Additional center personnel included after the initial activation will be notified when all 
requirements have been completed. 
 
6.3 Equipment requirements 
The following equipment must be available at each center to support study activities: 
• 
Trans-thoracic echocardiogram 

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e 
r u 
d 
e 
c 
o 
r P 
e 
r u 
d 
e 
c 
o 
r P 
• 
Renal angiography 
• 
Renal duplex ultrasound 
The maintenance and calibration of the equipment listed above will be assessed by 
the participating center following their normal processes. Clinical monitors will not 
monitor maintenance or calibration schedules. 
 
The sponsor will supply all required study materials for appropriate data collection 
before study start, like the office blood pressure monitors (OBPs). Medtronic will 
control the supply of devices and study materials 
 
6.4 Role of the sponsor representative during study procedures and 
follow up visits 
Sponsor representatives may provide support as required for the study under supervision 
of the Principal Investigator, including: 
• 
Provide study training relevant and pertinent to the involvement of personnel 
conducting study activities and investigator responsibilities 
• 
Technical support at the pulmonary vein isolation, renal denervation and Reveal 
LINQ insertion procedures under the supervision of a study investigator, but no 
data entry, shall be performed by Medtronic personnel or their representatives at 
sites 
• 
Monitoring and auditing activities 
• 
Follow up visit activities involving the Reveal LINQ device and CareLink 
 
6.5 Data collection 
Clinical data is collected at designated time points throughout the study. Data will be 
collected using an electronic data management system for clinical studies. 
Data will be stored in a secure, password-protected database which will be backed up 
nightly. Data will be reviewed using programmed and manual data checks. 
Data queries will be made available to study centers for resolution. Study management 
reports may be generated by Medtronic to monitor data quality and study progress. At 
the end of the study, the data will be frozen and retained indefinitely by Medtronic. Data 
collection requirements are summarized in Table 5. 
 
Table 5: Data collection and study procedure requirements at subject visits 
 
Repeat 
cryoablation 
Procedure (0- 
90 days), if 
performed 
Enrollment/Baseline 
CT Scan  
Cryoablation 
Procedure 
Renal Artery 
Denervation 
Reveal LINQ 
Insertion 
Hospital Discharge 
1 month 
6 month 
Every 6 months 
until study end 
closure12 month 
Unscheduled 
Exit 
Baseline 
Cryoablation 
Hospital Discharge 
Informed Consent 
x 
Inc/Exc criteria 
x 
x 
 
x 
x 
Medical history 
x 

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Repeat 
cryoablation 
Procedure (0- 
90 days), if 
performed 
Enrollment/Baseline 
CT Scan  
Cryoablation 
Procedure 
Renal Artery 
Denervation 
Reveal LINQ 
Insertion 
Hospital Discharge 
1 month 
6 month 
Every 6 months 
until study end 
closure12 month 
Unscheduled 
Exit 
Baseline 
Cryoablation 
Hospital Discharge 
Physical exam 
x 
x 
x 
x 
x 
x 
Trans-Thoracic 
Echocardiogram 
x (1) 
Review 
medications 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Office BP x3 
x 
 
 
 
x (8) x (8) x (8) 
x 
x 
Blood and urine 
labs: Serum 
Creatinine (sCr), 
Spot urine 
albumin and 
creatinine and 
Cystatin C 
x 
 
 
 
x 
x 
x 
x (2) 
Review of 
symptoms 
x 
 
 
 
x 
x 
x 
x 
Randomization 
x 
 
Pregnancy test 
x (3) 
 
 
 
Transesophageal 
Echocardiogram 
(TEE) (3) 
 
 
x (4) 
 
Renal angiogram 
for Treatment 
group only 
 
 
 
x 
Procedure 
information 
x 
x 
x 
x 
 
 
 
 
 
 
 
x 
CareLink in-office 
interrogation (5) 
 
 
 
x (6) 
x 
x 
x 
x 
 
 
 
CareLink manual 
home 
transmission 
 
 
 
 
 
x (5) 
 
x 
 
 
Renal Artery 
Imaging-Duplex 
Ultrasound 
 
 
 
 
 
 
x 
(7) 
 
 
 
 
 
Adverse Events, 
Reveal LINQ 
System 
Modification, 
Death, Study 
Deviation, Device 
Deficiencies 
As they occur 
1. 
For subjects with persistent AF, perform during the 12 month interval preceding the Consent Date, or 
between Consent Date and Procedure Date. 
2. 
Optional, if performed. 
3. 
Perform within 5 days prior to the Procedure. 
4. 
TEE at baseline to assess for LA thrombus as indicated by the 2012 HRS/EHRA/ECAS Expert 
Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation (Section 6.7). 
5. 
CareLink transmissions need to occur at a minimum one time per month. For the monthly CareLink 
transmissions that coincide with a scheduled follow-up visit (i.e. 1 or 6-month visits), a monthly transmission 

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is not required but perform an in-office device interrogation and data transfer to Medtronic.  A CareLink 
transmission may be used as a substitute for an in-office device interrogation. 
6. 
Ensure a device interrogation with final programmed settings is transferred to Medtronic. This may be at 
the time of insertion or prior to hospital discharge. 
7. 
Only for subjects who underwent the renal denervation procedure (randomized to the Treatment group). If 
clinically significant renal artery stenosis is suspected, a follow-up renal angiogram will be performed. 
8. 
Office blood pressure (according to guidelines in Appendix G), needs to be obtained if an office visit occurs 
or during alternative methods of data collection as described in section 6.18.1. 

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Figure 1: Study design flowchart 
 
 
 
 
Enrollment/Baseline 
CT scan and 
randomization 
Pulmonary vein 
isolation 
Control: LINQ 
insertion 
Treatment: renal
angiogram, 
renal
artery denervation
and LINQ insertion 
Hospital Discharge 
Hospital Discharge 
1 month and 6 
month 
1 month and 6 
month 
Every 6 months until 
study closure 
Every 6 months until 
study closure 

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6.6 Patient informed consent process 
Patient informed consent is defined as legally effective, documented confirmation of a 
subject’s (or their legally authorized representative or guardian) voluntary agreement to 
participate in a particular clinical study after information has been given to the subject 
on all aspects of the clinical study that are relevant to the subject’s decision to 
participate. This process includes obtaining Consent and an Authorization to Use and 
Disclose Personal Health Information/Research Authorization/other privacy language 
as required by law that has been approved by the investigational center’s IRB/MEC 
and signed and dated by the subject (or their legally authorized representative, US 
ONLY). A subject may only consent after information has been given to the subject on 
all aspects of the clinical investigation that are relevant to the subject’s decision to 
participate. 
Prior to enrolling subjects, each investigational center’s IRB/MEC will be required to 
approve the Consent Form, and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law. The 
document(s) must be controlled (i.e. versioned and/or dated) to ensure it is clear which 
version(s) were approved by the IRB/MEC. Any adaptation of the sample Consent 
Form must be reviewed by Medtronic and the IRB/MEC reviewing the application prior 
to enrolling subjects. Refer to Appendix D: Informed consent templates for the sample 
Consent Form. 
Prior to initiation of any study-specific procedures, patient informed consent must be 
obtained from the subject (or their legally authorized representative or guardian). The 
informed consent process must be conducted by the principal investigator or an 
authorized designee, and the Consent Form and Authorization to Use and Disclose 
Personal Health Information/Research Authorization/other privacy language as 
required by law must be given to the subject (or their legally authorized representative 
or guardian) in a language he/she is able to read and understand. The process of 
patient informed consent must not be conducted using coercion or undue improper 
influence on or inducement of the subject to participate by the investigator or other 
center personnel. 
The process of obtaining patient informed consent shall: 
• 
Not waive or appear to waive subject’s legal rights 
• 
Use language that is non-technical and understandable to the subject 
• 
Provide ample time for the subject to read and understand the informed 
consent form and to ask questions, receive answers and consider 
participation 
• 
Include a personally dated signature of the subject acknowledging that their 
participation in the study is voluntary 
 
In Europe, include a personally dated signature by the Principal Investigator or 
authorized designee responsible for conducting the informed consent process.  
 
If the Consent Form is obtained the same day the subject begins participating in study-
related procedures, it must be documented in the subject’s case history that consent 
was obtained prior to participation in any study-related procedures. It is best practice 
for the informed consent process to be documented in the subject’s case history, 

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regardless of circumstance. It is also best practice to document in the subject’s case 
history if they were re-consented for any reason. 
In the event the subject cannot read and/or write, witnessed (impartial third party) 
patient informed consent will be allowed, provided detailed documentation of the 
process is recorded in the subject’s case history and the witness signs and dates the 
patient informed consent. In Europe, when a subject cannot read and/or write, an 
independent witness shall be present throughout the process, the written PIC Form and 
any other information shall be read aloud and explained to the prospective subject. The 
subject should “make his mark” (sign or otherwise physically mark the document so as 
to indicate consent) on the Consent Form as well. The Consent Form should document 
the method used for communication with the prospective subject and the specific 
means by which the prospective subject communicated agreement to participate in the 
study. 
The original or a copy of the signed Consent Form must be filed in the hospital/clinical 
chart and with the subject’s study documents. 
The Consent Form and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be 
available for monitoring and auditing. Any Medtronic Field personnel who support 
study procedures must be able to review the subject’s signed and dated Consent 
Form and verify its completeness prior to proceeding with study procedures. In the 
event the Medtronic Field personnel identify patient informed consent as being 
incomplete, the study procedures will not be allowed to occur until the consent of the 
subject can be adequately and appropriately obtained. 
Any changes to a previously approved Informed Consent Form throughout the course 
of the study must be approved by Medtronic and the IRB/MEC reviewing the 
application before being used to consent a prospective study subject. The 
document(s) must be controlled (i.e. versioned and/or dated) to ensure it is clear which 
version(s) were approved by the IRB/MEC. All important new information should be 
provided to new and existing subjects throughout the study. 
 
6.7 Medications 
The collection of the following medications will take place during the course of this 
study: anticoagulants, those prescribed to treat atrial fibrillation, including those used 
for rate control, and those prescribed to treat hypertension. Information collected will 
include the medication name, purpose and start/stop dates. 
 
It is recommended to maintain all randomized subjects on their baseline hypertensive 
medications without changes until the 6-month visit. A study deviation is not required if 
changes are made to these medications. 
If a subject is on amiodarone, it is recommended to take them off 4-6 weeks before the 
end of the 90-day post cryoablation procedure blanking period. 
It is recommended that subjects be off all antiarrhythmic medications within 90 days 
post cryoablation procedure. 
Medication changes that occur specifically because the subject will undergo the study 
procedures should not be recorded. 
All medications are permitted in this study with the exception of investigational drugs 
that may confound the study results. 

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6.8 Enrollment and baseline 
When a patient signs and dates the Consent Form, he/she is considered a subject 
enrolled in the study. The date the subject signed the Consent Form and 
Authorization to Use and Disclose Personal Health Information/Research Authorization 
must be documented. The following evaluations will be performed after consent, unless 
previously performed as part of routine clinical evaluations within the specified 
windows: 
 
Within 12 months prior to the consent date or between consent date and 
procedure date 
If the subject has a diagnosis of persistent AF, confirm the left atrial volume index is ≤ 
40 ml/m2 by a trans-thoracic echocardiogram. 
A trans-thoracic echocardiogram on file can be used providing it is within the last year 
from the date of consent, if not, perform a trans-thoracic echocardiogram. 
 
After consent date but before the procedure date 
• 
Assessment of all factors specified for evaluation under Inclusion Criteria and 
Exclusion Criteria (Section 5.2). 
• 
Medical history including: assessment of risk factors, NYHA cardiac functional 
class, systemic history and cardiovascular history, assessment of atrial 
fibrillation history and symptoms and other arrhythmic episodes 
• 
Physical examination: height, weight, and heart rate. 
• 
Office blood pressure: To assess if the average of 3 office systolic blood 
pressures measured per guidelines (Appendix G: Blood Pressure 
Measurement Procedures) is > 140 mmHg. 
o If a subject’s average of 3 systolic blood pressures is ≤ 140 
mmHg, then repeat blood pressure measures (according to Appendix 
G: Blood Pressure Measurement Procedures) are allowed up to two 
times over the subsequent 2 weeks. Any subjects with an average 
office systolic blood pressure ≤ 140 mmHg after a total of three 
attempts will be excluded from the study. 
o For instructions on blood pressure measurement, see Appendix G: 
Blood Pressure Measurement Procedures. 
o This will be the baseline measurement for statistical comparison and 
inclusion criteria 
• 
Laboratory testing: Subjects should be instructed to avoid eating or drinking 
caffeine or alcohol for 10-12 hours prior to lab testing but should drink water 
normally (avoid other liquids) and take prescribed medications during this time. 
o Serum creatinine (sCr) to calculate eGFR for eligibility criteria and as 
a factor of baseline kidney function. eGFR should be calculated using 
the Modification of Diet in Renal Disease (MDRD) Formula: eGFR 
(mL/min/1.73 m2)=175 x (sCr/88.4)- 
1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if of African descent) 
(SI units). 
o Subjects with eGFR <30 mL/min/1.73m2 will be excluded from the 
study. 

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o Spot urine albumin and creatinine to evaluate the albumin to 
creatinine ratio (UACR) as a factor for baseline kidney function. 
o Blood test: Cystatin C to help detect and monitor acute and chronic 
kidney dysfunction. 
• 
Confirm the subject has eligible renal anatomy via computerized 
tomography (CT scan) 
• 
Perform randomization after eligibility has been confirmed, see 
Section 6.9. 
 
Performed within 5 days prior to the procedure date 
• 
Blood or urine test-Serum or urine human chorionic gonadotropin (hCG) 
Pregnancy test to confirm negative pregnancy status of females of 
childbearing potential. 
• 
Transesophageal Echocardiogram (TEE) 
Prior to undergoing an AF ablation procedure, a TEE should be performed in 
all subjects with atrial fibrillation more than 48 hours in duration or of an 
unknown duration if adequate systemic anticoagulation has not been 
maintained for at least 3 weeks prior to the ablation procedure. 
 
Performance of a TEE in subjects who are in sinus rhythm at the time of 
ablation or subjects with AF who are in AF but have been in AF for 48 hours or 
less prior to AF ablation may be considered but is not mandatory. 
 
Subjects noted to have left atrial thrombus on TEE will not undergo the 
procedure and will be exited from the study unless thrombus resolution is 
confirmed on a repeat TEE. 
 
6.9 Randomization 
Randomization schedules will be prepared for each site using a random permuted 
block design stratified by center and AF diagnosis. The schedules will allocate subjects 
in a 1:1 ratio to the treatment or control arm. 
Each center will receive a set of sequentially numbered envelopes labeled specifically 
for that center that is labeled with one randomization code per envelope. After a CT 
scan has been performed and confirmed that the renal anatomy meets eligibility 
requirements, the subject will be randomized. 
The next sequential envelope labeled with a randomization code will be used. The 
envelope number will be recorded for each randomized subject and communicated to 
Medtronic. The sequence of subject randomization will be checked to ensure it 
matches the sequence of envelope numbers. 
Randomization assignments are the following: 
• 
Treatment: 
o Perform the pulmonary vein isolation procedure, renal angiogram, 
renal artery denervation procedure and the Reveal LINQ insertion. 
• 
Control: 

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o Perform the pulmonary vein isolation procedure and the Reveal 
LINQ insertion.  Do NOT perform renal denervation. 
 
Enrolled subjects who were not randomized should be exited. See Section 9.2.2 if 
the subject has an ongoing adverse event. 
Subjects and center personnel will be blinded to the randomization assignment until 
after the pulmonary vein isolation procedure. 
Crossing over to the Treatment group once assigned to the Control group is not 
allowed at any point during the study. 
 
6.10 Pulmonary vein isolation procedure 
Perform the pulmonary vein isolation procedure first using Arctic Front Advance/Arctic 
Front Advance Pro. Investigator is to perform the procedure according to the 
procedural steps in this protocol and the Instructions for Use for the Arctic Front 
Advance/Arctic Front Advance Pro Cardiac Cryoablation System. Appropriate 
systemic anticoagulation and sedation should be attained at the investigators 
discretion according to their institutions pre- established procedures/guidelines at the 
time of the procedure. Current recommendations for anticoagulation are found in the 
2012 Expert Consensus Statement on the Ablation of atrial fibrillation.17 
6.10.1 Diaphragm Movement 
a. Phrenic nerve pacing or other phrenic nerve monitoring technique must be 
done for each cryoapplication, specifically those cryoapplications surrounding 
the RS and RI pulmonary veins 
b. Prior to the first cryoablation application, the Investigator will make a 
fluoroscopic recording of inspiratory and expiratory movement of the 
diaphragm 
c. After the last cryoablation application, the investigator will make a 
fluoroscopic recording of the inspiratory and expiratory movement of the 
diaphragm 
 
6.10.2 Balloon Pulmonary Vein (PV) Cryoablation 
a. Every effort consistent with subject welfare will be made to treat all PVs or 
their anomalous equivalents. 
b. The Arctic Front Advance/Arctic Front Advance Pro Cardiac Cryoablation 
Catheter will then be advanced into the LA and inflated. Once inflated, the 
catheter will be tracked over the wire and positioned at the entrance of the 
PV. 
c. Assess the positioning, contact and occlusion of the PV by the catheter’s 
balloon by ultrasound imaging, injection of contrast material or other 
technique. Reposition as needed. 
d. After one or more cryoapplications, each pulmonary vein should be minimally 
assessed for entrance block and, where assessable, exit block to demonstrate 
the cryoablation procedure endpoint of electrical isolation of the four major PVs. 
 
6.10.3 Gap or Touch Up Ablation 
At the Investigator’s discretion, a focal cryocatheter or a radio frequency catheter 
may be performed to complete electrical isolation of one or more PVs. 

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6.10.4 Other Ablations 
Subjects may have other cardiac rhythm abnormalities requiring treatment 
detected during the ablation procedure. This may include right/left atrial flutter 
or atrial fibrillation triggers. Treatment of such abnormalities is at the 
Investigator’s discretion. Such ablation will be fully documented in the relevant 
CRF. 
 
6.10.5 Procedure Documentation 
During the procedure the investigator will document the following: 
a. Catheter used for each ablation (i.e. Arctic Front Advance/Arctic Front Advance 
Pro, Freezor MAX or radiofrequency) 
b. Temperature for each application 
c. Duration of each application 
d. Vein location for each application (e.g. right superior pulmonary vein) 
e. Use of phrenic nerve pacing or other phrenic nerve monitoring technique for 
each application, specifically those applications surrounding the RS and RI 
pulmonary veins 
f. 
Demonstrated electrical block 
g. Adjunctive mapping or visualization devices, sedation type, procedure 
information, fluoroscopy time, contrast dye amount and concentration will be 
collected. 
 
6.11 Peri – procedural anticoagulation 
Heparin should be administered prior to or immediately following transseptal puncture 
during AF ablation procedures and adjusted to achieve and maintain an ACT of 300 to 
400 seconds. 
Performance of AF ablation in subjects systemically anticoagulated with warfarin does 
not alter the need for intravenous heparin to maintain a therapeutic ACT during the 
procedure. 
Administration of protamine following ablation to reverse heparin may be considered. 
 
6.12 Renal angiography 
Perform renal angiography if randomized to Treatment, following the pulmonary vein 
isolation procedure. 
Subjects should be prepped for a renal angiography according to standard 
procedures. For subjects with chronic kidney disease and/or risk factors for contrast-
induced nephropathy (CIN), the hospital’s standard-of-care protocol for CIN 
prevention should be utilized. 
An aortogram and selective renal angiography will be performed to confirm renal 
artery anatomy. Anatomic eligibility is defined as each kidney having at least one 
renal artery ≥3mm and ≤8mm in diameter and minimum treatable length per the 
Symplicity Spyral Catheter Instructions for Use, without significant stenosis or other 
abnormality. NOTE: All renal arteries with ≥3 mm and ≤ 8 mm diameter with minimum 
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treated, including dual renal arteries meeting these morphologic criteria. 
 
6.13 Renal artery denervation procedure 
If randomized to Treatment, the renal artery denervation procedure will be performed 
according to the supplied Symplicity Spyral Catheter Instructions for Use, Symplicity 
G3 Generator User Manual and associated training provided by Medtronic. 
Prior to this procedure, appropriate systemic anticoagulation and sedation should be 
attained. Blood pressure and heart rate should be closely monitored throughout the 
procedure. Investigators may choose to apply treatment to any renal artery that meets 
the anatomy eligibility criteria. The Symplicity Spyral Catheter will be delivered to the 
renal artery and the ablation treatments at multiple positions along the renal artery will 
be performed according to the procedures described in the Instructions for Use. 
Provide one copy of the renal angiogram cine procedure to Medtronic. 
Sedation type, procedure information, fluoroscopy time, contrast dye amount and 
concentration will be collected. 
 
6.14 LINQ insertion 
Before the subject is discharged from the hospital, preferable while still in the EP lab, 
insert the Reveal LINQ device. The insertion procedure will be performed in 
accordance with the hospital’s standard practice and in accordance with the Medtronic 
Reveal LINQ manual. Program Device Data Collection parameters and verify device 
sensing performance is acceptable. Subjects with an existing Reveal LINQ device may 
be enrolled if they have a minimum of 1 year remaining battery life. Ensure the device 
is programmed to the settings below. 
 
6.14.1 Programming Requirements 
Required programming: 
 
Parameter  
 
Required Setting  
 
Reason for Monitoring 
AF ablation 
Type of AT/AF detection 
AF only 
AF Detection 
Balanced sensitivity 
AT/AF Record of ECG of 
All episodes 
Ectopy Rejection 
Nominal 
 
Recommended programming: 
 
Parameter  
 
Required Setting  
 
Tachy detection 
OFF 
Brady detection 
OFF 
Pause detection 
OFF 
 
 
Perform a device interrogation and data transfer (e.g. save-to-disk, USB data transfer) 
with the final programmed settings. Final interrogation may be performed at hospital 
discharge. Ensure, at a minimum, Medtronic receives an interrogation with the final 
programmed settings. 

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6.15 Device deficiencies 
A device deficiency is defined as inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or performance. NOTE: Device deficiencies 
include malfunctions, use errors and inadequacy in the information supplied by the 
manufacturer including labeling. Device deficiencies that do not adversely affect the 
subject should be reported to Medtronic as a device deficiency and not as an adverse 
event. If the device deficiency is a reportable adverse event, the event should be 
reported as an adverse event not a device deficiency. Report device deficiencies for all 
Medtronic products used. 
 
6.16 Hospital discharge 
Prior to discharge, the following shall be collected: blood and urine samples, assess 
medications, assess adverse events, and review study requirements with the subject 
to help ensure compliance with follow-up procedures. 
The use of CareLink will then be reviewed and training will be given prior to discharge to 
the subject. 
Systemic anticoagulation with warfarin or a direct thrombin or Factor Xa inhibitor is 
recommended for at least two months following the AF ablation procedure. 
Decisions regarding the continuation of systemic anticoagulation agents more than two 
months following ablation should be based on the subject’s risk factors for stroke and 
not on the presence of AF. Discontinuation of systemic anticoagulation therapy post 
ablation is not recommended in subjects who are at high risk of stroke as estimated by 
currently recommended schemes (CHADS2 or CHA2DS2VASc). 
 
6.17 Scheduled follow-up visit windows 
After receiving notice of a subject pulmonary vein isolation procedure, Medtronic will 
provide the target dates and windows  to complete each visit either to the center, in-
home, virtually or by phone. Should a subject visit fall outside the pre-specified 
window, a study deviation must be reported, and the original follow-up schedule 
maintained for subsequent visits. 
Data analyses include data collected at late and early follow-up visits. Therefore, a late 
or early visit is preferred over a missed visit but must be accompanied by a deviation. 
Subjects will be followed until all subjects who underwent a pulmonary vein isolation 
procedure reach the 6-month visit. 
 
Table 6: Follow up visit windows 
 
Study Follow-up 
Visit 
Window 
(Calculated days post-procedure attempt) 
Window Start 
(# of days) 
Target 
(# of days) 
Window End 
(# of days) 
 
1 month 
30 
30 
46 
6 month 
180 
180 
194 
12 month 
335 
365 
395 
18 month 
515 
545 
575 
24 month 
700 
730 
760 
30 month 
880 
910 
940 

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36 month 
1065 
1095 
1125 
42 month 
1245 
1275 
1305 
Additional windows will be sent to centers if they extend beyond 42 months. 
 
6.18 Scheduled in-office follow-up visits 
 
6.18.1 One, Six and Every Six Month Visit Until Study Closure 
It is recommended that anti-hypertensive medications and dose not be changed 
through the 6 month visit unless medically necessary. It is recommended that 
subjects be off all antiarrhythmic medications within 90 days post cryoablation 
procedure. 
 
The following will be collected: 
• 
blood and urine samples (not required after the 6 month visit) 
• 
physical exam 
• 
vital signs (including 3 blood pressure measurements according to 
Appendix G: Blood Pressure Measurement Procedures) 
• 
review of medications 
• 
assess for adverse events 
• 
assess arrhythmias and symptoms, episodes of medical care suggestive 
of arrhythmia including hospitalizations, office or ER visits, or any AF-
related procedures such as cardioversions or additional ablations 
• 
interrogate the Reveal LINQ device, review prior CareLink reports and the 
current interrogation for possible AF related events 
 
Alternative methods of data collection may be necessary in the case of extenuating 
circumstances, such as a global pandemic, when subjects are prohibited from coming 
into the office for required assessments. For all assessments completed via alternative 
methods in these circumstances, sites are not required to enter a protocol deviation for 
missing, alternative, and/or late data collection. Data unable to be collected remotely or 
via an alternative method should be collected at the next possible in-person visit.  
In the event a subject is unable to return for an in-office follow-up visit, the alternative 
methods of obtaining follow-up assessments are listed below: 
• 
In-home visit by trained and delegated site personnel or designee, i.e. home 
health care personnel. The following assessments may not be completed with an 
in-home visit: 
o CareLink in-office interrogation. Guide a subject through a full 
interrogation (“Interrogate All”) at the end of the follow-up visit 
o Renal Artery Imaging: 
▪ 
Make every effort to schedule in-person renal artery imaging as 
soon as possible. 
When possible, subjects may be referred to a local imaging center for assessment. Local 
imaging technicians would require study training and delegation prior to assessment. In 
the event an in-home visit is not possible, the alternate methods for obtaining follow-up 
assessments are listed below: 

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• 
Virtual Visit, i.e. inclusive of video with study subject.  
▪ 
The following assessments may not be completed with a virtual visit: 
• 
Physical examination, limited review to be completed per physician 
discretion. 
• 
CareLink in-office interrogation. Guide a subject through a full 
interrogation (“Interrogate All”) at the end of the follow-up visit. 
• 
Laboratory Tests: 
o When possible, the subject should be referred to a local 
laboratory to collect samples. Laboratory Kits to be provided 
to subjects in advance of the visit by study site. 
• 
Renal Artery Imaging: 
o Make every effort to schedule in-person renal artery imaging 
as soon as possible. 
o When possible, the subjects could be referred to a local 
imaging center for assessment. Local imaging technicians 
would require study training and delegation prior to 
assessment. 
 
▪ 
Office blood pressure unit to be provided to the subjects in advance of the 
visit by study site. Measurements collected by the patient may be collected 
and designated in the case report form. 
 
• 
Phone visit, i.e. no video with the subject.   
▪ 
The following assessments may not be completed with a phone visit: 
• 
Physical examination limited review to be completed per physician 
discretion. 
• 
CareLink in-office interrogation. Guide a subject through a full 
interrogation (“Interrogate All”) at the end of the follow-up visit 
• 
Laboratory Tests: 
o When possible, the subject should be referred to a local 
laboratory to collect samples. Kits to be provided to subjects 
in advance of the visit by study site. 
• 
Renal Artery Imaging 
o Make every effort to schedule in-person renal artery imaging 
as soon as possible. 
o When possible, the subjects could be referred to a local 
imaging center for assessment. Local imaging technicians 
would require study training and delegation prior to 
assessment. 
 
▪ 
Office blood pressure unit to be provided to the subjects in advance of the 
visit. Measurements may be collected and designated as patient reported 
in the case report form.  
 
6.18.1.1 
Six month renal artery duplex ultrasound (Treatment group only) 
Renal artery duplex ultrasound (DUS) imaging will be performed only for subjects 
who underwent the renal artery denervation. DUS will be conducted as per the 
DUS protocol provided by the DUS Core Lab. The DUS will be assessed and if 
clinically significant stenosis (e.g. renal artery to aorta peak systolic velocity ratio 
>3.5, or peak systolic velocity >200 cm/s with evidence of post-stenotic turbulence) 

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is indicted, angiography will be performed. A Core Lab will be responsible for 
comparing 6 months angiogram with baseline angiography to evaluate any 
potential renal artery stenosis. 
 
6.18.2  Atrial Arrhythmia Management 
Subjects are required to have their Reveal LINQ interrogated monthly via CareLink 
transmissions. For the monthly CareLink transmissions that coincide with a 
scheduled follow-up visit (i.e. 1 or 6-month visits), a CareLink transmission is not 
required but a device interrogation and data transfer either by save-to-disk or USB 
data transfer should be performed at the follow-up visit. A CareLink transmission 
may be used as a substitute for an in-office device interrogation. If CareLink 
transmissions become unavailable, centers may be required to submit CareLink 
reports to Medtronic by uploading them to a secure server or by sending printed 
versions of the reports. Complete a final manual transmission upon study exit. 
 
6.19 Unscheduled follow-up visits 
An unscheduled visit is defined as any study-related visit which does not occur within 
the designated visit window of a scheduled follow up visit. Subjects who are seen 
outside of their regularly scheduled follow up visit for arrhythmia symptoms or 
suspected symptoms associated with renal denervation should have unscheduled 
procedures and data collection completed. 
The following will be collected: 
• 
blood and urine samples (optional) 
• 
physical exam 
• 
vital signs (including 3 blood pressure measurements according to 
Appendix G: Blood Pressure Measurement Procedures) 
• 
review of medications 
• 
assess for adverse events 
• 
assess arrhythmias and symptoms, episodes of medical care suggestive of 
arrhythmia including hospitalizations, office or ER visits, or any AF-related 
procedures such as cardioversions or additional ablations 
• 
interrogate the Reveal LINQ device, review prior CareLink reports and the 
current interrogation for possible AF related events 
 
6.20 System modification for Reveal LINQ 
A system modification will be reported in the event the Reveal LINQ requires invasive 
modification (e.g. reposition, explant, replacement). In the event of a system 
modification, the follow-up visit schedule for the subject will remain unchanged. If the 
device is explanted and a replacement will not be inserted, the subject should continue 
to stay in the study. 
 
6.21 Permissible repeat ablation 
All subjects may have one repeat ablation procedure within Days 0-90 after the first 
ablation if the following criteria are met: 
• 
Inclusion criteria: 
▪ 
Recurrent or a new onset atrial tachycardia 

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• 
Exclusion Criteria: 
▪ 
Active systemic infection 
▪ 
Condition where manipulation of the catheter within the heart would be 
unsafe (e.g. intracardiac mural thrombus) 
▪ 
Cryoglobulinemia 
▪ 
Myocardial infarction, unstable angina pectoris, syncope, PCI/PTCA, or 
coronary artery stenting within 3 months of the repeat ablation 
▪ 
Cerebrovascular accident or TIA within 1 month of the repeat 
ablation 
▪ 
Presence or a permanent pacemaker, biventricular pacemaker, atrial 
defibrillator or any type of implantable cardiac defibrillator (with or without 
biventricular pacing function) 
 
• 
Re-ablation assessment is performed as follows: 
o Physical examination, NYHA cardiac functional class, office blood 
pressure and review of medications and symptoms. 
o Study status post re-ablation: The subject’s procedures and follow up 
visit/assessments will continue based on the initial cryoablation 
procedure date. A re-ablation of a study subject under this section is not 
an AF Intervention. 
Other ablation techniques may be used as outlined in Section 6.10. 
 
6.22 Repeat renal artery denervations 
Repeat renal artery denervations are not allowed at any point during the study. 
 
6.23 Recurrence of atrial fibrillation 
Documentation of AF recurrence must be provided to the sponsor and additional source 
documents may be requested. Documentation of AF must include the following: 
• 
Reveal LINQ rhythm recording (EGM) 
 
6.24 Study exit 
Contact the subject to review medications, adverse events, episodes of medical care 
suggestive of arrhythmia including hospitalizations, office or ER visits, and any AF-
related procedures such as cardioversions or additional ablations. Have the subject 
manually transmit data from their Reveal LINQ device at study exit. 
Subjects may be exited from the study for any of the following situations: 
• 
Subject has completed follow-up 
• 
Subject with LINQ battery at end of life, having completed at least 6 months of 
study follow-up 
• 
Subject lost to follow-up 
• 
Subject death 
• 
Subject did not meet inclusion/exclusion criteria 

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• 
Subject not randomized 
• 
Subject did not provide consent or data protection authorization 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to 
another geographic location) 
• 
Investigator deems withdrawal necessary (e.g. medically justified, 
inclusion/exclusion criteria not met, failure of subject to maintain adequate 
study compliance) 
Once a subject is randomized, all efforts should be made to continue following the 
subject until study closure. 
 
6.24.1 Lost To Follow-Up 
In the case that the subject is determined to be lost to follow-up, details of a 
minimum of two attempts and the method of attempt (e.g., one letter and 
one phone record or two letters) to contact the subject must be recorded. In 
addition, follow the regulations set forth by the governing IRB/MEC. 
 
6.24.2 Subject-Initiated Withdrawal 
If subject chooses to withdraw, document date and reason for exit. 
 
6.24.3 Early Exit for Any Reason 
Prior to an early exit of a subject from the study, all efforts should be made 
to continue following the subject until all serious unresolved procedure or 
device related adverse events, as classified by the investigator, are 
resolved or they are unresolved with no further actions planned. Report any 
changes to the outcome before exiting the subject. 
 
7. INVESTIGATIONAL DEVICE STORAGE, HANDLING 
AND TRACEABILITY 
7.1 Symplicity Spyral Renal Denervation System 
In Europe, the study will utilize the commercially available Symplicity Spyral 
Renal Denervation System (Symplicity Spyral Catheter and Symplicity G3 
Generator) with no study driven changes to the product or labeling and are 
considered non-investigational. Product ordering is the responsibility of the 
center personnel. The products may be stored the same as other commercially 
released product.  
In the US, components of the Symplicity Spyral Renal Denervation System are 
considered investigational. Investigational product will be distributed to a center 
only when Medtronic has received all required documentation and has notified 
the center of center readiness. Distribution of the investigational product to 
study centers during the clinical study will be managed by Medtronic. 
Investigational product must be stored in a secure location at the center. It is 
the responsibility of the investigator to correctly handle, store, and track the 
investigational products. Investigational products will be used only in the study 
according to the CIP.  
For the US, sites, all Symplicity Spyral Renal Denervation System components 
used/attempted will be tracked and must be treated as investigational for this 

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study. Investigational product disposition logs will be provided to the center 
and used for tracking of all investigational products during the study. The 
investigational product distribution logs are to be used for the Symplicity 
Spyral Catheter, Symplicity G3 Generator, power cord and foot switch. The 
logs must be maintained at each US center and updated when investigational 
product is received, opened, used/attempted, disposed of or returned to 
Medtronic, see Table 7. 
 
7.2 Arctic Front Advance and Freezor MAX Cardiac Cryoablation 
Catheters 
In Europe, the study will utilize the market-released Arctic Front Advance/Arctic 
Front Advance Pro and Freezor MAX Cardiac Cryoablation Catheters with no 
study driven changes to the product or labeling and are considered non-
investigational. Product ordering is the responsibility of the center personnel. 
The products may be stored the same as other commercially released product.  
In the US, the Arctic Front Advance/Arctic Front Advance Pro and Freezor MAX 
Cardiac Cryoablation Catheters will be considered investigational when used in 
the persistent AF population with an AF episode duration of 6 months or longer, 
however, tracking of the catheter will start when the packaging is opened with 
the intention of using for the clinical study, regardless of the subjects AF 
diagnosis. Product ordering will be the responsibility of center personnel. The 
products may be stored the same as other commercially released product.  It is 
the responsibility of the investigator to correctly track the products. 
In the US, product disposition logs will be provided to the center and used for 
tracking of the Arctic Front Advance/Arctic Front Advance Pro and Freezor 
MAX Cardiac Cryoablation Catheters. The logs must be maintained at each 
center and updated when product is opened, used/attempted, disposed of or 
returned to Medtronic, see Table 7. 
 
7.3 Final product disposition 
In the US, all unused Symplicity Spyral Renal Denervation System components 
must be returned to Medtronic upon study closure at the center or earlier. The 
product disposition log must be updated with the final device disposition. If any 
Medtronic products are suspected in a device deficiency or Unanticipated 
Adverse Device Effect (UADE), make every effort to return them to Medtronic. 
Contact your local Medtronic field personnel or clinical study manager to receive 
a return mailer kit if used product needs to be sent back to Medtronic. 
 
Table 7: US Product tracking requirements 
 
Symplicity Renal Denervation 
System (Symplicity Spyral 
Catheter, Symplicity G3 Generator, 
power cord and foot switch) 
Cardiac Cryoablation 
Arctic Front 
Advance/Arctic Front 
Advance Pro and 
Freezor MAX 
Catheters 
Receipt 
x 
Opened 
x 
x 

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Used/Attempted 
x 
x 
Unopened 
x 
Returned or disposed 
x 
x 
 
8. STUDY DEVIATIONS 
A study deviation is defined as an event within a study that did not occur according to 
the CIP or CTA. 
Prior approval by Medtronic is expected in situations where the investigator 
anticipates, contemplates, or makes a conscious decision to deviate. Prior approval is 
not required when a deviation is necessary to protect the safety, rights or well-being of 
a subject in an emergency or in unforeseen situations beyond the investigator’s 
control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of 
data due to computer malfunction, inability to perform required procedures due to 
subject illness). A study deviation is not required if a subject misses a monthly LINQ 
manual interrogation. 
All study deviations must be reported on the CRF regardless of whether medically 
justifiable, pre-approved by Medtronic, an inadvertent occurrence, or taken to protect 
the subject in an emergency. 
In the event the deviation involves a failure to obtain a subject’s consent or is made to 
protect the life or physical well-being of a subject in an emergency, the deviation must 
be reported to the IRB/MEC as well as Medtronic within five working days. Reporting 
of all other study deviations should comply with IRB/MEC policies and must be 
reported to Medtronic as soon as possible upon the center becoming aware of the 
deviation. Refer to Investigator Reports, Table 11 for specific deviation reporting 
requirements and timeframes for reporting to Medtronic and the applicable regulatory 
body(s). 
Medtronic is responsible for analyzing deviations, assessing their significance, and 
identifying any additional corrective and/or preventive actions (e.g. amend the CIP, 
conduct additional training, or terminate the investigation). Repetitive or serious 
investigator compliance issues may result in initiation of a corrective action plan with 
the investigator and center, and in some cases, necessitate suspending enrollment 
until the problem is resolved or ultimately terminating the investigator's participation in 
the study. Medtronic will provide center-specific reports to investigators summarizing 
information on deviations that occurred at the investigational center on a periodic 
basis. 
 
9. ADVERSE EVENTS AND DEVICE DEFICIENCIES 
Timely, accurate, and complete reporting and analysis of safety information for 
clinical studies are crucial for the protection of subjects. Reporting and analysis of 
safety data are mandated by regulatory authorities. Medtronic has established 
procedures in conformity with regulatory requirements to ensure appropriate 
reporting of safety information. This study is conducted in accordance with these 
procedures and regulations. 
Since the safety reporting requirements and classification systems vary for each 
regulatory agency, requirements from all geographies are taken into account for the 

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collection and reporting of safety information. 
 
9.1 Adverse event and device deficiency definitions 
Where the definition indicates “device”, it refers to any device used in the study. 
This might be the devices under investigation or any market released 
component of the two systems. 
For the purpose of this study, all Adverse Events (AEs) and Device 
Deficiencies (DDs) will be classified according to ISO 14155:2011. 
 
Table 8: Adverse event definitions 
 
General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects whether or not 
related to the investigational medical device. (ISO 14155:2011 3.2)  
 
NOTE 1: This definition includes events related to the investigational medical 
device or the comparator.  
NOTE 2: This definition includes events related to the procedures involved.  
NOTE 3: For users or other persons, this definition is restricted to events related 
to investigational medical devices.  
Adverse Device Effect 
(ADE) 
 
Adverse event related to the use of a medical device (ISO 14155:2011 3.1) 
Note 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
medical device. 
Note 2: This definition includes any event resulting from an error 
use or from intentional misuse of the medical device. 
Hospitalization 
A hospital admission lasting more than 24 hours or which includes an overnight 
admission. 
 
 
Relatedness 
Procedure related 
An adverse event that occurs due to any portion of the cryoablation or renal 
denervation procedures related to the study. 
Cryoablation procedure related: event is related to any portion of the 
procedure that encompasses cryoablation. 
Renal angiogram: event is related to any portion of the procedure that 
encompasses the renal angiogram. 
Renal denervation procedure related: event is related to any portion of the 
procedure that encompasses renal denervation. 
Reveal LINQ insertion procedure related: event is related to any portion of the 
procedure that encompasses insertion of the Reveal LINQ device. 
Procedure related: if it cannot be determined which portion of the procedure an 
event is related to. 

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System related 
Cryoablation system related: event that results from the presence or 
performance (intended or otherwise) of the cryoablation system. 
Symplicity Renal Denervation system related: event that results from the 
presence or performance (intended or otherwise) of the Symplicity Renal 
Denervation system (Symplicity Spyral Catheter and Symplicity G3 Generator). 
Reveal LINQ system related: event that results from the presence or 
performance (intended or otherwise) of the Reveal LINQ device. 
Other system related: An adverse event that results from the presence or 
performance (intended or otherwise) of any device/tool used not related to the 
cryoablation, renal angiogram, renal denervation procedure or Reveal LINQ 
system. 
Cardiovascular related 
An adverse event relating to the heart and the blood vessels or circulation. 
Seriousness 
Unanticipated Adverse 
Device Effect (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, an (investigational) device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of 
incidence in the CIP or applicable (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. (21 CFR 812.3(s)) 
Serious Adverse Event 
(SAE) 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
• a life-threatening illness or injury, or 
• a permanent impairment of a body structure or a body function, or 
• in-patient or prolonged hospitalization, or 
• medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function, 
b) led to fetal distress, fetal death or a congenital abnormality or birth defect  
(ISO 14155:2011 3.37)  
 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not considered a 
serious adverse event. 
Serious Adverse 
Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event.  
(ISO 14155:2011 3.36)  
 

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Complication 
An adverse event that results in death, involves any termination of a significant 
device function, or requires intervention. 
Noninvasive: noninvasive, when applied to a diagnostic device or procedure, 
means one that does not by design or intention:  
(1) Penetrate or pierce the skin or mucous membranes of the body, the ocular 
cavity, or the urethra 
• 
Penetrate: to pass, extend, pierce, or diffuse into or through something; 
to enter by overcoming resistance; to gain entrance to 
• 
Pierce: to force a way into or through something or 
(2) enter the ear beyond the external auditory canal, the nose beyond the nares, 
the mouth beyond the pharynx, the anal canal beyond the rectum, or vagina 
beyond the cervical os. For purpose of this part, blood sampling that involves 
simple venipuncture is considered noninvasive, and the use of surplus samples 
of body fluids or tissues that are left over from samples taken for non-
investigational purposes is also considered noninvasive. (21 CFR 812.3(k)) 
Observation 
Any adverse event that is not a complication. 
Timing 
Pre-procedure 
An adverse event that occurs after the consent form has been signed but before 
access to the vasculature has occurred for the study required procedures. 
Cryoablation-procedure 
An adverse event that occurs during the cryoablation procedure from the time of 
the first sheath access to the vasculature until the last sheath for cardiac ablation 
is removed. 
Renal angiogram- 
procedure 
An adverse event that occurs during the renal angiogram procedure from the 
time of the first sheath access to the vasculature for the angiogram until the last 
sheath for angiogram is removed. 
Renal denervation- 
procedure 
An adverse event that occurs during the renal denervation procedure from the 
time of the first sheath access to the vasculature until the last sheath for renal 
denervation has been removed. 
Post-cryoablation/Post- 
renal denervation 
An adverse event that occurs after the removal of all cardiac ablation, renal 
denervation and EP catheters used in the procedures. 
 
Other 
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. (ISO 14155:2011 3.15)  
NOTE: Device deficiencies include malfunctions, use errors and inadequate 
labeling. 
Unavoidable Adverse 
Event 
An Adverse Event inherent to a surgical procedure that is expected to occur in all 
subjects for a projected duration according to the Investigator’s opinion, 
including, but not limited to those provided below. These are not reportable AEs 
unless they occur after or last longer than the timeframe. If any other events 
below are classified as serious they must be reported as an adverse event. 

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Event Description 
Timeframe 
(hours) from 
the Surgical 
Procedure 
Anesthesia related nausea / vomiting 
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Incisional pain 
72 
Mild to moderate bruising / ecchymosis 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Shoulder/arm/leg pain/discomfort/stiffness 
related to immobilization during procedure 
72 
 
 
9.2 Adverse event and device deficiency assessment 
 
9.2.1 Adverse Events 
To ensure that all AEs which are potentially relevant are collected, all system 
related, procedure related, cardiovascular related and serious AEs will be collected 
throughout the study duration, starting at the time of signing the consent form. 
Reporting of these events to Medtronic will occur on an AE form, including a 
description of the AE, date of AE onset, treatment, resolution, and assessment of 
both the seriousness and the relatedness to the device. 
Exceptions include: 
• 
Documented pre-existing conditions are not considered AEs unless the 
nature or severity of the condition has worsened 
• 
Recurrence of AF event unless an invasive action was taken 
• 
Unavoidable AEs unless the AE worsens or is present outside the 
stated timeframe listed in Table 8 
For AEs that require immediate reporting (see Table 9: Adverse Event Reporting), 
initial reporting may be done by phone, fax, email or on the CRF completing as 
much information as possible. The completed AE CRF must be submitted to 
Medtronic as soon as possible. Each AE must be recorded on a separate AE Form. 
Subject deaths are also required to be reported. Refer to Section 9.5 for Subject 
Death collection and reporting requirements. 
 
9.2.2 Device Deficiency 
Device deficiency information will be collected throughout the study and reported to 
Medtronic. Note that device deficiencies that result in an adverse device effect (ADE) 
to the subject should be captured as an Adverse Event only. 
 
Device deficiencies that did not lead to an AE but could have led to a Serious Adverse 
Device Effect (SADE) (i.e., if suitable action had not been taken, if intervention had 
not been made, or if the circumstances had been less fortunate) require immediate 
reporting (see Table 9). 
 
Initial reporting may be done on the CRF completing as much information as is 
available. The original completed Device Deficiency CRF must be sent to Medtronic 
as soon as possible. 

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9.2.3 Processing Updates and Resolution 
For any changes in status of a previously reported adverse event (i.e. change in 
actions taken, change in outcome, change in relatedness), an update to the original 
AE must be completed. All reported adverse events must be followed until the 
adverse event has been resolved, is unresolved with no further actions planned, the 
subject exits the study or until study closure, whichever occurs first. 
In the event that a subject is exited from the study prior to study closure, all efforts 
should be made to continue following the subject until all reported adverse events 
are resolved or they are unresolved with no further actions planned. 
At the time of study exit, all adverse events with an outcome of “Unresolved, further 
actions or treatment planned” must be reviewed and an update to the original AE 
must be reported. At a minimum, if there are no changes to the description, 
relatedness, test and procedures or actions taken, the outcome must be updated to 
reflect “Unresolved at study exit.” 
 
9.3 Market-released reporting requirements 
Product complaint reporting is applicable to devices that are market-released. This 
includes when an AE is related to a market-released device during the study. The 
reporting of product complaints is not part of the clinical study and should be done in 
addition to the Adverse Event reporting requirements. Refer to local regulations for 
reporting requirements. 
Product Complaint: Any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a medical device that has been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated 
with a medical device distributed by Medtronic, regardless whether they are related 
to intended use, misuse or abuse of the product. Reporting must be done 
immediately and via the regular channels for market-released products. 
Medtronic will notify the regulatory authorities as applicable for the following incidents 
immediately upon learning of them: 
• 
Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or instructions for 
use which led or might have led to the death or serious deterioration in the 
state of health of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the 
market by the manufacturer. 
• 
A serious deterioration in the state of heath includes: 
▪ 
Life-threatening illness or injury 
▪ 
Permanent impairment of a body function or permanent damage to 
a body structure 
▪ 
A condition necessitating medical or surgical intervention to 
prevent permanent impairment to a body structure or a body 
function 
9.4 Adverse event and reporting requirements 

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Regulatory reporting of AEs will be completed according to regulatory requirements. 
Refer to Table 9: Adverse Event Reporting for a list of required investigator reporting 
requirements and timeframes, and of required Medtronic reporting requirements and 
timeframes. 
It is the responsibility of the investigator to abide by any additional AE reporting 
requirements stipulated by the IRB/MEC. 
For AEs that require immediate reporting, initial reporting may be done by contacting 
the study sponsor per the sponsor contact information provided in this document. 
Table 9: Adverse Event and Device Deficiency Reporting Requirements 
 
Unanticipated Adverse Device Effects (UADEs) 
Investigator submit to: 
Medtronic 
US: Submit as soon as possible, but no later than within 10 working days after the investigator 
first learns of the event. (21 CFR 812.150(a)(1)) 
Europe: Immediately after the Investigator first learns of the event or of new information in 
relation with an already reported event. 
IRB/MEC 
US: Submit as soon as possible, but no later than within 10 working days after the investigator 
first learns of the event. (21 CFR 812.150(a)(1)) 
Europe: Submit to MEC per local reporting requirement. 
Regulatory 
Authorities 
Europe: Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
Investigator All geographies: Submit as soon as possible, but no later than within 10 working days 
after the sponsor first learns of the event. (21 CFR 812.150(b)(1)) 
Regulatory 
authorities 
US: Submit as soon as possible, but no later than within 10 working days after the 
sponsor first learns of the event. (21 CFR 812.150(b)(1)) 
Europe: Submit to regulatory authorities per local reporting requirement. 
 
IRB/MEC 
US: Submit as soon as possible, but no later than within 10 working days after the 
sponsor first learns of the event. (21 CFR 812.150(b)(1)) 
Europe: Submit to IRB/MEC per local reporting requirement 
All other Adverse Events 
Investigator submit to: 
Medtronic 
All geographies: Submit or report as required for local reporting requirements and protocol. 
IRB/MEC 
All geographies: Submit to IRB/MEC per local reporting requirements. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
Regulatory 
Authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
Device Deficiencies with SADE Potential 
Investigator submit to: 
Medtronic 
All geographies: Submit or report as required for local reporting requirements and protocol. 
IRB/MEC 
All geographies: Submit to IRB/MEC per local reporting requirements. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 

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Sponsor submit to: 
Regulatory 
Authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
All other Device Deficiencies  
Investigator submit to: 
Medtronic 
All geographies: Submit in a timely manner after the investigator first learns of the event. 
IRB/MEC 
All geographies: Submit to IRB/MEC per local reporting requirements. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
 
9.5 Subject death 
 
9.5.1 Death Data Collection 
All subject deaths must be reported by the investigator to Medtronic on an 
adverse event CRF (SAE leading to death) as soon as possible after the 
investigator first learns of the death. There should be one SAE with the outcome 
of death. 
A copy of the death certificate, if available and allowed by state/local law, should be 
sent to the Medtronic clinical study team. When a death occurs in a hospital, a copy 
of the death summary report and all relevant hospital records should be sent to the 
Medtronic clinical study team, if available. If an autopsy is conducted, the autopsy 
report should also be sent to the Medtronic clinical study team if available and 
allowed by state/local law.  When the death occurs at a remote center, it is the 
investigative center’s responsibility to attempt retrieval of information about the 
death. In summary, the following data will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death 
• 
Relatedness to system and/or procedure 
• 
Death summary/hospital records (if available and allowed by state/local 
law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 
 
9.5.2 Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s 
death. The Investigator shall classify each subject death per the following 
definitions: 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction 
of the heart. 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by 
abrupt loss of consciousness within one hour of the onset of acute symptoms; 
preexisting heart disease may have been known to be present, but the time and mode 
of death are unexpected. If time of onset cannot be determined, SCD will alternatively 
be defined as any unexpected cardiac death occurring out of the hospital or in the 

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emergency room as dead on arrival. 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden 
deaths, including all cardiac deaths of hospitalized subjects on inotropic support. 
Non-cardiac Death: A death not classified as a cardiac death. 
Unknown Cardiac Classification: Unknown death classification is intended for use 
only when there is insufficient or inadequate information to classify the death. 
The CEC will review deaths and provide a final adjudication of the cardiac 
classification. 
 
9.6 CEC review 
At regular intervals, an independent CEC will conduct a medical review of, at a minimum, 
all deaths and endpoint related events. 
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians 
that are not participating investigators for the study, including a CEC chairperson. At 
least two CEC members must adjudicate, at a minimum, all deaths and serious AEs 
related to any component of the systems under investigation. All other events may 
be adjudicated by at least one member of the CEC. 
The CEC members may be blinded to the subjects’ randomization assignment and/or 
other data or procedures that may influence their decision. 
Medtronic personnel may facilitate and participate in a CEC meeting but will be 
non-voting members. 
For adverse events, and deaths, reviewed by the CEC, Medtronic will provide the CEC 
with the Investigator’s description and classification. The CEC is responsible for 
reviewing the Investigator’s assessment and supportive documentation (when 
available), reviewing applicable definitions, and determining final classifications for all 
adjudication parameters. 
If the CEC disagrees with the investigator’s classification of the event, the rationale will 
be provided to the investigator. If the investigator agrees with the CEC’s adjudication, 
the CRF documenting the AE or AE update will be updated accordingly. 
If the investigator does not agree with the CEC’s adjudication classification, both 
determinations will be provided within the final report; however, the CEC’s adjudication 
will be used for data analysis. The disagreement will also be included in reporting to 
IRB/MEC and regulatory authorities, if required. 
 
9.7 Adverse event classification 
All reported adverse events and device deficiencies will be reviewed by a Medtronic 
representative. AEs will be classified according to the definitions provided. 
Upon receipt of adverse events at Medtronic, a Medtronic representative will review the 
adverse event/device deficiency for completeness and accuracy and when necessary 
will request clarification and/or additional information from the Investigator. Medtronic 
will utilize MedDRA, the Medical Dictionary for Regulatory Activities, to assign a 
MedDRA term for each adverse event based on the information provided by the 
investigator. 
Adverse Events and Deaths will be classified according to the standard definitions as 
outlined below: 

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Table 10: Adverse event and subject death classification responsibilities 
 
What is classified? Who classifies? Classification Parameters  
 
Timing of the Event Investigator 
Pre-procedure, cryo-procedure, renal denervation- 
procedure, assessment, post-procedure 
Relatedness 
Investigator 
Symplicity System, Arctic Front Cardiac Cryoablation System, 
renal artery denervation procedure, cryoablation procedure, 
Reveal LINQ system and procedure other procedures 
Sponsor 
Same as Investigator 
Severity 
Investigator 
SAE 
Sponsor 
SAE, UADE, Complication or Observation (for all system 
or procedure related adverse events) 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other 
supporting data 
Sponsor 
MedDRA term assigned based on the data provided by 
investigator 
Death 
Classification1 
Investigator 
Cardiac, Sudden Cardiac, Non-sudden Cardiac, Non- 
Cardiac, Unknown 
1Deaths will only be adjudicated to death classification. All other adjudications information will be taken from 
the corresponding AE with an outcome of death

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10. RISK ANALYSIS 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the 
life of a product, from the business analysis phase through development, market 
release, and post-market surveillance. 
There are potential risks and side effects associated with these procedures. The 
investigator shall describe risks in further detail when asked by the subject. The 
current Instructions for Use document should be referenced as the list below may only 
be updated periodically during the course of the study.   
Possible additional risks for participating in this study include the following (although 
others are possible): 
• 
Mild skin discomfort or irritation-redness sensitivity of the skin cause during 
or after the procedures (e.g. electrodes used with the ECG and Holter 
recorder might cause mild skin discomfort or irritation or some skin 
discomfort following electrode removal or tape removal). 
• 
Death-a complication or deterioration of health ultimately leading to a 
patient’s death. 
• 
Cardiopulmonary arrest-cessation of blood circulation and/or respiration 
due to dysfunction of the heart and/or lungs. 
• 
Coronary artery spasm-constriction of a blood vessel. 
• 
Heart rhythm disturbances/Arrhythmia-disruption of normal heart rate or 
rhythm, including bradycardia treated with atropine. 
• 
Embolism-formation and dislodgement of a blood clot (thrombus) or 
dislodgement of cholesterol/plaque within the blood vessel, which travels 
downstream into small vessels, blocking blood flow and causing temporary 
or permanent damage to organs distal to blockage. Emboli are known to 
cause myocardial infarction, stroke or kidney damage, peripheral ischemia 
and may ultimately lead to incapacitation or death. 
• 
Complications at catheter insertion site in the groin: 
o Pain-discomfort at the catheter insertion site that can range from mild 
to severe. 
o Hematoma/Bruising/Ecchymosis-a collection of blood in the tissue 
surrounding the catheter insertion site. 
o Pseudoaneurysm-a collection of blood in the tissue surrounding 
the catheter insertion site due to ongoing leaking of blood from a 
blood vessel. 
o AV fistula-an abnormal connection between an artery and a vein 
(i.e., cause by needle insertion through the femoral artery and 
vein). 
o Infection-localized redness, heat swelling and pain at the 
catheter insertion site. 
o Significant bleeding-blood loss from the catheter insertion site 
requiring surgery or transfusion of 2 or more units of packed red 
blood cells (PRBCs). 

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• 
Retroperitoneal bleeding-bleeding into the retroperitoneal space. 
• 
Vascular complications requiring surgery-damage to an artery (e.g. femoral) 
or vein requiring surgical repair. 
• 
Perforation of a blood vessel-unintended puncture through the wall of a 
blood vessel, such as a renal artery, requiring repair. 
• 
Dissection of a blood vessel/pulmonary vein dissection-a tear within the wall 
of a blood vessel, which allows blood to separate the wall layers. 
• 
Hypotension-low blood pressure. 
• 
Hypertension-high blood pressure. 
• 
Nausea-a sensation of unease and discomfort in the upper stomach with an 
urge to vomit. 
• 
Vomiting-forceful expulsion of stomach contents through the mouth and/or nose. 
• 
Pericardial effusion-fluid collecting in the sac that surrounds the heart. 
• 
Cardiac tamponade-pressure on the heart as a result of fluid collecting in the 
sac surrounding the heart. 
• 
Esophageal injury-damage to your swallowing tube 
o Atrio-esophageal fistula-abnormal passageway between the heart 
and esophagus. 
• 
Phrenic nerve injury-damage to the nerve that controls breathing. 
• 
Pulmonary vein stenosis-blockage in the blood vessels takes blood from the 
lungs to the heart. 
 
• 
Endocarditis-inflammation of the inner surface of the heart. 
• 
Infection (e.g. Pericarditis-inflammation of the sac that surrounds the heart, 
sepsis-infection throughout the body, urinary-infection of the urinary system). 
• 
Pneumothorax-collapsed lung. 
• 
Hemothorax-collection of blood around the lungs. 
• 
Pleural effusion-collection of extra fluid around the lungs. 
• 
Pneumonia-lung infection. 
• 
Pulmonary edema-excess fluid in the lungs. 
• 
Pulmonary hemorrhage-bleeding from the lungs. 
• 
Injury to lung (e.g. bronchial lesion, bronchial constriction, bronchial fistula) 
• 
Vagal nerve injury (e.g. Gastroparesis-delayed gastric emptying) 
• 
Visual changed (e.g. blurred vision) 
• 
Complications associated with contrast agents-adverse effects of contrast 
agents used during the procedure (e.g. allergic reaction or radio contrast 
nephropathy). 
• 
Complications associated with medications commonly utilized during the 

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procedure-known risks of medications commonly used during the procedure 
(e.g. narcotics, anxiolytics, other pain medications, anti-vasospasm agents). 
 
There are additional risks that could possibly be associated with the denervation 
procedure/therapy. These potential risks have not yet been quantified, but may include: 
• 
Pain-discomfort that can range from mild to severe that may occur peri- 
and/or post-procedure. 
• 
Damage to one or both kidneys and/or loss of kidney function-perforation of 
kidney or an occlusion or blood flow to the kidney (e.g. from stenosis or 
embolism) and/or reduction of glomerular filtration rate. If severe enough, 
this could require dialysis. 
• 
Renal artery aneurysm-localized weakening and ballooning of the renal 
artery from the interventional procedure or the delivery of RF energy. 
• 
Renal artery stenosis-narrowing of the renal artery due to the 
interventional procedure or the delivery of RF energy. 
• 
Arterial spasm or constriction-acute or chronic narrowing of the renal artery 
lumen diameter at denervation locations due to arterial muscle contraction, 
local tissue contraction or local edema. 
• 
Thermal injury to the vasculature or other structure from energy 
application- damage to an artery, vein or other structure due to the 
delivery of RF energy. 
• 
Hypertension-worsening high blood pressure. 
• 
Hypotension-low blood pressure. Blood pressure reduction may occur too 
far and/or too quickly and may cause end organ hypoperfusion. 
• 
Orthostatic hypotension-temporary reduction of blood pressure when going 
from lying to standing, coupled with symptoms (e.g. dizziness, light 
headedness). 
• 
Hematuria-blood in urine. 
• 
Hemorrhage-significant blood loss. 
• 
Proteinuria-elevated levels of protein in urine. 
• 
Electrolyte disturbances-an imbalance of the electrolytes (sodium, potassium). 
• 
Skin burn-damage to the skin caused by energy conduction via the ground 
pad used with the Symplicity Renal Denervation system (Symplicity Spyral 
Catheter and Symplicity G3 Generator). 
 
There are additional risks that could possibly be associated with the Reveal LINQ. 
 
• 
Rejection of the Reveal LINQ by your body, which may involve symptoms 
such as swelling, redness, or other irritation at, or near, the implant site. 
• 
Movement of the Reveal LINQ from its initial position or coming through the 
skin. 

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• 
Infection at the site of the implant. 
• 
Over-sensing or under-sensing (incorrectly identifying too many or too few) 
times where your heart may be showing a rhythm problem. 
 
There are additional risks that could possibly be associated with the tests and procedures 
performed for this study.  These potential risks are described below. 
There are risks related to the blood tests required for the trial [e.g., excessive bleeding, 
fainting or light headedness, hematoma (bruising), infection, or the requirement of multiple 
punctures to locate a vein to draw the sample]. 
The cryoablation and renal artery denervation involve exposure to a small amount of radiation 
as part of the fluoroscopy procedure. Possible risks associated with this are: 
• 
Increased risk of cancer and damage to the fetus of pregnant women. 
• 
Increased radiation exposure time if an additional ablation 
procedure is necessary. 
• 
Radiation injury resulting in skin inflammation and redness. 
There are risks of undergoing CT scan, Renal Angiography and chest x-rays. These include: 
medication patches that can cause a skin burn and allergic reaction to the contrast material (if 
used) and exposure to radiation. 
There is a possibility of risks to an unborn child. These risks are unknown. Women who are 
pregnant or expect to become pregnant during the course of the study are excluded from 
participating. 
This study may involve unknown or unforeseen side effects or complications other than those 
mentioned above. If the above complications occur, they may lead to repeat or prolonged 
hospitalization, repeat procedures, emergency surgery, other emergency procedures or in rare 
cases, death. 
 
10.1 Risk minimization 
The potential risks associated with these therapies were identified and have been 
successfully mitigated. Any potential risks associated with this study are further 
minimized by to following ways: 
• 
Selecting qualified investigators and training study personnel on the CIP. 
• 
Investigators and center staff will receive appropriate training prior to any 
study procedures. 
• 
The sponsor has also attempted to minimize risk to subjects 
implementing a Data Monitoring Committee to review safety issues as 
part of the study. Investigators will be actively involved in the procedures 
and follow-up of the subjects undergoing these therapies. After 
treatment, subjects in the Symplicity AF clinical study will be followed at 
regular intervals to monitor the condition of their treatment and to assess 
any adverse events. 
• 
Risks will be minimized by careful assessment of each subject prior 
to, during, and after procedures. Prior to treatment, it is 
recommended subjects undergo a complete cardiac evaluation. 
• 
Medtronic has further minimized the possibility of risks by: implementing 

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quality control measures into production processes, providing guidelines 
for subject selection and evaluation, and providing adequate instructions 
and labeling. 
 
10.2 Potential benefits 
Although no assurances or guarantees can be made, there is reasonable 
expectation that adding the renal denervation procedure to pulmonary vein 
isolation to treat paroxysmal and persistent AF may be beneficial to the subject. 
Treatment with this system may reduce the sympathetic nerve activity to and 
from the kidneys, and cause a reduction in blood pressure. Evidence in the 
literature suggests that reduction of efferent sympathetic nerve activity to the 
kidney can a) cause relief of renal vasoconstriction, resulting in improved 
kidney function; b) reduce sodium retention, which can improve the clinical 
condition of patients with medical problems related to excess salt and water; 
and c) reduce the release of renin-a renal produced hormone which is often 
elevated in patients with either severe hypertension or heart failure. 
Interference of afferent sympathetic nerve activity from the kidneys can reduce 
central sympathetic activity, also causing reduction of blood pressure.18,19,20   
The information gained from this study could result in the improved management of 
paroxysmal and persistent AF.  Additionally, information collected from this study 
may assist in the design of new product(s)/therapy(ies) and/or indications for use. 
 
11. PLANNED STUDY CLOSURE, EARLY TERMINATION OF 
STUDY OR STUDY SUSPENSION 
11.1 Planned study closure 
Study Closure is a process initiated by distribution of an initial study closure 
letter. Study closure is defined as closure of a clinical study that occurs when 
Medtronic and/or regulatory requirements have been satisfied per the CIP 
and/or by a decision by Medtronic or regulatory authority, whichever occurs 
first. The study closure process is complete upon distribution of the Final 
Report or after final payments, whichever occurs last. Ongoing IRB/MEC 
oversight is required until the overall study closure process is complete. 
 
11.2 Early termination or suspension 
Early Termination of the Study is the closure of the clinical study that occurs 
prior to meeting defined endpoints. This is possible for the whole study or a 
single center.  Study Suspension is a temporary postponement of study 
activities related to enrollment and distribution of the product. This is possible 
for the whole study or a single center. 
 
11.2.1 Study-Wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study include 
but are not limited to: 
• 
Adverse events associated with the system or product under investigation 
which might endanger the safety or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 

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• 
Decision by Medtronic or regulatory body 
• 
Recommendation of early termination by the DMC 
• 
Technical issues during the manufacturing process or with the systems 
 
11.2.2 Investigator/Center Termination or Suspension 
Possible reasons for clinical investigator or center termination or suspension include 
but are not limited to: 
• 
Failure to obtain initial IRB/MEC approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation (e.g. failure to 
adhere to inclusion/exclusion criteria, failure to follow subjects per 
scheduled follow-ups) 
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement 
(e.g. failure to submit data in a timely manner, failure to follow-up on data 
queries and monitoring findings in a timely manner, etc.) 
• 
IRB/MEC suspension of the center 
• 
Fraud or fraudulent misconduct is discovered 
• 
Investigator request (e.g. no longer able to support the study) 
 
11.3 Procedures for termination or suspension 
 
11.3.1 Medtronic-Initiated 
• 
Medtronic will promptly inform the clinical investigators of the termination or 
suspension and the reasons and inform the regulatory authority(ies) where 
required 
• 
In the case of study termination or suspension for reasons other than a 
temporary IRB/MEC approval lapse, the investigator will promptly inform the 
IRB/MEC 
• 
In the case of study termination, the investigator must inform the subjects and 
may inform the personal physician of the subjects to ensure appropriate care 
and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the 
suspension is lifted by Medtronic 
• 
In the case of a study suspension, enrolled subjects should continue to be 
followed out of consideration of their safety, rights and welfare 
11.3.2 Investigator-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written 
explanation of the termination or suspension 
• 
The investigator will promptly inform the institution 
• 
The investigator will promptly inform the IRB/MEC 
• 
The investigator will promptly inform the subjects and/or the personal 
physician of the subjects to ensure appropriate care and follow-up is 
provided 
• 
In the case of a study suspension, subjects enrolled should continue to be 
followed out of consideration of their safety, rights and welfare 

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11.3.3 IRB/MEC-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written 
explanation of the termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with 
IRB/MEC policy or its determination that an overriding safety concern or 
ethical issue is involved 
• 
The investigator will inform his/her institution 
• 
The investigator will promptly inform the subjects, or legally-authorized 
designees or guardians and/or the personal physician of the subjects, with the 
rationale for the study termination or suspension 
 
 
12. STATISTICAL METHODS AND DATA ANALYSIS 
Statisticians employed by Medtronic or their designees will perform the statistical 
analyses described in this section. 
 
12.1 Sample size determination 
The overall study sample size is 70 randomized subjects that undergo a 
pulmonary vein isolation procedure which is the required sample size for the 
primary effectiveness objective. 
 
Subjects that are enrolled in the study may not go on to be randomized due to a 
variety of reasons, including elective withdrawal prior to randomization, blood 
pressure measurements that do not meet study criteria, or renal anatomy that is 
found to be ineligible upon angiography. Based on the rate of randomization 
among enrolled subjects in trials with similar screening criteria, up to 245 
subjects may need to be enrolled and undergo screening in order to ensure that 
70 subjects are randomized. Subjects who are randomized and meet either of 
the following two conditions do not count toward the 70 subjects randomized: 
• 
exit the study without undergoing a pulmonary vein isolation procedure  
• 
subjects who are randomized to the treatment group and are found not 
to meet inclusion/exclusion criteria during the renal denervation 
procedure. 
 
All objectives will be analyzed once the last randomized subject has completed 
the 6-month follow-up visit. In addition, the primary effectiveness objective will be 
analyzed during interim analyses. These interim analyses may be performed after 
32 and 50 subjects have been randomized and completed their 6-month follow-up 
visit. If data are deemed to sufficiently characterize this study objective by the 
sponsor at one of these analyses, enrollment may be stopped. Analysis results 
will be included in the study report(s). 
 
12.2 General considerations 
A modified intention-to-treat analysis will be performed and will serve as the 
primary analysis for all objectives in this study. The modified intention-to-treat 

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cohort will include all randomized subjects that undergo a pulmonary vein 
isolation procedure (i.e. have a cryocatheter inserted). Patients that are 
randomized, and meet either of the following two conditions will not be included 
in this cohort: 
• 
exit the study without undergoing a pulmonary vein isolation procedure  
• 
subjects who are randomized to the treatment group and are found not 
to meet inclusion/exclusion criteria during the renal denervation 
procedure. 
The Statistical Analysis Plan (SAP) will include a comprehensive description of the 
statistical methods and reports to be included in the final study report. Any change to 
the data analysis methods described in the CIP will require an amendment only if it 
changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be 
described in the clinical study report. 
 
12.3 Primary safety objective 
The primary safety objective characterizes the rate of safety composite events (Table 
11) within each of the two study arms and also characterizes the difference in the rates 
between study arms. 
Safety Composite Events are events that are serious, occur within a specified time 
interval (see Table 11) starting when the subject undergoes the study pulmonary vein 
isolation procedure and meet the definition in Section 12.3.1. The CEC adjudication will 
be used to classify subjects for this endpoint. 
 
Table 11: Safety composite events and onset intervals 
 
 
Serious Adverse Event  
 
Onset Interval 
Death 
1 month 
End-stage renal disease 
1 month 
Significant embolic event 
1 month 
Renal artery perforation requiring intervention 
1 month 
Renal artery dissection requiring intervention 
1 month 
Vascular complications 
1 month 
Hospitalization for hypertensive crisis 
1 month 
New renal artery stenosis 
6 months 
Cardiac damage 
1 month 
Pulmonary vein stenosis 
6 months 
Atrio-esophageal fistula 
6 months 
Arrhythmia 
1 month 
Persistent phrenic nerve palsy 
6 months 
 
12.3.1 Event Definitions 
 
12.3.1.1 
End-stage renal disease defined as two or more eGFR measurements 
<15mL/min/1.73m2 at least 21 days apart and requiring dialysis for one or 
more of the following: volume management refractory to diuretics, 
hyperkalemia unmanageable by diet and diuretics, acidosis bicarbonate 
<18 unmanageable with HCO3 supplements, or symptoms of uremia, 

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nausea, vomiting. 
 
12.3.1.2 
Significant embolic event resulting in end-organ damage (e.g. 
kidney/bowel infarct, lower extremity ulceration or gangrene, stroke or 
doubling of serum creatinine confirmed by at least two measurements at 
least 21 days apart).  Stroke is defined as a) rapid onset of a focal or 
global neurological deficit with at least one of the following: change in level 
of consciousness, hemiplegia, hemiparesis, numbness or sensory loss 
affecting one side of the body, dysphasia or aphasia, hemianopia, 
amaurosis fugax, or other neurological signs or symptoms consistent with 
stroke, b) duration of a focal or global 
neurological deficit ≥24 h; OR <24h, if therapeutic intervention(s) were 
performed (e.g. thrombolytic therapy or intracranial angioplasty);OR the 
neurological deficit results in death, c) no other readily identifiable non-
stroke cause for the clinical presentation (e.g., brain tumor, trauma, 
infection, hypoglycemia, peripheral lesion, pharmacological influence), d) 
confirmation of the diagnosis by at least one of the following: neurology or 
neurosurgical specialist, neuroimaging procedure (MR or CT scan or 
cerebral angiography), lumbar puncture (i.e., spinal fluid analysis 
diagnostic or intracranial hemorrhage). 
 
12.3.1.3 
Vascular complications (e.g. clinically significant groin hematoma, 
arteriovenous fistula, pseudoaneurysm, excessive bleeding) requiring 
surgical repair, interventional procedure, thrombin injection, or blood 
transfusion (requiring more than 2 units of packed red blood cells within 
any 24-hour period during the first 7 days post procedure). 
 
12.3.1.4 
Hypertensive crisis/emergency is defined as severely elevated blood 
pressure, usually higher than 180/110 mm Hg, together with progressive 
or impending target organ damage, requiring in-patient hospitalization and 
typically admission to the Intensive Care Unit (e.g., with parenteral IV 
antihypertensive medications), not related to confirmed non-adherence 
with medication. 
 
12.3.1.5 
New renal artery stenosis defined as >70%, confirmed by angiography. 
 
12.3.1.6 
Cardiac damage due to any cause except pulmonary vein stenosis or 
atrio-esophageal fistula and including MI [the presence of any one of the 
following criteria: 1-detection of ECG changes indicative of new ischemia 
(new ST-T changes or new LBBB) which persist for more than one hour; 
2-development of new pathological Q waves on an ECG; 3-imaging 
evidence of new loss of viable myocardium or new regional wall motion 
abnormality]. 
 
12.3.1.7 
Pulmonary vein stenosis defined as >75% reduction in diameter of the 
baseline pulmonary vein area on CT or MRI. 
 
12.3.1.8 
Atrio-esophageal fistula defined as a connection between the atrium and 
the lumen of the esophagus. Evidence supporting this diagnosis includes 
documentation of esophageal erosion combined with evidence of a 
fistulous connection to the atrium such as air emboli, an embolic event, or 

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direct observation at the time of surgical repair. A CT scan or MRI scan 
are the most common methods of documentation of an atrial-esophageal 
fistula. 
 
12.3.1.9 
Arrhythmia excludes atrial fibrillation and including creation of new 
arrhythmias and/or worsening of existing arrhythmias. 
 
12.3.1.10 Persistent phrenic nerve palsy defined as absent phrenic nerve function 
as assessed by a sniff test or chest x-ray including inspiration/expiration 
films. Persistent is defined as lasting 6 months or longer, or lasting until 
the last known follow-up if the follow-up is less than 6 months. 
 
12.3.2 Hypothesis 
There is no hypothesis for this objective. 
 
12.3.3 Performance Requirements 
Given the exploratory nature of a feasibility study, there is no performance 
requirement for this objective. The rate of safety composite endpoints will be 
characterized by estimating the rate within each arm and estimating the difference in 
rate between arms. These event rate estimates will provide critical guidance for 
designing a possible subsequent pivotal study. 
 
12.3.4 Rationale for Performance Criteria 
This primary safety endpoint is a composite that combines the safety endpoints from 
current Medtronic hypertension and AF studies and is intended to include serious 
adverse events associated with either the renal artery denervation or cryoablation 
procedure. 
 
The safety composite event rate in the STOP-AF trial was 3.1% with a one-sided 
upper 95% confidence bound of 6.3%. The safety composite event rate in subjects 
undergoing renal artery denervation using the first generation Symplicity system 
(Symplicity Catheter and G2 Generator) in the Symplicity HTN-3 trial 1.4% (one-sided 
upper 95% confidence bound of 2.9%).16 If undergoing both pulmonary vein isolation 
and renal artery denervation procedures at once is as safe as undergoing each 
procedure separately, then the proportion of patients that would be expected to 
experience a composite safety event is approximately 4.5% (based on observed 
rates) to 9.2% (based on upper 95% confidence bounds). 
 
A DMC will periodically review accumulating safety data for the study, including the 
rate of safety composite events within each study arm and the difference in the rate 
between study arms. 
 
12.3.5 Analysis Methods 
For computing the proportion of subjects in each arm that experience safety 
composite events, Kaplan-Meier methods will be used. Since all components of the 
safety composite event include events through 30 days and four components include 
events through 6 months post-procedure, there is the potential for some subjects 
having incompletely assessed safety composite outcomes should they discontinue 
study participation prior to 6 months of post-procedure follow-up. 
Kaplan-Meier estimation uses the time that each subject is free from a safety 
composite event, defined from the date of procedure to the earliest date that an 

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event meeting one of the safety composite event component definitions occurs. For 
events that are typically confirmed at a clinic visit (e.g. renal artery stenosis 
confirmed with angiography), it can be difficult to determine the onset date exactly. 
Therefore, events whose onset date is equal to a follow-up visit date within the 6-
month visit window will be treated as having occurred at 180 days  
post-procedure. All subjects that are event-free through a completed 6-month 
follow-up visit within the 6-month visit window will be censored at 180 days. 
Otherwise, a subject’s event-free time will be from the date of procedure to the latest 
follow-up visit. Treating safety composite event dates and censoring dates that occur at 
6-month visits within the 6-month visit window as occurring at 
exactly 180 days post-procedure prevents bias in the Kaplan-Meier 6-month estimate. 
The log-log transformation will be used to calculate a two-sided 95% confidence 
interval for the rate of safety composite events within each study arm. 
 
The difference in event rate between arms will be estimated by the difference in 
Kaplan-Meier estimates at 6 months. A 95% confidence interval for the difference will 
be constructed by applying the delta method to the log-log transform of the difference 
in the Kaplan-Meier estimates. 
 
12.3.6 Determination of Patients/Data for Analysis 
All randomized subjects in the modified intention-to-treat cohort will be included in the 
analysis. 
 
12.3.7 Sample Size 
There are no sample size requirements for this objective. 
 
12.4 Primary effectiveness objective 
The primary effectiveness objective compares the rate of chronic treatment success 
between study arms. Chronic treatment success is freedom from chronic treatment 
failure. Therefore, comparing the rate of chronic treatment success is equivalent to 
comparing the risk of chronic treatment failure. 
Chronic treatment failure is defined as the occurrence of either 
1) a documented episode of AF recorded on Reveal LINQ 
2) an intervention for AF 
occurring after a blanked follow-up period of 90 days from the study treatment 
procedure. AF episodes and repeat ablations that occur within 90 days of the study 
treatment procedure will not constitute chronic treatment failure. 
Intervention for AF is defined as an invasive procedure intended for the definitive 
treatment of AF, including any ablation of the pulmonary veins or atrial triggers (other 
than protocol-specified ablation), interruption of AV nodal function, procedures to alter 
left atrial conduction or function such as the Maze procedure, or the implantation of an 
atrial pacemaker or atrial defibrillator; whether approved by relevant regulatory 
authorities or not for such indications; excluding electrical or pharmacologic 
cardioversion of arrhythmias and excluding procedures solely directed at the treatment 
of atrial flutter or atrial tachycardias. 
 
12.4.1 Hypothesis 

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The primary effectiveness objective will be assessed with the following hypothesis: 
 
H0: hControl (t) = hTreatment(t) for all t ≤ T years HA: 
hControl(t) ≠ hTreatment(t) for some t ≤ T years 
where h(t) is the hazard function (risk) of chronic treatment failure and T is the total 
study time. 
 
12.4.2 Performance Requirements 
If the hazard ratio for chronic treatment failure between the Treatment and Control 
only arms is less than one and the two-sided log-rank p-value is less 
than 0.05, it will be concluded that the pulmonary vein isolation and renal artery 
denervation procedure results in a higher rate of chronic treatment success. 
Given the feasibility nature of this study and relatively small sample size, even if the 
pulmonary vein isolation and renal artery denervation procedure results in a clinically 
meaningful improvement in the rate of chronic treatment success (e.g. an absolute 
10-15% higher chronic treatment success rate through 6 months), the log-rank test 
may not reach statistical significance (p<0.05). 
This study is intended to provide data to support the design of a pivotal trial. The 
estimates of the chronic treatment success rate for each study arm can provide 
that data whether the log-rank test is statistically significant or not. 
 
12.4.3 Rationale for Performance Criteria 
In the STOP-AF trial, subjects randomized to receive cryoablation had a 6- month 
chronic treatment success rate of 75.0%. In the patient population of this feasibility 
study, including patients with either paroxysmal AF or persistent AF and with 
uncontrolled hypertension, the rate of chronic treatment success is expected to be 
lower.  Also, use of intensive AF monitoring with the Reveal LINQ device has the 
potential to identify patients with recurrent AF that might not be detected with 
periodic trans-telephonic and Holter monitoring, as was performed in the STOP-AF 
trial, leading to a lower rate of chronic treatment success. In the treatment arm, the 
addition of the renal artery denervation procedure to the pulmonary vein isolation 
procedure for treatment of AF has the potential to increase the rate of chronic 
treatment success. While it’s uncertain to what degree these factors may affect the 
rate of chronic treatment success, this feasibility study is designed to be able to 
identify a difference in chronic treatment success rate if the rate through 6 months is 
at least 75% in the Treatment arm and 50% in the Control arm through 6 months. 
 
12.4.4 Analysis Methods 
A log-rank test will be used to perform this hypothesis test. The log-rank test uses 
the time that each subject is free from chronic treatment failure, defined from the 
date of procedure to the date of chronic treatment failure, if it occurs, or latest of 
the following: a) the last follow-up visit date, or b) the last date on which AF was 
assessed, if chronic treatment failure does not occur during the subject’s study 
follow-up. Subjects will be included through all available study follow-up. 
In addition to the log-rank test, Kaplan-Meier curves will be used to estimate the rate 
of chronic treatment success. Cox proportional hazards regression will be used to 
estimate the hazard ratio and its 95% confidence interval between study arms. 
 
12.4.5 Determination of Patients/Data for Analysis 

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All randomized subjects in the modified intention-to-treat cohort will be included in the 
analysis. 
 
12.4.6 Sample Size 
There will be at least 78% power to test this objective provided at least 70 subjects 
undergo randomization. 
 
The sample size calculation is based on the following assumptions: 
• 
1:1 randomization 
• 
Constant randomization rate over 16 months 
• 
Last enrolled subject followed through 6 months post-procedure 
• 
50% chronic treatment success in the PVI only arm versus 75% in the 
Treatment arm (equivalent to a hazard ratio of 0.415) through 6 months 
post-procedure 
• 
Constant hazard ratio over all follow-up 
• 
Cumulative alpha of 0.05.  Any planned interim analyses will be constructed 
so that the overall Type I error of the study is no greater than 0.05. 
• 
Constant attrition (dropout) of 5% per 6 months 
 
The sample size calculation was performed in PASS 2008 using the log-rank 
(Lakatos) procedure. Accounting for a study attrition rate of up to 5% per 6 months 
ensures that the study will maintain the planned power of 78% in case attrition is 
higher than expected (approximately 1% per 6 months). 
 
12.5 Secondary objective 
 
12.5.1 
Single Procedure Chronic Treatment Success 
The secondary effectiveness objective characterizes the rate of chronic treatment 
success in Treatment and Control arms in the subgroup of subjects that do not 
undergo an additional pulmonary vein ablation procedure during the 90-day blanked 
follow-up period. 
 
12.5.2 Hypothesis 
There is no hypothesis for this objective. 
 
12.5.3 Performance Requirements 
There is no performance requirement for this objective. 
 
12.5.4 Analysis Methods 
Kaplan-Meier curves will be used to estimate the rate of chronic treatment success 
for each study arm. Cox proportional hazards regression will be used to estimate 
the hazard ratio and its 95% confidence interval between study arms. 
 
12.5.5 Determination of Patients/Data for Analysis 
All randomized subjects in the modified intention-to-treat cohort that do not undergo 
a permissible repeat cryoablation will be included in the analysis. 

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12.6 Ancillary objectives 
The ancillary objective endpoints below will be compared between study arms in order 
to further characterize the differences in outcomes between patients randomized to 
pulmonary vein isolation only to those randomized to pulmonary vein isolation and 
renal artery denervation. Mean, standard deviation, median, and range will be used as 
descriptive statistics for continuous variables and counts and proportions for 
categorical variables. An ANCOVA model will be used to compare the mean change in 
continuous variables from baseline to 6 months 
between the study arms. The ANCOVA model will include change measurement (e.g. 
heart rate, blood pressure) from baseline to the 6-month follow-up visit as the 
response and study arm indicator and baseline measurement as covariates. For the 
symptoms ancillary objective, a logistic regression model will model presence of each 
symptom at 6 months as the response and study arm indicator and baseline presence 
of symptom as covariates. For the freedom from chronic treatment failure off anti-
arrhythmic drugs objective, a log-rank test over all available follow-up will be 
performed. For the AF burden objective, the Mann- Whitney U test will be used to 
compare the AF burden between study arms. This non-parametric test is used rather 
than the Student’s t-test since AF burden tends to have a skew distribution with many 
values near zero. The difference in AF burden will be characterized by the Hodges-
Lehmann estimator, the median of all pairwise differences in AF burden between study 
arms. 
• 
Office systolic and diastolic blood pressure at 6 months compared to 
baseline 
• 
Heart rate at 6 months compared to baseline 
• 
Procedural measures (total procedure time, cryoablation procedure time, 
renal artery denervation procedure time, ablation time, fluoroscopy time, dye 
usage) 
• 
Symptoms at 6 months compared to baseline 
• 
Freedom from chronic treatment failure and off Class I and III anti- 
arrhythmic drugs following the blanking period 
• 
AF burden (percent of time in AF) over all follow-up after the blanking 
period 
 
12.7 Subgroup analysis 
To characterize the consistency of the estimated treatment effect across AF diagnoses 
(paroxysmal or persistent AF), a score test will be performed on the interaction term in a 
Cox proportional hazards regression with study arm indicator, AF diagnosis, and 
interaction between study arm and AF diagnosis as factors. 
Similar sub-group analyses, assessing the interaction term in a regression model, will 
be performed for the secondary and ancillary objectives. In addition to the subgroup 
analysis by AF diagnosis, a subgroup analysis using the same methodology will be 
performed to characterize the consistency of the estimated treatment effect across 
patients who received touch-up ablations to complete the electrical isolation of one or 
more pulmonary veins with an RF catheter versus those whose pulmonary veins were 
treated only with cryoablation. 
 
12.8 Interim analysis 

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Interim analyses will be performed.  
Two interim analysis of the primary effectiveness objective may be performed after 
32 and 50 subjects have been randomized and completed their 6-month follow-up 
visits, respectively. Both the sponsor and the DMC will assess the results of the 
interim analyses of the primary effectiveness objective and based on this 
assessment, the sponsor may decide to stop enrollment.  
 
Time Point of Interim Analyses of the 
Primary Effectiveness Objective 
Cumulative 
Alpha 
Boundary* Pass/Fail Primary 
Effectiveness Objective 
After 32 subjects were randomized 
and completed their 6-month visit 
0.01 
0.01 
If a two-sided p-value ≤ 0.01, 
in favor of the treatment 
group, then the study passed 
the primary effectiveness 
objective  
After 50 subjects were randomized 
and completed their 6-month visit 
0.015 
0.008 
If a two-sided p-value ≤ 
0.008, in favor of the 
treatment group, then the 
study passed the primary 
effectiveness objective 
Final Analysis:  
After 70 subjects were randomized 
and completed their 6-month visit 
0.05 
0.04 
If a two-sided p-value ≤ 0.04, 
in favor of the treatment 
group, then the study passed 
the primary effectiveness 
objective 
*Boundaries were calculated using EAST 6.4.1 
 
In addition to reviewing the effectiveness data from the interim analyses, the DMC 
will be responsible for assessing the accumulating data on safety of the procedures 
during the study. The primary responsibility of the DMC is to safeguard the interests 
of study participants. The DMC also monitors the overall conduct of the clinical study. 
Further information regarding the DMC is found in Appendix C: Data Monitoring 
Committee. 
 
12.9 Pooling of study centers for analysis 
 
Data from study centers will be pooled for analysis. Descriptive statistics of endpoints 
may be performed for groups of centers based on regional criteria. However, no 
statistical analysis will be performed to test center variation for the primary effectiveness 
objective. The study is expected to be conducted at up to 12 centers located in the 
United States and up to three centers in Europe with a total of 70 randomized subjects in 
the modified-intent-to-treat cohort. Given the small sample size, a formal test of 
interaction between randomization group and center will likely not be powered to detect 
a statistically significant difference for the primary endpoint if one exists. Likewise, the 
small sample size may not allow the use of a model adjusting for center as a random 
effect. 
 
12.10 Missing data 

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Sensitivity analyses will be conducted to assess the robustness of the primary 
analyses to missing data should the issue of missing data arise in the study. 
Sensitivity analyses include, but are not limited to, tipping point analyses. 
 
13. DATA AND QUALITY MANAGEMENT 
Data will be collected using an electronic data management system for clinical 
studies. CRF data will be stored in a secure, password-protected database which will 
be backed up nightly. Data will be reviewed using programmed and manual data 
checks. Data queries will be made available to centers for resolution. Study 
management reports may be generated to monitor data quality and study progress.  
At the end of the study, the data will be frozen and will be retained indefinitely by 
Medtronic. 
The data reported on the CRFs shall be derived from source documents and be 
consistent with these source documents, and any discrepancies shall be explained in 
writing. 
The sponsor or regulatory bodies may audit the study center to evaluate the conduct 
of the study. The clinical investigator(s)/institution(s) shall allow study related 
monitoring, audits, IRB/MEC review and regulatory inspection by providing direct 
access to source data/documents. 
 
14. WARRANTY/INSURANCE INFORMATION 
Warranty information is provided in the product packaging. Additional copies are 
available upon request. 
 
Insurance (US) 
Medtronic Inc. maintains appropriate clinical study liability insurance coverage as 
required under applicable laws and regulations and will comply with applicable law and 
custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the IRB. The study is conducted in multiple 
countries, therefore, reimbursement and indemnification will be addressed on a country 
specific basis in the study documents and center Clinical Trial Agreements. 
 
Insurance (Europe) 
Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic, Inc., 
which as the parent company of such entity maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply 
with applicable local law and custom concerning specific insurance coverage. If required, 
a Clinical Trial insurance statement/certificate will be provided to the Ethics Committee. 
 
15. MONITORING 
It is the responsibility of Medtronic to ensure proper monitoring of this clinical 
investigation per regulations. Trained Medtronic personnel or delegates appointed by 
Medtronic may perform study monitoring at the study center in order to ensure that 
the study is conducted in accordance with the CIP, the Clinical Trial Agreement, and 
applicable regulatory and local requirements. Medtronic, or delegates, must 
therefore be allowed access to the subjects’ case histories (clinic and hospital 
records, and other source data/documentation) upon request as per the Consent 

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Form, Privacy Authorization, Research Authorization (where applicable) and Clinical 
Trial Agreement. 
 
15.1 Monitoring visits 
Frequency of monitoring visits will be based upon subject enrollment, duration 
of the study, study compliance, number of adverse events, findings from 
previous monitoring visits and any suspected inconsistency in data that 
requires investigation.  Regulatory documents may be reviewed at each study 
center. 
 
Monitoring for the study will be done in accordance to the Medtronic internal 
study monitoring plan. 
Monitoring visits may be conducted periodically to assess center study 
progress, the investigator’s adherence to the CIP, regulatory compliance 
including but not limited to IRB/MEC approval and review of the study, 
maintenance of records and reports, and review of source documents against 
subject CRFs (source verification). 
 
When source data verification is performed, the monitor must have direct 
access to original source documentation or certified copies of the original 
source must be provided. 
If electronic source documentation is used at the site, the site must provide to 
the monitor: 
1) Direct access to the electronic medical record (e.g. the monitor is given a 
guest password to directly access the system) or 
2) Direct access to the electronic medical record by reviewing 
alongside appropriate study staff (e.g. a research coordinator) or 
3) Certified copies of the electronic medical record. The site shall provide 
adequate documentation to the monitor describing their process for 
providing complete and accurate certified copies for required source 
documentation. 
The monitor shall verify that he/she has complete access to all original source 
documentation required for the study (e.g. the monitor does not have a lower 
level of access to the original source documentation than the research 
coordinator or Principal Investigator necessary for the study). 
Monitors review center regulatory and study compliance by identifying findings 
of non-compliance and communicating those findings along with 
recommendations for preventative/corrective actions to center personnel. 
Monitors may work with study personnel to determine appropriate corrective 
action recommendations and to identify trends within the study or at a 
particular center. 
 
16. REQUIRED RECORDS AND REPORTS 
16.1 Investigator records 
The investigator is responsible for the preparation and retention of the records 
cited below. All of the below records, with the exception of case history records 

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and CRFs, should be kept in the Investigator Center File (i.e., the study binder 
provided to the investigator) or Subject Study Binder. CRFs may be maintained 
and signed electronically within the electronic data capture system during the 
study. The following records are subject to inspection and must be retained for 
a period of two years (or longer as local law or hospital administration requires) 
after the investigation is terminated. 
• 
All correspondence between the IRB/MEC, sponsor, monitor, regulatory 
bodies and/or the investigator that pertains to the investigation, including 
required reports. 
• 
Subject’s case history records, including: 
o Signed and dated informed consent form signed by subject 
o Observations of adverse events and device deficiencies 
o Medical history 
o Procedure and follow-up data 
o Documentation of the dates and rationale for any deviation from 
the protocol 
o Electronically signed and dated CRFs 
o Device disposition records 
• 
All approved versions of the CIP 
• 
Report of Prior Investigations 
• 
Executed Clinical Trial Agreement 
• 
Curriculum vitae for each investigator 
• 
Delegated task list 
• 
IRB/MEC approval documentation. Written information that the investigator 
or other study staff, when a member of the IRB/MEC, did not participate in 
the approval process. IRB/MEC approval of the current version of the CIP 
and Informed Consent Form and acknowledgment of the Report of Prior 
Investigations. 
• 
Study training records for center staff 
• 
Financial disclosure 
• 
Any other records that regulatory bodies require to be maintained 
• 
Final Study Report including the statistical analysis 
• 
Any other regulatory authority or required records 
 
16.2 Investigator reports 
The investigator is responsible for the preparation (review and signature) and 
submission to the sponsor of all CRFs, AEs and device deficiencies, deaths, and any 
deviations from the CIP. If any action is taken by an IRB/MEC with respect to this 
clinical study, copies of all pertinent documentation must be forwarded to Medtronic in 
a timely manner. Reports are subject to inspection and to the retention requirements 
as described above for investigator records. 
Safety data investigator reporting requirements are listed in Section 9 of the Adverse 
Event section. The investigator shall prepare and submit in a complete, accurate and 
timely manner the reports listed in this section. 

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Table 12: Investigator reports 
Report 
Submit to 
Description/Constraints  
 
Withdrawal of 
IRB/MEC 
approval 
(either 
suspension or 
Sponsor and 
Relevant 
Authorities 
US: The investigator must report a withdrawal of approval by 
the reviewing IRB/MEC of the investigator’s part of the 
investigation within 5 working days. (21 CFR 812.150(a)(2)) 
Europe: Report if required by local law. 
Progress report 
Sponsor and 
IRB/MEC 
US: The investigator must submit this report to the sponsor and 
IRB/MEC at regular intervals, but in no event less than yearly. (21 
CFR 812.150 (3)). 
Europe: Provide if required by local law or IRB/MEC. 
Study deviations Sponsor and 
IRB/MEC 
US: Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon as 
possible, but no later than 5 working days after the emergency 
occurred. Except in such emergency, prior approval is required for 
changes in the plan or deviations. If the deviation may affect the 
scientific soundness of the plan or the rights, safety and welfare of 
the subjects, the deviation must be approved by Medtronic, the 
IRB/MEC, and the FDA/applicable regulatory authorities. If the 
deviation does not affect these issues then only Medtronic must 
approve it.  (21 CFR 812.150(a)(4)) 
Europe: Any deviation from the CIP shall be recorded together 
with an explanation for the deviation. Deviations shall be reported 
to the sponsor who is responsible for analyzing them and 
assessing their significance.  
Note: When relevant, ethics committees, competent authorities or 
the appropriate regulatory bodies should be informed.  
Failure to obtain 
informed consent 
prior to 
investigational 
device use 
Sponsor and 
IRB/MEC 
US: If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use within 5 working 
days after device use.  (21 CFR 812.150(a)(5)) 
Europe: Informed consent shall be obtained in writing and 
documented before a subject is enrolled into the clinical 
investigation. 
Final report 
Sponsor and 
IRB/MECs 
All geographies: This report must be submitted within 3 months of 
study completion or termination of the investigation or the 
investigator’s part of the investigation. (21 CFR 812.150(a)(6)) 
Other 
IRB/MEC and 
FDA 
US: An investigator shall, upon request by a reviewing IRB/MEC, 
FDA or any other regulatory agency, provide accurate, complete, 
and current information about any aspect of the investigation. (21 
CFR 812.150(a)(7)) 
 
 
 
16.3 Sponsor records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Investigational device traceability record containing model and serial 
numbers of devices, shipping date and name and address of person that 
received shipped device, location (if different than person shipped to), 
transfer and receipt by Medtronic dates 
• 
Signed and dated Confidential Disclosure Agreements or documentation of a 
Master Agreement 

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• 
Executed Clinical Trial Agreements, financial disclosure, curriculum vitae of 
each investigator and delegated task list 
• 
All signed and dated CRFs submitted by investigator, including reports of 
AEs, and device deficiencies, and CRF corrections 
• 
Samples of informed consents, and other information provided to the 
subjects, including translations (if applicable) 
• 
Copies of all IRB/MEC approval letters and relevant IRB/MEC 
correspondence and IRB/MEC voting list/roster/letter of assurance 
• 
Names of the institutions in which the clinical investigation will be 
conducted 
• 
Names/contact addresses of monitors 
• 
Statistical analyses and underlying supporting data 
• 
Final Report of the clinical investigation 
• 
The CIP, CRFs, Report of Prior Investigations and study related reports, and 
revisions 
• 
Study training records for center personnel and Medtronic personnel 
involved in the study 
• 
Any other records that local regulatory agencies require to be maintained 
 
16.4 Sponsor reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports 
listed in the tables below. In addition to the reports listed below, Medtronic shall, upon 
request of reviewing IRB/MEC and regulatory bodies, provide accurate, complete and 
current information about any aspect of the investigation. Safety data Medtronic reporting 
requirements are listed in Table 9 of the Adverse Event section. 
 
Table 13: Sponsor reports 
Report 
Submit to 
Description/Constraints 
Withdrawal of IRB/MEC 
approval 
Investigators, 
IRB/MEC, and FDA 
US: Notification within five working days. 
(21 CFR 812.150(b)(2)) 
Premature termination or 
suspension of the clinical 
investigation 
Investigators, IRB/MEC, 
Relevant authorities and 
Head of the Institution 
Europe: Provide prompt notification of 
termination or suspension and reason(s). 
(ISO 14155:2011) 
Withdrawal of FDA 
approval 
Investigators and 
IRB/MEC 
US: Notification within five working days. 
(21 CFR 812.150(b)(3)) 
Withdrawal of CA 
approval 
Investigators, Head of 
Institution, IRB/MEC, and 
relevant authorities 
Europe: Investigators, IRBs/MECs will 
be notified only if required by local laws 
or by the IRB/MEC. 
Investigator List 
FDA 
US: Submit at 6-month intervals, a current list of the 
names and addresses of all investigators participating 
in the investigation.  (21 CFR 812.150(b)(4)) 
Progress Reports 
IRB/MEC and FDA 
US: Progress reports will be submitted at least 
annually. (21 CFR 812.150(b)(4)(5), 812.36(f) 
Europe: This will be submitted to the IRB/MEC only 
if required by the IRB/MEC. 

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Report 
Submit to 
Description/Constraints 
Recall and device 
disposition 
Investigators, IRB/MEC 
and FDA 
US: Notification within 30 working days and will 
include the reasons for any request that an 
investigator return, repair, or otherwise dispose of 
any devices. (21 CFR 812.150(b)(6)) 
Failure to obtain 
informed consent 
FDA 
US: Investigator’s report will be submitted to FDA 
within five working days of notification.  (21 CFR 
812.150(b)(8)) 
Final report 
Investigators, IRB/MEC 
and FDA 
US: Medtronic will notify FDA within 30 working days 
of the completion or termination of the investigation. A 
final report will be submitted to the FDA, investigators, 
and IRB/MECs within six months after completion or 
termination of this study. 
(21 CFR 812.150(b)(7)) 
Study deviation 
Investigators 
US: Ensure that all deviations from the Clinical 
Investigation Plan are reviewed with the appropriate 
clinical investigator(s), are reported on the case 
report forms and the final report of the clinical 
investigation. 
Europe: Ensure that all deviations from the Clinical 
Investigation Plan are reviewed with the appropriate 
clinical Investigator(s), are reported on the case 
report forms and the final report of the clinical 
investigation. 
 
Center specific study deviations will be submitted to 
Investigators periodically. 
Other 
IRB/MEC, FDA 
US: Accurate, complete, and current information 
about any aspect of the clinical investigation. (21 
CFR 812.150(b)(10)) 
 
Medtronic records and reports will be maintained in a password-protected document 
management system, and paper documents (where applicable) will be stored in stored 
in secured file cabinets at Medtronic during the course of this study. 
 
After closure of the study Medtronic will archive records and reports indefinitely. 

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APPENDIX A: DRAFT DATA COLLECTION ELEMENTS 
Final CRFs will be provided to centers via the electronic data management system after 
the center has fulfilled all requirements for database access. 

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APPENDIX B: PRELIMINARY PUBLICATION PLAN 
Publications from the Symplicity AF will be handled according to the Clinical 
Investigation Plan, Medtronic procedures and as indicated in the Clinical Trial 
Agreement. 
 
Publication Committee 
Medtronic may form the Symplicity AF Publication Committee from study investigators. 
Medtronic personnel may serve as members of the committee. This committee will 
manage study publications with the goal of publishing findings from the data. The 
Publication Committee will develop the final Publication Plan as a separate document. 
The Publication Committee’s role is to: 1) manage elements addressed in the publication 
plan as outlined in this appendix, 2) develop the final Publication Plan under separate 
cover, 3) execute the Publication Plan, 4) oversee the publication of primary, secondary 
and ancillary study results, 5) review and prioritize publication proposals, 6) provide input 
on publication content, and 7) determine authorship.  In addition, the committee will 
apply and reinforce the authorship guidelines set forth in the Publication Plan. 
Membership in the Publication Committee does not guarantee authorship. The 
committee will meet at regular intervals. 
 
Management of Primary, Secondary and Ancillary Publications 
The Publication Committee reviews, prioritizes and manages all publications including 
primary, secondary and ancillary publications. Primary and secondary publications are 
those that address analyses of any or all primary objectives or secondary objectives, 
respectively, as specified in the Clinical Investigation Plan. 
An ancillary publication is any publication that does not address the study objectives 
identified in the Clinical Investigation Plan. They include publications proposed and 
developed by other Medtronic departments or entities, clinicians participating in this 
clinical study and clinicians not participating in this clinical study. The committee will 
work with Medtronic to ensure that requests do not present conflicts with other 
proposals, are not duplicative and to determine which ancillary publication proposals, if 
any, will be supported. 
The committee may decide that no publications, including abstracts, will be published 
prior to the end of the study or with individual center data. Requests for publications on 
study objectives utilizing subset data will be evaluated for scientific validity and the ability 
of Medtronic to provide resources. 
 
Criteria for Determining Authorship 
Publications will adhere to authorship criteria defined by the International Committee of 
Medical Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to 
biomedical journals, www.icmje.org). Individual authorship criteria defined by the target 
journal or conference will be followed when it differs from ICMJE criteria. 
Authors, including Medtronic personnel, must at a minimum meet all of the conditions 
below: 
• 
Substantial contribution to conception and design, or acquisition of data, or 
analysis and interpretation of data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 

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Decisions regarding authorship and contributor-ship will be made by the committee. The 
selected authors will be responsible for drafting the publication. All selected authors 
must fulfill the authorship conditions stated above to be listed as authors, and all 
contributors who fulfill the conditions must be listed as authors. 
All investigators not listed as co-authors will be acknowledged as the “Medtronic 
Symplicity AF Clinical Study Investigators” and will be individually listed according to the 
guidelines of the applicable scientific journal when possible. Any other contributors will 
be acknowledged by name with their specific contribution indicated. 
 
Transparency 
Transparency of study results will be maintained by the following means: 
• 
a Final Report, describing the results of all objectives and analysis, will be 
distributed to all investigators and IRB/MECs 
• 
registering and posting the study results on ClinicalTrials.gov based on the 
posting rules stipulated 
• 
submitting for publication the primary study results after the study ends 
• 
disclosing financial interests of the co-authors of publications according to 
the policies set forth by the corresponding journals and conferences 
• 
making an individual centers study data accessible to the corresponding 
investigator after the completion of the study, if requested 

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APPENDIX C: DATA MONITORING COMMITTEE 
Ongoing oversight for this study will be provided by an independent DMC. The DMC will 
have one statistician, and at least two physicians specializing in either cardiac ablation, 
renal denervation, managing atrial fibrillation and/or managing blood pressure. None of 
the DMC members are participating in the Symplicity AF study. A chairperson from 
among those members has been identified. A DMC charter has been approved by the 
members. 
The DMC will be responsible for assessing the primary effectiveness data as well as 
accumulating data on safety of the procedures during the study. The DMC will be 
responsible for safeguarding the interests of study participants and for monitoring the 
overall conduct of the clinical study. To enhance the integrity of the study, the DMC may 
also formulate recommendations related to the selection, recruitment, and retention of 
subjects, their management, improvement of adherence to protocol-specified regimens 
and procedures for data management and quality control.  The DMC may also provide 
recommendations for early termination of the study for the safety of study participants. 
Analyses of the study objectives for review by the DMC will be performed by a Medtronic 
statistician other than the lead statistician for the study. The lead study statistician will be 
blinded to all DMC analyses of study objectives. The unblinded statisticians will keep 
results strictly confidential per the DMC charter during the study. 

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APPENDIX D: INFORMED CONSENT TEMPLATES 
The informed consent template will be distributed under separate cover.

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APPENDIX E: PARTICIPATING INVESTIGATORS, 
INSTITUTIONS AND IRB/MECS 
A complete list of participating investigators, institutions and IRB/MECs where study activities 
will be conducted will be distributed under a separate cover when available. 

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APPENDIX F: LABELING 
Labeling for all system components can be found with each package insert. The 
Symplicity Spyral Catheter and the Symplicity G3 Generator will be labeled 
investigational in the United States. Labeling of CE marked devices follows local 
language requirements. 
The Arctic Front Advance, Arctic Front Advance Pro, Freezor MAX and the Reveal LINQ 
System will not be labeled as investigational in the United States. Commercially available 
product will be used for the study in all geographies. 
 
 
 
 

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APPENDIX G: BLOOD PRESSURE MEASUREMENT 
PROCEDURES 
 
1. Office blood pressure 
 
All office blood pressure (OBP) measurements must be taken with the automatic BP 
Monitor and printer provided by Medtronic. 
 
All attempts should be made to measure the subjects BP within the same approximate 
timeframe of the day (i.e., morning, afternoon, or evening). 
 
A. Arm selection 
1. With the subject prepped for “Preparation” section below, measure BP in 
each arm. Print and label each measure. 
2. Use the arm with the higher BP for screening measurements and all 
subsequent measurements. If there is a reason to use a particular arm, 
document the reason and use that arm for all measurements. 
 
B. Preparation at all visits 
1. Confirm the subject has taken all indicated anti-hypertensive medications 
prior to the measurements. 
2. Ensure the Date and Time has been set on the automatic BP Monitor and 
confirm the printer, if available, is operational. 
3. Confirm the subject did not drink coffee or alcohol, smoke or exercise within 
30 minutes prior to the measurement. 
4. Request the subject to use the bathroom prior to measurements (a full 
bladder can affect the reading). 
5. The subject should be seated comfortably with the back supported and the 
upper arm bared without constrictive clothing. The legs should not be 
crossed. 
6. Ensure the BP cuff is appropriately sized (see below) and the upper arm is 
supported at the level of the heart (e.g. resting on a table at the level of 
his/her heart). 
 
Table 14: Cuff size chart 
 
Cuff size* 
Fits arm circumference 
of (inches) 
Small 
7-9 
Medium 
9-13 
Large 
13-17 
Extra Large** 
17-20 
*Opt for the larger of the two sizes if a subject is on the border of two cuff sizes. 
**Subjects requiring greater than an extra-large cuff size at time of the screening must 
be excluded from the study. 
 
7. Perform a “test” BP measure. Print (if available) and label the measure. 
8. Have the subject sit comfortable and quietly for 5 minutes, with back 
supported and feet flat on the ground (i.e. not on an exam table, legs not 
crossed). 

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C. Method for taking BP at all visits 
1. With subject prepped for “Preparation” section above and using arm selected 
at Screening, take at least three seated BP measurements in order to obtain 
the BP average. 
a. Wait at least 1 minute between each measurement. Ensure the BP 
monitor time clock is used for tracking the time intervals. 
b. Print (if available) and label after each measurement. 
2. Three consecutive, consistent seated BP measurements must be obtained 
for the BP average. 
a. If the lowest and highest systolic BP vales of 3 consecutive 
measurements are more than 15 mmHg apart, take one additional 
reading and average the last 3 consecutive measurements 
(measurements 2-4). If the measurements are still more than 15 
mmHg apart, take one additional reading and average the last 3 
consecutive measurements (measurements (3-5). If more than 15 
mmHg apart, continue to the sixth and final measurement. 
b. If less than a 15 mmHg difference cannot be obtained after at least 6 
documented measurements, a 20 mmHg difference will be acceptable. 
c. At Screening: if the lowest and highest systolic BP values for the 
readings are more than 20 mmHg apart after 6 measurements, the 
subject must be excluded from the study. 
3. Record the last 3 consecutive, consistent readings for the case report form 
(do not pick the “best” 3). 
 
 

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APPENDIX H: BIBLIOGRAPHY AND PRECLINICAL AND 
CLINICAL INVESTIGATIONS 
A complete bibliography, summary of relevant literature, summary and results of 
preclinical testing and summary and results of previous clinical investigational is 
provided in the Report of Prior Investigations. 

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APPENDIX I: MODIFICATIONS TO THE CLINICAL 
INVESTIGATION PLAN 
Table 15 summarizes modifications made from previous version of CIP to the current 
version of CIP. 
 
Table 15: CIP change history 
 
Version 
Applicable 
Sections 
Change 
Rationale 
Number of 
subject enrolled 
1.0 
Not applicable 
Not applicable 
First release 
0 
2.0 
1.1 
Added a possible proposed 
indication should Medtronic 
choose to study this further. 
Per recommendation 
from FDA 
0 
2.0 
1.2, 12.1, 12.4.6 Sample size updated to include 
attrition 
Per recommendation 
from FDA 
0 
2.0 
5.2 
Updated inclusion criteria: 
Office-based systolic blood 
pressure of ≥150 mm Hg based 
on average of three blood 
pressure readings despite 
treatment with 2 or more 
antihypertensive medications of 
different classes (one of these 
must be a diuretic) at maximum 
tolerated dose, highest tolerated 
dose, or highest appropriate 
dose for the patient per Principal 
Investigator’s best clinical 
judgment.  The subject should 
be on a stable antihypertensive 
drug regimen with no changes 
for a minimum of 2 weeks prior 
to enrollment and expected to 
be maintained on that regimen 
for at least 6 months. 
Per recommendation 
from FDA 
0 
2.0 
5.1, 12.3 
Change to primary safety 
objective to compare rate of 
safety composite between 
treatment and control subjects. 
Per recommendation 
from FDA 
0 
2.0 
12.5 
Changed Secondary Objective 
to Single Procedure Chronic 
Treatment Success 
Adding the new 
secondary was per 
recommendation from 
FDA. The previous 
secondary became the 
new primary safety 
objective. 
0 

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Version 
Applicable 
Sections 
Change 
Rationale 
Number of 
subject enrolled 
2.0 
5.1, 12.6 
Added two new ancillary 
objectives: 
• 
Freedom from atrial 
tachyarrhythmias 
(including AF, atrial flutter 
and atrial tachycardia) of 
30 seconds or longer 
• 
Chronic treatment Success 
off Class I and III anti- 
arrhythmic drugs following 
the blanking period 
Per recommendation 
from FDA 
0 
2.0 
5.2.1 
Defined drug refractory as: failed 
(drug is  ineffective  or  patient     
is  intolerant)  at  least  one     
Class I or III anti-arrhythmic drug 
Per recommendation 
from FDA 
0 
2.0 
5.2.2, 6.4 (Table 
4), 6.7 
Added requirement for TEE and 
exclusion of subjects when 
indicated 
Per recommendation 
from FDA 
0 
2.0 
5.2.2 
Added exclusion: NYHA Class 
IV heart failure with in the past 6 
months 
Per recommendation 
from FDA 
0 
2.0 
5.2.2 
Updated exclusion in include 
hyperaldosteronism: 
Pheochromocytoma, Cushing’s 
Disease (adrenal insufficiency), 
coarctation of the aorta, 
untreated hyperthyroidism, 
primary hyperparathyroidism or 
hyperaldosteronism 
Per recommendation 
from FDA 
0 
2.0 
5.3, 6.11 
Clarified randomization strategy 
and process 
Per recommendation 
from FDA 
0 
2.0 
5.4, 12.7, 
APPENDIX C 
Clarified interim analysis plans 
and DMC responsibility 
Per recommendation 
from FDA 
0 
2.0 
6.4, 6.16.1, 6.16.2, 
6.20 
TTM: 
Weekly TTMs added between 
90 days and 12 Months post 
ablation procedure 
Updated symptomatic TTM to 
start after blanking period 
concurrent with weekly TTMs 
Per recommendation 
from FDA 
0 
2.0 
6.8 
Added additional detail 
concerning the cryoablation 
procedure, including Phrenic 
nerve monitoring, anti- 
coagulation, procedure steps, 
clarification of other ablations, 
clarification of procedure 
documentation. 
Per recommendation 
from FDA 
0 
2.0 
6.9, 6.14 
Details on peri and post- 
procedural anticoagulation 
including target ACT. 
Per recommendation 
from FDA 
0 
 
 
 

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Version 
Applicable 
Sections 
Change 
Rationale 
Number of 
subject enrolled 
2.0 
6.15 
Updated Follow-up visit windows 
to correct 18 and 24 months 
windows and add 30 month 
Correction 
0 
2.0 
10 
Risk Analysis: added additional 
risks possible for the 
cryoablation procedure 
Per recommendation 
from FDA 
0 
2.0 
12.3 
Added definitions to some of the 
safety composite events 
Per recommendation 
from FDA 
0 
2.0 
12.2, 12.6 Various Typographical errors, omissions 
and clarifications 
Clarity 
0 
3.0 
1.1 
Modified a possible proposed 
indication should Medtronic 
choose to study this further 
Per recommendation 
from FDA 
0 
3.0 
5.2.1 
Inclusion criteria updated to 
include definition of full dose 
anti-hypertensive medication 
Per recommendation 
from FDA 
0 
3.0 
5.2.2 
Removed adrenal insufficiency 
from the exclusion criteria 
Per recommendation 
from FDA 
0 
3.0 
6.6 
Added definition of full dose of 
anti-hypertensive medication 
and stated it must be 
documented 
Per recommendation 
from FDA 
0 
3.0 
6.8.2 
Added PVI endpoint definition: 
After one or more 
cryoapplications, each 
pulmonary vein should be 
minimally assessed for entrance 
block and, where assessable, 
exit block to demonstrate the 
endpoint of electrical isolation. 
Per recommendation 
from FDA 
0 
3.0 
6.8.5 
Clarified that demonstrated 
electrical block is collected on 
the case report form 
Per recommendation 
from FDA 
0 
3.0 
6.14 
Added post procedure 
anticoagulation instructions 
Per recommendation 
from FDA 
0 
3.0 
12.3 
Removed definitions in Table 10 
and added a new section that 
provides further details 
regarding the safety events 
Per recommendation 
from FDA 
0 
3.0 
12.6 
Clarified the ancillary objective 
Freedom from atrial 
tachyarrhythmias (including AF, 
atrial flutter and atrial 
tachycardia) of 30 seconds or 
longer and off Class I and III 
anti-arrhythmic drugs following 
the blanking period 
Per recommendation 
from FDA 
0 
4.0 
6.6 
Clarified definition of anti- 
hypertensive medication dosing 
Correction 
0 
5.0 
12.3.1.2, 12.3.1.8, 
12.3.1.10 
Clarified safety event definitions 
Per recommendation 
from FDA 
0 
 
 
 
 

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Version 
Applicable 
Sections 
Change 
Rationale 
Number of 
subject enrolled 
6.0 
1.1, 5.1.2, 5.2.1 
Inclusion of patients with 
persistent AF 
Characterize results 
along the AF disease 
continuum 
0 
6.0 
1.2, 5.3, 6.9, 12.1, 
12.4.6 
Randomization will occur in a 
1:1 ratio which decreased the 
sample size to 70 subjects and 
upper enrollment limit to 245 
subjects. This adjustment 
decreased the total study 
duration. 
Primary reason for 2:1 
randomization was to 
collect additional safety 
data but strong safety 
results from the 
Symplicity HTN-3 study 
lowered the safety risk 
level 
0 
6.0 
3.0, 6.13, 6.15, 
6.17, 6.18, 6.22, 9 
Included the Reveal LINQ 
device which replaced trans- 
telephonic monitors and holters 
for recurrent AF detection. 
Reveal LINQ has been 
commercially launched 
in the United States, 
allows unique 
opportunity to 
continuously monitor for 
recurrent AF and collect 
AF burden 
0 
6.0 
3.1, 5.2.2, 6.10, 
6.12 
Added the Symplicity Spyral 
catheter and Symplicity G3 
Generator. The Symplicity 
catheter remains in the CIP as a 
backup catheter for unforeseen 
circumstances with Symplicity 
Spyral or generator. 
Technology 
improvements with the 
next generation 
catheter 
0 
6.0 
4 
Elaborated on what is part of 
regulatory compliance 
Clarification 
0 
6.0 
5.2.1 
Added inclusion criteria for 
home monitoring 
New information 
0 
6.0 
5.2.2 
Clarified that subjects may have 
one repeat TEE. 
Clarification 
0 
6.0 
5.2.2 
Removed loop recorders from 
exclusion criteria. 
Removed because 
Reveal LINQ is allowed 
0 
6.0 
6.2, 16.1, 16.3 
Added Financial Disclosure 
requirement 
Clarification 
0 
6.0 
6.6 
Clarified that dose, units, 
frequency is only required for 
anti-hypertensive medications 
Clarification 
0 
6.0 
6.7 
Added a CT scan to screen for 
renal anatomy eligibility followed 
directly by randomization rather 
than screening for renal 
anatomy directly after the 
pulmonary vein isolation 
procedure. 
Allows for more 
efficiency with planning 
of the renal denervation 
procedure. 
0 
 
 
 
 
 
 
 
 
 
 
 

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Version 
Applicable 
Sections 
Change 
Rationale 
Number of 
subject enrolled 
6.0 
6.7, 6.17, 12.6 
Changed trans-thoracic 
echocardiogram measurement 
to only left atrial volume index 
for subjects diagnosed 
persistent AF. 
 
The repeat trans-thoracic 
echocardiogram at 6 months 
was removed 
Want to exclude 
subjects who are very 
far along the AF 
disease continuum so 
that the two groups, 
paroxysmal and 
persistent aren’t too 
dissimilar 
Likelihood of seeing a 
meaningful difference 
six months post 
procedure did not 
warrant this objective 
0 
6.0 
6.7, 6.17, 12.6 
Removed quality of life 
questionnaire 
Likelihood of seeing a 
meaningful difference 
six months post 
procedure did not 
warrant this objective 
0 
6.0 
5.2.1, 6.7, 6.17, 
12.6 
Removed ambulatory blood 
pressure monitoring requirement 
and follow up visit 
measurements 
Deemed not critical for 
this study based on 
HTN-3 results 
0 
6.0 
6.14 
Changed the definition of device 
deficiency 
New information 
0 
6.0 
6.17 
Removed the 3 month follow up 
visit 
Primary reason for the 3 
month follow up visit 
was to address any 
potential safety issues 
with the renal artery 
denervation procedure, 
risk level has been 
lowered with recent 
results from the 
Symplicity HTN-3 study 
0 
6.0 
6.18 
Included System Modification 
instructions for the Reveal LINQ 
device 
New information 
0 
6.0 
6.20 
Clarified criteria for permissible 
retreatments 
Unnecessary restriction 
in this feasibility study 
0 
6.0 
7 
Added instructions for device 
disposition with the Arctic Front 
Advance catheter 
Result of including the 
persistent AF 
population in the study 
0 
6.0 
9 
Clarified that only system 
related, procedure related, 
cardiovascular related and 
serious AEs will be collected 
rather than all AEs 
Safety risk level has 
been lowered with 
recent results from the 
Symplicity HTN-3 study 
0 
6.0 
9 
Changed Adverse Events 
Adjudication Committee (AEAC) 
to Clinical Events Committee 
(CEC) 
Clarification because 
the committee will 
review more than 
adverse events 
0 
6.0 
9.1 
Added chest pain to the 
unavoidable AE table 
Reasonable expectation 
of occurrence 
0 
 
 

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6.0 
9.3 
Elaborated market-release 
reporting requirements 
Clarification 
0 
6.0 
10 
Added risks associated with the 
Reveal LINQ device 
New information 
0 
6.0 
12.3.4 
Updated performance criteria 
with recent Symplicity HTN-3 
study results 
New information from 
the Symplicity HTN-3 
study 
0 
6.0 
12.4 
Updated primary effectiveness 
objective because of how events 
are collected with the Reveal 
LINQ device 
Continuous AF 
detection which wasn’t 
possible with Holter 
and TTM 
0 
6.0 
12.6 
Added AF burden to ancillary 
objectives 
Reveal LINQ calculates 
daily AF burden which 
is of interest in this 
patient population 
0 
6.0 
12.6 
Removed freedom from atrial 
tachyarrhythmias ancillary 
objective 
Reveal LINQ does not 
have the capability to 
discriminate all atrial 
arrhythmias without 
making tradeoffs on AF 
collection 
0 
6.0 
12.7 
Added subgroup analysis 
A result of including 
persistent AF patients in 
the study 
0 
6.0 
Appendix E 
Included institutions and IRBs 
that are expected to participate 
in the study 
New information 
0 
6.0 
Appendix F 
Clarified that commercially 
released Arctic Front Advance 
Cryoablation Systems will be 
used in the study and not 
relabeled as investigational 
Clarification 
0 
7.0 
3.0 and throughout 
Removed reference to the first 
generation Symplicity catheter 
and RF Generator 
Only the next 
generation Symplicity 
Spyral catheter and 
Symplicity G3 
Generator will be used 
in the study 
11 
7.0 
9.1 
Removed chest pain from 
unavoidable AEs 
Per FDA 
recommendation 
11 
7.0 
12.7 
Subgroup analysis group added 
for those who receive touch up 
RF vs. not. 
Per FDA 
recommendation 
11 
8.0 
Throughout 
Added Arctic Front Advance ST 
This device is approved 
for use in the United 
States 
0 
8.0 
3.3 
Added one sentence regarding 
the AF detection algorithm 
Clarification 
0 
8.0 
6.4 
Added Role of the sponsor 
representative during study 
procedures and follow up visits 
Clarification 
0 
 
 
 
 
 

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6.7 
Removed outdated reference to 
a 3-month visit 
Correction. Missed on 
prior revision when the 
3-month visit was 
removed. 
0 
8.0 
6.14 
Subjects with existing Reveal 
LINQ devices may be enrolled 
Clarification 
0 
8.0 
6.17 
Changed the visit window 
calculation to date of pulmonary 
vein isolation procedure 
Clarification 
0 
8.0 
10 
Added two risks 
Known risks reported in 
literature and field 
performance data 
0 
8.0 
12.4 
Added language stating the 
primary effectiveness objective 
analysis includes AF detected 
from Reveal LINQ 
Clarification 
0 
8.0 
Appendix E 
Updated center information 
New information 
0 
9.0 
Throughout 
Removed Arctic Front Advance 
ST 
Business decision 
0 
9.0 
6.23 
Removed alternative sources to 
document AF recurrence. 
Reveal LINQ is the only 
source for recurrent AF 
allowed per protocol 
0 
9.0 
12.4 
Removed ECG and Holter as 
contributing to the definition of 
treatment failure for document 
AF recurrence. 
Reveal LINQ is the only 
source for recurrent AF 
allowed per protocol 
0 
10.0 
1.2 
Updated study duration 
New information 
Not applicable 
10.0 
5.2.1 and 6.8 
Inclusion criteria for blood 
pressure was lowered 
Supports a larger cohort 
of patients who 
continue to have 
increased sympathetic 
tone 
Not applicable 
10.0 
5.2.1 and 6.7 
Inclusion criteria for number of 
antihypertension medications 
was lowered 
Supports a larger cohort 
of patients who have 
uncontrolled 
hypertension on one 
antihypertensive 
medication 
Not applicable 
10.0 
5.2.1 and 6.7 
Inclusion criteria for 
hypertension medication at 
maximum dose was removed 
Supports a larger cohort 
of patients who are not 
on maximum 
antihypertensive 
medication dose: avoids 
medication adherence 
identified in this 
population 
Not applicable 
10.0 
5.2.2 
Removed exclusion criteria for a 
condition where manipulation of 
the catheter within the heart 
would be unsafe but retained the 
evaluation as a requirement to 
occur prior to the ablation 
procedure. 
Generally not assessed 
at the Baseline exam 
because the ablation 
procedure date has not 
been scheduled 
Not applicable 
10.0 
6.7 
Removed discouragement to 
enroll subjects on amiodarone. 
Changed because of 
enrollment barrier 
Not applicable 
 
 

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6.9 
Removed the word sealed from 
the randomization envelops, 
envelops have a blinded code 
label. 
Clarification 
Not applicable 
10.0 
6.15 
Added “labeling” to the end of 
the sentences starting with 
NOTE. 
Inadvertently missed so 
complete text was 
added 
Not applicable 
10.0 
9.3 
Added “impairment to a body 
structure or a body function” to 
the bullet point that begins with 
A condition necessitating 
medical or surgical intervention 
to prevent permanent 
Inadvertently missed so 
complete text was 
added 
Not applicable 
10.0 
9.5.1 
Reworded the first paragraph to 
align with the CRF name and 
noted that’s it should be a SAE 
that led to death. 
Clarification 
Not applicable 
10.0 
9.5.2 
In the Unknown Cardiac 
Classification, corrected 
sufficient to insufficient 
Typo 
Not applicable 
10.0 
10 
Added lung lesion and 
Gastroparesis 
Known risks reported in 
literature and field 
performance data 
New information 
10.0 
12.4.4 
Changed day zero to date of 
procedure, not dated of 
randomization and revised 
assessment of time to event. 
Clarification 
Not applicable 
10.0 
Appendix C 
A DMC charter has been written 
New information 
Not applicable 
10.0 
Appendix E 
Updated center information 
New information 
Not applicable 
11.0 
5.2.1 
The inclusion criteria for blood 
pressure and antihypertensive 
medications was modified to 
include: subjects whose 
antihypertensive drug regimen is 
not expected to change for at 
least 6 months, as determined 
by their referring cardiologist 
and/or the investigator 
Safety consideration for 
those subjects with 
uncontrolled 
hypertension during the 
first 6 months post 
procedure 
Not applicable 
11.0 
6.7 
Included the requirement to 
collect medication purpose 
Inadvertently removed 
during prior revisions 
Not applicable 
11.0 
6.8 
Subjects with an average of 3 
systolic blood pressure 
measurements ≤ 140 mmHg 
may have a repeat blood 
pressure assessment. The last 
version of this CIP stated 
>140mmHg. 
Typo 
Not applicable 
11.0 
6.8 
The TEE section was reworded 
to state: “Subjects noted to have 
left atrial thrombus on TEE will 
not undergo the procedure and 
will be exited from the study 
unless thrombus resolution is 
confirmed on a repeat TEE.” 
Clarification 
Not applicable 
 
 
 

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subject enrolled 
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5.2.1 
The inclusion criteria for blood 
pressure and antihypertensive 
medications was modified to 
include: The subject should be 
on a stable antihypertensive 
drug regimen with no changes 
for a minimum of 2 weeks prior 
to enrollment and the 
antihypertensive drug regimen is 
not expected to change for at 
least 6 months, as determined 
by the subject’s referring 
cardiologist and/or the 
investigator. 
Clarification 
17 
13.0 
Title Page / Table 1 Added European contacts 
European expansion 
Not applicable 
13.0 
Table 2 
Added core lab information 
New Information 
Not applicable 
13.0 
Section 1 
Added European device/study 
status information and 
expansion of 3 sites 
Include additional 
European centers to aid 
enrollment rate 
Not applicable 
13.0 
Section 1.2 
Increased center randomization 
cap from 30% to 50% 
Allow high enrolling sites 
to continue enrollment to 
meet overall enrollment 
target 
Not applicable 
13.0 
Section 3 
Added European information for 
system description and intended 
use 
European expansion 
Not applicable 
13.0 
Section 3.4 
Added Achieve AdvanceTM as 
an additional system component 
Newly approved device 
available for use 
Not applicable 
13.0 
Section 4 
Added European regulatory 
compliance information 
European expansion 
Not applicable 
13.0 
Section 4 
Added explanation of 
requirements for revisions to the 
CIP 
Clarification 
Not applicable 
13.0 
Table 5 
Switched order of CT Scan and 
Cryoablation Procedure to 
chronological order 
Typo 
Not applicable 
13.0 
Section 6.2 
Added European center 
activation requirements 
European expansion 
Not applicable 
13.0 
Section 6.6 
Added European patient 
informed consent process 
requirements 
European expansion 
Not applicable 
13.0 
Section 6.12 
Removed statement “If the 
angiogram confirms anatomy 
eligibility, the subject will be 
randomized” 
Typo- subject is 
randomized after CT 
scan 
Not applicable 
13.0 
Section 6.17 
Added additional follow up visit 
windows in Table 6 
Study length increase 
Not applicable 
13.0 
Section 7 
Added European requirements 
for device storage, handling and 
traceability 
European expansion 
Not applicable 

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subject enrolled 
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Section 8 
Added note that study 
deviations are not required if a 
subject misses a monthly LINQ 
manual interrogation 
Nightly automatic 
transmissions can be 
reviewed for AF 
episodes 
Not applicable 
13.0 
Section 9 
Added European adverse event 
and device deficiency 
requirements 
European expansion 
Not applicable 
13.0 
Section 12 
Added: subjects who are 
randomized to the treatment 
group and are found not to meet 
inclusion/exclusion criteria 
during the renal denervation 
procedure will not count toward 
the 70 subjects randomized and 
will be included in a modified 
intention-to-treat analysis 
Clarification 
Not applicable 
13.0 
Section 12.9 
Added a section regarding 
method for pooling of study 
centers for analysis 
Clarification 
Not applicable 
13.0 
Section 14 
Added insurance information 
Clarification 
Not applicable 
13.0 
Section 16 
Added European requirements 
for required records and reports 
European expansion 
Not applicable 
13.0 
Appendix E 
Participating investigators, 
institutions and IRB/MECs 
updated to current status 
New Information 
Not applicable 
13.0 
Appendix F 
Added European labeling 
information 
European expansion 
Not applicable 
13.0 
Throughout 
Added reference to medical 
ethics committee (MEC) and 
regulatory bodies throughout 
European expansion 
Not applicable 
14.0 
Throughout 
Sponsor internal distribution 
only 
Sponsor internal 
discussion 
Not applicable 
15.0 
Table 1 
Revised Study sponsors and 
contacts 
Updated information 
47 
15.0 
Section 5.2.2 
Removed exclusion criteria for 
pacemakers and defibrillators 
Supports a larger cohort 
of patients contributing 
to enrollment 
47 
15.0 
Section 5.2.2 and 
6.12 
Added the maximum renal 
artery diameter acceptable for 
the exclusion criteria 
Typo 
47 

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Section 6.5 and 
6.18.2 
Allow a CareLink transmission 
from the subject’s home as a 
substitution for an in-office 
device interrogation 
Clarification 
47 
15.0 
Section 7.1 and 7.3 Changed pedal to switch 
Typo 
47 
15.0 
Section 7.2, Table 7 
and Appendix F 
Added Freezor MAX 
Clarification 
47 
15.0 
Section 10 
Modified risks to align with the 
current Arctic Front Advance 
IFU and added that the current 
Arctic Front Advance IFU should 
be referenced with respect to 
the possible risks 
Updated to reflect 
recently approved 
labeling for the 
commercialized device 
47 
15.0 
Section 12.3 
Added text to the Safety 
Composite Event definition 
Clinical Events 
Committee clarification 
request 
47 
15.0 
Appendix E 
Participating investigators, 
institutions and IRB/MECs 
updated to current status 
New Information 
47 
16.0 
Table 1 
Revised Study sponsors and 
contacts 
Updated information 
55 
16.0 
Table 2 
Revised Study Core Labs 
Updated information 
55 
16.0 
Table 3 
Revised Committee contact 
information 
Clarification of Steering 
Committee 
55 
16.0 
Section 1.2 
Revised Study description 
Updated expected total 
study duration and 
months of enrollment 
given time needed to 
reach required subject 
treatment numbers 
55 
16.0 
Section 1.2 
Revised Study description 
Updated to include 
provisions for the 
conduct of interim 
analyses 
55 

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16.0 
Section 2 
Revised section to include 
recently published renal 
denervation study results 
New information 
55 
16.0 
Section 2 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
16.0 
Table 4 
Added Model Number(s) for 
AFA Pro Cardiac Cryoablation 
Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
16.0 
Section 3.2 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
16.0 
Section 5.2.2 
Reinstated prior exclusion 
criteria for pacemakers and 
defibrillators 
Protocol required LINQ 
monitoring for recurrent 
AF is not recommended 
in subjects with 
implantable Medtronic 
pacemakers and 
defibrillators; CareLink 
monitor unable to 
distinguish specific 
device for pairing; to 
ensure all recurrent AF 
in this study is captured 
via LINQ, implanted 
pacemakers and 
defibrillators from 
varying manufacturers 
will not be allowed 
55 
16.0 
Section 6.1 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
16.0 
Section 6.10 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
16.0 
Section 6.24 
Revised Study exit to allow for 
exit of subject with Reveal LINQ 
battery reaching end of life after 
completing at least 6 months of 
study follow-up 
Support study subject 
safety and study 
participation satisfaction 
by not requiring repeat 
LINQ implant when 
study objective data is 
available and additional 
implant not clinically 
warranted 
55 
16.0 
Section 7.2 and 
Table 7 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 

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Rationale 
Number of 
subject enrolled 
16.0 
Section 12.1 
Added clarification for objective 
analyses and timepoints for 
potential interim analyses 
Clarification and new 
information 
55 
16.0 
Section 12.4.6 
Revised power and sample size 
calculation assumptions 
Provide new information 
resulting from provisions 
to conduct potential 
interim analyses 
55 
16.0 
Section 12.8 
Included the conduct of interim 
analyses 
Aid sponsor decisions 
for continuing study 
55 
16.0 
Section 12.8 
Table added to show timepoints 
at which interim analyses may 
be conducted 
Provide information 
regarding the pass/fail of 
primary effectiveness 
objectives for each 
scenario 
55 
16.0 
Section 12.8 
Added clarification of DMC’s 
role in reviewing effectiveness 
data 
Revised to reflect the 
conduct of interim 
analyses and the review 
of effectiveness data by 
the DMC 
55 
16.0 
Appendix C 
Added clarification of DMC’s 
role in reviewing effectiveness 
data 
Revised to reflect DMC 
review of effectiveness 
data generated by the 
conduct of interim 
analyses 
55 
16.0 
Appendix E;  
Table 14 
Participating investigators, 
institutions and IRB/MECs 
updated to current status 
New information 
55 
16.0 
Appendix F 
Included use of Arctic Front 
Advance Pro Cardiac 
Cryoablation Catheter 
AFA Pro recently 
granted FDA approval 
and CE mark 
55 
17.0 
Section 6.18 
Added alternate Follow-up 
methods 
To allow for extenuating 
circumstances, such as 
a global pandemic. 
98 
17.0 
Table 1 
Updated Study sponsors and 
contacts 
Updated information 
98 
17.0 
Section 3 
Added MyCareLink Patient 
Monitor Model number 24952 
24952 Model number is 
available on the market 
in Europe 
98 

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17.0 
Throughout 
Document 
Minor administrative and 
formatting updates 
Updated information 
98 
17.0 
Throughout 
Document 
Updated based on received 
FDA approval of Arctic Front 
Advance, Arctic Front Pro and 
Freezor MAX with the Persistent 
AF expanded indication for the 
treatment of drug refractory 
recurrent symptomatic 
paroxysmal and persistent atrial 
fibrillation (episode duration less 
than 6 months) 
Updated information 
98 
17.0 
APPENDIX E: 
Removed PARTICIPATING 
INVESTIGATORS, 
INSTITUTIONS AND IRB/MECS 
list  
 
A complete list of 
participating 
investigators, institutions 
and IRB/MECs where 
study activities will be 
conducted will be 
distributed under a 
separate cover  
 
98 
18.0 
Section 6.18 
Administrative update to remove 
the following sentence from the 
section 6.18.  “Scheduled in-
office follow-up visits”. These 
alternative methods have no 
potential impact on patient 
safety, do not affect data 
integrity and do not introduce 
study bias.’  This sentence was 
added in version 17.0 of the CIP 
which was not implemented 
prior to version 18.0. 
Per recommendation 
from FDA 
100 
 
 
 
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3 Kannel WB, Abbott RD, Savage DD, et al. Epidemiologic features of chronic atrial 
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4 Healey JS, Connolly SJ. Atrial fibrillation: hypertension as a causative agent, risk factor for 
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8 Ciaroni S, Cuenoud L, Bloch A. Clinical study to investigate the predictive parameters for the 
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10 Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in 
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11 Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial 
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16 Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of pulmonary vein 
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17 Calkins, H., et al., HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical 
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18 Mancia G. Blood pressure reduction and cardiovascular outcomes: Past, present, and future. 
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19 Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death 
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20 Staessen JA, Gasowski J, Wang JG, Thijs L, Den Hond E, Boissel JP, Cooper J, Ekborn T, 
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