Amplatzer Cardiac Plug Clinical Trial
Phase: NA
Conditions: Atrial Fibrillation, Ischemic Stroke, Peripheral Thromboembolism
Sponsor: Abbott Medical Devices

CONFIDENTIAL AND PROPRIETARY 
© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in 
part without the express written permission of AGA Medical Corporation. 
 
 
 
 
 
 
 
 
AMPLATZER™ Cardiac Plug (ACP) 
 
Clinical Investigational Plan 
 
Revision 06 Amendment 
September 2014 
 
IDE# G080150 
 
 
 
 
 
 
 
Sponsored by: 
 
AGA Medical LLC 
5050 Nathan Lane North 
Plymouth, MN 55442 
Phone:  888-546-4407 
Fax:  763-647-5900 
 
 
 

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Investigational Plan 
 
 
 
ACP Clinical Trial 
 
Investigational Plan Signature Page 
I have read and agree to adhere to the investigational plan and all regulatory requirements 
applicable in conducting this clinical study.  I will provide copies of this investigational plan 
and all pertinent information to study personnel and will discuss this information with them 
and ensure they are fully informed regarding the investigational device and the conduct of 
the study according to 21 CFR parts 50, 54, 56 and 812, to other applicable regulations, to 
applicable laws, and to hospital Institutional Review Board (IRB). 
 
 
 
Investigator: 
 
 
 
 
Print or Type Name  
 
 
 
 
Signature 
  
 
 
 
 
Date 
 
 

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TABLE OF CONTENTS 
 
1. 
PURPOSE............................................................................................................................ 5 
1.1 
NAME AND INTENDED USE OF THE DEVICE ................................................... 5 
1.2 
STUDY OBJECTIVES ......................................................................................... 5 
1.3 
STUDY DESIGN .................................................................................................. 5 
1.4 
STUDY ENDPOINTS ........................................................................................... 5 
1.5 
DURATION OF THE INVESTIGATION AND SAMPLE SIZE ................................ 8 
2. 
CLINICAL PROTOCOL ........................................................................................................ 8 
2.1 
BACKGROUND INFORMATION ......................................................................... 8 
2.2 
RATIONALE ...................................................................................................... 11 
2.3 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ................... 11 
2.4 
LITERATURE AND CLINICAL DATA ................................................................. 12 
2.5 
ELIGIBILITY CRITERIA ..................................................................................... 12 
2.6 
SUBJECT PARTICIPATION AND INFORMED CONSENT ................................ 14 
2.7 
ENROLLMENT .................................................................................................. 15 
2.8 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA .............................. 16 
2.9 
BASELINE EVALUATION .................................................................................. 16 
2.10 
RANDOMIZATION ............................................................................................. 18 
2.11 
AMPLATZER CARDIAC PLUG IMPLANTATION PROCEDURE ........................ 18 
2.12 
FOLLOW-UP REQUIREMENTS ........................................................................ 22 
2.13 
ADVERSE EVENTS .......................................................................................... 26 
2.14 
ADVERSE EVENT REPORTING ....................................................................... 29 
2.15 
HYPOTHESIS AND STATISTICAL ANALYSIS .................................................. 29 
2.16 
ADVISORY COMMITTEES ................................................................................ 66 
2.17 
STUDY MANAGEMENT .................................................................................... 68 
2.18 
ADMINISTRATIVE REQUIREMENTS ............................................................... 68 
2.19 
TRAINING THROUGHOUT THE STUDY .......................................................... 68 
2.20 
PROTOCOL ADHERENCE AND AMENDMENTS ............................................. 68 
2.21 
CLINICAL STUDY COMPLIANCE ..................................................................... 71 
2.22 
INSTITUTIONAL REVIEW BOARD .................................................................... 71 
2.23 
DEVICE ACCOUNTABILITY .............................................................................. 72 
2.24 
DATA ENTRY AND CRF SUBMISSION ............................................................ 72 
2.25 
DATA MANAGEMENT ....................................................................................... 72 
2.26 
INSTITUTIONAL AUDITS .................................................................................. 72 
2.27 
CONFLICT OF INTEREST ................................................................................ 73 
2.28 
PUBLICATION POLICY ..................................................................................... 73 
2.29 
ECONOMIC AND QUALITY OF LIFE SUB-STUDY ........................................... 73 
2.30 
REFERENCES .................................................................................................. 73 
2.31 
DEFINITIONS .................................................................................................... 80 
3. 
RISK ANALYSIS ................................................................................................................ 85 
3.1 
RISK: BENEFIT ASSESSMENT OF THE DEVICE ARM .................................... 85 
3.2 
RISK: BENEFIT ASSESSMENT OF THE CONTROL ARM ................................ 86 
3.3 
MINIMIZING THE RISKS ................................................................................... 88 
4. 
DESCRIPTION OF DEVICE .............................................................................................. 90 
5.  
MONITORING PROCEDURES ......................................................................................... 91 

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6.  
SAMPLE SUBJECT IDENTIFICATION CARDs ................................................................ 92 
7.  
CONSENT MATERIALS .................................................................................................... 93 
8.  
IRB INFORMATION ......................................................................................................... 114 
9. 
OTHER INStITUTIONS .................................................................................................... 114 
10.  
ADDITIONAL RECORDS AND REPORTS ..................................................................... 115 
10.1 
DOCUMENTING STUDY CORRESPONDENCE ............................................. 116 
10.2 
RECORD RETENTION .................................................................................... 116 
10.3 
RECORD CUSTODY ....................................................................................... 117 
10.4 
REPORTS ....................................................................................................... 117 
APPENDIX: A - Transesophageal Echocardiography (TEE) Protocol ........................................ 118 
APPENDIX: B - Transthoracic Echocardiogram (TTE) Protocol ................................................. 121 
APPENDIX: C - American Heart Association Recommendations for Prophylaxis ...................... 122 
 
 

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1. 
PURPOSE 
 
CESSATION OF ENROLLMENT 
Refer to Appendix D for update on enrollment and changes to follow-up schedules for already 
enrolled patients.   
 
1.1 
NAME AND INTENDED USE OF THE DEVICE 
The AMPLATZER™ Cardiac Plug (ACP) is a percutaneous transcatheter device intended to 
prevent thrombus embolization from the left atrial appendage (LAA) in subjects who have 
nonvalvular atrial fibrillation. 
 
1.2 
STUDY OBJECTIVES 
The objective of this study is to evaluate the safety and effectiveness of the ACP in subjects 
with nonvalvular atrial fibrillation by demonstrating that the device is non-inferior to optimal 
medical therapy (OMT) with respect to the primary effectiveness endpoint and superior to OMT 
with respect to primary safety endpoint. 
 
The OMT control will include subjects managed with oral anticoagulation therapy (warfarin or 
dabigatran) with therapy choice determined by the clinical judgment of the investigator.  
 
1.3 
STUDY DESIGN 
The ACP will be clinically evaluated through a prospective, randomized, multicenter, active 
control study to evaluate safety and effectiveness. The randomization scheme will be 2:1, 
stratified by study center, oral anticoagulant therapy (OAC) (warfarin or dabigatran), and 
baseline concomitant aspirin usage. Twice as many subjects will be randomized to the 
treatment arm (device arm) than to the control arm (OMT), respectively. The study will be 
initiated under a feasibility phase to be followed by an expanded pivotal phase. 
 
Feasibility phase-Following randomization, the first 30 subjects to receive the device will 
constitute the feasibility subset.  The 45 day results (reported AEs and TEE) for these initial 30 
subjects who receive the device or who undergo an implant attempt will be reviewed and 
adjudicated by the DSMB and then reported to the FDA.  Subject enrollment will be temporarily 
halted while the feasibility subset data are being collected and reviewed by the DSMB and 
FDA.   
 
1.4 
STUDY ENDPOINTS 
1.4.1 Feasibility Study Endpoint - 45 day Serious Adverse (SAE) Event Rate  
The 45 day results (SAE rate and TEE) in the first 30 subjects who receive the device 
or who undergo an implant attempt will be reported to the FDA.  All reported AEs will 
be adjudicated to determine their severity in subjects in whom device placement is 
attempted, from the time of the procedure through 45 days post procedure.  
 
1.4.2 Pivotal Study Endpoints 

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1.4.2.1 Primary Safety Endpoint 
The primary safety endpoint will be evaluated through two hypotheses: 
 
1. Acute safety -This analysis compares the rate of procedure related serious 
adverse events as listed below, that occur in the device arm from the time of 
randomization until hospital discharge to a performance goal (PG) determined 
from literature reported rates for similar procedural techniques. 
 
• Procedure-related death (i.e., death occurring during the implantation 
procedure) 
• Pericardial effusion requiring treatment 
• Device embolization 
• Access site-related bleeding requiring transfusion ≥ 2 units 
• Damage to other cardiac or major non-cardiac cardiovascular structures 
 
2. Long-term safety -This analysis compares safety events as listed below, that 
occur between the device arm and the control arm. For both the device arm 
and the control arm these events will be evaluated from the time of 
randomization to 2 years. 
 
1. 
All-cause death 
2. 
Major bleeding defined as: 
• Symptomatic intracerebral or intraventricular hemorrhage; or 
subdural, subarachnoid, epidural, or ocular hemorrhage; or  
• Major non-cerebral bleed-defined as transfusion requiring ≥2 units, 
hospitalization requiring any transfusion or surgical or percutaneous 
interventional procedure to treat bleeding. 
Note: procedure-related pericardial effusions requiring 
treatment will not be counted as a major non-cerebral bleed. 
 
1.4.2.2 Primary Effectiveness Endpoint 
The primary effectiveness endpoint is the occurrence of ischemic stroke and 
peripheral thromboembolism. 
 
Ischemic Stroke is defined as acute focal neurological deficit presumed to be 
due to focal ischemia, with either symptoms persisting 24 hours or greater, or 
symptoms persisting less than 24 hours, associated with MR or CT findings of a 
new, neuroanatomically relevant, cerebral infarct. 
 
Peripheral Thromboembolism is defined as an abrupt vascular insufficiency 
associated with clinical and radiological evidence of arterial occlusion in the 
absence of another likely mechanism. 
 
 

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1.4.3 Secondary Endpoints 
Secondary Endpoints to be assessed are: 
 
1. In-hospital procedure success - defined as successful implantation of the ACP 
device with no reported in-hospital serious adverse events in subjects randomized to 
the treatment arm 
 
2. “Day 45” clinical success - defined as in-hospital procedure success, closure of LAA 
documented at Day 45 TEE, no ischemic stroke or peripheral thromboembolism, and 
discontinuation of warfarin or dabigatran 
 
3. Long-term clinical success - defined as in-hospital procedure success, closure of 
LAA documented at Day 45 TEE, no ischemic stroke or peripheral 
thromboembolism, and sustained discontinuation of dabigatran or warfarin (without 
temporary re-administration) at last available follow-up. ‘Sustained discontinuation’ is 
defined as the subject’s ability to remain off of dabigatran or warfarin for a minimum 
of 6 months following discontinuation except in subjects with less than 6 months of 
follow-up (see below).  
 
‘Sustained discontinuation’ for those subjects who have less than 6 months of follow-
up is defined as the subject’s ability to remain off of  dabigatran or warfarin for a 
minimum of 3 months following discontinuation. 
 
4. Device or procedure-related adverse events to include: 
 
• Device embolization 
• Myocardial perforation (hemopericardium) or any pericardial effusion requiring 
drainage 
• Endocarditis 
• Thrombus on device 
 
5. Asymptomatic intracerebral or intraventricular hemorrhage 
 
6. Atrial Fibrillation status - specifically defined as those subjects who progress from 
paroxysmal to persistent AF, or those subjects who progress from persistent to 
permanent AF 
 
7. Technical success – defined as delivery and release of the ACP device, including 
recapture and/or replacement, as necessary.  This success rate will be calculated 
among subjects in whom the delivery system enters the body. 
 
8. Transient Ischemic Attack - defined as acute focal neurological deficit (such as focal 
motor deficit, aphasia, difficulty walking, hemisensory deficit, amaurosis fugax, 

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blindness, or focal visual deficit) presumed due to focal ischemia, with symptoms 
persisting greater than or equal to 5 minutes and less than 24 hours, and that is not 
associated with MR or CT findings of a new cerebral infarct. 
 
9. Complete closure – defined as the absence of flow into the LAA at six (6) months as 
assessed by TEE. 
 
1.5 
DURATION OF THE INVESTIGATION AND SAMPLE SIZE (REFER TO APPENDIX D) 
The ACP clinical trial will enroll a minimum of 400 and maximum of 3000 subjects at a 
maximum of 80 investigative sites in the United States and a maximum of 10 sites in Canada.  
The anticipated study duration is approximately 5 years.  Safety and effectiveness data 
collected from the randomized subjects will be used to support a PMA submission. 
 
2. 
CLINICAL PROTOCOL 
 
2.1 
BACKGROUND INFORMATION 
DISEASE TO BE TREATED 
Atrial fibrillation (AF) is the most common sustained heart rhythm disorder (Fuster 2006).  
During AF there are multiple simultaneous waves of contraction which spread in a chaotic 
manner through both atria.  This arrhythmia results in rapid, uncoordinated contractions which 
decrease the blood pumped through the atria. 
 
Atrial fibrillation is classified as valvular, nonvalvular, or lone.  Nonvalvular AF refers to cases 
without rheumatic mitral valve disease, prosthetic heart valve, or valve repair.  Nonvalvular AF 
can be further classified according to the AHA/ACC/ESC guidelines as paroxysmal, persistent, 
and/or permanent.  Paroxysmal AF has been reported in an estimated 25 to 90% of subjects 
with AF (Kannel 1983, Davidson 1989, Phillips 1990, Gajewski 1981, and Takahashi 1981) 
although 90% of cases of paroxysmal AF are asymptomatic and therefore the prevalence may 
not be known (Israel 2004, Page 1994).  Paroxysmal AF terminates spontaneously whereas 
persistent AF is sustained for a minimum of seven days.  Persistent or paroxysmal AF, if 
sustained for greater than a year, may lead to permanent AF.  
 
Left Atrial Appendage (LAA) and Nonvalvular Atrial Fibrillation 
The loss of mechanical efficiency during AF leads to insufficient contraction in the left atrium 
(LA) (Ostermayer 2005).  Stagnation of blood flow in the LA leads to hypercoagulability and 
thus increased risk for thrombus formation in the left atrium or left atrial appendage.  
Approximately 90% of all thrombi in subjects with nonvalvular AF forming in the LA originate in 
the LAA (Blacksheer 1996).  The thrombus formation, in turn, exposes the subject to 
thromboembolic events. Approximately 6% of embolic events result in peripheral embolism as 
opposed to ischemic stroke (Go 2003).   
 
Echocardiographic risk factors for LAA thrombus formation include echocardiographic 
evidence of decreased LAA flow velocity and spontaneous echo contrast (SEC) within the LA 
and LAA (Stollberger 2003 and Miller 1993).  The normal flow pattern of the LAA is the ejection 
of blood from the appendage following atrial contraction at a velocity greater than 40cm/s 

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(Alizadeh 2006).  Agmon et al (1999), found that the relative risk reduction of ischemic stroke 
was 2.6 times greater in subjects with LAA flow velocities <20cm/s than those with higher LAA 
velocities. 
 
Ischemic strokes in subjects with AF have been found to cause major deficits as compared to 
ischemic strokes in subjects with carotid disease.   Subjects with AF have also been found to 
have silent infarcts in the SPINAF study in which a CT scan was performed both initially and 
then again at the end of the follow-up period (Ezekowitz 1995). 
 
Nonvalvular AF subjects can be further assessed to determine the risk of stroke based on the 
existence of independent risk factors.  In a study by Gage et al (2001), the CHADS2\ index was 
found to be the most accurate in predicting the risk of stroke in subjects with AF.  The CHADS2 
score assigns one point each for the presence of congestive heart failure, hypertension, age 
greater than 75, and diabetes mellitus, and two points for history of stroke or TIA.  The study 
found that AF subjects who were not treated with antithrombotics had an increased risk of 
stroke from 1.5% to 18.2% based on the score of 1 and 6 respectively.  A second study 
reviewed outcome data (11,526 subjects) in a large primary care setting and confirmed that 
thromboembolic risk increases progressively with CHADS2 score.  The study also noted that 
oral anticoagulation with warfarin reduces risk of stroke in most subjects with the exception of 
those at lowest risk (CHADS2 score of zero) and highest risk (CHADS2 of ≥5) (Go et al, 2003). 
 
STATISTICS  
An estimated 2.3 million people in North America and 4.5 million people in the European Union 
have paroxysmal or persistent AF (Go 2001).  The estimated prevalence of AF is 0.4% to 1% 
in the general population, increasing with age to 8% in those older than 80 (Vural 2005 and 
Frost 2000).   
 
Atrial fibrillation is responsible for 15% to 20% of ischemic stroke (Crystal 2004).  AF accounts 
for one fourth of all strokes in the elderly and is responsible for 70,000 strokes per year in the 
United States (AHA statistics).  The risk of stroke in subjects with nonvalvular AF is 
approximately 5% per year in subjects under 65 years and it increases to over 8% per year in 
subjects over 75 (AF Investigators Arch Intern Med 1994).  Based on risk factors and treatment 
or the lack thereof the risk of stroke can be as high as 18.2% per year in select subjects (Gage 
2001). 
 
CURRENT TREATMENT OPTIONS 
Medical Management for AF 
Treatment for AF includes both pharmacological and/or interventional based on the subject’s 
type of AF.  Anti-arrhythmic or rate control drugs are commonly used to treat subjects with AF.  
Medical interventions include electrical cardioversion, cardiac catheter ablation, atrial 
defibrillators, pacemakers, or maze procedure.  Regardless of the type of treatment modality 
chosen for rate or rhythm control, the need for anticoagulation therapy should still be based on 
stroke risk and not on whether proper heart rhythm is maintained (Fuster and Ryden 2006).   
 
The evidence indicates that both OAC and aspirin are effective for prevention of systemic 
embolism in subjects with nonvalvular AF (Petersen 1989, SPAF 1991, BAATAF 1990, 

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Connolly 1991, Ezekowitz 1992, EAFT 1993).  In a meta-analysis conducted by Anderson et al 
(2008), warfarin was found to be superior to ASA and placebo in reducing the risk of both 
stroke and systemic embolism in subjects with nonvalvular AF. Hart et al (2007) reported that 
adjusted dose warfarin reduces stroke by 64% (six trials) and antiplatelet agents reduce stroke 
risk by 22% (8 trials).  The study also reported the risk of intracranial hemorrhage was doubled 
with adjusted dose warfarin compared with aspirin, although the absolute risk increase was 
small (0.2% per year) and all-cause mortality was substantially reduced (26% [CI, 3% to 43%]) 
by adjusted-dose warfarin vs. control.  Subjects are often poorly compliant with 
anticoagulation, and anticoagulants are contraindicated in selected subsets of subjects. 
 
More recently, new drugs have been developed with less dietary and pharmacological 
interactions and less stringent requirements for frequent INR monitoring. Major trials such as 
RE-LY and ROCKET AF have demonstrated that dabigatran and rivaroxaban are non-inferior 
to warfarin in the prevention of stroke and systemic embolism. For example in the RE-LY 
study, the overall annual major bleeding rate with dabigatran was lower than with warfarin 
(2.71%/3.11% for 110/150 mg dabigatran vs. 3.36% for warfarin) but GI bleeding for both 
doses of dabigatran was (non-significantly) higher than for warfarin (1.12%/1.51% for 110/150 
mg dabigatran vs. 1.02% for warfarin) (Connolly et al 2009, Patel et al 2011).  In view of the 
bleeding associated with warfarin and new OAC drugs, especially, patients who are at high risk 
for stroke as well as for bleeding may benefit from alternative stroke prevention therapies. 
 
Surgical Closure of the LAA 
Surgical removal/closure of the LAA has been performed in subjects undergoing mitral valve 
surgery or the maze procedure.  Garcia-Fernandez et al (2003) completed a retrospective 
analysis of 58 subjects who underwent ligation of the LAA during mitral valve surgery.  The 
study reported a residual shunt rate of 10% in these subjects.  Residual shunting correlated 
with an increased risk of late embolism.  However, in a prospective study conducted by 
Almahameed et al (2007) the rate of thromboembolism post LAA exclusion was not statistically 
significantly less than subjects treated with warfarin. 
 
Percutaneous Closure of LAA 
LAA obliteration is now feasible via a percutaneous approach.  A device to reduce the risk of 
embolization from LAA thrombi, especially when associated anticoagulation is a relative or 
absolute contraindication, would be a desired option in such subjects.  Studies comparing 
investigational percutaneous LAA occlusion techniques with traditional anticoagulation are 
ongoing. 
 
Sievert et al (2002) reported on 15 subjects with chronic AF and a contraindication to warfarin 
implanted with the PLAATO Device (manufactured by ev3) for LAA occlusion.  Complete 
closure was observed in all subjects and there were no reported complications. 
 
Ostermeyer et al (2005) also reported preliminary results with the PLAATO Device.  
Successful LAA occlusion was achieved in 108/111 (97.3%) subjects. 
 
Sick et al (2007) reported the early results of a small feasibility study performed with the 
WATCHMAN System (manufactured by Atritech).  Sixty-six (66) patients were enrolled at centers 

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in both the U.S. and internationally and included patients who had chronic or paroxysmal atrial 
fibrillation and a CHADS2 score of one or greater.  Two (2) patients experienced systemic embolic 
events which were a safety endpoint in the study and 4 patients developed thrombus on the 
device. 
 
A multi-center, prospective, randomized study (PROTECT AF), comparing the WATCHMAN 
device to long-term warfarin therapy, demonstrating the treatment arm is non-inferior to the 
control arm completed enrollment in June 2008.  The primary endpoint of this study is to 
characterize the rates of all stroke, systemic embolism and cardiovascular death in patients with 
non-valvular atrial fibrillation who require treatment for potential thrombus formation and are 
eligible for warfarin therapy.  PROTECT AF demonstrated that LAA closure is non-inferior to 
warfarin for all-cause stroke and all-cause mortality, reducing stroke and all-cause death by 32% 
compared to warfarin.  Although the non-inferiority endpoint was met, the results were not 
statistically significant for superiority. 
 
Currently, the PREVAIL (Prospective Randomized EVAluation of the Watchman LAA Closure 
Device In Patients with Atrial Fibrillation Versus Long Term Warfarin Therapy) trial is enrolling AF 
patients at risk for stroke to be randomized to either anticoagulation therapy or implantation of the 
WATCHMAN device.  The primary endpoint is the occurrence of stroke, cardiovascular death and 
systemic embolism. The study plans for enrollment of 475 patients who will be followed for 5 
years. 
 
Recent experience with the ACP device in Europe includes 204 high risk subjects enrolled in the 
ACP EU Prospective Observational Study. Subjects’ risk factors for stroke (mean CHADS2: 2.6) 
included hypertension and age > 75 years.  Furthermore, 80 subjects had a previous stroke or 
TIA prior to implantation of the ACP. In 80% of the subjects, percutaneous LAA occlusion was 
indicated by a high bleeding risk and 3.9% were on active anticoagulation therapy at the time of 
enrollment.  High closure success rates of 99.5% were found immediately after successful 
implantation and at discharge and remained high at six months post implant (98.9%). 
 
2.2 
RATIONALE 
The rationale for the ACP clinical investigation is to potentially offer a device that is safe and 
effective in preventing thrombus from migrating from the left atrial appendage (LAA) in subjects 
who have nonvalvular atrial fibrillation and is a potential alternative to long-term anticoagulation 
therapy. 
 
2.3 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
The AMPLATZER Cardiac Plug (ACP) is a transcatheter, self-expanding device constructed 
from a nitinol mesh and polyester patch.  The ACP consists of a lobe and a disc connected by 
a central waist.  It is available in eight diameter sizes (16, 18, 20, 22, 24, 26, 28, and 30 mm).  
The lobe has stabilizing wires to improve device placement and retention.  The device has 
threaded screw attachments at each end for connection to the delivery and loading cable.  The 
device also has radio-opaque markers at each end and at the stabilizing wires. The ACP is 
designed to prevent thrombus embolization from the left atrial appendage (LAA) in subjects 
who have nonvalvular atrial fibrillation.   

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2.4 
LITERATURE AND CLINICAL DATA 
A complete bibliography is provided in Section 2.30. 
 
2.5 
ELIGIBILITY CRITERIA 
A subject is eligible to participate in the study if he/she meets all inclusion criteria and meets 
no exclusion criteria.  A screening log will be kept at each site to document subjects who fail to 
meet the entry criteria or refuse to participate in the clinical trial. All screened subjects will be 
documented on the screening Case Report Form (CRF). 
 
Inclusion Criteria 
1. 
Subject must have a documented history of paroxysmal, persistent or permanent 
nonvalvular atrial fibrillation (documentation must include an electrocardiogram (EKG), 
Holter, or event recorder) 
2. 
Subject must be ≥18 years of age 
3. 
Subject must be on warfarin therapy or dabigatran therapy* for a minimum of one 
month immediately prior to enrollment. For those subjects who are on warfarin 
therapy, at least two International Normalized Ratios (INRs) between 2-3 must be 
achieved during this time. Subjects whose INR is not in the target range may return for 
rescreening once target INR is achieved.  
4. 
Subject must be eligible for long term warfarin or dabigatran therapy* 
*Dabigatran dosing (75 mg or 150 mg bid) should be in accordance with its approved directions for use 
5. 
Subject must have a CHADS2 score of 2 or greater (score all criteria according to the 
following chart) 
 
  CHADS2 Risk Criteria 
  Score 
        Prior stroke or TIA 
2 
Age >75 y 
1 
Hypertension 
1 
Diabetes mellitus 
1 
Heart Failure 
1 
 
Exclusion criteria 
1. 
Subject who requires warfarin or dabigatran for a condition other than AF 
2. 
Subject who is on clopidogrel or another P2Y12 platelet inhibitor such as prasugrel or 
ticagrelor (subject may be rescreened after 7 days) 
3. 
Subject with an New York Heart Association (NYHA) classification equal to IV 
4. 
Subject with an implanted atrial septal defect (ASD) device or patent foramen ovale 
(PFO) device   

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5. 
Subject with a history of surgical ASD or PFO repair 
6. 
Subject with a history of stroke and unrepaired PFO  
7. 
Subject with aortic valve stenosis with valve area <1cm2 
8. 
Subject with mitral valve stenosis with valve area <1.5cm2 
9. 
Subject with aortic or mitral valve regurgitation of Grade 2+ or greater (Grade 2+ is 
defined as jet length ≥ 1.5 and <3.0cm and jet area ≥ 1.5 and <3.0 cm2)  
10. Subject with mitral or aortic prosthetic valve 
11. Subject with left ventricular ejection fraction (LVEF) of ≤ 30 
12. Subject with evidence of pericardial effusion 
13. Subject with complex atheroma with mobile plaque of the descending aorta and/or 
aortic arch 
14. Subject with evidence of an intracardiac thrombus (subject can be rescreened after  
appropriate thrombolytic therapy and confirmed absence of thrombus) 
15. Subject with carotid disease as assessed by the investigator, requiring treatment, 
which includes revascularization and/or medical treatment  
16. Subject with LAA landing zone that measures with a width <12.6mm or >28.5mm (via 
TEE)  
17. Subject without sufficient space (minimum 10 mm) distal to the LAA orifice to 
accommodate insertion of the dilator and sheath (via TEE)  
18. Subject with active infection or active endocarditis 
19. Subject with history of acute or recent myocardial infarction (MI) or unstable angina 
(within six months from the date of signing informed consent)  
20. Subject with a history of hemorrhagic or aneurysmal stroke 
21. Subject with a history of stroke and a Modified Rankin Score of ≥3 
22. Subject with a history of coronary artery bypass graft (CABG) surgery (within six 
months from the date of signing informed consent) 
23. Subject who is/or wishes to participate in any other concurrent clinical trial that may 
confound the results of this study (i.e. AF drug study, RF ablation study for AF) 
24. Subject who has a planned cardioversion within 30 days post-device implantation 
25. Subject who has uncontrolled AF (e.g., resting heart rate>110 bpm) 
26. Subject who has transient AF secondary to surgical procedure or RF ablation 
27. Subject who has a history of thrombosis occurring at a young age (i.e., less than 40 
years of age) 
28. Subject who has a history of idiopathic or recurrent venous thromboembolism 
29. Subject who has a history of thrombosis at an unusual site (cerebral veins, hepatic 
veins, renal veins, Inferior Vena Cava, mesenteric veins) 

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30. Subject who has a history of recurrent thrombosis while adequately anticoagulated  
31. Subject who has uncontrolled hypertension (SBP >180 mm Hg or DBP >100 mm Hg)  
32. Subject who has thrombocytopenia (<100,000 platelets/mm3) or anemia with Hb of< 
10 g/dl  
33. Subject with a history of previous radio frequency (RF) ablation for atrial fibrillation 
34. Subject who has an absolute or relative contraindication to both warfarin and 
dabigatran 
35. Subject who has an absolute or relative contraindication to aspirin 
36. Subject who is on medication which may interact with aspirin, warfarin, or dabigatran 
37. Subject who is on or intends to be on rivaroxaban 
38. Subject who is on aspirin therapy dosage greater than 81 mg/day at time of 
enrollment (Subject may be rescreened after 7 days) 
39. Subject with history of deep vein thrombosis (DVT) or pulmonary embolism within six 
months from the date of signing informed consent  
40. Subjects with an estimated serum creatinine clearance of ≤ 30 ml/min (Cockcroft and 
Gault) 
41. Subject with inferior vena cava (IVC) filter 
42. Subject with a body mass index (BMI) ≥40 
43. Subject with known malignancy or other illness where life expectancy is less than two 
years 
44. Subject who is pregnant or desires to become pregnant during the course of the trial  
45. Subject or legally authorized representative who is unable to provide informed 
consent  
46. Subject who will not be able to be followed for the duration of the clinical trial 
47. Subject with any medical disorder that would interfere with completion or evaluation 
of clinical trial results 
 
2.6 
SUBJECT PARTICIPATION AND INFORMED CONSENT 
Subjects or their legally authorized representative will be informed of the study and invited to 
participate.  Informed consent must be obtained from each subject or legally authorized 
representative prior to any clinical investigation participation (including the Baseline Phase), 
using the Informed Consent Form (ICF) HIPAA authorization form or any other applicable 
permission form(s) required by law approved by the IRB.   The subject/legally authorized 
representative will be provided with a copy of the Informed Consent Form and HIPAA 
authorization form or any other applicable permission form(s) required by law and its content 
will be reviewed verbally with the subject/legally authorized representative by the study 
investigator or authorize delegate, allowing adequate time for review and questions.  The study 
investigator or authorized delegate will fully explain to the subject or legal representative the 

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nature of the research, clinical investigation procedures, anticipated benefits, and potential 
risks of participation in the clinical investigation.  All information pertinent to the study shall be 
provided in writing and in native, non-technical language that is understandable to the subject 
or subject’s legally authorized representative.  
 
Once the subject/legally authorized representative has read and understands the Informed 
Consent Form and HIPAA authorization form or any other applicable permission form(s) 
required by law, he/she will indicate his/her willingness to participate in the study by signing the 
form(s). 
 
If a subject or legally authorized representative is unable to read or write, the informed consent 
shall be obtained through a supervised oral process.  An independent witness shall be present 
throughout the process. Upon completion of the supervised oral process, the Informed 
Consent Form, HIPAA authorization form or any other applicable permission form(s) required 
by law must be signed and dated by the subject or legal representative and by the person 
obtaining the consent attesting that the information was accurately explained and that informed 
consent was freely given. 
 
The informed consent process will be fully documented by the investigator or authorized 
delegate in the medical record and include the date on which the consent was obtained. The 
original signed consent form HIPAA authorization form or any other applicable permission 
form(s) required by law will be retained in the subject’s study records. A copy of the signed 
informed consent HIPAA authorization form or any other applicable permission form(s) 
required by law will be provided to the subject or legal representative and a copy placed in the 
subject’s medical record.   Following signing of the consent and HIPAA authorization form or 
any other applicable permission form required by law  the subject’s eligibility for the study will 
be determined.   
 
If new information becomes available during the study that can significantly affect a subject’s 
future health and medical care, or willingness to continue in the study, that information will be 
provided to the subject(s) in writing. 
 
2.7 
ENROLLMENT 
Subjects will be considered enrolled d in the study after informed consent and HIPAA 
authorization form or any other applicable permission form required by law has been signed 
and the subject has been randomized.  The following terms will be used to describe potential 
study participants who do not fully implement the assigned therapy: 
 
• Non-Consented Screen Failure - Subject who are screened to participate in the study 
but do not sign the Informed Consent Form and HIPAA authorization form or any other 
applicable permission form required by law.  These subjects will not be considered 
enrolled in the study. 
 
• Consented Screen Failure - Subject/legally authorized representative who signs the 
Informed Consent Form and HIPAA authorization form or any other applicable permission 

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form required by law, but the subject does not meet eligibility criteria.  These subjects will 
not be considered enrolled in the study. 
 
• Intent-to-Treat - A subject will be considered part of the intent-to-treat analysis 
population as long as she/he is randomized into the study, with no adjustment made for 
whether the device was implanted, compliance with treatment, or events occurring after 
randomization.  These subjects will be enrolled in the study and included in the primary 
endpoint analysis.  
 
2.8 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
A subject may be considered discontinued from the study if (including but not limited to): 
• Subject/legally authorized representative withdraws consent; 
• Subject is lost to follow-up;* 
• Subject dies; 
• Subject completes the study-required follow-up; 
• Study management decision by Sponsor to end the study as a whole or just at a particular 
study location; 
• Subject discontinued due to medical necessity by investigator or upon request of a 
regulatory body; or 
• Study site prematurely terminates its participation in the study; 
*The following actions will be undertaken prior to categorizing a subject as lost to follow-up. Two attempts 
will be made to contact the subject via phone, email, or mail. If no response is obtained, a registered or 
certified letter will be sent to the subject as a last means of contact. 
 
2.9 
BASELINE EVALUATION 
Informed consent will be obtained from the subject/legally authorized representative prior to 
conducting any study related activities. 
 
The following baseline testing will be performed: 
1. 
Medical History 
2. 
Physical exam (PE) 
3. 
National Institute of Health (NIH) Stroke Scale - All personnel conducting any study 
required NIHSS evaluations are required to have received training and certification per 
nationally accepted guidelines such as American Stroke Association, or American 
Academy of Neurology, or National Institute of Neurological Disorders and Stroke 
4. 
Modified Rankin  
5. 
Magnetic Resonance Imaging (MRI) of the head/brain must include FLAIR, DWI, ADC 
maps, and gradient echo (GRE) among other sequences.  

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Note: If medically contraindicated to MRI, subjects should have a Computed Tomography 
(CT) of the head performed 
6. 
CHADS2 assessment 
7. 
Pregnancy test (required only for females of child bearing potential) 
8. 
12 Lead ECG 
9. 
Transesophageal echocardiography (TEE) - If thrombus is detected, subject may be 
rescreened by TEE, after 12 weeks of anticoagulation therapy for consideration of device 
placement following documentation of absence of intracardiac thrombus 
10. INR assessment (only for subjects who are warfarin therapy) – Subjects on warfarin 
whose INR is not in the target range (at baseline) may return for rescreening once target 
INR is achieved.  During rescreening, subjects must demonstrate two consecutive INRs 
within the target range (2-3). 
11. Medication Determination and Assessment  
OMT and concomitant use of aspirin therapy prior to randomization:  
The principal investigator should determine appropriate OMT and need for concomitant 
aspirin therapy as medically indicated for each subject.  Subjects must remain on the 
assigned OMT (warfarin or dabigatran with or without concomitant aspirin therapy) for one 
month prior to enrollment (defined as time of informed consent, HIPPA and 
randomization).  Should the subject’s medical condition change, the Principal Investigator 
may make changes in the OMT and / or aspirin therapy regimen as needed; however, the 
subject must take the newly assigned OMT for a minimum of one month prior to 
randomization. Re-screening rules pertaining to both inclusion and exclusion criteria will 
apply. All medication changes and accompanying rationale must be documented on the 
medication log. 
12. Hematology Parameters 
a. Hemoglobin 
b. Hematocrit 
c. Serum Creatinine 
d. Platelets 
13. Coagulation parameters 
a. Fibrinogen antigen  
b. Quantitative D-dimer 
c. Von-Willebrand antigen 
d. Thrombin-Antithrombin complex  
e. Prothrombin fragment 1.2 
f. Homocysteine 
g. tPA antigen 
h. PAI-1 antigen 
14. Neurological Symptoms Interview 

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15. Quality of Life Interview (EQ-5D-3L) 
 
2.10 
RANDOMIZATION 
After subject has signed informed consent, HIPAA authorization form or any other applicable 
permission form required by law and meets all inclusion and none of the exclusion criteria, the 
subject will be randomized.  
 
A medical management decision, treatment with warfarin or dabigatran* will be made by the 
principal investigator prior to randomization. The principal investigator must document the 
optimal medical therapy including the concomitant use of aspirin prior to randomization on the 
baseline case report form. Subjects will be randomized to either the device arm or the control 
arm respectively in a 2:1 ratio. Randomization will be stratified by study center, oral 
anticoagulant therapy (warfarin or dabigatran), and baseline concomitant aspirin usage.  
Randomization into the concomitant aspirin strata will be capped at 20% of total study 
enrollment.  
*Dabigatran dosing (75 mg or 150 mg bid) should be in accordance with its approved directions for use. 
 
Subjects in both groups will be assigned a subject ID number at the time of consent. Subjects 
who are randomized to the device arm must follow the pre-procedure care instructions 
(Section 2.11.1). The implant procedure must be performed within fourteen (14) days of 
randomization. 
 
Subjects who are randomized to the control arm must continue taking the OMT that has been 
assigned by the principal investigator until a primary endpoint is met or the study is completed. 
Those subjects on warfarin should maintain an INR between 2-3 with adjustment of dosage as 
needed. Discontinuation of designated OAC (warfarin, dabigatran) or addition of other 
anticoagulants or antiplatelet medications is not allowed unless medically necessary.  
 
2.11 
AMPLATZER CARDIAC PLUG IMPLANTATION PROCEDURE 
 
2.11.1 
PRE PROCEDURE CARE 
 
a. 
Bridge regimen for subjects on warfarin 
• 
Stop warfarin 4 days prior to the day of procedure 
• 
Start Lovenox 2 days prior to the day of procedure at 1 mg/kg 
subcutaneously every 12 hours for 2 days (subjects with renal dysfunction 
may require dosage adjustment as determined by the physician)  
• 
On day of the procedure do not administer Lovenox or warfarin  
 
Example:  Day 5 is day of procedure:  
o 
Day 1 – stop warfarin 
o 
Day 2 – no medications (Lovenox or warfarin) 
o 
Day 3 – begin Lovenox at 1 mg/ kg subcutaneously every 12 hours 

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o 
Day 4 – continue Lovenox at same dosage 
o 
Day 5 - procedure day, no Lovenox (or warfarin)  
 
INR Test 
INR must be tested within 24 hours prior to the procedure. An INR should be 
≤1.5 in order to proceed with the device implantation procedure. 
 
b. 
Bridge regimen for subjects on dabigatran 
 
Discontinue dabigatran 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 
mL/min) before invasive or surgical procedures (see dabigatran prescribing 
information by manufacturer). 
 
 
2.11.2 
PROCEDURE (RANDOMIZED TO DEVICE ARM) 
• 
Procedure must be performed within 14 days from the date of 
randomization. 
• 
Procedure will be performed under TEE and angiographic guidance. 
• 
On an angiogram assessment, if a subject has an LAA landing zone 
measured with a width of less than 12.6mm (at its widest point) or greater 
than 28.5mm at its widest point, the subject will not proceed with device 
implantation. These subjects will be considered intent to treat. 
• 
On an angiogram assessment, if a subject has insufficient space 
(minimum 10 mm) distal to the LAA orifice to accommodate insertion of 
the dilator and sheath, the subject will not proceed with device placement. 
These subjects will be considered as intent to treat. 
• 
Refer to the Instructions for Use for the recommended device size, 
delivery sheath selection, and ACP implantation procedure. 
 
 
 

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2.11.3 ENROLLMENT SCHEME 
 
Potential Subject 
Inclusion/Exclusion 
criteria assessment 
(pre-echo)
Non Consented 
Screen Failure
Informed Consent 
obtained. Baseline 
testing performed 
(including TEE)
All I/E 
criteria met
All I/E 
criteria not 
met
Consented 
Screen 
Failure
Subject 
enrolled and 
randomized
Device Group
Procedure-
follow up 
begins
Control 
Group – 
follow up 
begins
Attempt 
to Treat
First 30 device subjects 
will have 45 day F/U 
and this will constitute 
feasibility data
Enrollment 
halted during 
FDA review
Submit data 
to FDA 
Resume 
enrollment 
following receipt of 
positive response 
from FDA
This section pertains to the feasibility phase which is complete

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2.11.4 
POST PROCEDURE CARE THROUGH HOSPITAL DISCHARGE 
 
2.11.4.1 
Post procedure care for the device arm (for subjects who are randomized 
to the device arm and receive the device) is to be as follows: 
 
• 
Subjects must be kept overnight (24 hour stay) for observation. 
• 
Subjects must return to OMT (assigned by the principal investigator at 
time of randomization) as described below. 
 
2.11.4.1.1  Device Subjects Assigned to Warfarin 
• Subjects will be discharged from the hospital on warfarin (adjustment of 
dosage to keep an INR between 2-3 must be made during the study while 
subjects are on warfarin).Until the subject’s INR is between 2 and 3, 
Lovenox 1mg/kg subcutaneously twice a day should be administered 
starting within 24 hours  after the procedure. 
• INR testing should commence 2-3 days after the initiation of warfarin 
therapy and be tested frequently until a stable dose/INR has been achieved 
and then at least every 4 weeks subsequently. 
 
2.11.4.1.2 Device Subjects Assigned to Dabigatran 
• Dabigatran therapy* should be re-started after wound hemostasis is 
satisfactory in accordance with its approved directions for use). Subjects will 
be discharged from the hospital on dabigatran. Dabigatran dosing* should 
be in accordance with its approved directions for use. 
*Dabigatran dosing (75 mg or 150 mg bid) should be in accordance with its approved 
directions for use. 
2.11.4.2 
Post procedure care for subjects who are randomized to the device arm 
but do not receive a device (or device is removed) is required as follows: 
 
2.11.4.2.1 Device Subjects Assigned Warfarin 
• Subjects are discharged from the hospital on warfarin and will continue to 
take warfarin throughout the duration of the clinical trial (adjustment of 
dosage to keep an INR between 2-3 must be made during the study while 
subjects are on warfarin), or until a primary endpoint is met or the study is 
completed. 
• For attempt to treat subjects who stopped warfarin, until the subject’s INR is 
between 2 and 3, Lovenox 1mg/kg sq, twice a day, should be administered 
starting the day after the procedure. 
• INR testing should commence 2-3 days after the initiation of warfarin 
therapy and be tested frequently until a stable dose/INR has been achieved 
and then at least every 4 weeks subsequently. 

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• Discontinuation of warfarin or addition of other anticoagulants or antiplatelet 
medications is not allowed unless medically necessary. 
 
2.11.4.2.2 Device Subjects Assigned to Dabigatran  
• Subjects will be discharged from the hospital on dabigatran and will 
continue to take dabigatran throughout the duration of the clinical trial or 
until a primary endpoint is met or the study is completed.   
• Discontinuation of dabigatran or addition of other anticoagulants or 
antiplatelet medications is not allowed unless medically necessary. 
 
2.12 
FOLLOW-UP REQUIREMENTS (REFER TO APPENDIX D) 
1. 
Refer to section 2.12.1, 2.12.2, and 2.12.3. 
2. 
Adverse events for all randomized subjects will be collected from the time of informed 
consent through discontinuation or end of the study.  
3. 
For subjects randomized to control arm and those subjects who are randomized to device 
arm but do not undergo an implant attempt, follow-up windows are calculated based on 
the day of randomization. For subjects who undergo an implant attempt and/or receive 
the device, follow-up windows are calculated from the date of procedure.  Subjects who 
are on warfarin should maintain an INR between 2-3 INR levels must be documented on 
an INR log. (REFER TO APPENDIX D) 
4. 
Post procedure TEE requirements for the device arm subsequent to hospital discharge: 
Refer to TEE flow chart below.  
5. 
For subjects randomized to the device arm, once OAC therapy is discontinued, aspirin 
(325 mg daily) must be started and continued throughout the duration of the trial. If the 
subject is already on aspirin 81 mg daily, increase dosage to 325 mg daily. 
6. 
Bacterial endocarditis prophylaxis should be carried out for at least six months post 
procedure (see Appendix C). 
7. 
For subjects who receive the device, a telephone call must be scheduled 3 months (+/- 10 
days) post discontinuation of OAC therapy to inquire if subjects have restarted OAC 
therapy. Telephone call will be documented as an Interim Visit. 
8. 
If during a phone follow-up, a serious adverse event is reported or a response of “Yes” or 
“Don’t know” to any question on Neurological Symptom Interview is elicited, an in-person 
interim office visit is required. 
9. 
If asymptomatic cerebral hemorrhage is detected through imaging, please note that there 
are no standardized clinical guidelines or treatment recommendation for the use of 
antithrombotic therapy based on MR Imaging findings. These subjects in both groups 
(device and medical management) should be managed per institutional or investigator 
standard of care.  
10. As part of the health economic and quality of life sub-study, hospital bills of enrolled 
subjects will be collected up to 2 years or until the study is completed. (REFER TO 
APPENDIX D) 

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Transesophageal Echocardiogram (TEE) Imaging Schedule  
Flow Diagram for Subjects who are randomized to the device arm 
 
 
45 Day Transesophageal 
Echocardiogram Results
(TEE)
Subjects achieve 
complete closure of LAA
(Group A)
Subjects achieve flow 
≤ 3mm jet into LAA
(Group B)
Subjects with > 3mm jet 
into LAA
(Group C)
OAC Discontinued; 
6 month TEE required
OAC Discontinued; 
6 month TEE required
Subjects continue to 
receive OAC; 6 month 
TEE required
6 month Transesophageal 
Echocardiogram Results
(TEE)
Group B 
(≤ 3mm jet at D45) 
achieves complete 
closure of LAA
▪OAC Discontinued; TTE 
required at 12 month and 
2 year to assess for 
thrombus formation
Group C
(>3mm jet at D45)
achieves complete 
closure of LAA
▪OAC Discontinued; TTE 
required at 12 month and 
2 year to assess for 
thrombus formation
▪OAC Discontinued; TEE 
required at 12 month to 
assess for closure & 
thrombus formation
Group C
(>3mm jet at D45)
achieves ≤ 3mm 
jet into LAA
Group C
(>3mm jet at D45)
Jet remains > 
3mm
▪Continue OAC; TEE 
required at 12 month to 
assess for closure & 
thrombus formation
12 month Transesophageal 
Echocardiogram Results
(TEE)
Group C
(>3mm jet at 6M)
Jet remains > 3mm
Group C
(≤3mm or >3mm jet at 6M)
achieves complete 
closure of LAA
Group C
(≤3mm or >3mm jet at 6M) 
achieves ≤ 3mm jet into 
LAA
Continue OAC; TEE 
required at 2 year to 
assess for closure & 
thrombus formation
OAC Discontinued; TEE 
required at 2 year to 
assess for closure & 
thrombus formation
OAC Discontinued; TTE 
required at 2 year to 
assess for thrombus 
formation
Group B
(≤ 3mm jet at D45)
remains ≤ 3mm 
jet into LAA
 

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2.12.1 ASSESSMENT AND FOLLOW-UP SCHEDULE; SUBJECTS WHO RECEIVE THE 
DEVICE (REFER TO APPENDIX D) 
 
1Urine pregnancy test must be done within 24 hours prior to the procedure (for female subjects of childbearing 
potential) 
2Review and record all and any changes to antiarrhythmic and antiplatelet medications 
3INR must be tested within 24 hours prior to the procedure (for those subjects on warfarin).  Post procedure- INR 
testing should commence 2-3 days after the initiation of warfarin therapy and be tested frequently until a stable 
dose / INR has been achieved and then at least every 4 weeks subsequently. Subjects are recommended to 
maintain a target INR between 2-3 while they are on warfarin 
4Follow-up visits after 2 years will be via telephone  
5If during a telephone visit, an SAE is reported or a response of Yes or Don’t know to any question on the 
Neurological Symptoms Interview is elicited an in-person interim office visit is required 
6Refer to flowchart above 
7MRI must include FLAIR, DWI, ADC maps, and GRE among other sequences. If subject is medically 
contraindicated to MRI, a CT of the head must be performed. If asymptomatic cerebral hemorrhage is detected 
through imaging, please note that there are no standardized clinical guidelines or treatment recommendation for 
the use of antithrombotic therapy based on MR Imaging findings. These subjects in both groups (device and 
medical management) should be managed per institutional or investigator standard of care.  
8 This phone visit must be performed 3 months after a subject stops taking OAC (Note: OAC must be discontinued 
once no flow or ≤3mm jet into the LAA (via TEE) has been demonstrated 
One week equals 7 days. One month = 30 days. One year= 365 days 
 
Procedure 
Pre-discharge  
(+ 1 day) 
45 days  
(+/-5 days) 
3 Month (+/- 10 days) 
Post OAC 
Discontinuation 
Phone Visit 8 
6 months 
(+/- 30 days)
12 months  
(+/-30 days) 
18 months 
(+/-60 days)  
2 years 
(+/- 60 days ) 
Annually thereafter 
(+/- 60 days) 
phone visit 4 
Physical Exam 
 
X 
X 
 
X 
X 
X 
X 
 
Neurological Symptoms Interview 
 
 
X 
 
X 
X 
X 
X 
X 5 
Urine Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
12 lead Electrocardiogram  
 
X 
X 
 
X 
X 
X 
X 
 
2-D Color Flow 
 Doppler Transthoracic 
 Echo (TTE) 
 
X 
 
 
 
X 6 
 
X 6 
 
Transesophageal Echocardiogram 
(TEE)  
X 
 
X 
 
 X  
X 6 
 
X 6 
 
MRI of head/brain 7 
 
 
 
 
 
X 
 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessment 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR Assessment 3 
 
 
 
 
 
 
 
 
 
Quality of Life  Assessment(s) 
 
 
 
 
 
X 
 
X 
 

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2.12.2 ASSESSMENT AND FOLLOW-UP SCHEDULE: CONTROL SUBJECTS AND 
SUBJECTS RANDOMIZED TO THE DEVICE AND DO NOT RECEIVE THE DEVICE 
 
Procedure2 
Pre-discharge2  
(+ 1 day) 
45 days  
(+/-5 days) 
6 months 
(+/- 30 days) 
12 months  
(+/-30 days) 
18 months 
(+/-60 days) 
2 years 
(+/- 60 days ) 
Annually 
thereafter 
(+/- 60 days 
phone visit)5 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
 
Neurological Symptoms Interview 
 
 
X 
X 
X 
X 6 
X 
X 6 
Urine Pregnancy Test 
X 1 
 
 
 
 
 
 
 
12 lead Electrocardiogram 
 
X 
X 
X 
X 
X 
X 
 
Transthoracic Echocardiogram (TTE)2 
 
X 
 
 
 
 
 
 
Transesophageal Echocardiogram 
(TEE)2 
X 
 
 
 
 
 
 
 
MRI of head/brain7 
 
 
 
 
X 
 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
INR Assessment4 
 
 
 
 
 
 
 
 
Quality of Life  Assessment(s) 
 
 
 
 
X 
 
X 
 
1For device attempt female subjects of childbearing potential.  Must be performed within 24 hours prior to the 
procedure  
2For device attempt subjects 
3Review and record all changes to antiarrhythmic and antiplatelet medications 
4INR must be tested with 24 hours prior to the procedure for device attempt subjects only (for those subjects on 
warfarin). INR testing should commence 2-3 days after the initiation of warfarin therapy and be tested frequently 
until a stable dose/INR has been achieved and then at least every 4 weeks subsequently. Subjects are 
recommended to maintain a target INR between 2-3 while they are on warfarin 
5Follow-up visits after 2 years will be via telephone 
6If during a telephone visit, an SAE is reported or a response of Yes or Don’t know to any question on the 
Neurological Symptoms Interview is elicited an in-person interim office visit is required 
7MRI must include FLAIR, DWI, ADC maps, and GRE among other sequences. If subject is medically 
contraindicated to MRI, a CT of the head must be performed. If asymptomatic cerebral hemorrhage is detected 
through imaging, please note that there are no standardized clinical guidelines or treatment recommendation for 
the use of antithrombotic therapy based on MR Imaging findings. These subjects in both groups (device and 
medical management) should be managed per institutional or investigator standard of care. 
One week equals 7 days. One month = 30 days. One year = 365 days 

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2.12.3 ASSESSMENT AND FOLLOW-UP SCHEDULE: SUSPECTED STROKE, TIA, OR 
PERIPHERAL THROMBOEMBOLISM 
If stroke, TIA, or peripheral thromboembolism is suspected at any time after randomization, further 
evaluation should be performed within 14 days from the date the site becomes aware of the event. 
For a suspected stroke or TIA, a MRI or CT must be performed within 10 days of the event 
occurrence. For peripheral thromboembolism, evaluate per physician standard of care. All source 
documentation for primary endpoints must be sent in to AGA Medical as soon as possible. 
 
Suspected Stroke or TIA Assessment1 
Neurologic Assessment 
•  NIH Stroke Scale2 
•  Modified Rankin 
MRI (or CT if medically contraindicated to MRI) must be performed 
within 10 days of event (should include FLAIR, DWI, ADC maps, 
among other sequences ) 
•  Submit Report and Films to AGA Medical 
Transesophageal Echo3 
•  Submit Report and Videotape or DICOM CD to AGA Medical 
Follow-up Form 
Adverse Event Form  
1All subjects are followed until completion of trial 
2All personnel conducting any study required NIHSS evaluations are required to have received training and certification per 
nationally accepted guidelines such as American Stroke Association, or American Academy of Neurology, or National 
Institute of Neurological Disorders and Stroke 
3TEE is required only on device subjects with confirmed stroke  
 
Peripheral Thomboembolism1 
Follow-up Form 
Adverse Event Form  
1All subjects are followed until completion of trial 
 
 
2.13 
ADVERSE EVENTS 
2.13.1 UNANTICIPATED ADVERSE DEVICE EFFECT 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan, including a supplementary plan or application, or any other unanticipated serious 
problem associated with the device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3 (s)).   
 
 
 

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2.13.2 ADVERSE EVENTS 
Adverse Events will be classified as Serious Adverse Event, Adverse Event, or Observations. 
 
Serious Adverse Event - is defined as those adverse events resulting in the following:  death, 
life-threatening adverse event, inpatient hospitalization or prolongation of existing hospital stay, 
persistent or significant disability/incapacity, or medically significant event. 
 
Serious adverse events are further classified as either device- or procedure-related. 
 
Adverse Event - is defined as an event which does not meet the definition of a serious 
adverse event but is still an undesirable clinical occurrence and is a negative change from 
baseline, whether or not device related 
 
 Observation - an observation is a subset of adverse events that are usually 
transient and do not require clinician prescribed intervention. The event does not 
generally interfere with usual activities of daily living (e.g. fatigue, common cold, 
strained muscle). 
 
Potential Anticipated Adverse Events include but are not limited to:  
• 
Air embolus – symptomatic event resulting from introduction of air into circulatory 
system 
• 
Allergic contrast reaction – idiosyncratic reaction to contrast used in imaging 
• 
Allergic drug reaction – idiosyncratic reaction to drugs  
• 
Allergic device reaction - idiosyncratic reaction to the device implanted 
• 
Anemia- a decrease in the number of red blood cells (RBC's) or hemoglobin, resulting 
in a lower ability for the blood to carry oxygen to body tissues 
• 
Anesthesia reaction – undesired reaction to anesthetic agent 
• 
Arrhythmia – cardiac rhythm disturbance 
• 
Bacterial endocarditis – inflammation and infection of the heart   
• 
Bleeding – >5g/dl drop in hemoglobin or loss of blood requiring transfusion   
• 
Brachial plexus injury – damage to brachial plexus 
• 
Bruising – blood leakage under the skin at the groin, catheter access site 
• 
Cardiac arrest – failure of the heart to contract 
• 
Cardiac perforation –  penetration of the heart wall 
• 
Cardiac tamponade – constriction of the heart causing inefficient contraction resulting 
from accumulation of excess fluid in the pericardium 
• 
Congestive heart failure – inability of the heart to keep up with its demands, 
specifically, failure of the heart to pump blood with normal efficiency 
• 
Death –  permanent cessation of all vital bodily functions 
• 
Delivery system failure – the cable with the screw mechanism that the device is 
attached to when it is being placed in the heart does not work properly 

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• 
Device embolization – movement of  device from its intended location 
• 
Device thrombus – blood clot on the device 
• 
Device migration – movement of device within the intended location 
• 
Dyspepsia - indigestion 
• 
Erosion - rubbing of device against myocardium or cardiac structure 
• 
Fever – defined as body temperature greater than 101.5° F 
• 
Foreign body embolization – movement of device material, delivery system material, 
or other material from its intended location 
• 
Gastrointestinal pain and/or bleeding – pain or bleeding in the gastrointestinal tract 
• 
Hypotension – sustained systolic BP < 40mmHg 
• 
Hypertension – Systolic blood pressure of >160mmHg 
• 
Hypoventilation – the state in which a reduced amount of air enters the  in the lungs  
• 
Hemorrhagic Stroke - acute focal neurological deficit presumed to be due to focal 
ischemia, with either symptoms persisting 24 hours or greater, or symptoms persisting 
less than 24 hours,  associated with MR or CT findings of a new, neuroanatomically 
relevant, cerebral infarct with hemorrhagic conversion 
• 
Infection – invasion and growth of a pathogenic organism within the body  
• 
Ischemic Stroke –  acute focal neurological deficit presumed to be due to focal 
ischemia, with either symptoms persisting 24 hours or greater, or symptoms persisting 
less than 24 hours,  associated with MR or CT findings of a new, neuroanatomically 
relevant, cerebral infarct  
• 
Myocardial infarction (heart attack) – the death of heart muscle from the sudden 
blockage of a coronary artery by a blood clot   
• 
Myocardial ischemia – inadequate blood flow to the heart 
• 
Nickel sensitization- alteration of the responsiveness of the body to nickel 
• 
Pericardial effusion – abnormal fluid collection around heart without hemodynamic 
compromise 
• 
Peripheral thromboembolism – blood clot in the peripheral vasculature 
• 
Perforation – physical penetration of vessel or organ 
• 
Pleural Effusion - abnormal fluid collection around the lungs 
• 
Renal failure – inability of kidneys to perform normal functions 
• 
Respiratory failure – inability of the lungs to perform normal functions  
• 
Respiratory insufficiency – the condition in which the lungs cannot take in sufficient 
oxygen or expel sufficient carbon dioxide to meet the needs of the cells of the body  
• 
Seizure – uncontrolled electrical activity in the brain, which may produce a physical 
convulsion, minor physical signs, thought disturbances, or a combination of symptoms 
• 
Sepsis – the presence of bacteria or other infectious organisms or their toxins in the 
blood or in other tissue of the body  

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• 
Septicemia – systemic (body wide) illness with toxicity due to invasion of the 
bloodstream by virulent bacteria coming from a local seat of infection 
• 
Systemic Embolism - an abrupt vascular insufficiency associated with clinical and 
radiological evidence of arterial occlusion in the absence of another likely mechanism 
• 
Thrombus – a blood clot 
• 
Thrombophlebitis - inflammation of a vein due to a blood clot 
• 
Tissue damage - damage to cardiac tissue 
• 
Transient Ischemic Attack (TIA) - acute focal neurological deficit (such as focal motor 
deficit, aphasia, difficulty walking, hemisensory deficit, amaurosis fugax, blindness, or 
focal visual deficit) presumed due to focal ischemia, with symptoms persisting greater 
than or equal to 5 minutes and less than 24 hours, that is not associated with MR or CT 
findings of a new cerebral infarct 
• 
Valvular regurgitation / insufficiency –  backflow of blood during contraction of the 
heart; caused by a defective heart valve 
• 
Vascular dissection - the process of cutting apart or separating vessel tissue  
• 
Vascular access site injury – damage at vascular access site (e.g., AV fistula, 
hematoma, and aneurysm) 
 
2.14 
ADVERSE EVENT REPORTING 
2.14.1 REPORTING ALL ADVERSE EVENTS 
Investigators are responsible for promptly reporting all adverse events to AGA Medical 
by completing the Adverse Event CRF.  All unresolved adverse events should be 
followed by the investigator until resolution; Adverse Event Follow-up CRF(s) must be 
completed. 
 
2.14.2 REPORTING UNANTICIPATED ADVERSE DEVICE EFFECTS 
An investigator shall submit to the Sponsor and the reviewing IRB a report of any 
unanticipated adverse device effect occurring during an investigation as soon as 
possible, but in no event later than ten (10) working days after the investigator first 
learns of the effect (21 CFR 812.150 (a) (1)). 
 
2.15 
HYPOTHESIS AND STATISTICAL ANALYSIS 
The ACP will be clinically evaluated for safety and effectiveness in subjects with nonvalvular 
atrial fibrillation who are at risk for ischemic strokes, and peripheral thromboembolism through 
a two arm, randomized, multi-center, controlled clinical trial.  Subjects will be randomized to 
either the device arm or the control arm.  The randomization ratio of device subjects to control 
subjects will be 2:1, that is, twice as many subjects will receive the device than receive 
warfarin therapy. The randomization will be stratified by study center, oral anticoagulant 
therapy (warfarin or dabigatran), and baseline concomitant aspirin usage.  The ACP clinical 
trial will have two groups of subjects.  The first 30 device subjects (plus any subjects with 
implant attempts) will constitute the feasibility group and all subjects (including the feasibility 

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group) will constitute the pivotal group.  The primary safety and efficacy analysis will consist of 
all randomized subjects.   
 
2.15.1 Feasibility Subset 
The first 30 subjects who receive the ACP device (plus any subjects with device implant 
attempts), will compose the feasibility subset.  The primary aim of this subset is to 
assess the incidence of serious adverse events (SAE) in the first 45 days after 
procedure.  The 45-day SAE and TEE data for these first 30 device subjects will be 
submitted to the FDA.  Enrollment will halt while the 30 day safety data are collected, 
analyzed, and submitted to FDA for review, although follow-up will continue among the 
device and control subjects already enrolled in the trial.  The DSMB and/or CEC will 
also review this data prior to submission. 
 
The date of the first attempted implant procedure will determine the subjects that qualify 
for this group.  Since it may be difficult to determine which subject had the 30th ACP 
implant procedure, any subject with the same initial procedure date as another subject 
in this group will be reported among the feasibility group.  This may increase the 
feasibility sample size beyond 30 subjects.  In addition, subjects with an attempted, but 
not implanted device will be analyzed in this group but will not count towards the limit of 
30; this may also increase the sample size beyond 30 subjects. 
 
2.15.2 Pivotal Group 
This group will consist of any subject in the study, randomized to either the device arm 
or the control arm (subjects treated with warfarin and dabigatran) in either the feasibility 
or pivotal group. 
 
2.15.3 Study Design (REFER TO APPENDIX D) 
The study is intended to determine the difference in efficacy and safety between the 
device arm and control arm (subjects treated with OMT). 
 
The ACP clinical trial is an adaptive design with interim sample size analyses that use 
current data and project the necessary sample size and follow-up time based upon 
observed efficacy and safety event rates in the device and control subjects. 
 
Three primary endpoints and hypotheses are being evaluated in the ACP clinical trial 
 
1. 
An efficacy endpoint which compares the 2-year event rates of ischemic stroke and 
peripheral thromboembolism.  This is a non-inferiority analysis where the device 
will be deemed efficacious if the risk ratio is < 1.75 or the risk difference in two 
years event rates is < 2.87. 
2. 
 A long-term safety endpoint which compares long-term composite rates of all-
cause mortality and major bleed.  This is a superiority analysis where the device 
will be deemed safe if the safety event rate in the device arm is proven superior to 
the safety event rate in the control arm (OMT). 
3. 
An acute safety (short-term) endpoint which compares the rate of device or 
procedure related serious adverse events against a performance goal (PG). If this 

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rate is less than 5%, the device is considered to have met the acute safety 
endpoint. 
 
The primary efficacy and primary long-term safety hypotheses are included in the 
adaptive design.  The study will accrue subjects until there is high predictive probability 
that the sample size is sufficient to meet the efficacy and long term safety endpoints or 
until it is evident that in spite of enrolling to the maximum sample size it is unlikely to 
meet the efficacy and long-term safety endpoints. 
 
The analysis for the primary acute safety endpoint will be performed on the entire 
sample size as determined by the adaptive design governed by the efficacy and long 
term safety endpoints. 
 
The ACP clinical trial is powered to concurrently prove the non-inferiority efficacy 
endpoint, along with the acute and long-term safety endpoints.  The precise follow-up 
time may vary in this adaptive design. 
Interim sample size analyses will be performed when 400 subjects are enrolled, then 
again every 50 subjects until a possible maximum of 3000 subjects are obtained.  Once 
subject accrual is stopped and the predictive probability of trial success for both efficacy 
and long-term safety is high, all subjects will be followed for at least 6 months. 
Additional analyses will be performed at 12, 18, and 24 months after accrual stops if the 
primary endpoints have not been met. For all subjects, assessment of primary 
endpoints begins at the time of randomization.  Type I error is controlled for multiple 
sample size selection analyses and for multiple potential analyses at the end of accrual. 
 
The statistical model is described in detail in subsequent sections.  But at each interim 
analysis, two predictive probabilities are calculated: 
 
a. 
The predictive probability of meeting the non-inferiority criteria for efficacy and the 
superiority criteria for long-term safety is calculated if subject accrual is stopped at 
the current sample size and enrolled subjects are continued to be followed for an 
additional two years.  If this joint predictive probability exceeds the predictive 
success stopping boundaries, Sn, in Table 1, then accrual stops and enrolled 
subjects are continued to be followed.  The first possible final analysis may be 
performed in 6 months with subsequent analyses possible at 12, 18, and 24 
months after accrual ends. 
 

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Table 1: Cutoffs for stopping the trial forpredicted success, Sn, or failure, Fn.   
 
Stopping Boundaries 
n 
S
n 
Fn 
400 ≤ n < 500 
0.97 
0.00 
500 ≤ n < 600 
0.97 
0.01 
600 ≤ n < 700 
0.95 
0.02 
700 ≤ n < 800 
0.95 
0.03 
800 ≤ n < 900 
0.95 
0.04 
900 ≤ n < 1000 
0.95 
0.05 
1000 ≤ n < 3000 
0.90 
0.05 
 
b. 
The predictive probability of meeting the non inferiority criteria for efficacy and 
the superiority criteria for long-term safety is calculated if subject accrual is 
continued to the 3000 subject study maximum and then continue to follow all 
subjects for additional 2 years.  If this predictive probability is less than the futility 
stopping bounds, Fn, in Table 1, then accrual ends and the trial stops for futility. 
 
The total enrollment in the study will be a minimum of 400 and a maximum of 3000 
subjects.  Since the first interim analysis after the halting of subject accrual will be 
performed at six months, the minimum follow-up for any subject not lost to follow-up in 
the trial will be six months.  The maximum length of follow-up will be the total duration of 
the trial plus at least 6 months (up to 2 years).  Even if the trial stops for predicted 
success at the first interim analysis, with the expected accrual rate of 25 subject-per-
month, the efficacy and safety are demonstrated at the first analysis at 6 months and 
250 subjects would have 1 or more years of follow-up.  This is the minimum possible 
exposure.  As demonstrated in the operating characteristics (2.15.5), longer trials are 
expected. 
 
2.15.3.1 
Adaptive Design 
The efficacy and long-term safety endpoints are modeled separately, but their combined 
probability of success is incorporated throughout the adaptive design.  Statistical 
models for each are described separately in the following sections. 
 
2.15.3.2 
Primary Effectiveness Endpoint and Hypothesis 
The primary effectiveness endpoint for the ACP study is the two-year annualized rate of 
ischemic stroke and peripheral thromboembolism.  The rate will be calculated in each 
treatment arm using a piecewise exponential model (non-constant hazard rate) and 
assessing the number of primary endpoint events divided by the number of subject-
years of follow-up within each timeframe.  The 2-year event rate is then found by the 
product of not having an event during each segment.  For subjects who have already 
experienced an endpoint, additional endpoints or follow-up time will not be factored into 

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this calculation.  If a subject experiences a non-fatal safety event, he or she is still 
tracked for efficacy events. 
 
Separate estimates will be performed for the posterior probability distributions for the 
two-year event rate in the subjects randomized to the device arm and for the two-year 
event rate for subjects randomized to the control arm.  Once these estimates are 
obtained, the posterior probability distributions for both the risk ratio (device rate / 
control rate) and risk difference (device rate minus control rate) will be calculated.  
 
Non-inferiority criterion will be considered met if either the hazard ratio of device to 
control rate is significantly less than 1.75, or if the risk difference is less than 2.87 
percentage points.   
 
Let πDEVICE be the primary effectiveness endpoint rate in the device arm, while πCONTROL 
is the corresponding rate in the control arm. Specifically, the following null and 
alternative hypotheses will be tested: 
 
H0: πDEVICE / πCONTROL > 1.75 
Ha: πDEVICE / πCONTROL < 1.75 
 
where πDEVICE equals the two-year event rate in the device arm and πCONTROL equals the 
two-year efficacy event rate in the control arm. The null hypothesis will be rejected and 
non-inferiority to OMT will be concluded if the upper bound of the two-sided 97.6% 
Bayesian confidence interval for the ratio between the device rate and control rate is 
less than 1.75.  This is equivalent to testing whether the posterior probability, Pr(πDEVICE 
/ πCONTROL > 1.75) > 0.988. 
 
 
For the Risk Difference, the following hypotheses will be tested. 
 
H0: πDEVICE- πCONTROL > 2.87% 
Ha: πDEVICE - πCONTROL < 2.87%   
 
 
 
The null hypothesis will be rejected and non-inferiority to OMT will be concluded if the 
upper bound of the two-sided 97.6% Bayesian confidence interval for the difference 
between the two-year device rate and two-year control rate is less than 2.87%. This is 
equivalent to testing whether the posterior probability, Pr(πDEVICE / πCONTROL > 1.75) > 
0.988. 
 
97.6% confidence intervals are used so that the Type I error for the composite 
hypothesis test is not above a one-sided 2.5%. 
 
With this combination of allowable risk ratio (1.75) and risk difference (2.87%) the Type I 
error rate is highest at πCONTROL = 3.82% and πDEVICE = 6.69 -- the point where πDEVICE / 

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πCONTROL = 1.75 and πDEVICE - πCONTROL = 2.87%.  The type I error rate for this scenario is 
shown in Table 5. 
 
If the device endpoint rate is shown to be successful for non-inferiority to control, it will 
then be tested for superiority.  In that event, the following null and alternative 
hypotheses will be tested: 
 
H0: πDEVICE - πCONTROL > 0 
Ha: πDEVICE - πCONTROL < 0 
 
While the above hypotheses are stated as a subtraction of rates, it is equivalent to 
testing whether the ratio of the rates is lower than 1.0. 
 
The following describes the Bayesian adaptive design for the primary efficacy endpoint.  
This design was created by Berry Consultants, (Austin, Texas) using the specific model 
assumptions for this trial. 
 
The two-year event rates are calculated using a piecewise exponential model that 
recognizes that event rates may change during the course of subject follow-up. 
 
The control arm uses a 7-piece model while the device arm uses an 8-piece model as 
described below: 
 
Time intervals for the control arm:  
• 
Day 0- Day 6 
• 
Day 7- Day 30 
• 
Day31- Day 60 
• 
Day 61- 6 months 
• 
6 months-12 months 
• 
12 months -18 months 
• 
18 months-24 months  
 
Time intervals for the device arm:  
• 
Day 0 (randomization) to Day before Procedure Day (the procedure must occur 
by 14-days after randomization) 
• 
Procedure Day to Procedure Day + 6 days 
• 
Procedure Day + 7 days to Day 30 
• 
Day 31- Day 60  
• 
Day 61- 6 months 
• 
6 months -12 months 
• 
12 months-18 months 
• 
18 months-24 months  
 

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For tracking events and exposure, the last interval is open ended.  This ensures all 
events observed are counted (e.g. an event that occurs at 2 years + 1 day will count 
toward the composite 2-year event rate by contributing to the 18-24 month interval).  
 
The segments comprising the piecewise exponential are slightly different in the first 30 
days between the two treatment arms.  The benefit of this model is that it separately 
estimates: 
• the risk from randomization to procedure (procedure day varies by 
subject, may range from 0 to 14), 
• risk on the day of procedure and immediately afterward (a 7-day period 
for all subjects) and 
• the risk in remainder of the first month (segment varies by subject, may 
range from 9 to 23 days) 
 
The segments in the piecewise exponential are the same for the control and device 
arms after 30-days:  30-60 days, 61 days-6 months, then 6-month intervals thereafter. 
 
The segments for the control arm (G=1) and device arm (G=2) are formally: 
 
λG=C(t) =
λC,1
1≤t < 7
λC,2
7 ≤t < 30
λC,3
30 ≤t < 60
λC,4
60 ≤t <182.5
λC,5
182.5 ≤t < 365
λC,6
365 ≤t < 547.5
λC,7
547.5 ≤t < 730
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
λG= D(t) =
λD,0
0 ≤t < ProcDay
λD,1
ProcDay ≤t < ProcDay + 7
λD,2
ProcDay + 7 ≤t < 30
λD,3
30 ≤t < 60
λD,4
60 ≤t <182.5
λD,5
182.5 ≤t < 365
λD,6
365 ≤t < 547.5
λD,7
547.5 ≤t < 730
 
 
 
 
 
  
 
 
 
 
 
 
 
 
For estimating the two-year event rates the exponential distribution and the at-risk time 
in each period is used.  For estimating the two-year event rates in the device arm, it is 
assumed that the procedure takes place on day 10 following randomization. 
 

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(
)
(
)
7,
6,
5,
4
,
3,
2
,
1,
5.
182
5.
182
5.
182
5.
122
30
24
6
exp
1
)
Group
 
Control
in 
 
years
 2
by 
Event 
Pr(
C
C
C
C
C
C
C
C
λ
λ
λ
λ
λ
λ
λ
π
+
+
+
+
+
+
−
−
=
=
 
 
 
πD = Pr(Event by 2 years in ACP Device Group)
=1−exp −10λD,0 + 7λD,1 +13λD,2 + 30λD,3 +122.5λD,4 +182.5λD,5 +182.5λD,6 +182.5λD,7
(
)
(
) 
 
A sensitivity analysis will also calculate the posterior distributions for 2-year event rates 
based upon the observed average day of procedure and compare it to the a priori 
assumption of Day 10 (assuming it takes on an average 10 days for procedure to 
occur).  The fixed value of day 10 is important for the algorithm used at each interim 
analysis of the adaptive design. 
 
Each piecewise event rate estimate uses a vague prior distribution in both the device 
and control arms. 
 
λG, j ~ Γ(a = 0.0000438,b =1.0) 
 
Where G=D or C for the event or device arm, respectively.  Upon observing EVj events 
during EXPj subject-days of follow-up in group j, the posterior distribution becomes: 
 
λG, j | EVG, j,EXPG, j ~ Γ(a + EVG, j,b + EXPG, j) 
 
The model is parameterized in terms of subject-days.  This prior has mean 0.016 events 
per subject-year (365 × a ÷ b = 0.016) and has the equivalent of just one subject-day of 
follow-up. Therefore the prior is rapidly overcome by the accumulating data. 
 
Once posterior distributions are obtained for each segment, one can calculate the 
posterior distribution for each two-year event rate, and then calculate the posterior 
distribution  for πD/πC and πD - πC  If Pr(πD/πC < 1.75 |  EVC, EXPC, EVD, EXPD) > 0.988 or 
Pr(πD - πC < 0.0287 |  EVC, EXPC, EVD, EXPD) > 0.988, then the null hypothesis will be 
rejected and the trial will conclude that the relative risk is less than 1.75 and/or risk 
difference is less than 2.87%.   
 
As long as the trial does not stop for futility, up to four predefined analyses will be 
performed. The first analysis will occur 6 months after the final subject is randomized.   
If non-inferiority for efficacy and superiority for safety are not declared, subsequent 
analyses will be performed every 6 months with the final analysis 24 months after the 
final subject is enrolled and randomized.  A 98.8% posterior probability will be used, this 
is equivalent to a two-sided equitailed 97.6% CI.  This is to conserve Type I error at 
2.5% -- Type I error can be inflated in three ways in the efficacy part of the trial: 
because the risk ratio or risk difference may be used to demonstrate non-inferiority, 
because multiple same size looks are made, and because 4 possible final analysis 
between 6 and 24 may be conducted. 
 

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The trial will stop in one of three circumstances:  (a) the trial stops early for futility, (b) 
the non-inferiority definition is not met by any of the 4 analysis -6, 12, 18, or 24 months 
after the final subject is randomized, (c) the non-inferiority definition is met in one of the 
four analyses described above. Only circumstance (c) results in an efficacy success.  
 
2.15.3.3 
Primary Effectiveness Endpoint Interim Analyses 
The interim sample size analyses within the adaptive design will be used to 
determine sample size.  At each interim analysis predictive probabilities of trial 
success are calculated based upon the current sample size and enrolling to the 
maximum sample size. 
 
Once 400 subjects are enrolled, then again for every 50 subjects up to a 
maximum of 3000, an analysis will be performed that could stop the study for 
futility, or stop accrual if there is a sufficient predictive probability of showing 
success.  The interim analyses are used solely to select a sample size.  If accrual 
ends for predicted success, then the final analyses are conducted as described 
in the previous section starting six months later. 
 
 
At each interim analysis, observe the number of composite events, EVG,j,  and 
subject-years of follow up, EXPG,j, in interval j, for group G = C (control) or D 
(device) for each segment.  Using the informative prior  
 
λG, j ~ Γ(a = 0.5,b =11406.25) 
 
the current posterior probability distribution for each event rate is calculated 
 
λG, j | EVG, j,EXPG, j ~ Γ(a = 0.5 + EVG, j,b =11406.25 + EXPG, j) 
 
The mildly informative prior has the equivalent of one-half a subject’s worth of 
information with a mean of 0.016 events per subject year within each segment 
(365 × 0.5 ÷ 11406.25 =0.016 events per subject-year).  These priors are used 
only to help select the sample size – they are not used for the final analysis.  
Again the prior is in patient-days of exposure, but we transform these to 2-year 
event rates in the analysis. 
 
Subjects who have experienced an endpoint event provide complete data. 
Subjects who have not experienced an event inform the posterior distribution 
through their exposure time. But whether and when such a subject will 
experience an event remains uncertain, and therefore it has a probability 
distribution. Based on the posterior distributions of the λG,j at each analysis one 
can find the predictive distributions of the number of events (and their timing) for 
all subjects currently in the trial (by treatment arm) if they continue to be tracked. 
 

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This probability is calculated by first sampling each λG,j from their respective 
posterior distribution and using a sect of logical statements constructing if and 
when each subject would experience an event within the remaining trial duration.  
Then each simulation for each ‘completed trial’ can total the number of observed 
events, EV*G (EVG will have been truly observed and the rest imputed) and total 
exposure EXP*G.  Then using this set of piecewise exponentials, the posterior 
distribution for the 2-year event rate πG, is calculated for each group.  This is 
used to track whether Pr(πD/πC  < 1.75) > 0.988 and/or Pr(πD – πC < 2.87%) > 
0.988.  This process is repeated 1000 times which has the effect of integrating 
over the uncertainty present in the current distribution of πj . The proportion of 
simulations in which Pr(πD/πC  < 1.75) > 0.988 and/or Pr(πD – πC < 2.87%) > 0.988 
is the predictive probability of demonstrating non-inferiority for efficacy.   
 
Because there may be little long-term follow-up at the early interim analyses it is 
assumed that λC,5=λC,6=λC,7 and λD,5=λD,6=λD,7 in the interim analyses.  Again this 
assumption is only used during the interim analyses to select sample size.  The 
final analysis uses the model where each segment has its own distribution. 
 
2.15.3.4 
Primary Safety Endpoints and Hypotheses 
The primary safety endpoint for the ACP study has two components: acute 
safety and long-term safety. 
 
a. 
Acute safety consists of procedure related serious adverse events that 
qualify as one of the following: 
 
• procedure-related death (i.e., death occurring during the implantation 
procedure). 
• pericardial effusion requiring treatment. 
• device embolization. 
• access site-related bleeding requiring transfusion ≥ 2 units. 
• damage to other cardiac or major non-cardiac cardiovascular 
structures 
 
The acute analysis does not inform the adaptive design in that its 
probability of success does not affect the adaptive sample size algorithm.  
 
In the acute safety analysis, the rate of device or procedure related 
serious adverse events from the time of randomization until hospital 
discharge is compared against a performance goal (PG) of 5.0% chosen 
from the literature. 
 
Let πDEVICE be this pre-discharge event rate in the device arm.  
Specifically, the following null and alternative hypotheses will be tested: 
 

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H0: πDEVICE ≥ (PG = 5.0%)  
Ha: πDEVICE < (PG = 5.0%) 
 
The null hypothesis will be rejected and the performance goal will be 
considered met if the upper bound of the one-sided confidence interval for 
the device rate is less than 5.0%. 
 
b. 
Long-term safety events can occur in either the device arm or the control 
arm and consist of the following: 
 
1. 
All-cause death; or 
2. 
Major bleeding defined as: 
a. Symptomatic intracerebral or intraventricular hemorrhage; or 
subdural, subarachnoid, epidural, or ocular hemorrhage; or  
b. Major non-cerebral bleed-defined as transfusion requiring ≥ 
2units, hospitalization requiring any transfusion or surgical or 
percutaneous interventional procedure to treat bleeding 
 
Note: procedure-related pericardial effusions requiring 
treatment will not be counted as a major non-cerebral bleed 
 
Subjects who experience a non-fatal efficacy event are still followed and included 
in the safety analysis. 
 
The long-term safety analysis is a two-arm analysis that compares the safety 
events defined above between the device and the control arm.  For both the 
device arm and the control arm, the events will be evaluated from the time of 
randomization until two years.  This analysis will test for superiority of the device 
arm versus the control arm. 
 
Let γDEVICE be the long-term safety endpoint rate in the device arm, while γCONTROL 
is the corresponding rate in the control arm. Specifically, the following null and 
alternative hypotheses will be tested: 
 
H0: γDEVICE / γCONTROL > 1.0 
Ha: γDEVICE / γCONTROL < 1.0   
 
 
 
The null hypothesis will be rejected and superiority to warfarin therapy will be 
concluded if the upper bound of the two-sided 98.4% confidence interval for the 
ratio between the device rate and control rate is less than 1.0. 
 
To test this, the number of events, EVSG and amount of exposure EXPSG are 
tracked within each group.  Vague gamma priors are employed for the safety 
event rates in each group G=C for control or D for device. 
 

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γG ~ Γ(0.0002356, 1) 
 
that have mean 0.086 events per subject-year (365 × a ÷ b = 0.086) with the 
equivalent of one subject-day of follow-up.  The posterior distributions become 
 
γG  | EVS G, EXPS G ~  Γ(0.0002356 + EVS G + , 1 + EXPS G) 
 
Each final analysis calculates the posteriors for the device (G=D) and control 
(G=C) groups and the posterior distribution for the risk ratio γD / γC. If the 
equitailed 98.4% confidence interval is less than 1.0, then the long-term safety 
rate is proven superior to control.  This is the equivalent of Pr(γD / γC < 1.0) > 
0.992. 
 
2.15.3.5 
Long-term Safety Interim Analyses 
Similar to the primary efficacy endpoint, an interim analysis is performed to 
determine the long-term safety. This analysis will be performed after 400 subjects 
are enrolled and will occur at every 50 subjects enrolled up to a maximum of 
3000 to calculate the predictive probability.    
 
At each interim analysis, observe the number of long-term safety events, EVSG, 
and subject-years of follow up, EXPSG, in each group G = C (control) or D 
(device) for each segment.  Using the informative prior  
 
γG ~ Γ(a = 0.5,b = 2122.093) 
 
the current posterior probability distribution for each event rate is calculated 
 
γG | EVSG,EXPG ~ Γ(a = 0.5 + EVSG,b = 2122.093+ EXPSG) 
 
The mildly informative prior has the equivalent of one-half a subjects worth of 
information with a mean of 0.086 events per subject year (365 × 0.5 ÷ 
2122.093=0.086 events per subject-year).  These priors assist in selecting the 
sample size and are not used for the final analysis. 
 
Subjects who have experienced a long-term safety endpoint event provide 
complete data. Subjects who have not experienced such event inform the 
posterior distribution through their exposure time. But whether and when such a 
subject will experience an event remains uncertain, and therefore it has a 
probability distribution. Based on the posterior distributions of the γG at each 
analysis the predictive distributions of the number of safety events (and their 
timing) can be determined. This determination can be made for all subjects 
currently in the trial (by treatment arm) if they continue to be tracked. 
 
This probability is calculated by first sampling γG from its respective posterior 
distribution at the current interim analysis, then times to safety events are 

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generated for all subjects remaining at risk at the interim analysis (these events 
may be censored as time left in trial is accounted for). Using this full dataset 
imagining the subjects are tracked for an additional time period, one can 
calculate the total number of events EVS*G and exposure time EXPS*G in each 
group.  Once this is obtained, a final analysis is performed using the methods 
described in the previous section and calculate the Pr(γD/γC < 1.0).  If this value is 
greater than  0.992 it predicts a win on the long-term safety endpoint.  Repeating 
this process 1000 times at each interim analysis estimates the predictive 
probability of demonstrating long-term safety superiority. 
 
2.15.3.6 
Predictive Probability Calculations 
 
The predictive probabilities of meeting the non-inferiority efficacy goal and 
superiority safety goal are calculated at each interim analysis as described in 
sections 2.15.3.3 and 2.15.3.5.  Likewise the joint predictive probability of 
achieving the efficacy and safety goals are calculated assuming accrual stops at 
the current sample size and if it continues to the maximum sample size.  
 
Pn,n is the predictive probability of demonstrating non-inferiority (via the risk ratio 
OR the risk difference) for efficacy AND superiority for long-term safety if the 
study stops accruing subjects and wait for 24 months to perform the final 
analysis. 
 
By continuing to enroll from the current sample size n subjects to the  3000 
subject  maximum, and then tracking all subjects another 2-years, , the predictive 
probability Pn,3000 of demonstrating non-inferiority (via the risk ratio OR the risk 
difference) for efficacy AND superiority for long-term safety can be calculated. 
 
If Pn,n is large, then there is a high probability that stopping accrual and following 
subjects for an additional two years will result in a final analysis that 
demonstrates sufficient efficacy and long-term safety.   If Pn,n > Sn (as shown in 
Table 1) then the DSMB and/or CEC is informed that the algorithm indicates that 
accrual should stop.  
 
If Pn,3000 < Fn, then there is a small chance of trial success even if the study runs 
to its maximum sample size and again the DSMB/CEC will be informed that the 
algorithm indicates that the trial should stop for futility. The subjects will be 
informed of this circumstance and enrollment will end. Enrolled subjects will be 
followed for a total of additional two years.  
 
If Fn < Pn,3000 and Pn,n > Sn, the enrolling of subjects continues. Another sample 
size re-estimation will be performed once another 50 subjects are enrolled.  
Sample size analyses continue every 50 subjects until Pn,n > Sn, or Pn,3000 < Fn, or 
the maximum number of subjects,3000, is reached.  
 

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If Pn,n > Sn or the maximum number of subjects is obtained, analyses will be 
performed every 6 months as described in the previous section up to 24 
months after the date the last patient is enrolled.  
 
2.15.4 Analysis of Secondary Endpoints (REFER TO APPENDIX D) 
Three comparisons for secondary endpoints will be made between the OMT 
control group and the device group at the end of the trial. The secondary 
endpoints of rate of TIA and asymptomatic intracerebral or intraventricular 
hemorrhage will be considered for labeling. Therefore a Type I error rate of 
0.05/2 =.025 for each of these two endpoint analysis will be used. 
 
• Rate of Transient Ischemic Attacks - The rate of TIAs will be compared 
between the device arm and control arm and tested for significance.  The null 
and alternative hypotheses for this comparison are given below: 
 
           H0:  τDEVICE = τCONTROL 
                HA:  τDEVICE ≠ τCONTROL 
 
where τDEVICE is the rate of TIAs in the device arm per 100 subject years, while 
τCONTROL is the corresponding rate in the control arm.  The test will be a two sided 
test with a Type I error of 0.025.  However superiority will only be claimed if the 
observed rate of TIAs in the device arm is less than the control rate.   The TIA 
events are expected to be Poisson distributed. However, unlike the primary 
effectiveness endpoint it will be tested for superiority rather than non-inferiority. 
 
The expected rate of TIAs in the control arm is expected to be 1.1 events per 100 
subject years.  This estimate is made from combining results found in meta-
analyses by Aguilar (2008) and Reynolds (2004).  The expected rate in the 
device arm is not known, but expected to be lower since TIAs are correlated with 
stroke. 
 
• Asymptomatic intracerebral or intraventricular hemorrhage - The rate of 
asymptomatic intracerebral or intraventricular hemorrhage will be summarized 
for differences between the device and control arms   
 
           H0:  φDEVICE = φCONTROL 
                HA:  φDEVICE ≠ φCONTROL 
 
where φDEVICE is the rate of hemorrhage in the device arm per 100 subject years, 
while φCONTROL is the corresponding rate in the control arm.  The test will be a two 
sided test with a Type I error of 0.025.  However superiority will only be claimed if 
the observed rate of hemorrhage in the device arm is less than the control rate.   
The hemorrhage events are expected to be Poisson distributed. However, unlike 
the primary effectiveness endpoint it will be tested for superiority rather than non-
inferiority. 

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• Atrial fibrillation status - The rate of atrial fibrillation status, defined as 
subjects who progress from paroxysmal to persistent AF, or subjects who 
progress from persistent to permanent AF, will be summarized for differences 
between the device and control arms.  The rates for each group will be 
summarized, and the difference between the two expressed as an estimate 
with a corresponding two sided 95% confidence interval. This endpoint will 
not be considered for labeling purposes. 
 
While the above endpoints will compare the two treatment arms, the following 
endpoints will only be assessed in the device arm.  They will be summarized as 
estimated rates with corresponding two sided 95% confidence intervals.  No 
formal hypotheses will be performed for these tests. 
 
• Device or Procedure Related Adverse Events - The rate of the following 
device or procedure related adverse event components will be summarized.  
However confidence intervals will only be summarized for the composite 
rate, that is, for the percentage of subjects who experience any one of these 
events.  
 
• Device embolization 
• Myocardial perforation (hemopericardium) or any pericardial 
effusion requiring drainage 
• Endocarditis 
• Thrombus on device 
 
• In-hospital procedure success: Successful implantation of the ACP with 
no in-hospital serious adverse events in subjects randomized to the 
treatment arm 
 
• “Day 45” clinical success: In-hospital procedure success, closure of LAA 
documented at Day 45 TEE, no ischemic stroke or peripheral 
thromboembolism, and discontinuation of warfarin or dabigatran 
 
• Long-term clinical success: In-hospital procedure success, closure of 
LAA documented at Day 45 TEE, no ischemic stroke or peripheral 
thromboembolism, and sustained discontinuation of warfarin  or dabigatran 
(without temporary re-administration of warfarin or dabigatran) at last 
available follow-up.  Subjects who continue or restart warfarin or dabigatran 
due to medical necessity (e.g. for DVT treatment) rather than LAA closure 
status will not be considered device failures for the purpose of this analysis. 
 
• Technical Success and Complete Closure - The secondary endpoints of 
technical success, and complete closure will only be evaluated in the device 
arm and will each be summarized as a point estimate with a corresponding 

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99.5% confidence interval.  However, no formal hypotheses will be tested 
for these endpoints. 
 
2.15.5 Derivation of the operating characteristics for both device and  control 
 
arms 
 
2.15.5.1 
Primary Effectiveness 
 
2.15.5.1.1 
Primary Effectiveness - Control 
The Bayesian simulation models for the current study design require two-
year rate estimates for effectiveness analysis and one-year rates for 
safety. 
 
The two-year rate for the control effectiveness endpoint of ischemic 
stroke, and peripheral thromboembolism was derived from a literature 
review. There were three primary sources (Table 2) used for determining 
this rate. 
 
The first source was the pivotal study report of dabigatran published by 
Connolly et al (NEJM 2009). This study compared the primary outcome of 
stroke and systemic embolization in subjects randomized between 
warfarin and either 110 mg or 150 mg of dabigatran. Connolly, 2009 
reported the following endpoints among 12,098 subjects (randomized to 
warfarin or 150mg dabigatran). 
 
Primary Efficacy – (n=6022 warfarin) = 2.55% (two years) 
Primary Efficacy – (n=6076 dabigatran) = 2.12% (two years) 
 
The second source was the ARISTOTLE trial (Granger et al, NEJM 2011), 
which reported the following endpoint component rates among 9081 
control subjects (randomized to warfarin). 
 
Primary Efficacy – (n=9081 warfarin) = 2.27% (two years) 
 
The third source was the ROCKET AF trial (Patel et al, NEJM 2011), 
which reported the following endpoint component rates among 7133 
control subjects (randomized to warfarin). 
 
Primary Efficacy – (n=7133 warfarin) = 3.81% (two years) 
 
 

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Table 2. Derivation of primary long term efficacy control rates for ACPɸ 
Trial/ 
Arm 
Smple Size 
Mean CHADS(2) 
Primary endpoint* 
rate (%) 
Ischemic. (or 
unknown) Rate(%) 
Hemorrhagic 
stroke Rate(%) 
Systemic 
Embolization 
Rate(%) 
Ischemic. (or 
unknown) + 
Systemic 
Embolization(%)
Study Weight 
RE-LY 
Dabigatran 
6076 
2.2 
1.11 
0.92 
0.10 
0.15 
1.07 
50% 
RE-LY 
Warfarin 
6022 
2.1 
1.69 
1.20 
0.38 
0.09 
1.29 
10% 
weighted 
by 
sample 
size 
ARISTOTLE 
Warfarin 
9081 
2.1 
1.60 
1.05 
0.47 
0.10 
1.15 
ROCKET-AF 
Warfarin 
7090 
3.46 
2.42 
1.72ψ 
0.48ψ 
0.22ψ 
1.94 
40% 
*Composite endpoint of stroke and/or systemic embolism. Stroke defined as ischemic, hemorrhagic, or 
of uncertain type. 
ψIn the ROCKET AF trial, primary efficacy endpoints in the Intent-to-treat cohort were reported only in a 
composite form. “Safety Population” effectiveness data reported in document #EDMS-ERI-
24510755:2.0 Advisory Committee Briefing Document was used to determine the proportion of the 
overall rate represented by each type of event (ischemic/unknown stroke = 71%; hemorrhagic 
stroke=20%; and systemic embolization = 9%). These proportions were applied to the “Intent-to-treat 
population” overall rate (2.42%) to estimate the rate of each component. 
ɸRates listed in table 2 are one year rates 
 
 
The two-year weighted average of these three trials (assuming a 50% 
adoption rate of dabigatran) is 2.95%1 endpoint events. 
 
2.15.5.1.2 
Primary Effectiveness - Device 
The two-year rate for the device effectiveness pivotal endpoint of ischemic 
stroke and peripheral thromboembolism was derived from published 
experience to-date with the ACP device. There were two primary sources 
used for determining this rate. 
 
The first source was the 30 subjects from the feasibility phase that were 
randomized and received a device  
 
 Ischemic stroke – 1.0 event (six months) 
 Peripheral thromboembolism – 0.0 events (six months) 
 
In this phase, one event out of 30 (1/30, 3.3%) occurred over six months 
of follow up. 
 
                                            
1 Two-year rates calculated using the following formula for change over time (=1-exp(2*0.016)) 

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The second source was derived from subjects enrolled in the ACP 
Registry (ACPR) (Park et al), which reported the following endpoint 
component rates among 197 subjects. 
 
 Ischemic stroke – 2.0 events (six months) 
 Peripheral thromboembolism – 0.0  (six months) 
 
The calculated rate in the ACPR is (2/197) 1.0%. 
 
The weighted average of these two trials is 1.32% endpoint events per six 
months.  To estimate a two-year rate from these six-month endpoints, 
Kaplan-Meier curves were analyzed from the PROTECT AF study 
(SSED). This analysis showed an increase of 124% from six months to 
two years for the primary effectiveness endpoint. Employing this percent 
change over time corresponds to an estimated two-year rate of 2.96%. For 
non-inferiority assumptions 2.95% will be used to match the control 
primary effectiveness estimated rate from above. 
 
 
2.15.5.2 
Primary Safety 
 
2.15.5.2.1 
  Procedural (Acute) Safety-  This analysis compares the 
rate of procedure related serious adverse events (SAE) as listed below, that 
occur in the device arm from the time of randomization until hospital 
discharge to a performance goal (PG) chosen from the literature.  The 
endpoint will be considered met if the 96% credible interval for the in-hospital 
event rate is entirely less than the PG. 
• 
procedure-related death (i.e., death occurring during the 
implantation procedure). 
• 
pericardial effusion requiring treatment. 
• 
device embolization. 
• 
access site-related bleeding requiring transfusion ≥ 2 units. 
• 
damage to other cardiac or major non-cardiac cardiovascular 
structures 
 
A literature search was conducted in order to establish a PG. The search 
criteria included catheter ablation for atrial fibrillation. This criterion was 
chosen because catheter ablation utilizes transseptal puncture to access 
the left atrium which is the common technique used to access the left 
atrial appendage and implant the ACP device. The search included 
electrophysiologic (EP) studies and summaries of safety and 
effectiveness (SSED). 
 
In all, 29 sources (27 published articles and two SSEDs) were examined 
for reported complications of procedure related SAE (as listed above). 
Serious Adverse Events of procedure-related death (i.e., death occurring 

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during the implantation procedure), access site-related bleeding requiring 
transfusion ≥ 2 units and device embolization was clearly reported. The 
Atritech SSED served to provide an estimate of the rate for device 
embolization since the EP literature would lack this complication. 
However, in order to categorize literature reported complication against 
‘pericardial effusion requiring treatment’ and ‘Damage to other cardiac or 
major non-cardiac cardiovascular structures’ the following criteria were 
used: 
• 
Pericardial effusion requiring treatment included pericardial effusions 
that required pericardiocentesis and cardiac tamponade. Also 
included within this category are pericardial effusions that were 
medically treated, or where treatment was not specified. Please note 
this category does not include effusions that were spontaneously 
resolved. 
• 
Damage to other cardiac or major non-cardiac cardiovascular 
structures included serious complications requiring more than 
conservative medical attention such as pleural effusion, pneumo- or 
hemothorax, lung injury , pulmonary edema, valve damage, vascular 
injury including arteriovenous fistulae requiring surgical intervention, 
aortic dissection, ,aortic root puncture and coronary sinus perforation.  
 
The average weighted complication rate derived from literature Meta-
analysis is provided in Table 3. 
 
Table 3- Performance Goal 
Death 
(procedure-
related) 
Device 
Embolization 
Access Site 
Bleeding 
(requiring ≥ 2 units) 
Damage to Other Cardiac 
or Major Non-Cardiac 
Cardiovascular Structures 
Pericardial Effusion 
(requiring treatment) 
0.05% 
0.22
% 
2.97% 
0.46% 
1.23% 
Average Weighted Complication Rate= 4.93% 
 
Therefore a performance goal of 5% is being established, against which 
the acute safety profile of the ACP device will be compared. A 
performance goal of 5% provides confidence that it adequately 
represents a threshold between event rates observed in literature and is 
clinically relevant. The ACP trial will meet its acute safety success if the 
two-sided 95% credible interval lies entirely below this PG. 
 
2.15.5.3 
Long-Term Safety 
 
2.15.5.3.1 
Long-term Safety – Control 
The one-year rate for the control safety endpoint of major bleeds and all-
cause mortality was derived from the same literature review as cited 

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above (Connolly 2009, Granger 2011, Patel 2011) for effectiveness 
endpoint determination. 
In sum: 
Safety event rates from the OAC literature listed the following one-year 
event rates: 
 
 RE-LY treatment arm (N=6076, dabigatran) = 6.75% 
 RE-LY control arm (N=6022, warfarin) = 7.49% 
 ARISTOTLE control arm (N=9081, warfarin) = 7.03% 
 ROCKET AF control arm (N=7133, warfarin) = 8.37% 
 
The weighted average of these three trials is 7.17% (assuming a 50% 
adoption rate of dabigatran) endpoint events per year. 
 
The distribution of dabigatran and warfarin use will be monitored during 
the course of the trial. If a significant deviation from the expected adoption 
rate is observed, its potential impact will be assessed and appropriate 
adjustments to base rates and sample size calculations may be re-visited 
and/or re-modeled as appropriate. 
 
 
2.15.5.3.2 
Long-term Safety – Device 
The one-year rate for the device safety pivotal endpoint of major bleeds 
and all-cause mortality was also derived from published experience to-
date with the ACP device. 
 
 Safety endpoints from the feasibility phase were: 
 
1/30 (3.3%) (six months) 
 
 Safety endpoints from the ACP Registry (ACPR) were: 
 
10/197 (5.1%) (six months) 
 
The weighted average of these two trials is 4.85% endpoint events per six 
months. To estimate a one-year rate from these six-month endpoints, 
Kaplan-Meier curves were analyzed from the PROTECT AF study 
(SSED). This analysis showed an increase of 6.2% from six months to one 
year for the primary safety endpoint. Employing this percent change over 
time corresponds to a one-year rate of 5.15%, the primary rate used for 
the calculations of the device safety endpoint. 
 
2.15.5.3.3 
Operating Characteristics, Power, and Type I Error 
For the Bayesian adaptive design the power will be calculated using 
simulations. Besides design features described above, three other factors 
contribute to the study’s power: the true unknown event rate, the unknown 
accrual rate, and the lost-to-follow-up rate observed in study subjects. The 
accrual rate can be controlled to some extent by the number of sites and 

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inclusion criteria, and the event rate can be projected based on the study’s 
inclusion criteria. 
 
To find operating characteristics, 1000 trials are simulated from each of 10 
different scenarios.  To simulate trials the following assumptions are made 
about the data-generating process.  These are necessary to estimate 
operating characteristics but will not be used in the analysis of the actual 
trial. 
 
 Times to efficacy events have an exponential distribution within 
each time period in both the device and control arms with the 
specified rate 
 Times to safety events have an exponential distribution in both the 
device and control arms with the specified event rate 
 There is 5% yearly lost-to-follow-up.   
 Accrual is constant 25 subjects per month. (While accrual is not 
expected to be constant during the ACP trial, it is expected to be lower 
earlier and then stabilize after all sites have begun enrollment.  If this is 
the case, then early subjects will have greater follow-up and the power 
calculations below will be underestimates.) 
 
Operating characteristics have been calculated for a variety of accrual 
rates, efficacy event rates and safety event rates.  
 
Tables 4a and 4b illustrate the 10 scenarios used. Each row shows one 
parameter used to generate trial data used in the simulations. 
 
Scenarios 1-4 in Table 4a represent Scenarios in the null space where 
Type I error should be 2.5% or less.  Scenario 1 is when the device is 
neither non-inferior for efficacy nor superior for safety.  Scenario 2 fails to 
meet the definition for efficacy non-inferiority, Scenario 3 fails to meet the 
definition for superiority for safety.  The efficacy scenarios are shown 
where Type I error should be the highest.  Scenario 4 shows the Type I 
error rate for the expected control event rate for efficacy.  The six 
scenarios in Table 4b illustrate cases where the ACP device is non-
inferior for efficacy and superior for safety. 
 

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Table 4a.  Scenarios for 4 NULL cases where non-inferior efficacy  
and/or superiority safety case is not met. 
 
Scenario 
1 
2 
3 
4 
λC,1 
0.019497 
0.019497 
0.014972 
0.019497 
λC,2 
0.019497 
0.019497 
0.014972 
0.019497 
λC,3 
0.019497 
0.019497 
0.014972 
0.019497 
λC,4 
0.019497 
0.019497 
0.014972 
0.019497 
λC,5 
0.019497 
0.019497 
0.014972 
0.019497 
λC,6 
0.019497 
0.019497 
0.014972 
0.019497 
λC,7 
0.019497 
0.019497 
0.014972 
0.019497 
λD,0 
0.034635 
0.034635 
0.014972 
0.034635 
λD,1 
0.034635 
0.77 
0.77 
0.77 
λD,2 
0.034635 
0.0274 
0.00756 
0.0274 
λD,3 
0.034635 
0.0274 
0.00756 
0.0274 
λD,4 
0.034635 
0.0274 
0.00756 
0.0274 
λD,5 
0.034635 
0.0274 
0.00756 
0.0274 
λD,6 
0.034635 
0.0274 
0.00756 
0.0274 
λD,7 
0.034635 
0.0274 
0.00756 
0.0274 
πC 
3.82% 
3.82% 
2.95% 
3.82% 
πD 
6.69% 
6.69% 
2.95% 
6.69% 
πD - πC 
2.87% 
2.87% 
0.00% 
2.87% 
πD / πC 
1.75 
1.75 
1.0000 
1.75 
γC 
0.0717 
0.0717 
0.0717 
0.0717 
γD 
0.0717 
0.0717 
0.0717 
0.0515 
γD / γC 
1 
1 
1 
0.718 
Efficacy 
NULL 
NULL 
Non-inf 
NULL 
Safety  
NULL 
NULL 
NULL 
Superior 
 

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Table 4b.  Scenarios for 6 cases where non-inferior efficacy  
and superiority safety case are met. 
 
Scenario 
5 
6 
7 
8 
9 
10 
λC,1 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,2 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,3 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,4 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,5 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,6 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λC,7 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λD,0 
0.01497 
0.01497 
0.01497 
0.01497 
0.00749 
0.02246 
λD,1 
0.77 
0.01497 
0.4 
0.114 
0.385 
1.155 
λD,2 
0.00756 
0.01497 
0.068 
0.114 
0.00378 
0.01134 
λD,3 
0.00756 
0.01497 
0.068 
0.114 
0.00378 
0.01134 
λD,4 
0.00756 
0.01497 
0.00756 
0.00756 
0.00378 
0.01134 
λD,5 
0.00756 
0.01497 
0.00756 
0.00756 
0.00378 
0.01134 
λD,6 
0.00756 
0.01497 
0.00756 
0.00756 
0.00378 
0.01134 
λD,7 
0.00756 
0.01497 
0.00756 
0.00756 
0.00378 
0.01134 
πC 
2.95% 
2.95% 
2.95% 
2.95% 
1.49% 
4.39% 
πD 
2.95% 
2.95% 
2.95% 
2.95% 
1.49% 
4.39% 
πD - πC 
0.00% 
0.00% 
0.00% 
0.00% 
0.00% 
0.00% 
πD / πC 
1.00 
1.00 
1.00 
1.00 
1.00 
1.00 
γC 
0.0717 
0.0717 
0.0717 
0.0717 
0.0717 
0.0717 
γD 
0.0515 
0.0515 
0.0515 
0.0515 
0.0515 
0.0515 
γD / γC 
0.7183 
0.7183 
0.7183 
0.7183 
0.7183 
0.7183 
Efficacy 
Non-inf 
Non-inf 
Non-inf 
Non-inf 
Non-inf 
Non-inf 
Safety  
Superior 
Superior 
Superior 
Superior 
Superior 
Superior 

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Table 5 summarized the operating characteristics for each scenario.  Each two rows show one 
scenario.  The columns reflect the summary statistics for the 1000 simulations per scenario: 
 
 
Mean N 
Mean sample size 
 
SD N 
Standard deviation of sample size 
 
Stop Early 
Proportion of trials that stop early for predicted success 
 
Stop Max 
Proportion of trials that accrue to maximum 3000 subjects 
 
Stop Futility  
Proportion of trials that stop early for futility 
 
Efficacy Power 
Proportion of trials that meet either definition of non-inferiority efficacy 
success 
 
     Ratio 
Proportion of trials with Pr(πD/πc< 1.75) ≥ 0.988 
 
     Diff 
Proportion of trials with Pr(πD - πc< 2.87%) ≥ 0.988 
 
Safety Power  
Proportion of trials that meet safety definition of superiority success, 
Pr(γD / γC < 1.0) ≥ 0.992. 
 
Power 
Proportion of trials meeting both efficacy and safety goals. 
 
N 0-1 
Mean number of patients with less than 1 year of follow-up in 
successful trials (trials meeting efficacy and safety endpoints) 
 
N 1-2 
Mean number of patients with 1-2 years of follow-up in successful 
trials (trials meeting efficacy and safety endpoints) 
 
N 2+  
Mean number of patients with greater than 2 years of follow-up in 
successful trials (trials meeting efficacy and safety endpoints) 
 
 
The second line in each scenario shows the same success probabilities if the analysis is 
repeated using an as-treated analysis that censors subjects randomized to the device who 
crossover and use warfarin 45 days or more after their procedure. Simulations verify that 
adequate power is maintained to interpret the primary effectiveness endpoint. For a detailed 
calculation please refer to the second line (AT = As Treated) under each scenario in Table 5. 
Here we assume 9% of subjects crossover immediately, 12.5% are censored at 45-days, then 
5% are censored per year. 
 
 
Scenarios 1-4 and show that Type I errors rate are all ≤2.5% (in bold).  In these situations trials 
stop early for futility 88 – 100% of the time.  The same “Power” column shows powers for the 
safe and efficacious scenarios.  For example Scenario 5, the expected scenario, has 91% 
power.  For other safe (superior) and efficacious (non-inferior) scenarios the trial offers ≥89% 
power. 
 
In this expected scenario (5) the average sample size is 1880 subjects and the trial stops early 
for predicted success 88% of the time.  The average trial size in the null cases is 906-1919. 
 
While the trial’s sample size may range from 400 to 3000 subjects, the average trial size, 
which varies by scenario, ranges from 906 to 2350 subjects for the scenarios shown here. 
 

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Scenarios 5-9 illustrate safe and efficacious cases. In these scenarios, the average number of 
patients with two or more years of follow-up ranges from 1303-1816 patients. 
 

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Table 5- Operating Characteristics for Bayesian Adaptive Design 
 
Scenario 
Mean 
N 
SD 
N 
Stop 
Early 
Stop  
Max 
Stop 
Futility 
Efficacy 
Power 
 
Ratio 
 
Diff 
Safety 
Win 
Power 
N 
0-1 
N 
1-2 
N 
2+ 
 
Analysis 
1 
906 
396 
0.000 
0.000 
1.000 
0.000 
0.000 
0.000 
0.000 
0.000 
-
-- 
--- 
--- 
ITT 
 
 
 
 
 
 
0.000 
0.000 
0.000 
0.000 
0.000 
-
-- 
--- 
--- 
AT 
2 
1046 
524 
0.001 
0.002 
0.997 
0.002 
0.001 
0.002 
0.001 
0.001 
205 
316 
579 
ITT 
 
 
 
 
 
 
0.001 
0.001 
0.001 
0.001 
0.001 
417 
276 
407 
AT 
3 
1549 
765 
0.016 
0.057 
0.93 
0.072 
0.043 
0.072 
0.018 
0.018 
241 
344 1751 
ITT 
 
 
 
 
 
 
0.018 
0.008 
0.018 
0.004 
0.004 
640 
305 
843 
AT 
4 
1919 
832 
0.010 
0.11 
0.88 
0.022 
0.016 
0.017 
0.117 
0.022 
245 
369 2100 
ITT 
 
 
 
 
 
 
0.010 
0.009 
0.010 
0.020 
0.010 
806 
347 1346 
AT 
5 
1880 
645 
0.88 
0.060 
0.059 
0.93 
0.38 
0.93 
0.93 
0.91 
232 
356 1356 
ITT 
 
 
 
 
 
 
0.84 
0.28 
0.84 
0.61 
0.55 
670 
320 
996 
AT 
6 
2350 
712 
0.57 
0.32 
0.11 
0.89 
0.55 
0.89 
0.89 
0.88 
260 
380 1816 
ITT 
 
 
 
 
 
 
0.87 
0.39 
0.87 
0.68 
0.67 
814 
354 1316 
AT 
7 
1941 
672 
0.84 
0.094 
0.069 
0.93 
0.41 
0.93 
0.92 
0.92 
234 
355 1431 
ITT 
 
 
 
 
 
 
0.85 
0.32 
0.85 
0.63 
0.58 
683 
321 1023 
AT 
8 
1991 
707 
0.79 
0.12 
0.091 
0.90 
0.43 
0.90 
0.90 
0.90 
241 
362 1493 
ITT 
 
 
 
 
 
 
0.85 
0.34 
0.85 
0.64 
0.60 
705 
28 
1069 
AT 
9 
1819 
648 
0.88 
0.050 
0.070 
0.93 
0.20 
0.93 
0.92 
0.92 
229 
351 1303 
ITT 
 
 
 
 
 
 
0.90 
0.16 
0.90 
0.59 
0.58 
636 
311 
917 
AT 
10 
2163 
726 
0.68 
0.23 
0.087 
0.88 
0.69 
0.88 
0.90 
0.87 
247 
369 1629 
ITT 
 
 
 
 
 
 
0.76 
0.55 
0.76 
0.64 
0.55 
757 
342 1180 
AT 

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Scenario 5 is illustrated below. The first section shows the number of simulations and design 
characteristics as described above. 
 
Simulations              =       1000 
 Minimum Sample Size      =       400 
 Frequency of looks (pts) =        50 
 Maximum Sample Size      =      3000 
 Accrual Rate             =      25.0 
 Posterior Prob Win Eff   =    0.9880 
 Posterior Prob Win Saf   =    0.9920 
 Ratio < to Win           =    1.7500 
 Diff < to Win            =    0.0287 
   
   
The second section shows the parameters used to simulate the efficacy events.  The bottom lines 
within the “True Efficacy Event Rate” subsection show the 2-year event rate (2.15% vs. 3.15% here) 
and the ratio & difference.  The “True Safety Event Rate” subsection shows the event rate assumed 
through follow-up for the warfarin group and after day discharge for the device group.  This also 
shows the risk ratio and risk difference. 
 
 
True Efficacy Event Rate 
  Month   Control      Month      Treatment 
 True Efficacy Event Rate 
                        0-proc    0.0150 
 0 -  6    0.0150      pr -p+6    0.7700 
 6 - 30    0.0150      p+7- 30    0.0076 
31 - 60    0.0150      31 - 60    0.0076 
60 - 6m    0.0150      60 - 6m    0.0076 
 6 - 12    0.0150      6m - 12    0.0076 
12 - 18    0.0150      12 - 18    0.0076 
18 - 24    0.0150      18 - 24    0.0076 
 2-year    0.0295       2-year    0.0295 
Ratio =    1.0000       Diff =    0.0000 
   
 True Safety Event Rate  
 Annual    0.0717       Annual    0.0515 
Ratio =    0.7183       Diff =   -0.0202 
   
 
The final section shows the operating characteristics. 
 
MaxN   Acc  MeanN   SD N    Mnth  SGood  StEnd  StFut  EffWn  Ratio   Diff  SFwin E&SWin   
3000  25.0  1880.   645.    81.7  0.881  0.060  0.059  0.925  0.384  0.925  0.928  0.914    
 
             CEEv  TEEv   CEExp   TEExp  CSEv  CSEv   CSExp   TSExp    0-1    1-2     2+ 
              32.   51.   2145.   4302.  135.  202.   1882.   3925.   232.   356.  1356. 
                                            
                                           AS TREATED  AnyWn  Ratio   Diff  SFwin E&SWin  
                                                       0.840  0.283  0.840  0.605  0.552    
 
 
These show the maximum sample size (MaxN) and accrual rate (Acc) plus the mean (MeanN) and 
standard deviation (SD N) of the sample size and the proportions of simulated trials that stop early for 
predicted success (SGood), run to the maximum sample size (StEnd), and stop for futility (StFut).  In 
this scenario 88.1% stopped for predicted success, 5.9% ran to 3000 subjects and 5.9% stopped 
early for futility.  
 
The next five values show the statistical power. The probability of demonstrating efficacy non-
inferiority is shown (EffWn) and further broken down by the proportion that achieve the risk ratio < 
1.75 (Ratio) or risk difference < 2.87% (Diff).  The probability of demonstrating superiority for safety 

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(SFwin) and both non-inferiority for efficacy and superiority for safety (E&SWin) are also shown.  Here 
there is a 92.5% chance of achieving the efficacy goal, predominantly via the risk difference, a 92.8% 
chance of achieving the safety goal, and a 91.4% chance of achieving both. 
 
The second line summarizes the events and exposure.  CEEv, DEEv, CEExp, and DEExp show the 
mean number of efficacy events in the control group, efficacy events in the device group, years of 
exposure for efficacy in the control group, and years of exposure for efficacy in the device group.  
CSEv, DSEv, CSExp, and DSExp are the same for safety events.   
 
The final three values 0-1, 1-2, and 2+ show the mean number of subjects with 0 to 1, 1 to 2, or 2 
more years of exposure for successful trials.  These last three figures summarize only trials in which 
the efficacy and safety goal are met, the idea being to relay the expected amount of follow-up times if 
success is declared. 
 
The final line shows the win rates in the as treated analysis.  These analyses are performed only if 
both the efficacy and safety goals are met in the intent-to-treat analysis. 
 
2.15.6 Endpoints and Labeling 
 
The following primary and secondary endpoints will be included in product labeling for 
the ACP device. 
 
• Primary Effectiveness Endpoint (rate of ischemic stroke and peripheral 
thromboembolism per 100 subject years) 
• Primary Safety Endpoints (procedure related adverse events as previously 
defined, as well as all-cause mortality and major bleeding) 
• Secondary Endpoints 
o 
Rate of Transient Ischemic Attacks 
o 
Asymptomatic intracerebral or intraventricular hemorrhage 
 
All of the above endpoints will contain inferential findings of either an acceptance or 
rejection of the null hypothesis (for primary endpoints), a p-value for the difference 
between treatments (for secondary endpoints tested in both treatment arms). Endpoints 
not listed above will not be summarized in product labeling.  
 
 
2.15.7 Primary Analysis (REFER TO APPENDIX D) 
 
2.15.7.1 
Intent-to-Treat Analyses 
Subjects are considered enrolled in the ACP clinical trial after informed consent 
and HIPAA authorization form or any other applicable permission form required 
by law has been signed and the subject has been randomized.  All primary 
endpoint analyses will be based on the “intent-to-treat” principle.  Specifically, 
subjects will be considered part of the intent-to-treat analysis population as long 
as they are randomized into the study, with no adjustment made for whether 

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the device was implanted, compliance with treatment, or events occurring after 
randomization.   
 
2.15.8 Secondary Analyses (REFER TO APPENDIX D) 
 
In addition to the intent-to-treat analysis, secondary analyses will be performed 
on the three following analysis populations (two per protocol analyses and one 
as-treated): 
 
2.15.8.1 
Per Protocol Analysis 
a. This analysis does not count subjects who did not follow the protocol.  
 
 
This cohort is defined as all subjects who: 
• Receive the device (for subjects in the device arm) or were randomized 
to receive the device but did not receive the device due to a procedural 
adverse event or adverse event related to the pre-procedural termination 
of warfarin or dabigatran, such as ischemic stroke or thrombus observed 
in the left atrium/atrial appendage at or prior to the implant procedure. 
• As directed by the protocol, discontinue OMT(for subjects in the device 
arm) given the absence of flow or a minimal flow of ≤3mm into the LAA, 
as demonstrated by TEE, or continue OMT due to more than minimal 
flow present on TEE. 
• Are started on and comply with warfarin or dabigatran use (device and 
control  arms). 
• Achieve and maintain a therapeutic INR (subjects in device and control 
arms who are on warfarin therapy). Have at least monthly monitoring 
with at least 70% of visits made and 60% time in therapeutic range (INR 
2.0-3.0).  
 
Subjects (device and control arms) who switch to an alternative 
anticoagulant approved for the treatment of atrial fibrillation other than 
warfarin or dabigatran will be excluded from this analysis. 
 
b. Assessment of Proof of Concept: This analysis will be conducted to assess 
outcomes in subjects who receive the ACP device and follow the protocol-
mandated post implant medication regimen compared to subjects treated 
appropriately with warfarin or dabigatran. This analysis does not count 
subjects who are randomized to device but do not receive a device, device 
subjects with LAA closure who fail to stop warfarin or dabigatran at day 45, 
and all subjects) who deviate from therapeutic warfarin administration and 
monitoring (For device subjects this is from day of procedure to day 45 and 
for control subjects it is from day of randomization onward).  
 

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This cohort is defined as: 
 
• Receive the device (for subjects in the device arm). 
• As directed by the protocol, discontinue warfarin or dabigatran (for 
subjects in the device arm) given the absence of flow or a minimal flow 
of ≤3mm into the LAA, as demonstrated by TEE. 
• Are started on and comply with warfarin or dabigatran use (device and 
control arms). 
• Achieve and maintain a therapeutic INR (for subjects on warfarin in 
device and control arms). At least monthly monitoring with at least 70% 
of visits made and 60% time in therapeutic range (INR 2.0-3.0). 
 
2.15.8.2 
As Treated Analysis 
Device subjects unable to discontinue OMT therapy may bias the intent to treat 
analysis toward success on the efficacy endpoint due to a sizable number of 
subjects in each group receiving similar treatment (success may be more difficult 
to achieve, however, on the safety superiority endpoint).  In order to address this 
possibility, an “as treated” analysis will be performed that will restrict analysis of 
device subjects to subjects who generally experience long-term success.  This 
analysis will compare subjects in the control arm, where applicable, against 
subjects in the device arm which includes: 
 
• Received the device, discontinue OMT at six months and subsequently 
continue to remain off of OMT (analyzed as device) 
• Subjects randomized to the control arm and continue a protocol OMT 
(analyzed as control) 
• Subjects who are randomized to the device arm, never receive a device 
and continue a protocol OMT (analyzed as control) 
 
This analysis will not necessarily disqualify subjects who violate one of the above 
criteria but instead will censor subjects at the earliest time point where they no 
longer comply with the above criteria.  The primary efficacy and safety analyses 
will be redone using these populations and checked for level of agreement with 
the intent to treat population. 
 
2.15.8.3 Secondary Analyses General Considerations 
Other deviations that justify exclusion may be discovered as the trial progresses.  
These deviations will also disqualify subjects from the secondary analyses and 
will be discussed explicitly in the study’s statistical analysis plan. 
 
Subjects who are non-compliant or lost to follow-up after the procedure or after 
there is absence of flow or a minimal flow of ≤3mm into the LAA, as 
demonstrated by TEE,  will not be entirely excluded from the secondary 
analyses. Rather, information obtained before the point of non-compliance will be 

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preserved in the analyses, with subsequent information excluded.  In all 
likelihood, however, subjects who are lost to follow-up will have no subsequent 
information to exclude. 
 
The intent-to-treat and secondary analyses will be compared for level of 
agreement. It is expected that the two subject populations will be similar; 
however, any substantial differences between the two will be analyzed 
appropriately to elucidate the cause of these differences. 
 
2.15.9 Other Analyses (REFER TO APPENDIX D) 
 
2.15.9.1 
Subgroup Analysis 
Separate analyses will be conducted for the device versus warfarin and device 
vs. dabigatran arms.  Because subjects are stratified at or before randomization 
subjects randomized to device will have a label for whether they would have 
been prescribed warfarin or dabigatran had they been randomized to OMT.  The 
primary efficacy and safety analyses will be performed in both groups.  
Parameter estimates for the risk difference and risk ratios for efficacy and safety 
and 95% confidence intervals will be provided. No formal statistical test will be 
performed since the trial is not powered to meet the objectives in each subgroup. 
 
Furthermore the subgroup analysis will be repeated in the further sub-divided 
groups of subjects receiving just warfarin, just dabigatran, warfarin plus aspirin, 
and dabigatran plus aspirin. Additional subgroup analysis will be repeated for 
baseline aspirin usage. 
 
This subgroup analysis serves a sensitivity analysis to better understand the 
subject populations in which the ACP devices offers the best or most robust 
benefit. 
 
Gender analysis will also be performed to provide the results of the primary 
endpoints and inferential secondary endpoints for male/female subgroups.  
 
An additional analysis of the major safety and effectiveness outcomes measured 
as a function of CHADS(2)-VASC score will be performed. 
 
2.15.9.2 
Adverse Events Categorization 
Adverse Events will be categorized as serious adverse event (SAE), adverse 
event, or observation, as well as whether each SAE is device and/or procedure 
related, with separate tables reporting the same.  In each table, SAE and 
adverse events will be summarized between the two treatment arms and 
compared for significant differences. 
 
In addition, data for each subject in the trial who experienced a neurologic or 
embolic event, a bleeding event, or device associated thrombus will be 

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summarized.  This will detail warfarin use, the last recorded INR, dabigatran 
use, and antiplatelet medication use at the time of the event. 
 
2.15.9.3 
Residual Flow in LAA 
Data on all subjects in whom there is absence of flow or a minimal flow of ≤3mm 
into the LAA, as demonstrated by TEE at 45 days will be summarized.  Since this 
criterion is only attained in the device arm, this analysis will only be performed on 
the subjects in the device arm, and will not involve comparisons between the two 
treatment arms. Additionally, data on subjects in the device arm with flow of less 
than or equal to 3mm who did not discontinue warfarin or dabigatran will be 
summarized.  This will include the reasons the subjects did not discontinue 
warfarin or dabigatran. 
 
2.15.9.4 
Primary Effectiveness Component Analysis 
Although the primary effectiveness endpoint for the study is the combined rate of 
ischemic stroke, and peripheral thromboembolism, each component rate will be 
analyzed separately for differences between the treatment arms.  P-values will 
be calculated for each rate.  However, since the study is not powered to examine 
the component differences, it is possible that overall study success may occur 
without significant differences among the component rates. In addition, these 
component rates will be summarized at separate time points.  Each will be 
summarized at 45 days, 6 months, 1 year, 18 months and annually.  In addition 
to the primary endpoint analysis, the composite endpoint of ischemic stroke and 
thromboembolism will be summarized at 45 days, 6 months, 1 year, 18 months, 
and annually. 
 
2.15.9.5 
Poolability Analysis 
Poolability of results across sites will be analyzed to determine if differences exist 
among the primary safety endpoints and to determine if potential predictive 
covariates differ.  For this poolability analysis, all centers will be compared for 
site differences with no centers combined in the analysis.  Fisher’s exact test will 
be used to test for comparability in terms of the primary endpoints and in terms of 
variables such as gender, medical history, and risk factors. 
 
2.15.9.6 
Center Effect 
All of the primary and secondary analyses described above, as well as any 
description of baseline covariates, will be broken down by center to illustrate 
potential differences among the study sites. 
 
Other analysis, such as the random effect model, may be performed to assess 
the possible site effect on the primary endpoints. 
 
 
2.15.9.7 
Analysis of Demographics 
Summary statistics will be generated for all relevant demographic, medical 
history, and risk factor variables, and will consist of numbers and percentages of 

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responses in each category for discrete measures, and of means, standard 
deviations, number of observations, minimums, maximums, and 95% confidence 
intervals, as appropriate, for continuous measures.  In addition, adverse event 
types will be summarized across treatment arms and analyzed for treatment 
differences for adjudicated events. 
 
2.15.9.8 
CHADS2 Score Distribution 
Since the ACP trial is a randomized clinical trial, there is not expected to be a 
difference in baseline (at the time of enrollment) CHADS score between the two 
treatment arms.  However, the scores will be compared and tested for a 
significant treatment effect.  If such an effect is found, an adjustment involving 
stratification will be made to the primary endpoint analysis.  No adjustment will be 
made for CHADS2 scores after baseline.  This is because some components of 
CHADS2, are dependent variables in this trial, and thus any differences may be 
due to the treatment effect that the trial is attempting to measure. 
 
2.15.9.9 
Time within therapeutic range (TTR) for INR for subjects 
assigned to warfarin 
TTR will be calculated using the method employed in the ACTIVE W trial 
(Circulation, 2008).  Specifically, for each subject the total number of days of TTR 
will be calculated and divided by the total number of treatment days in order to 
provide the percentage of days of TTR.  Since the recording of INR after 
achieving therapeutic range will generally occur monthly, linear interpolation will 
be used to determine the number of TTR days in cases where one observation is 
within range while the preceding or subsequent observation is out of range. 
 
• The ACTIVE W trial excluded certain follow-up days from this TTR 
calculation.  These exclusions will also be followed in the ACP trial.  The 
trial’s calculation of TTR will not use follow-up data points which include: 
 
• Within the first seven days after warfarin is started or re-started 
• After permanent discontinuation of warfarin 
• After five days from temporary discontinuation of warfarin 
 
Analyses will also be performed within the device and control arms to determine 
the percentage of time the subjects in each group were on warfarin and the 
percentage of time subjects were on anti-platelet medications. 
 
2.15.9.10 
Effect of Learning Curve 
An analysis will also be made to assess the “learning curve” among physicians 
who implant the ACP device.  It is hypothesized that the rate of serious adverse 
events and technical success may be a function of an operator’s experience with 
the ACP procedure.  In order to assess this, each operator’s procedures will be 
categorized in groups of five according to the order in which the procedures 
occurred.  These groups will be compared against each other in order to 
compare the rate of device related and procedure related adverse events.  In 

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addition to this physician specific comparison, the groups will be pooled among 
all physicians in order to examine a global association of these rates with 
procedure order.  Procedures may be categorized into larger groups, or other 
longitudinal analyses may be performed, if suggested by the data. 
 
The analysis of primary endpoint events over time could potentially be sensitive 
to the overall length of follow-up among subjects, and therefore dependent on the 
number of subjects at each level of follow-up.  However, this is not expected to 
have a major impact on the analysis of the ACP Clinical Trial. 
 
There are four main reasons for this.  First of all, the primary endpoint (events 
per 100 subject years) is already normalized for total follow-up, and thus the 
major contributor of follow-up time to the number of endpoint events would be 
eliminated.  In addition, enrollment into the trial is not based on an index event or 
any other event after which endpoint events are immediately likely to 
occur.  Also, there is no evidence of substantial increase or decrease in the 
endpoint component rates over time in nonvalvular AF subjects on 
warfarin.  Finally, since the trial is randomized, any departures from homogeneity 
over time would likely be distributed across the two treatment arms. 
 
Although the follow-up times are not expected to differ between the two arms, 
they will be compared for serious departures.  If such departures are found, 
supplementary analyses will be performed to examine their impact on the 
analysis of the primary endpoint. 
 
2.15.9.11 
Handling of Missing Data 
The primary efficacy endpoint is ischemic stroke or peripheral thromboembolism. 
Subjects are tracked continually, with data used to calculate and compare 2-year 
event rates in both treatment arms. The 2-year event rates are based upon a 
piecewise exponential model which assumes non-constant event rates over the 
course of the study. 
 
The primary safety endpoint is long-term composite rates of all-cause mortality 
and major bleed. Rates are compared in a manner similar to the efficacy 
endpoint comparison. Both primary analyses are intent-to-treat analyses where 
subjects are considered a part of the group to which they were randomized. 
Subject data is considered a part of the efficacy analysis until 
(a) They experience their first efficacy event, 
(b) They die, 
(c) They become lost-to-follow-up, or 
(d) The study ends. 
 
All subjects are tracked until the study ends rather than being followed for a fixed 
maximum time period (e.g. 2 years). Subjects meeting criteria (a) are treated as 
experiencing an event. Subjects first reaching (b), (c), or (d) are considered 
censored. 

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Likewise subjects contribute data to the safety analysis until 
(a) They experience a safety event (including death), 
(b) They become lost-to-follow-up, or 
(c) The study ends 
 
Subjects reaching (b) or (c) before experiencing an event are considered 
censored. Subjects who experience a non-fatal event contributing toward the 
efficacy endpoint are still followed for safety and vice versa. The operating 
characteristics in the original design document and those shown below assume a 
5% dropout rate per year in both groups. 
 
The primary efficacy and safety analysis assume that all censored subjects 
contribute data until their time of last visit. It is assumed that all censoring is non-
informative censoring. If so, the parameter estimates for each group are 
unbiased. Such an analysis is also assumed during each interim analysis used to 
select the sample size. At the conclusion of the trial, a variety of sensitivity 
analyses will be performed in case censoring is not non-informative. There is a 
concern that subjects who are lost-to- follow-up may not be non-informatively 
censored. 
 
First, the piecewise model for efficacy will be analyzed for differences in lost-to-
follow- up rates by group and by period. This will include illustrating the censoring 
pattern by showing Kaplan-Meier curves of time-to-lost-to-follow by group. The 
primary analysis will also be repeated using Bayesian multiple imputation. Using 
a technique similar to that used at each interim analysis for subjects being 
tracked, posterior distributions for the event rates will be used to draw event 
times for all lost-to-follow-up subjects and to calculate the predictive probability of 
success had the lost-to-follow-up subjects been tracked until the study’s end. By 
repeating this process 10,000 times, it will have the effect of including missing 
subjects in the final analysis and will incorporate the uncertainty that surrounds 
the estimates of the times they would have experienced an event. In addition, 
Cox proportional hazards models will be performed that include baseline and 
time-to-event variables such as age, gender, CHADS2 components, coagulation 
parameter test values, and any baseline variable subsequently discovered to 
have an overall association with the study endpoint. The results of these models 
will compare the coefficient and 95% confidence interval for the hazard ratio of 
the treatment group variable, as well as explore any interactions between 
baseline covariates and treatment effect. The primary analysis can also be 
repeated assuming subjects have an event instead of being lost-to-follow-up. 
This is an extreme situation analysis in which assumes that being lost-to-follow-
up is a likely indicator of experiencing an event. Each of these sensitivity 
analyses will be performed for both the efficacy analysis and the safety analysis, 
in the intent to treat study populations. Sensitivity analyses may be performed for 
other analyses as deemed appropriate. 
 

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Additionally a worse case and tipping point sensitivity analyses will also be 
performed. 
 
2.15.9.12 
Worst–case analysis 
Throughout the duration of the ACP clinical trial all efforts will be made to 
minimize any expected lost to follow-up. For the worst case scenario analysis, we 
will consider subjects in the device group as having events at the time they are 
declared lost-to-follow-up and subjects in the control group as having their follow-
up end with no event at the time they are declared lost-to-follow-up. 
This analysis will be performed once for the efficacy analysis and once for the 
safety analysis. 
 
For the efficacy analysis, a worst case scenario dataset will be created. This 
dataset will consist of: 
• Observations which are unchanged for subjects not lost to follow-up or lost 
to follow-up in the control group. 
• Observations which are modified, for subjects lost to follow-up in the 
device group, to events experienced at the time of discontinuation 
 
For the purposes of the sensitivity analysis, “Lost to follow-up” is defined as any 
subject who discontinues before the trial’s conclusion without an endpoint event, 
regardless of the reason given for discontinuation. 
 
This dataset will then be used with the piecewise exponential model for the 
efficacy endpoint. Using this dataset, posterior distributions for each group’s 2-
year event rate, their ratio, and their difference will be calculated. The primary set 
of tests will be performed according to protocol. 
 
Lost-to-follow-up subjects will be analyzed in an analogous manner in the safety 
analysis. Lost-to-follow-up device group subjects will be considered to have had 
a safety event at the time they were lost. Lost-to-follow-up control group subjects 
will be considered not to have had an event but have their exposure ending at 
the time they are lost to follow-up. Data from all other subjects (subjects that are 
not lost to follow-up) will remain unchanged, with the safety analysis will be 
performed as described in the protocol. 
Tipping point analysis- Furthermore we will perform a tipping point analysis for 
both the safety and efficacy endpoints. 
 
The sufficient statistics for the safety analysis are the total number events (Ev) 
and the total exposure (Expos) in each group. The primary test for safety is 
 
 
which is equivalent to testing whether the two-sided 98.4% credible interval for 
the hazard ratio is entirely less than 1.0. 

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The primary analysis will be performed considering lost-to-follow-up subjects as 
censored. For the tipping point analysis, the exposure times in both groups will 
be considered fixed. The number of events in each group can possibly range 
from a minimum of EvT and EvC (the observed number of safety events in the 
treatment and control groups, respectively, assuming lost-to-follow-up subjects 
are censored without events) to EvT+MT and EvC+MC (the observed number of 
safety events plus the number of subjects lost-to-follow-up in each group which 
combined with the fixed exposure times assumes that all lost-to-follow-up 
subjects had events at the exact time they were considered lost-to-follow-up). 
 
We will repeat the safety analysis for every pair of events {EvT, EvT+1, … 
EvT+MT} × {EvC, EvC+1, …, EvC+MC}. We will show a plot that illustrates which 
pairs lead to successful safety claims, Pr(γT / γC < 1.0) ≥ 0.992 shown with green 
dots, and which do not shown with red dots, thus producing a boundary of trials 
that meet the predetermined safety criteria and those that do not. 
 
We will perform a similar analysis for the primary efficacy analysis. This is slightly 
complicated because the statistical model uses a piecewise exponential. 
Therefore all events are not exchangeable – they can have slightly different 
effects depending in which segment of the piecewise model the event is 
assumed to have occurred. 
 
We observe number of events and total exposure time within each treatment 
group (g) x time period (T) then use these to calculate posterior distributions for 
each time segment’s event rates, λg,T. Then we combine these posterior 
distributions to calculate the posterior distribution for the probability of an event 
by 2 years for the treatment group 
 
 
and control groups 
 
 
 
Finally we use the posterior distributions for λT and λC to calculate the risk ratio 
and risk difference. If Pr(λD/λC < 1.75) > 0.988 and/or Pr(λD-λC < 2.87%) > 0.988 
then the trial has reached the non-inferiority threshold. 
 
When considering from 0 to MT and 0 to MC of the lost-to-follow-up subjects as 
having events, it is unlikely that the timing of the event will be the difference 
between a successful vs. unsuccessful trial, e.g. assuming a patient lost-to-

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follow-up during the first segment has an event vs. assuming a patient lost-to-
follow-up in the final segment has an event has negligible effect on the final 
posterior probability of non-inferiority. Therefore it is unlikely that assuming an 
event occurs in one segment vs. another will be the difference in meeting or 
failing to meeting the efficacy success criteria. 
 
Nevertheless, we will explore all possibilities. Assuming we observe EvT and EvC 
efficacy events in the treatment and control groups, respectively, and MT and MC 
subjects are lost-to-follow-up, we will perform the analysis for every pair of 
possible efficacy events: {EvT, EvT+1, … EvT+MT} × {EvC, EvC+1, …, EvC+MC}. 
 
Here, however, an event may occur in any one of 8 treatment segments of the 
piecewise exponential or any one of 7 control segments of the piecewise 
exponential. 
 
For example, if there are 3 subjects with missing data, 2 might be lost-to-follow-
up in the 30-60 day period and the other might be lost-to-follow-up in the 12-18 
month period. We will perform the analysis assuming 0, 1, 2, and 3 of the lost-to-
follow-up subjects have events. Our imputation step when assuming 1 event out 
of the 3 lost-to-follow-up subjects will perform the analysis as if the event 
occurred in the 30-60 day period, and then repeat it assuming it occurred in the 
12-18 day period. Instead of the plot showing a simple green or red for 
successfully meeting the efficacy endpoint vs. failing to meet the efficacy 
endpoint, we will show the proportion of imputed trials (out of 3 possible here) 
that result in trials demonstrating non-inferiority according to the prespecified 
rule. According to our exploration it is unlikely that the placement of a missing 
event will determine whether or not the success definition is met. The number of 
event, far more than their location, is the determinant. 
 
Therefore the final analysis will be presented as a grid showing all possible study 
outcomes from EvT to EvT+MT treatment events vs. EvC to EvC+MC control 
events. Most points are likely to show simply green (for all possible combinations 
of those event counts meeting the non-inferiority criterion) or red (for all possible 
combinations of those event counts failing to meet the non-inferiority criterion). 
But some points may show a proportion indicating the probability that 
combination of treatment and control events results in a successful trial in the 
rare event that the timing of the assumed events determines success vs. failure. 
 
Version 9.0 or higher of the SAS statistical software package or R 2.14 or other 
widely accepted statistical software will be used to provide all non-Bayesian 
statistical analyses. 
 
2.16 
ADVISORY COMMITTEES 
 
2.16.1 STEERING COMMITTEE 

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The Steering Committee will be composed of medical practitioners who are experts in 
the field of the proposed indication for the study. The Committee will serve as an 
advisory board during the course of the study as well as after its completion. Specific 
responsibilities of the members will depend upon the consulting expertise needed by the 
Sponsor.  
 
2.16.2 DATA SAFETY MONITORING BOARD AND CLINICAL EVENTS 
COMMITTEE (REFER TO APPENDIX D) 
Both an independent Data Safety Monitoring Board (DSMB) and Clinical Events 
Committee (CEC) will be utilized to regularly review study progress with regard to 
safety. The CEC will be blinded to subject’s treatment assignment. Members of these 
boards cannot be investigators on the ACP Clinical Trial.  Board membership includes: 
cardiologists, neurologists, and biostatisticians.  The primary responsibilities of the 
DSMB and CEC include: 
 
• 
Review and refine adverse event definitions as necessary during the conduct of 
the clinical investigation 
• 
Review and adjudicate adverse events and primary endpoints as they occur over 
the course of the clinical investigation 
• 
Review and validate the subject sample (i.e., review inclusion/exclusion deviations 
and other protocol deviations) 
• 
Provide oversight for issues affecting general subject welfare 
• 
Recommend premature study termination 
 
At any time during the course of the study, the DSMB and CEC may offer opinions or 
make formal recommendations concerning aspects of the study that impact subject 
safety (e.g., safety-related protocol changes or input regarding adverse event rates 
associated with the investigational study).  Additionally, the DSMB and CEC may act as 
an advisory panel for questions regarding informed consent, subject enrollment, 
protocol implementation, study endpoints, data discrepancies, and other issues that 
may present during the course of the study. 
 
2.16.3 ECHO CORE LAB 
An independent Echo Core Lab/Board will analyze all TEEs and TTEs as required 
during the trial.  Members of the Echo Core Lab will have no affiliation with the ACP 
Clinical Trial.  
 
2.16.4 BRAIN IMAGING CORE LAB 
An independent core lab will be utilized to review any MRI and/or CT (if performed) 
conducted at baseline and at designated follow up visits to determine endpoint event 
occurrence.  Members of the Brain Imaging Core Lab will have no affiliation with the 
ACP Clinical Trial. 
 
2.16.5 BLOOD WORK CORE LAB (REFER TO APPENDIX D) 

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An independent core lab will be utilized to perform baseline hematology and coagulation 
tests (as described in section 2.9).  Members of the Blood Work Core Lab will have no 
affiliation with the ACP Clinical Trial.  
 
2.17 
STUDY MANAGEMENT 
2.17.1 CLINICAL PROJECT MANAGEMENT 
An AGA Medical clinical project team will be developed and trained to select qualified 
investigators, train investigative sites, monitor the clinical trial, ensure IRB approvals 
and renewals are obtained, and to inform the IRB and FDA of any significant new 
information about the clinical trial.  The team will adhere to AGA Medical LLC internal 
procedures, 21 CFR parts 54, 56, 812, and all other applicable regulations. 
 
2.18 
ADMINISTRATIVE REQUIREMENTS 
2.18.1 INVESTIGATOR SELECTION AND TRAINING 
AGA Medical will select qualified investigators and provide them with the necessary 
information and training on the investigational plan and ACP implantation procedure in 
order for them to conduct the investigation properly.  Investigators who are selected to 
participate in the ACP trial will be required to attend SimSuite training (procedure 
simulation which is specific to implantation of the ACP device) and didactic training on 
the ACP protocol and implantation procedure.  Other training may be provided as 
necessary on an individual or group basis. 
 
2.19 
TRAINING THROUGHOUT THE STUDY 
Training may be conducted throughout the course of the clinical trial if changes are 
made to the investigational plan, for non-compliance, and/or for changes in site 
personnel during the clinical trial.  Training may include investigator meetings, additional 
proctoring, conference calls, and/or web-based training sessions. 
 
2.20 
PROTOCOL ADHERENCE AND AMENDMENTS 
2.20.1 PROTOCOL DEVIATION 
A protocol deviation is any deviation from the investigational plan.  Deviations from the 
investigational plan will be recorded on the Deviation Case Report Form (CRF).  If 
applicable, the site is responsible for notifying their IRB of any deviations. AGA Medical 
should be informed of all IRB notifications. 
 
 
 
Deviations from the investigational plan include but are not limited to: 
 
• 
Required testing not completed or done outside window 
• 
Subject follow-up not completed or completed outside of window 
• 
SAE not reported 

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• 
Study-required testing done prior to signing the Informed Consent 
Form 
• 
Other Informed Consent issues 
• 
Inclusion/exclusion criteria not met for enrolled subjects 
• 
Enrolling subjects after an IRB lapse 
• 
Continued collection of subject study related data during an IRB 
lapse 
 
Investigator compliance will be continuously assessed by the AGA 
Clinical Affairs management team and appropriate corrective action will 
be taken when necessary.  
 
2.20.2 PROTOCOL AMENDMENTS 
Protocol amendments may occur during the course of the study and will be reviewed 
prior to implementation to determine if the changes affect the:  validity of the data; 
subject risk-to-benefit ratio; scientific soundness of the investigational plan; or the rights, 
safety, or welfare of the human subjects involved in the clinical trial. 
 
Protocol amendments that affect any of the above criteria will require FDA and IRB 
approval prior to implementation.  Protocol amendments that do not meet the criteria 
above will be reported to the FDA according to 21 CFR 812.35. 
 
 
2.20.3 EMERGENCY DEVIATIONS FROM INVESTIGATIONAL PLAN 
If a deviation from the investigational plan is necessary to protect the life or physical 
well-being of a subject in an emergency, the investigator must notify AGA Medical LLC 
and the appropriate IRB within five (5) working days. 
 
2.20.4 CONFIDENTIALITY 
All subject information collected during the course of this study will be kept strictly 
confidential according to applicable country-specific laws and regulations. All data and 
information concerning subjects and their participation in this study are considered 
confidential by Sponsor, and its affiliates (located in the U.S.A. and European Economic 
Area (EEA), Canada, and other countries), and other people who work for Sponsor to 
provide services related to the device and this study (collectively referred to as “AGA”). 
All public reporting of the results of the study will eliminate identifiable references to the 
subjects.  Information on paper will be kept in secured locations. Electronic information 
will be kept on password-protected computers. 
 
Personal data, including medical and health information, will be processed both by 
computer and manually, during and after the study by Sponsor, and its affiliates, its 
designated third party data processors, the IRB, the institution conducting the study, the 
study doctors and other healthcare personnel involved in the study for the purposes of 
this study. The electronic data stored for this study will be kept in an Sponsor database, 
in compliance with part 11 of the us code of federal regulations.  Subject data will not 

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contain details of study subject identity. The data will be stored on a secure server and 
backed up routinely. All records and reports required by or prepared in connection with 
this study shall be maintained by the institution and the site principal investigator in a 
secure location for a minimum period of 2 years post approval or longer as may be 
otherwise required by local law. Personal data will be key-coded to prevent subject 
identification, except by the institution, study doctors and other healthcare personnel 
involved in the study, if necessary for the purpose of the study, for regulatory 
inspections, and to comply with sponsor reporting obligations. 
 
Study subjects have a right to gain access and to correct inaccuracies in information 
about them as permitted by applicable law.  In order to help keep subject medical 
records and personal information confidential only certain authorized investigators and 
sponsor personnel, or approved contracted agents of sponsor, will have access to 
confidential records. These include researchers in the hospital who are part of this 
study, sponsor and its affiliates and representatives that perform study-related services 
who may be located in the U.S.A., Canada, European Economic Area (EEA) and other 
countries. The IRB and other regulatory authorities also have the right to inspect and 
copy records pertinent to this study. It is necessary for them to review study data, 
portions of study subject records and information so that they can follow the study 
progress, which may include without limitation: 
 
• 
monitor the accuracy and completeness of the study 
• 
perform scientific analysis and develop the medical product  
• 
and/or obtain approval to market the medical products in the USA, Canada, 
EEA, and other countries. 
 
Any information about subjects that leaves the institution conducting the study will be 
modified to remove certain information that could identify the subject (e.g., subject’s 
name, age on the day of enrollment, address, and hospital number) and only be 
identifiable by a study id code. Study data provided to sponsor that is published in 
medical journals and/or presented at scientific conferences will not allow the 
identification of study subjects.  
 
The results of the study will be made available to sponsor and its affiliates (located in 
the U.S.A., EEA, Canada, and other countries) and other people who work for sponsor 
to provide services related to the device and this study and study center. 
 
A summary of the information on all subjects may be provided to governmental 
agencies (including regulatory agencies), regulatory authorities in the U.S.A., Canada, 
EEA and other countries who may also need to review study data and portions of 
medical records.  Results from this study may also be published in scientific journals or 
presented at conferences as an oral or poster presentation; however, the identity of a 
study subject will not be disclosed. 
 
2.20.5 INFORMED CONSENT COMPLIANCE 
 

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express written permission of AGA Medical LLC. 
Informed consent must be obtained using the IRB approved informed consent and 
according to the IRB’s requirements.  Informed consent deviations include but are not 
limited to: 
 
• Failure to consent subject 
• Failure to obtain subject signature 
• Failure to obtain date/time of subject signature (if applicable) 
• Failure to obtain signature of person conducting the informed consent process 
• Failure to obtain witness signature, if applicable 
• Unapproved consent form used 
• Failure to obtain HIPAA Authorization 
 
 
2.21 
CLINICAL STUDY COMPLIANCE 
AGA Medical will review and monitor investigator compliance and determine if there is a 
need for corrective action based on the severity and/or trends in non-compliance to the 
signed agreement with AGA Medical LLC, the investigational plan, the applicable 
regulations, or any conditions of approval imposed by the reviewing IRB or FDA (21 
CFR 812.46 (a)).  Depending on the severity and/or trend in non-compliance, the 
investigator may receive a formal warning, or retraining through a site visit or 
conference call.  AGA Medical may terminate the investigator’s participation in the 
clinical trial or suspend enrollment if repeat non-compliance occurs. 
 
2.22 
INSTITUTIONAL REVIEW BOARD 
All IRBs must comply with applicable IRB regulation (21 CFR 56) and IDE regulations (21 CFR 
812) in reviewing and approving device investigations. 
 
2.22.1 RESPONSIBILITIES 
An IRB shall safeguard the rights, safety, and well being of all study subjects. 
 
2.22.2 COMPOSITION 
The IRB shall be composed of members meeting the minimum requirements set forth in 
21 CFR 56.107. 
 
2.22.3 INITIAL IRB APPROVAL 
Prior to shipment of investigational devices for this study, AGA Medical will require 
documentation of IRB approval of the investigational plan and subject informed consent. 
 
2.22.4 ANNUAL IRB RENEWAL 
An IRB shall conduct continuing review of the clinical trial at intervals appropriate to the 
degree of risk posed by the device, but not less than once per year (21 CFR 56.109).  
 
 

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express written permission of AGA Medical LLC. 
2.23 
DEVICE ACCOUNTABILITY 
Upon receipt of the ACP, investigators will maintain the following accurate, complete, and 
current records relating to device accountability.  Records of receipt, use, or disposition of 
device including: 
• 
Type and quantity of devices 
• 
Date of receipt 
• 
Serial number 
• 
Names of all persons who received, used or disposed of each unit, and 
• 
Why and how many units of the device have been returned to the sponsor, repaired, 
or otherwise disposed of 
 
All investigational products must be accounted for and returned at the end of the trial. 
 
2.23.1 TECHNICAL INCIDENTS 
Complete a Technical Incident CRF if the ACP or the Delivery System does not perform 
to your expectations or you experience any technical malfunctions. 
 
2.24 
DATA ENTRY AND CRF SUBMISSION 
The Principal Investigators and/or authorized study center designees may complete 
the CRFs. 
 
• The investigator and site staff will be trained on data entry and CRF submission 
during the site initiation visit 
• The investigator is responsible for assuring accuracy, completeness, and timeliness 
of the CRFs sent to AGA Medical 
• Data reported on the CRFs should be consistent with the source documents or the 
discrepancies should be explained 
• Manual or automatic Data Clarification Forms (DCF) will be generated by AGA 
Medical for incomplete or inaccurate data points and sent to the site for completion 
 
2.25 
DATA MANAGEMENT 
A Data Management Plan (DMP) will be completed as part of the database development.  The 
DMP will be updated as necessary during the clinical trial.  A clinical database will be 
developed and validated for the ACP clinical trial.  A record will be created in the database for 
each subject in the clinical trial.  Data collected during this clinical trial will be analyzed, and 
submitted in the form of a Premarket Approval (PMA). 
 
2.26 
INSTITUTIONAL AUDITS 
The ACP clinical trial will be audited to internal and external regulations, standards, and 
procedures to assess compliance.  The investigator will permit study-related auditing and 
inspections of all study-related documents by the IRB, government regulatory agencies, and 

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express written permission of AGA Medical LLC. 
AGA Medical.  The investigator will allocate time for these activities, allow access to all study-
related documents and facilities, and provide adequate space to conduct these visits. 
 
2.27 
CONFLICT OF INTEREST 
Investigators who have a conflict of interest with this study (such as patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution) must fully 
disclose the nature of the conflict of interest in accordance with AGA Medical and applicable 
federal, state and local laws and regulations.  Investigators will be required to submit a 
financial disclosure prior to study participation. 
 
2.28 
PUBLICATION POLICY 
No study results obtained under this protocol, nor any information provided to the investigator 
for the purposes of performing the study, will be published or passed on to any third party 
without the consent of AGA Medical.  Investigators are obligated to follow the AGA Medical 
publication policy. 
 
2.29 
ECONOMIC AND QUALITY OF LIFE SUB-STUDY (REFER TO APPENDIX D) 
In conjunction with the pivotal phase of clinical study, the costs and benefits of treatment will 
be evaluated through  an economic and quality of life analysis .  Medical resource use, cost 
and health-related quality of life within the trial period will be compared between treatment 
groups.  If ACP therapy is found to be effective, its long term cost-effectiveness analysis will be 
assessed.  The economic and quality of life analysis will be fully integrated into the clinical trial, 
with a common informed consent form and collection of subject reported resource use in the 
case report form. Hospital bills reporting hospital care for study subjects during the study 
period will also be collected at least through 2 years and until the study is completed. 
 
2.30 
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arrhythmias. PACE. 2001;24:1541-1558. 
86. Shah D et al. Nonpulmonary vein foci: Do they exist? PACE. 2003;26:1631-1635. 
87. Sick PB, Schuler G, Hauptmann KE, Grube E, Yakubov S, Turi ZG, Miskel G, 
Almany S, Holmes DR.  Initial world wide experience with the WATCHMAN left atrial 
appendage system for stroke prevention in atrial fibrillation.  J Am Coll Cardiol. 2007 
Apr 3;49(13):1490-5 
88. Sievert H, Lesh MD, Trepels T, Omran H, Bartorelli A, Della Bella P, Nakai T, 
Reisman M, DiMario C, Block P, Kramer P, Fleschenberg D, Krumsdorf U, Scherer 
D.  Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in 
high-risk subjects with atrial fibrillation: early clinical experience.  Circulation. 2002 
Apr 23;105(16):1887-9 

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89. Spragg D et al. Complications of catheter ablation for atrial fibrillation: Incidence and 
predictors. Journal Cardiovascular Electrophysiology. 2008;19:627-631. 
90. Stollberger C, Schneider B, Finsterer J. Elimination of the left atrial appendage to 
prevent stroke or embolism? Anatomic, physiologic, and pathophysologic 
conderations. Chest 2003 Dec;124(6):2356-62. Review. 
91. Stuart J. Connolly, Janice Pogue, John Eikelboom, Gregory Flaker, Patrick 
Commerford, Maria Grazia Franzosi, Jeffrey S. Healey, Salim Yusuf and on behalf of 
the ACTIVE W Investigators. Benefit of Oral Anticoagulant Over Antiplatelet Therapy 
in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control 
Achieved by Centers and Countries as Measured by Time in Therapeutic Range. 
Circulation 2008;118;2029-2037; originally published online Oct 27, 2008 
92. Takahashi N, Akira S, Imataka K, Fujii J. Clinical features of paroxysmal atrial 
fibrillation. An observeation of 94 subjects. Jpn Heart J. 1981 March 22(2);143-49. 
93. The effect of low-dose warfarin on the risk of stroke in subjects with nonrheumatic 
atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation 
Investigators. N Engl J Med. 1990 Nov 29;323(22):1505-11. (Abstract only) 
94. Transient Ischemic Attack – Proposal for a New Definition.  TIA working group.  N 
Engl J Med, Vol. 347, No. 21 · November 21, 2002 
95. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, 
Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van 
Veldhuisen DJ, Van den Berg MP; RACE II Investigators. Lenient versus strict rate 
control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363-73. 
96. Van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, Petersen P, 
Koudstaal PJ, Chang Y, Hellemons B. Oral anticoagulants vs Aspirin in nonvalvular 
atrial fibrillation: an individual patient meta-analysis; JAMA. 2002 Nov 
20;288(19):2441-8. 
97. Vural A, Agacdiken A, Ural D, Sahin T, Kozdag G, Kahraman G, Ural F, Akbas H, 
Suzer K, Komsuoglu B.  Effects of cardiac resynchronization therapy on left atrial 
appendage function and pulmonary venous flow pattern. Int J Cardiol. 2005 Jun 
22;10(1):103-9. 
98. Walsh K, et al. Left Atrial Appendage Closure With the AMPLATZER Cardiac Plug: 
Results of the European Prospective Observational Study. Paper presented at: 
EuroPCR, 2012 May 15-18; Paris. 
 
2.31 
DEFINITIONS  
Atrial Fibrillation (AF) – Rapid, incomplete, disorganized activity of the upper 
chambers of the heart (atria) resulting in rapid, irregular, and uncoordinated movement. 
On ECG, characterized by rapid baseline oscillations that vary in size, shape, and 
timing, usually recognized as having rates greater than 320 beats per minute. 
Paroxysmal AF –Characterized as episodes of self-terminating, atrial fibrillation 
that generally last seven days or less (usually less than 24 hours); may be 
recurrent 

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Persistent AF –Refers to subjects in whom the AF episodes were not self 
terminating and last greater than seven days or lasts less than seven days if they 
required cardioversion 
Permanent AF - Permanent AF is defined as a condition in which sinus rhythm 
cannot be sustained for seven days after cardioversion or the patient and 
physician have decided against further efforts to restore sinus rhythm. It includes 
cases of long-standing AF (e.g., greater than one year)  
Audit – A systematic and independent examination of study-related activities 
documents to determine whether the evaluated study-related activities were conducted, 
and the data were recorded, analyzed, and accurately reported according to the 
protocol, Sponsor’s standard operating procedures (SOPs), and applicable regulatory 
requirements. 
Budget – The amount of money designated by the Sponsor for conducting the clinical 
trial. 
Case report form (CRF) – A printed, optical, or electronic document designed to record 
all of the protocol-required information to be reported to the Sponsor on each study 
subject. 
CHADS2 Risk Criteria 
Prior stroke or TIA (defined as stroke or TIA occurring prior to the first documented 
onset of AF by the physician.  Subjects diagnosed with stroke or TIA on the same day 
as diagnosing AF must be excluded from the CHADS2 assessment) 
• Age greater than 75 years 
• Hypertension with (with a systolic BP of > 160mmHg at the time of screening) 
• Diabetes Mellitus (defined by history of a fasting glucose of at least 140mg/dl or a 
random glucose of at least 200mcg/dl, or use of insulin or hypoglycemic 
medications) 
• Heart Failure (recent CHF or LVEF less than or equal to 35%) 
Clinical study – A study to evaluate a product using human subjects, in the treatment, 
prevention, or diagnosis of a disease or condition, as determined by the product’s 
benefits relative to its risks. 
Confidentiality – Prevention of disclosure to other than authorized individuals, of a 
Sponsor’s proprietary information or a subject’s identity and medical information. 
Contract – A written, dated, and signed agreement between two or more involved 
parties that sets out any arrangements on delegation and distribution of tasks and 
obligations and, if appropriate, on financial matters. 
Diabetes mellitus – History of a fasting glucose of at least 140mg/dl or a random 
glucose of at least 200mg/dl, or use of insulin or hypoglycemic medications. 

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Edit Logic – Programmed rules (in the form of edit checks) applied to a study database 
to catch any unexpected errors on CRFs.  A DCF can be automatically generated when 
the logic of the edit check is met. 
Good clinical practice – A standard established by the International Conference on 
Harmonization (ICH) for the design, conduct, performance, monitoring, auditing, 
recording, analyses, and reporting of clinical studies that provides assurance the data 
and reported results are credible and accurate, and the rights, integrity, and 
confidentiality of study subjects are protected. 
Hemorrhagic Stroke-acute focal neurological deficit presumed to be due to focal 
ischemia, with either symptoms persisting 24 hours or greater, or symptoms persisting 
less than 24 hours,  associated with MR or CT findings of a new, neuroanatomically 
relevant, cerebral infarct with hemorrhagic conversion 
Institutional review board (IRB) – An independent body constituted of medical, 
scientific, and non-scientific members, whose responsibility it is to ensure the protection 
of the rights, safety, and well-being of human subjects involved in a research study by, 
among other things, reviewing, approving, and providing continuing review of studies, of 
protocols and amendments, and of the methods and material to be used in obtaining 
and documenting informed consent of the study subjects. 
Investigational medical device – A medical device (including an in vitro diagnostic 
device) being tested or used in a clinical trial, including a product with a marketing 
authorization when used or assembled in a way different from the approved form, or 
when used for an unapproved indication, or when used to gain further information about 
an approved use. 
Investigator – An individual who conducts a clinical investigation, under whose 
immediate direction the test article is administered, dispensed to, or used involving a 
subject; or in the event of an investigation’s conduct by a team of individuals, is the 
responsible leader of the team. 
Ischemic Stroke acute focal neurological deficit presumed to be due to focal ischemia, 
with either symptoms persisting 24 hours or greater, or symptoms persisting less than 
24 hours,  associated with MR or CT findings of a new, neuroanatomically relevant, 
cerebral infarct 
Legally authorized representative – An individual or judicial or other body authorized 
under applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the procedures(s) involved in the research.  
Monitoring – The act of overseeing the progress of a clinical trial, and of ensuring that 
it is conducted, recorded, and reported in accordance with the protocol, SOPs, and 
applicable regulatory requirement(s). 
NYHA Functional Classification 
• Class I: No symptoms and no limitation in ordinary physical activity  

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• Class II: Mild symptoms and slight limitation during ordinary activity Comfortable at 
rest 
• Class III: Marked limitation in activity due to symptoms even during less than 
ordinary activity. Comfortable only at rest  
• Class IV: Severe limitations. Experiences symptoms even while at rest  
Oral Anticoagulation (OAC) – A class of drugs that prevents coagulation of blood. 
Within this investigational protocol, OAC refers to warfarin and/or dabigatran. 
Optimal Medical Therapy (OMT) – Within this investigational protocol, OMT refers to 
warfarin or dabigatran with or without concomitant aspirin. This is determined for each 
subject by the investigator at baseline. This does not include rivaroxaban which is 
excluded in this trial. 
Peripheral Thromboembolism - An abrupt vascular insufficiency associated with 
clinical and radiological evidence of arterial occlusion in the absence of another likely 
mechanism 
Protocol Deviation – A deviation from the investigational plan 
Quality assurance – All planned and systematic actions established to ensure the 
study is performed and data are generated, documented (recorded), and reported in 
compliance with GCP and the applicable regulatory requirement(s). 
Screening – The process of evaluating potential clinical trial subjects to determine if 
they meet protocol eligibility criteria before enrolment. 
Study close-out visit – The final visit made to a site after the study has been 
completed or terminated.  
Subject – An individual who participates in a clinical trial, either as a recipient of the 
investigational drug or medical device, or as a control. The terms subject and participant 
are used synonymously. 
Subject identification code – A unique identifier assigned by the investigator or the 
Sponsor to each study subject to protect the subject’s identity and used in lieu of the 
subject’s name when the investigator reports adverse events and/or other study-related 
data. 
Sustained discontinuation of warfarin or dabigatran- The subject’s ability to remain 
off of warfarin or dabigatran for a minimum of 6 months following discontinuation of 
warfarin or dabigatran except in subjects with less than 6 months of follow-up. 
‘Sustained discontinuation’ for those subjects who have less than 6 months of follow-up 
is defined as the subject’s ability to remain off of warfarin or dabigatran for a minimum of 
3 months following discontinuation of warfarin or dabigatran. 
Transient Ischemic Attack acute focal neurological deficit (such as focal motor deficit, 
aphasia, difficulty walking, hemisensory deficit, amaurosis fugax, blindness, or focal 
visual deficit) presumed due to focal ischemia, with symptoms persisting greater than or 

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equal to 5 minutes and less than 24 hours, that is not associated with MR or CT findings 
of a new cerebral infarct 
 

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3. 
RISK ANALYSIS 
3.1 
RISK: BENEFIT ASSESSMENT OF THE DEVICE ARM 
 
3.1.1 Risks Associated With the Procedure 
The risks associated with the ACP procedure are similar to those of other cardiac 
catheterization procedures. Some of the potential risks associated with the procedure 
may include, allergic reactions during the procedure to contrast, drugs, products (latex), 
or anesthesia; adverse events related to vascular access; and/or adverse events related 
to catheter manipulation.  Other adverse events associated with cardiac catheterizations 
may include, but are not limited to the following; arrhythmia, brachial plexus injury, 
cardiac arrest, cardiac tamponade, fever, infection, kidney damage, myocardial 
ischemia/infarction, pericardial effusion, and death. Refer to Section 2.13.2 for a 
complete list of anticipated adverse events. 
 
Radiation risks associated with the procedure will be comparable to a diagnostic 
catheterization procedure. 
 
3.1.2 Product Risks 
The risks associated with ACP are similar to other implantable cardiac occlusion 
devices.  Some of the potential risks include but are not limited to those listed below: 
 
• Device Embolization  
Device embolization may occur if an improper device size is used or the 
device is incorrectly seated. If the device embolizes prior to release, it can be 
partially pulled inside the delivery catheter for repositioning.  If the device 
embolizes after release, it should be removed as soon as possible; surgery 
may be necessary. 
 
• Bacterial Endocarditis  
The ACP is a foreign body which will be permanently implanted and therefore 
subjects are at risk of bacterial endocarditis.  Bacterial endocarditis may 
contribute to heart failure, arrhythmias, damage to the heart muscle and blood 
clots. If left untreated, bacterial endocarditis can lead to death. 
 
• Device Thrombus  
Thrombus formation on the device could potentially result in subsequent 
embolization, infectious endocarditis, arrhythmias, stroke/TIA, or death. 
 
• Pericardial Effusion 
ACP may perforate the visceral pericardium and lead to accumulation of fluid 
in the pericardial cavity which may result in cardiac tamponade. 
 
 
 

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• Cardiac Tamponade 
If pericardial effusion becomes sufficiently large, cardiac contractility maybe 
compromised leading to low cardiac output and possibly cardiogenic shock or 
death. 
 
• Allergic device reaction 
 
Idiosyncratic reaction to the device implanted. 
 
• Nickel sensitization 
 
Alteration of the responsiveness of the body to nickel 
 
• Carcinogenicity 
Potential carcinogenicity risk. The ACP device consists of a nickel-titanium 
alloy.  In vitro testing has demonstrated that that nickel is released from this 
device for a minimum of 60 days.  Some forms of nickel have also been 
associated with carcinogenicity (ability to cause cancer) in animal models. In 
humans, carcinogenicity has been demonstrated only through an inhalation 
route (breathing nickel in), which will not occur with this procedure. 
 
3.1.3 Potential Benefits 
The primary potential benefit is that the subjects may not need to be on long-term 
warfarin or dabigatran therapy and thus will not be exposed to its associated 
complications.  In addition, the ACP will be implanted via transcatheter approach.  
Subjects who receive the device may also decrease the associated risk of 
thromboembolism.  
 
3.2 
RISK: BENEFIT ASSESSMENT OF THE CONTROL ARM 
3.2.1 Risks Associated With Warfarin 
 
 
Warfarin therapy requires continuous monitoring and dose management to optimize 
therapy and avoid associated adverse events. The anticoagulant effect of warfarin is 
influenced by concomitant use of antiplatelet agents.  Furthermore, many other 
medications, as well as diet, interfere with the metabolism of warfarin, either potentiating 
or inhibiting its anticoagulant effects. 
 
 
Warfarin levels which are either too high or too low have associated risks.   
Subtherapeutic levels do not lessen the risk of thromboembolic events. Levels which 
are too high may result in bleeding.  The bleeding risk appears higher in subjects with a 
history of prior stroke or gastrointestinal bleeding.  Another important, but uncommon 
adverse effect of warfarin is skin necrosis. 
 
 
Warfarin is associated with a 2.2% increased risk of major fatal or nonfatal bleeding, 
and 7.7% increase in minor hemorrhagic complications per year (Gullov 1994).   
 
 

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3.2.2 Risks Associated With Dabigatran 
 
Dabigatran increases the risk of bleeding and can cause significant and sometimes fatal 
bleeding. Risk factors for bleeding include the use of other drugs that increase the risk 
of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of 
Non-steroidal anti-inflammatory drugs (NSAIDs)). 
 
Dabigatran’s anticoagulant activity and half-life are increased in subjects with renal 
impairment. 
 
A specific reversal agent for dabigatran is not available. 
 
3.2.3 Risks of Concomitant Use of OACs and Aspirin 
 
Cardiovascular professional society guidelines recommending concomitant aspirin 
usage with OACs vary based on targeted patient population and/or disease type to be 
treated. Current professional society guidelines for use of concomitant aspirin with oral 
anticoagulation / antiplatelet therapy for subjects likely to be treated under this clinical 
protocol are summarized in the table below.   
 
Summary of Professional Guidelines and Concomitant Aspirin Usage 
Guideline* 
Recommendation 
ACC/AHA/SCAI 2007 Guideline Update 
for Percutaneous Coronary Intervention 
In pts. requiring warfarin, clopidogrel, and 
aspirin after PCI, target INR of 2.0–2.5  
is recommended with low-dose aspirin (75–
81 mg) and a 75-mg dose of 
clopidogrel 
ACC/AHA 2007 Guidelines for the 
Management of Patients with ST- 
Elevation Myocardial Infarction 
If indication for anticoagulation, add warfarin 
(INR 2.0–3.0) to aspirin  
AHA/ASA 2006 Guidelines for Prevention 
of Stroke in Patients with Ischemic Stroke 
or Transient Ischemic Attack 
Warfarin (INR 2.0–3.0) + aspirin <162 mg 
daily  
ACC/AHA 2007 Guidelines for the 
Management of Patients with Unstable 
Angina/Non–ST-Elevation Myocardial 
Infarction 
Low-dose aspirin 75–81 mg daily + warfarin 
(INR 2.0–2.5)  
2011 ACCF/AHA/HRS Focused Updates 
Incorporated Into the ACC/AHA/ESC: 
2006 Guidelines for the Management of 
Patients with Atrial Fibrillation 
When warfarin is given in combination with 
clopidogrel or low-dose aspirin, dose 
intensity must be carefully regulated 
AHA/ACC Guidelines for Secondary 
Prevention for Patients with Other 
Atherosclerotic Vascular Disease: 2006 
Update: Endorsed by the National Heart, 
Lung, and Blood Institute 
Add warfarin (INR 2.0–3.0) when clinically 
indicated 
*Note: this table is a representative sample of guidelines as of the date of this protocol 
revision (Revision 06, August 2012). Please refer to current professional guidelines for the 
most recent updates. 

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Despite the recommendations above, aspirin may offer only modest protection against 
stroke for patients with atrial fibrillation (Fuster 2011), thus the clinical utility of aspirin 
use in non-valvular atrial fibrillation is an area of uncertainty. The risk of concomitant 
use of oral anticoagulants and aspirin may be associated with an increase in bleeding 
risk. As such, the concomitant use of OACs and aspirin is considered a matter of clinical 
judgment by the treating physician understanding that the potential benefits of continued 
aspirin outweigh the potential bleeding risks. 
 
It is further recommended that when warfarin is given in combination with low-dose 
aspirin, the dose intensity must be carefully monitored. For further information refer to 
the package insert for warfarin (Coumadin® product insert, Bristol-Myers Squibb, 
293US11PBS01503). 
 
Based on available published literature, i.e. RE-LY trial (Connolly et al 2009), the 
concomitant use of aspirin with dabigatran in non valvular AF patients resulted in an 
annual stroke and systemic embolism rate of 1.07% but may also be associated with 
increased risk I bleeding. This included 20-30% of patients taking concomitant aspirin 
with dabigatran. There may also be an associated risk of increased bleeding. Among 
patients receiving concomitant aspirin or clopidogrel in RE-LY, an increased risk of 
major bleeding was observed (HR 1.76, 95% CI 1.55–2.00), which was similar for 
dabigatran 110 mg, 150 mg or warfarin (Dans 2011).  Therefore, similar caution is 
recommended for treating physicians considering co-administration of dabigatran with 
other anticoagulants or antiplatelet agents.  
 
3.2.4 Potential Benefit 
 
The potential benefit is that the information obtained from this study may change future 
treatment of subjects with nonvalvular AF. 
3.3 
MINIMIZING THE RISKS 
 
To minimize potential clinical risks to subjects participating in this clinical trial: 
 
• This study will undergo a review and approval process to be monitored by 
investigational site Institutional Review Boards (IRBs). The IRBs will also review all 
study-related documents such as the protocol, participant recruitment 
announcements, and consent forms.  
• The FDA will also review the protocol and consent forms. 
• Investigators will be carefully selected based on their knowledge of, and 
experience treating AF. 
• Investigators will be trained with regards to implantation technique of the ACP. 
• Investigators will be provided with detailed Instructions For Use as a reference.  
• The DSMB and/or CEC will have oversight throughout the clinical trial. 

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• The Steering Committee will act as an advisory board for the pivotal phase. 
• Investigators will be required to follow The American Heart Association 
recommendations for endocarditis prophylaxis during the clinical trial; and 
• Investigators or designated personnel administering the NIH Stroke Scale 
questionnaire will be certified. 
 
In addition, to reduce the risks of specific device related adverse events: 
• The subject eligibility criteria include minimum and maximum LAA dimensions to 
be treated with the ACP, which should minimize the risk of device embolization, 
device migration and perforation; and 
• Subjects will be administered Heparin during the procedure and OMT therapy after 
the procedure; once warfarin/dabigatran therapy is discontinued, 325mg of aspirin 
will begin.

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4. 
DESCRIPTION OF DEVICE 
 
The AMPLATZER Cardiac Plug (ACP) is a transcatheter self-expanding device constructed 
from a nitinol mesh and polyester patch. ACP consists of a lobe and a disc connected by a 
central waist. The ACP is available in 8 diameters sizes, 16, 18, 20, 22, 24, 26, 28, and 30 mm. 
The device is designed to prevent thrombus embolization from the left atrial appendage (LAA) 
in subjects who have nonvalvular atrial fibrillation.  The lobe has stabilizing wires to improve 
device placement and retention.  The device has threaded screw attachments at each end for 
connection to the delivery and loading cable as well as radiopaque markers at each end and at 
the stabilizing wires. 
 
Order number 
Lobe diameter (mm) 
Disc diameter (mm) 
Length of the lobe 
9-ACP-IDE-016 
16 mm 
20 mm 
6.5mm 
9-ACP-IDE-018 
18 mm 
22 mm 
6.5mm 
9-ACP-IDE-020 
20 mm 
24 mm 
6.5mm 
9-ACP-IDE-022 
22 mm 
26 mm 
6.5mm 
9-ACP-IDE-024 
24 mm 
28 mm 
6.5mm 
9-ACP-IDE-026 
26 mm 
30 mm 
6.5mm 
9-ACP-IDE-028 
28 mm 
32 mm 
6.5mm 
9-ACP-IDE-030 
30 mm 
34 mm 
6.5mm 
 
 
The AMPLATZER TorqVue Delivery Systems consists of a Delivery Sheath and Dilator.  
 
AMPLATZER Cardiac Plug 
Compatible AMPLATZER TorqVue Delivery Systems 
9-ACP-IDE-016 
9-TV45x45-9F 
9-TV-LA1-9F 
9-TV-LA2-9F 
9-ACP-IDE-018 
9-TV45x45-10F 
9-TV-LA1-10F 
9-TV-LA2-10F 
9-ACP-IDE-020 
9-ACP-IDE-022 
9-ACP-IDE-024 
9-TV45x45-13F 
9-TV-LA1-13F 
9-TV-LA2-13F 
9-ACP-IDE-026 
9-ACP-IDE-028 
9-ACP-IDE-030 
 

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5.  MONITORING PROCEDURES 
 
As indicated by the guidelines established for Investigational Device Exemptions by the FDA 
(21 CFR 812).  AGA Medical will comply with external and internal monitoring requirements, 
including development of a monitoring plan, for this investigational study.  Monitoring will be 
conducted by AGA Medical clinical personnel; overall monitoring oversight is the responsibility 
of Clinical Monitoring Manager. 

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6.  SAMPLE SUBJECT IDENTIFICATION CARDS 
 
All study participants are provided with a Subject Identification/Follow up Card regardless of the 
randomization assignment. 
 
 
 
SAMPLE PATIENT ID/FOLLOW-UP CARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLE DEVICE ID CARD 
 
Only subjects who receive an ACP device receive the card below. 
 
 
 
 
Front of 
Back of 
 
- Static magnetic field of 3.0 Tesla or less 
- Spatial gradient field less than or equal to 30 T/m 
- Maximum whole-body-averaged specific absorption rate (SAR)  
   of 2.0 W/kg (normal operating mode) for 15 minutes of scanning 
The carrier of this card has been treated with an implantable device and is in a 
clinical trial. The study (investigational) device is NON-FERROMAGNETIC / MR 
conditional and can be scanned safely under the following conditions: 
Notify your doctor if there is a change in your medical condition or address. 
  
If you experience shortness of breath or chest pain:  
- Seek medical attention immediately 
- An echocardiogram may be required 
  
If a stroke or TIA (mini-stroke) is suspected:  
- Seek medical attention immediately 
- A brain MRI must be performed within 10 days of the event as part of the trial.  
- A brain CT scan should be performed instead of a MRI if a MRI is contraindicated 
(medical reason not to perform)   
Manufactured by: AGA Medical (St. Jude Medical), 5050 Nathan Lane N  
Plymouth, MN 55442 (U.S.A.)  Phone 1-888-546-4407 / www.sjm.com 
Patient Initials:  
Trial ID Number: 
  
Hospital/Clinic: 
Doctor Name: 
Doctor Phone: 
  
Implant Date: 
(mm-dd-yyyy) 
  
Product Name:  
Product Number: 
Lot Number: 
Serial Number: 
 AMPLATZER™ Cardiac Plug Clinical Trial 
Device Identification Card 
AMPLATZER™ Cardiac Plug Clinical Trial 
Follow-up Schedule 
Scheduling Window (mm-dd-yyyy) 
( 02-10-2010  -  02-20-2010 ) 
( 05-31-2010  -  07-30-2010 ) 
( 12-02-2010  -  01-31-2011 ) 
( 05-01-2011  -  08-29-2011 ) 
( 11-02-2011  -  03-01-2012 ) 
( 11-01-2012  -  03-01-2013 ) 
( 11-01-2013  -  03-01-2014 ) 
( 11-01-2014  -  03-01-2015 )  
 
 Front of 
 Back of 
  
The holder of this card is participating in the  
AMPLATZER Cardiac Plug (ACP) Clinical Trial  
sponsored by AGA Medical (St. Jude Medical) 
 Patient Initials :  
Trial ID Number: 
Enrollment Date: 
(mm-dd-yyyy) 
Hospital/Clinic: 
Doctor Name: 
Doctor Phone: 
ABC  
123-ACP-456 
01-01-2010 
  
Heart Hospital USA 
John Doe, MD 
(555)-555-5555 
Trial Visit 
45 days 
6 month 
12 month 
18 month 
2 year  
3 year 
4 year 
5 year 
AGA Medical (St. Jude Medical) 
1-888-546-4407 www.sjm.com 
AMPLATZER™ Cardiac Plug Clinical Trial 
Patient Identification Card 

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7.  CONSENT MATERIALS 
Informed Consent Template  
AMPLATZER™ Cardiac Plug (ACP) Clinical Study 
 
 
Patient Consent Form authorizing participation in a clinical research trial with assignment to 
either treatment with the device under clinical investigation, or warfarin or dabigatran (current 
standard of care) in patients with non-valvular atrial fibrillation. 
 
Participant’s Name:  
 
 
 
 
 
 
 
 
 
 
Date:   
 
 
 
You are being asked to read this form so that you understand the nature of this clinical study 
and how you might take part in it.  Signing this form will show that you understand and that you 
agree to take part in this clinical study. Written informed consent is required before you can 
take part in this clinical research study. 
 
Why am I being asked to read this form? 
You are being asked to take part in this study because your doctor has told you that you have 
or have had an abnormal heart rhythm called atrial fibrillation (AF).  Normally electrical signals 
from the upper chambers of the heart (atria) travel through to the lower chambers of the heart 
(ventricles) and cause them to beat in a very regular way.  During AF, the electrical signals in 
your heart are abnormal, and cause the upper chambers of the heart (atria) to beat too fast 
and irregularly. 
 
This irregular beating of the heart leads to slowing of the blood in the upper chambers.  In the 
left upper chamber there is a small pouch called the left atrial appendage (LAA).  Slowing of 
blood, especially in the LAA, may cause blood clots to form.  The clots may move from the 
LAA and travel to the brain, causing a stroke or transient ischemic attack (TIA), also called a 
mini-stroke.  These blood clots may also travel to other parts of the body and block blood 
vessels. This clinical research study is designed to evaluate a new device the AMPLATZER 
Cardiac Plug (ACP) to close your LAA which may decrease the chance of a new blood clot 
forming and moving from the LAA. 
 
Your doctor has given you this form to tell you about this research study and to ask whether you 
are willing to participate in this study. If given, your consent to join this study will be documented 
by your signature on the last page of this form only after you fully understand the study. Your 
participation is voluntary. You will also be able to ask questions before you agree to be in this 
study. 
 
Why is this study being done? 
The purpose of this research is to evaluate the safety and effectiveness of the AMPLATZER 
Cardiac Plug. This will be done by comparing the results of this device to standard therapy with 
the medicines warfarin or dabigatran.  Warfarin (Coumadin®) and dabigatran (Pradaxa®) are 

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medicines that help to thin your blood and prevent blood clots from forming. These are 
common medications given to people who have AF.  
 
Who is the study Sponsor? 
AGA Medical LLC, a U.S. medical device company is the Sponsor of this study and will be 
providing financial support for this clinical study. The principal investigator and co-
investigator(s) in this study are also healthcare providers.  They are interested in the 
knowledge to be gained from this study and in your well-being.  The health care facility and 
investigators will receive financial support for conducting the research.   
 
What is the study device? 
The AMPLATZER Cardiac Plug (ACP) is a self-expanding device which is made from a nitinol 
(nickel-titanium alloy) mesh and which has a lobe and a disc connected by a central waist. The 
device is designed to prevent blood clots from moving out of the left atrial appendage (LAA).  
The lobe has small stabilizing wires that help keep the device in place.  The device has fabric 
sewn into the disc and the lobe. This polyester material is the same as that used in other heart 
devices and by surgeons to repair heart problems. The fabric helps stop the flow of blood into 
the LAA. The device has screw attachments at each end so it can be placed in the heart. The 
study device sizes range from 16 mm to 30 mm. This device is investigational which means it 
has not been approved by the FDA for commercial use in the United States. 
 
 
 
 
 
 
 
 
 
ACP Device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Device implanted heart 
 
 
Device in left atrial appendage 
 
 
 
How long will I be in the study? 
Your total study participation is expected to last about 5 years.  
 
About how many participants will be in the study? 
The study will include up a minimum of 400 and maximum of 3000 participants at a maximum of  
80 sites in the United States and up to 10 sites in Canada. An initial safety study was conducted 
in 2010-2011 which enrolled 45 subjects and now the study is continuing and expanding.   
 
What tests, procedures and treatments will I have as part of the study? 
If you decide to participate, you will have medical tests to see if you qualify to be part of the 
study. During your participation in the study, you may have more medical tests and/or 
procedures.  Some tests may be done more than once.  
 
Study-Specified Tests/Procedures 
 
Baseline Testing 
You will have the following tests once you sign this form and agree to be in this study. These 
are common tests for someone with atrial fibrillation and might be performed even if you do not 
join this study. You should be aware that some of the tests performed may need to be 
repeated. You will have a physical exam and be asked questions about your medical and 
medication history. 
 
Blood tests will be performed to test for abnormal clotting factors and some additional 
standardized blood tests.  A needle will be placed in a vein in your arm or hand and about 10-
12 ml (approximately 2-3 teaspoons) of blood will be drawn. Some of this blood testing will be 
sent to an outside lab for testing.  If your study doctor indicates you should be taking warfarin, 
you will need to undergo regular blood tests called the International Normalized Ratio (INR). 
This will occur at the time of starting this study and then every month (four weeks) to make 

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sure your warfarin dose is correct. The amount of blood drawn may be a few drops to about 2-
3 teaspoons each time.   
 
Electrocardiogram (ECG/EKG) is a type of test that uses small electrodes placed on your 
body with a gentle adhesive.  The electrodes pick up the electronic signals of your heart and 
translate them into a report that helps your doctor understand your heart rhythms.   
 
Magnetic resonance imaging (MRI) uses a powerful magnetic field to produce detailed 
pictures of organs, tissues, bone and other body parts. For this study, a MRI of your head 
(brain) will be performed. You will lie on a table that moves into a large tube so that a large 
magnet can pass over your body.  
 
Computed Tomography (CT) Scan is a type of x-ray that provides detailed pictures of body 
parts.  For this study, a CT of your head will only be done if you are not able to have a MRI of 
your head performed due to medical conditions. 
 
Pregnancy test for all women of childbearing potential will require a urine and/or blood 
sample.  Women who are pregnant or plan to become pregnant throughout the duration of the 
study should not enter the study.  If you suspect that you have become pregnant during the 
study, please inform the study coordinator or doctor immediately. 
 
Transesophageal echocardiogram (TEE) is a type of echocardiogram (also called an echo), 
which is an ultrasound test that allows your doctor to look at the chambers of your heart using 
sound waves.  You will receive medicine that will make you sleep (sedation). During this test, a 
small imaging probe is placed into your mouth and down your esophagus (your swallowing 
tube) in order to take pictures of your heart that may be seen on a video screen.  Your throat 
may be a little sore for about one week after the test. 
 
National Institute of Health Stroke Scale (NIHSS) is a set of questions that provides 
information about how your brain and nerves are working, especially at the time of or after a 
stroke. 
 
Modified Rankin Scale is a score which measures the general level of functioning, especially 
after having a stroke.  
 
CHADS2 assessment is set of questions used to assess the level of risk of a future stroke in 
patients with atrial fibrillation. 
 
Physical Exam is an evaluation of the body to determine state of health. 
 
Quality of Life Assessment is a set of questions asking about your general health, wellbeing, 
and if you are able to do your usual activities. This data can be used to compare the two 
treatment groups.  
 
 

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Randomization 
If after baseline testing and exams you meet all study requirements, you will be randomly 
assigned to one of two different study groups (the device group  or the medicine group). 
Randomization is the process by which chance is used to assign you to a group (like pulling 
numbers out of a hat). In this study, you have twice as much chance of being assigned to the 
device arm as you do to the medicine group.  Once you have signed this form and been 
assigned to a group, you will be officially enrolled in this study. You may not switch groups once 
assigned so you should be comfortable with the decision to go into either group if you want to 
participate in this study.  
 
Medicine Group 
If you are randomly assigned to the medicine group, you will continue to take either warfarin or 
dabigatran also called an oral anticoagulant (medicine used to “thin” your blood). Your doctor 
will decide the type and amount of medicine that is the best for you.  If you take warfarin, blood 
samples (approximately 2-3 teaspoons or a finger prick) will be taken at a minimum of every 
month (four weeks) to make sure the right dose of medicine is being given to you.  It is 
important to follow your doctor’s instructions while taking blood thinning drugs.  You will not 
have the ACP device implanted in your heart if you are assigned to the medicine group.  In 
addition, your doctor may also have you take low dose aspirin (81 mg/day) with warfarin or 
dabigatran. Carefully follow your doctor’s instructions on these medications. Immediately 
inform your study doctor any changes in the blood thinning medications you are taking.  
 
Device Group 
If you are randomly assigned to the device group, within 14 days of your randomization, the 
ACP device will be implanted (placed) in your heart to close your LAA. The ACP device will 
permanently remain in your heart.  
 
Pre-Procedure Medication Change  
If you are assigned to the device group and taking warfarin, you will stop taking warfarin four 
days before the implant procedure. Your doctor will have you start a new medicine called 
Lovenox (enoxaparin) two days before the procedure. Lovenox is another type of blood 
thinning medicine you will take by way of shots (injections). On the day of procedure, you will 
stop taking Lovenox. This change in medicine is required so that your blood is not too thin 
during the implant. You will have a blood test within 24 hours prior to the implant. If your blood 
is too thin, your implant procedure may need to be re-scheduled. Your doctor will provide you 
with more details about this process. 
 
Example:  Day 5 is day of procedure:  
• Day 1 – stop warfarin 
• Day 2 – no medications (Lovenox or warfarin) 
• Day 3 – begin Lovenox 
• Day 4 – continue Lovenox 
• Day 5 - procedure day, no Lovenox (or warfarin)  
 

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If you are assigned to the device group and taking dabigatran, you will stop dabigatran prior to 
your implant.  Your doctor will provide you with more details about this process 
 
 
Implant Procedure 
The implant procedure will occur in the cardiac catheterization laboratory, or “cath lab”.  
Conscious sedation (medicine that will make you relaxed and sleepy yet awake) or general 
anesthesia (medicine that will make you sleep) will be used.  This is a non-surgical procedure 
done using an angiogram in which a catheter is put into a blood vessel in your groin and up 
into your heart.  An angiogram is a test using x-rays where a liquid (contrast) is injected into a 
blood vessel which allows your doctor to view pictures of your heart and blood flow. A catheter 
is a sterile, flexible, hollow tube that is put into a blood vessel to let fluids go into or out of your 
body, or to deliver devices to your heart.  After the procedure, you may have some minor pain 
in the groin area where the catheter was inserted. 
 
To help your doctor evaluate your LAA during the procedure, you will also have a 
transesophagael echocardiogram (TEE).  If a blood clot is found in your heart, your doctor will 
not proceed with device placement.  If no blood clot is found in your heart, then your doctor will 
take measurements of your LAA.  The doctor will make a small puncture through the septum, 
muscular tissue that separates the two sides of the upper heart, in order to gain entry into the 
upper left heart chamber. An appropriate size ACP device will be passed through the catheter 
and placed in your LAA.  After your doctor is satisfied with the position of the device and 
catheter are removed. The procedure will take about 1-2 hours.  The device will remain in your 
heart. Over time, the tissue in your body will cover and grow around the device to further 
secure (hold) the device in place. If your doctor is unable to place a device you will still come in 
for follow-up visits for the remainder of the trial.   
 
After the Procedure 
After the procedure but before you are discharged from the hospital, you will undergo a follow-
up visit which will include a physical exam, ECG, and a transthoracic echocardiogram (TTE). A 
TTE is another type of echocardiogram that uses high-pitched sound waves that are sent 
through a transducer (hand-held plastic instrument which looks like a microphone) which is 
placed on different areas of your chest. The transducer picks up echoes of the sound waves as 
they bounce off the different parts of your heart and turns them into moving pictures of your 
heart that can be seen on a video screen. A TTE is done to verify the position of the device in 
your heart and to check for any potential complications after the implant. You will be asked to 
continue to take warfarin or dabigatran after the implant. 
 
If you are taking warfarin, you will have INR blood tests to ensure that you are taking the 
correct amount of medicine. In addition to warfarin, you may also take Lovenox for a short time 
until your INR is in the correct range.  If you are taking dabigatran, follow your doctor’s orders 
on when to start taking the medicine after you leave the hospital. 
 
To prevent certain bacterial infections, you may need to take an antibiotic medication during the 
first 6 months following the placement of the device, especially if you are planning to undergo 

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procedures such as dental cleanings.  Your doctor may have you continue to receive antibiotics 
for certain procedures. 
 
If you need to have a MRI scan after the implant, it is safe to do under certain conditions. Let 
your doctor or the technician know that you have an implanted device and show your patient 
identification card (device ID card).  Also, your ACP device will not set off alarms when going 
through airport security. 
 
Health Economic Sub-study 
The Sponsor is also conducting a health economic sub-study.  This sub-study will evaluate the 
costs and benefits of treatment. This information is being collected so the Sponsor can 
understand the cost effects of the treatment in the ACP study.  During the health economic 
sub-study, information about your reported resource use and hospital bills reporting hospital 
care will be collected. This information about your hospital bills will be collected by the 
Sponsor’s independent contractor who will perform the health economic sub-study.  You will 
not be personally contacted by the Sponsor, the Investigator, or the independent contractor 
and asked to obtain your billing data for the purpose of providing it to the independent 
contractor for this research purpose. This resource use information and your hospital bills 
related to any hospitalization will be collected at least through 2 years and until the study is 
done.  Medical resource use, cost and health-related quality of life within the trial period will be 
compared between study subjects in the medicine group and the device group. 
 
Follow-up Visits and Testing 
The ACP study requires both groups have follow-up visits at 45 days, 6 months, 12 months, 18 
months, 2 years and every year after that until the study is done. If you receive a device and 
can stop taking warfarin or dabigatran per your echocardiogram results, you will have a phone 
follow up 3 months after you stop taking warfarin or dabigatran to check on your medications 
and general health. 
 
Below is a chart listing the requirements for people in both the medicine and device groups.  
 
 
45 days 
3 months  
after stopping 
warfarin or 
dabigatran 
(phone visit) 
6 months 
 
12 months 
 
18 months 
 
2 years 
Annually 
thereafter 
(phone visit) 
Physical exam 
X 
 
X 
X 
X 
X 
 
Neurological Symptoms Interview 
X 
 
X 
X 
X 
X 
X 
12 lead Electrocardiogram 
X 
 
X 
X 
X 
X 
 
MRI of brain (or CT scan if medically 
indicated) 
 
 
 
X 
 
X 
 

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Medication check (only people who receive the 
device and discontinue warfarin/dabigatran) 
 
X 
 
 
 
 
 
Quality of Life Interview 
 
 
 
    X 
 
  X 
 
Hospital bills  
X  -  Until completion of the study 
 
The neurological interview which takes place at each visit contains a series of eight short 
questions about whether you have had any symptoms of a stroke or TIA.  Additional testing 
may be performed by your doctor if medically necessary.   
 
If your doctor suspects you may have had a new stroke or TIA, you will have two neurologic 
assessments (NIHSS and Modified Rankin) and a MRI or CT of your head. The MRI or CT 
scan must be performed within 10 days of the onset of the new stroke or TIA.  You may need 
to set up extra appointments to complete these tests. If a stroke is confirmed, subjects who 
received a device will also have a TEE.   
 
If at any time you have symptoms of a stroke or TIA, you should call 911 or be seen 
immediately by a doctor. Symptoms of stroke or TIA may be one or more of the following: 
 
• Sudden numbness or weakness on the face, arm, leg, especially on one side of the 
body 
• Sudden confusion, trouble speaking or understanding 
• Sudden trouble seeing in one or both eyes 
• Sudden trouble waking, dizziness, loss of balance or coordinator 
• Sudden, severe headache with no known cause 
 
Let your study doctor know about any symptoms as soon as possible after you are evaluated 
or receive treatment or are in the hospital for any reason. Do not wait until your next scheduled 
visit to let the study team know what happened.  Call your study doctor or have a family 
member do so if you go to the emergency room, are hospitalized, or have any procedures at a 
different medical center from where you see your study doctor.  Make sure to inform all heath 
care professionals who treat you outside of the study that you are participating in a medical 
device trial. 
 
As part of the research study, you will be periodically asked to complete a questionnaire on 
your general well-being (quality of life). This information allows the Sponsor to gather data 
which may impact future health care policy and health insurance coverage of new medical 
devices. 
 
If your study doctor has prescribed warfarin, this study requires that at all times you are taking 
warfarin; you must have your INR tested every month (4 weeks) until the study is completed or 
until you are taken off warfarin. This includes in you are taking warfarin in the medicine group 
or are taking warfarin in the device group. These INR tests are to make sure that your INR is 
stable and that the warfarin dose you are taking is correct.  
 

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For people in the device group and who receive a device, you will have some additional 
echocardiograms or echoes.  These are being done for a number of different reasons.  
 
1)  Your doctor will use this test to determine that the device is in the correct position, to 
see whether or not there are any clots on the device, and to look for any changes in 
your heart after the implant. 
 
2)  If your LAA is closed or partially closed (just a little blood flow is seen moving into or out 
of the left atrial appendage) you will be able to stop taking warfarin or dabigatran 
 
3)  Once your left atrial appendage is closed and depending on the visit, you may have a 
transthoracic echo (chest echo) instead of a transesophageal echo (swallowing tube 
echo).  
 
The flow chart below shows the requirements for the type of echo you will receive if you are 
randomly assigned to the device group. The flow chart describes echo assessments starting at 
the 45 day follow-up visit through the remainder of the study and indicates whether or not you 
may be able to discontinue warfarin or dabigatran during the study. 

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Transesophageal Echo Schedule for Patients Randomly Assigned to the Device 
 
45 Day 
TEE
Is your LAA at 
least partially 
closed?
Yes
No
Discontinue 
warfarin/
dabigatran
 Continue 
warfarin /
dabigatran
6 Month 
TEE
6 Month  
TEE
Is your LAA 
closed?
Is your LAA 
closed?
Yes
Yes
No
No
12 Month
TTE
2 Year  
TTE
12 Month 
TTE
2 Year  
TTE
Discontinue 
warfarin / 
dabigatran
12 Month 
TEE
2 Year  
TTE
(TEE may be 
performed if LAA 
is not closed)
Is your LAA 
partially closed?
Yes
No
Discontinue 
warfarin / 
dabigatran
Continue warfarin /
dabigatran
12 Month and 2 
Year
TEE
(TTE may be 
performed if your 
LAA is closed)
12 Month and 2 
Year
TEE
(TTE may be 
performed if your 
LAA is closed)
 
 
 
Starting after the 2 year visit, your doctor may allow a phone follow-up to take place instead of 
an office visit. 
 

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During each visit, you will be asked about your health since your previous visit. You should 
report all changes in health to your doctor 
 
It is important to keep all follow-up appointments scheduled for you. You will be given a card 
listing the times of when all visits should take place.  
 
Are any of tests or procedures in this study experimental? 
The AMPLATZER Cardiac Plug and implant procedure is considered by the United States Food 
and Drug Administration (FDA) to be an experimental.  
 
What are the possible risks or discomforts of being in the study? 
The risks associated with the implant procedure include, but are not limited to:    
• Air embolus – leakage of air into the veins or heart 
• Allergic reaction to contrast dye or medications used in the study  
• Allergic reaction to the device implanted 
• Anemia-a decrease in the number of red blood cells (RBC) or hemoglobin, resulting in a 
lower ability for the blood to carry oxygen to body tissues 
• Anesthesia reaction 
• Arrhythmia – abnormal heart beat 
• Bacterial endocarditis – inflammation and infection of the heart 
• Bleeding – loss of blood requiring blood transfusion 
• Brachial plexus injury – injury to a group of nerves around the shoulder 
• Bruising – blood leakage under the skin at the groin, catheter access site 
• Cardiac arrest – failure of the heart to beat 
• Cardiac perforation – tear or puncture of the heart wall caused by the guidewire or 
catheter 
• Cardiac tamponade – a large amount of fluid in the sac which surrounds your heart and 
makes it difficult for the heart to beat strongly 
• Congestive heart failure – failure of the heart to pump blood with normal efficiency 
• Death  
• Delivery system failure – the cable with the screw mechanism that the device is 
attached to when it is being placed in the heart does not work properly 
• Device embolization – movement of a device from the intended location 
• Device migration – movement of the device within the intended location 
• Device thrombus – blood clot on the device 
• Dyspepsia – upset stomach 
• Erosion - rubbing of device against the heart wall or blood vessel and may lead to a tear 
or hole in the heart 
• Fever – defined as body temperature greater than or equal to 101.5°F 
• Foreign body embolization – movement of device material, delivery system material, or 
 
other material from the intended location 
• Gastrointestinal pain and/or bleeding – pain or bleeding from the any of the following 
areas; esophagus, stomach, small intestine, large intestine, rectum, and anus 
• Hypertension – high blood pressure 

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• Hypotension – low blood pressure 
• Hypoventilation – the state in which a reduced amount of air enters the lungs  
• Infection – abnormal growth of germs in the body 
• Myocardial infarction – a heart attack  
• Myocardial ischemia – low blood flow to the heart 
• Nickel sensitization – develop nickel allergy 
• Perforation – tear or puncture of a blood vessel or organ  
• Pericardial effusion – abnormal fluid collection around the heart 
• 
Peripheral thromboembolism – blood clot anywhere in the blood vessels except in the 
heart and brain 
• Pleural effusion – an abnormal collection of fluid around the lungs 
• Renal failure – failure of kidneys to perform normal functions 
• Respiratory failure – inability of the lungs to function 
• Respiratory insufficiency – inability of the lungs to function normally 
• Seizure – abnormal electrical activity in the brain, which may produce a physical 
convulsion 
• Sepsis – the presence of bacteria or their poisonous products in the bloodstream 
• Septicemia – body wide illness due to infection by bacteria  
• Stroke – A sudden loss of brain function caused by a blockage or rupture of a blood 
vessel to the brain 
• Systemic embolism – blood clot that travels through the circulation system and 
becomes stuck in an artery, blocking blood flow 
• Thrombophlebitis – inflammation of a vein due to a blood clot 
• Thrombus – a blood clot  
• Tissue damage - damage to heart tissue 
• Transient ischemic attack (mini stroke) – temporary interruption of blood flow to an area 
of the brain, causing symptoms like a stroke which last for less than 24 hours 
• Valvular regurgitation/insufficiency – back flow of blood through any of the four heart 
valves 
• Vascular access site injury – bleeding, discomfort, and/or bruising around the place 
where the catheter was put in the groin  
• Vascular dissection - the process of cutting apart or separating blood vessel tissue  
 
 
 
 
Potential risks when taking blood thinning medicines (wafarin, Lovenox, dabigatran, 
aspirin) 
Reported risks associated with medicines used to thin the blood include, but are not limited to:  
increased bleeding time, bleeding from the stomach or bowels, bleeding in the brain, 
drowsiness, dizziness, headache, heartburn, stomach pain, loss of appetite, nausea, vomiting, 
and hives, rash, itching and bruising.  Other risks include swelling of the eyes, face, lips, 
tongue, hands, feet, ankles, lower legs and throat, joint or muscle ache, wheezing or difficulty 
breathing, hoarseness, fast heartbeat, fast breathing, cold clammy skin, yellowing of the eyes 

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or skin, ringing in the ears or loss of hearing, difficulty swallowing, chest pain, fever, infection, 
diarrhea. If you are taking aspirin together with either warfarin or dabigatran, there is an 
increased risk of bleeding. Taking blood thinning medications can cause harm to an embryo, 
fetus or nursing infant. There may be other risks related to medicine used to thin the blood that 
are unknown at this time. 
 
What other risks and discomforts might there be? 
Risks involving nickel: 
• 
This device is made up of a nickel-titanium alloy (mixture of metals), which is generally 
considered safe.  However, lab testing shows that nickel is released from the implanted 
device for at least 120 days. Subjects who are allergic to nickel may have an allergic 
reaction to this device, especially those subjects with a history of reacting to metals 
such as jewelry, buttons, snaps, belt buckles, etc.  Some allergic reactions can be 
serious; you should notify your doctor immediately if you have difficulty breathing or 
inflammation (reddening) of your face or throat. 
• 
Some subjects may also develop an allergy to nickel if this device is implanted. 
• 
Some forms of nickel have been associated with carcinogenicity (ability to cause 
cancer) in animal models.  In humans, carcinogenicity has been demonstrated only 
through inhalation (breathing in nickel dust), which will not occur with this procedure.  
 
If during the implant procedure (or post-implant) the device were to move out of position, the 
device may need to be removed by a catheterization procedure or surgically (open heart 
surgery). Cardiac surgery following device placement may be more difficult with additional 
risks.   
 
There are also risks involved in the TEE.  The most common risk of having a TEE is a sore 
throat; other possible risks include bleeding, breathing or heart problems, gagging, vomiting, 
pain when swallowing, dental injury, and damage or tear to your esophagus.  
 
You may experience some brief and /or minor discomfort associated with drawing blood.  For 
example, you may experience pain or bruising associated with the needle from the blood 
draw.  Fainting and local infection can also occur although this is rare.  
 
There is a risk of exposure to radiation during the x-ray procedures performed during the 
implant procedure (device subjects only). This risk is no different than any other standard cath 
lab procedure 
 
There may be other risks that are unknown at this time.  There may be unknown risks to an 
embryo, fetus or nursing infant if you become pregnant during this study. 
 
What are the possible benefits of being in the study? 
There may be no direct benefit to you for participating in this study. The information obtained 
from your participation may change the future treatment of people with atrial fibrillation. 
 
 

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express written permission of AGA Medical LLC. 
Potential Benefits to the Device Group 
The potential benefit is that the information obtained from this study may change future 
treatment of patients with atrial fibrillation. 
 
Potential Benefits to the Medicine Group 
The potential benefit is that the information obtained from this study may change future 
treatment of patients with atrial fibrillation. 
 
What information can I show other health care professionals about this study? 
You will receive a study participation and follow up card if you enroll in this trial. The card is the 
size of a plastic credit card and will contain information specific to your involvement in the study. 
The card lists when you were enrolled in the study and all time periods when you should return 
for study visits.  Those participants assigned to the device group who have the device implanted, 
will also receive a device ID card with details on the implanted device.   
 
 
Sample Patient ID/Follow-up Card (both groups will receive this) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample Device ID Card (only people who have an ACP device implanted will receive this) 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMPLATZER™ Cardiac Plug Clinical Trial 
Follow-up Schedule 
Scheduling Window (mm-dd-yyyy) 
( 02-10-2010  -  02-20-2010 ) 
( 05-31-2010  -  07-30-2010 ) 
( 12-02-2010  -  01-31-2011 ) 
( 05-01-2011  -  08-29-2011 ) 
( 11-02-2011  -  03-01-2012 ) 
( 11-01-2012  -  03-01-2013 ) 
( 11-01-2013  -  03-01-2014 ) 
( 11-01-2014  -  03-01-2015 )  
 
 Front of 
 Back of 
  
The holder of this card is participating in the  
AMPLATZER Cardiac Plug (ACP) Clinical Trial  
sponsored by AGA Medical (St. Jude Medical) 
 Patient Initials :  
Trial ID Number: 
Enrollment Date: 
(mm-dd-yyyy) 
Hospital/Clinic: 
Doctor Name: 
Doctor Phone: 
ABC  
123-ACP-456 
01-01-2010 
  
Heart Hospital USA 
John Doe, MD 
(555)-555-5555 
Trial Visit 
45 days 
6 month 
12 month 
18 month 
2 year  
3 year 
4 year 
5 year 
AGA Medical (St. Jude Medical) 
1-888-546-4407 www.sjm.com 
AMPLATZER™ Cardiac Plug Clinical Trial 
Patient Identification Card 
Front of 
Back of 
 
- Static magnetic field of 3.0 Tesla or less 
- Spatial gradient field less than or equal to 30 T/m 
- Maximum whole-body-averaged specific absorption rate (SAR)  
   of 2.0 W/kg (normal operating mode) for 15 minutes of scanning 
The carrier of this card has been treated with an implantable device and is in a 
clinical trial. The study (investigational) device is NON-FERROMAGNETIC / MR 
conditional and can be scanned safely under the following conditions: 
Notify your doctor if there is a change in your medical condition or address. 
  
If you experience shortness of breath or chest pain:  
- Seek medical attention immediately 
- An echocardiogram may be required 
  
If a stroke or TIA (mini-stroke) is suspected:  
- Seek medical attention immediately 
- A brain MRI must be performed within 10 days of the event as part of the trial.  
- A brain CT scan should be performed instead of a MRI if a MRI is contraindicated 
(medical reason not to perform)   
Manufactured by: AGA Medical (St. Jude Medical), 5050 Nathan Lane N  
Plymouth, MN 55442 (U.S.A.)  Phone 1-888-546-4407 / www.sjm.com 
Patient Initials:  
Trial ID Number: 
  
Hospital/Clinic: 
Doctor Name: 
Doctor Phone: 
  
Implant Date: 
(mm-dd-yyyy) 
  
Product Name:  
Product Number: 
Lot Number: 
Serial Number: 
 AMPLATZER™ Cardiac Plug Clinical Trial 
Device Identification Card 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
What other choices do I have if I choose not to be in the study? 
If you choose not to participate in this study at this time, your doctor will discuss alternative 
treatments with you.  Treatment options may include the use of drugs other than those planned 
for this study to prevent the occurrence of clots which can cause stroke, or not having any 
treatment at all. 
 
Who will have access to my medical records?   
Your confidentiality will be respected.  However, research records and health or other source 
records identifying you may be inspected in the presence of the Investigator or his or her 
designate, by Sponsor (a U.S. company) and its affiliated companies (located in the U.S. and 
other countries), representatives designees of Sponsor that provide services related to the 
device and/or this study, Health Canada, the U.S. Food and Drug Administration, and the 
Research Ethics Board (REB) for the purpose of: 1)  monitoring the research; 2) accurately 
document and report any adverse events that may occur during your participation in this study 3) 
satisfy any other requirements imposed by government authorities located throughout the world, 
including the U.S. FDA and Health Canada.  No information or records that disclose your identity 
will be published without your consent, nor will any information or records that disclose your 
identity be removed or released without your consent unless otherwise permitted by law.  Upon 
your approval, your regular doctor will be told of your participation in the study. 
 
You will be assigned a unique study number as a subject by the Sponsor in this study.  This 
number will be used on any research-related information collected about you during the course 
of this study, so that your identity [i.e. your name or any other information that could identify you] 
as a subject in this study will be kept confidential.  Information that contains your identity will 
remain only with the study investigator and/or designate.  The list that matches your name to the 
unique study number that is used on your research-related information will not be removed or 
released without your consent unless required by law. 
 
The Sponsor’s independent contractor performing the health economic sub-study will receive a 
copy of your signed informed consent (which contains your name) so that they may contact your 
study doctor as well as hospital(s) to obtain copies of your medical bills.  This information will be 
used as part of the health economic sub-study.  Your personal health information obtained for 
this Study and the economic sub-study is confidential and will be treated as such to the extent 
required by law.  No identifying information will be shared outside of the independent contractor 
and your care providers. This information is being collected so we can understand the cost 
effects of the treatment in the ACP study.  
 
If you are hospitalized at a different facility that is not participating in this study or the sub-study, 
the non-study facility may not release your billing data without your permission.  The 
independent contractor may work with the non-study facility to obtain this billing information.  
The non-study facility may require an additional review or ask you to provide a separate written 
permission in order to provider you billing information to the independent contractor.  You will not 
be personally contacted by the Sponsor or the independent contractor and asked to obtain your 
billing data for the economic sub-study. 
 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
Your rights to privacy are legally protected by federal and provincial laws that require safeguards 
to insure that your privacy is respected and also give you the right of access to the information 
about you that has been provided to the sponsor and, if need be, an opportunity to correct any 
errors in this information.  Further details about these laws are available on request to your study 
doctor. 
 
Because this is a study that also falls under U.S. regulation, in some circumstances the U.S. 
Food and Drug Administration (U.S. FDA) may seek to copy records that contain your personal 
information.  If this occurs, you will be informed before the records are copied, but your consent 
may not be sought.  You should be aware that privacy protections on personal information may 
differ in other countries.  
 
Any study related data sent outside of Canadian borders may increase the risk of disclosure of 
information because the laws in those dealing with protection of information may not be as strict 
as in Canada.  However, all study related data that might be transferred outside of Canada will 
be coded (this means it will not contain your name or personal identifying information) before 
leaving the study site.  By signing this consent form, you are consenting to the transfer of your 
information, to organizations located outside of Canada.  Study related data collected about you 
will be coded and transferred to Sponsor (a U.S. company). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
Will I receive payment if I am in the study? 
You will not receive any payments for participating in this study.   
 
What if I am injured during the study? 
If you were to suffer harm of any kind as a direct result of this study, treatment for that injury 
including surgery, first aid, and emergency care will be available as needed.  The hospital or clinic 
where you received treatment will bill your insurance company for the routine costs of care 
available under your health care plan and you may also have to pay some costs such as co-pays 
or deductibles. 
 
If you followed all study instructions and are hurt during the study as a direct result of the study 
device or study procedures (not part of your routine medical care available under your health 
plan), AGA Medical will pay for reasonable and necessary medical and hospital expenses. This 
may include treatment(s) of a bad side effect affecting your health as a direct result of the study 
device that are not paid by your insurance company or other third parties.  
 
AGA Medical will not cover the cost of injuries to the extent that they are caused by your failure 
to follow study instructions or other negligence, or that of the hospital or study doctor, the natural 
progression of an underlying condition (whether diagnosed or not) or pre-existing condition, or 
events that would have been expected from the standard treatment using currently approved 
therapies for your condition. 

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CONFIDENTIAL AND PROPRIETARY 
© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
 
Signing this consent form in no way limits your legal rights against the Sponsor, investigators, or 
anyone else, and you do not release the study doctors or participating institutions from their legal 
and professional responsibilities.   
 
Whom should I contact if I have questions or if I am injured during the study? 
During the course of this clinical study, if you have any further questions, concerns, or research 
related injuries as a result of your participation, please contact [add Principal Investigator 
contact information here]. 
 
For questions regarding your rights as a research subject, please contact the hospital ethics board 
(often called an IRB or Institutional Review Board) at [add IRB contact information here]. 
 
Can I refuse to participate in the study or stop participating once I am in the study?  
Your participation in this research is VOLUNTARY.  Your decision whether or not to participate will 
not affect your current or future relationship with your doctor or their institution.  If you decide to 
participate, you are free to withdraw your consent and stop participation at any time. You will not be 
penalized or have any loss of benefits for deciding not to participate or for dropping out of the study.  
Information that has already been gathered before you leave the study may still be used and given 
to others as described in this form.  If you decide to leave the study, you should tell your doctor so 
that appropriate continuation of care may be arranged for you.   
 
What are the consequences if I decide to drop out of the study?  
If you decide to drop out of the study, information about you will no longer be sent to the study 
Sponsor, and you may not have as many visits to your doctor and some tests may not be done.  
You will receive the same quality of care even if you decide not to stay in the study. 
 
Can my participation in the study be stopped even if I don’t ask to drop out? 
Your doctor may stop your participation in this study if he/she believes it is best for you.  The 
decision may be made either to protect your health and safety, or because it is part of the research 
plan that people who develop certain conditions may not continue to participate. The study may 
also be stopped for administrative, medical, or other reasons as determined by AGA Medical LLC 
or the FDA, Health Canada and other applicable regulatory bodies. Again, information that has 
already been gathered before you leave the study may still be used and given to others as 
described in this form. 
 
What if new information about the device is found during the study? 
Any significant new information that develops during the course of the study that may affect your 
decision to participate will be provided to you.  You may be asked to sign a new consent form with 
this new information. 
 
What are the additional or anticipated costs to me if I am in the study?  
Your health insurance (such as Medicare) will be billed for the routine costs that may be 
available under your plan that are associated with this study.  You should check your insurance 
policy to know exactly what is included. If there are any co-payments or deductibles, you will be 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
responsible for making those payments. If you have any questions about your health insurance, 
or possible expenses, please talk with the study doctor and your health insurer or Medicare. The 
Sponsor cannot cover the costs that are part of your usual medical care and that would have been 
incurred regardless of your enrollment in the study. This includes but is not limited to warfarin (and 
INR testing), dabigatran, and aspirin as these drugs are considered standard treatment for people 
with AF.  
 
What are my responsibilities if I am in the study? 
As study participant, you are asked to follow study requirements, follow medical instructions 
given by your study doctor, inform your study doctor of any changes in your health, and inform 
your study doctor of any other medical care or drugs you are receiving (whether prescribed by a 
physician or bought over the counter).  
 
By signing below I am indicating that: 
 
√   I have read and understood the patient/subject information of this study and the research 
staff has answered all of my questions regarding the study. 
 
√   I agree to participate in and comply with the requirements of this study 
 
√   I understand and agree that personal information about me will be collected from my medical 
records and processed by AGA Medical LLC or any other entity involved in the study. 
 
√  I authorize and instruct my physician(s) and the institution to release personal information about 
me necessary to conduct this study. 
 
√  I agree to tell my family I am in this study and let them know how to reach my study doctor if I am 
unable to do so myself. 
 
√   I agree to tell all medical care professionals who treat me outside of where I see my study 
doctor that I am in a research trial so all clinicians are well informed of my health and 
medicines I am taking.  
 
√    I understand that I may cancel my participation in this study at any time by telling the study 
coordinator or my doctor. 
 
Subject Signature 
 
Subject Signature _____________________________     Date_______________ 
 
Printed Name of Subject ____________________________________________ 
 
 
 
 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
Subject’s Legal Representative (if necessary) Signature 
 
Signature ____________________________________Date________________ 
 
Printed Name of Legal Representative___________________________________ 
 
 
Person Conducting Informed Consent Discussion 
Signature ___________________________________    Date ________________ 
Printed Name ____________________________________ 
 
If you have questions concerning the rights of research subjects please contact: 
 
___________________________       
IRB 
 
____________________________ 
Phone Number 
 
 
 
 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
AUTHORIZATION TO USE AND DISCLOSE HEALTH INFORMATION 
 
I agree to permit {add Investigator name here} and staff members and AGA Medical LLC, the 
sponsor of the ACP clinical trial to use and disclose health information that identifies me for the 
purposes described below.  I also agree to permit {add hospital/clinical study site 
information here}, my doctors, and my other health care providers to disclose health 
information in my medical records to the Researchers, AGA Medical LLC, and the FDA, Health 
Canada or other regulatory bodies for the purposes described below. 
 
1. 
The health information that may be used and disclosed includes: 
• All information collected during the research as described in the Informed 
Consent Form, which includes my hospital bills and other health care 
resource use information; and 
• 
Health information in my medical records that is relevant to the research 
 
described in the Informed Consent Form. 
 
2. 
The Researchers may: 
• 
Use and share my health information to conduct the research; 
• 
Disclose my health information to the Sponsor of research, AGA Medical 
Corporation and its affiliated companies (located  in the U.S. and other 
countries), representatives designees that provide services related to the 
device and/or this study; 
• 
Disclose my hospital bills and information regarding my use of health care 
resources to Sponsor’s independent contractor in order to conduct the 
health economic cost analysis related to this study; 
• 
Disclose my health information as required by law; 
• 
Disclose my health information to representatives of government 
 
organizations and other persons who are required to watch over the safety 
 
and effectiveness of medical products and therapies and the conduct of 
 
research; and  
• 
Remove from my health information my name and other information that 
 
could be used to identify me. 
 
3. 
AGA Medical LLC and its affiliated companies (located  in the U.S. and other 
countries), representatives designees that provide services related to the device 
and/or this study may; 
•      Use and share my health information to conduct the research; 
• 
Disclose my health information as described in the Informed Consent 
• 
Disclose my health information as required by law;  
• 
Disclose my health information to representatives of government 
organizations and other persons who are required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of 
research; and  

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CONFIDENTIAL AND PROPRIETARY 
© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
• 
Remove from my health information my name and other information that 
could be used to identify me. 
 
4. 
Once information that could be used to identify me has been removed, the 
information that remains is no longer subject to this Authorization and may be 
used and disclosed by the Researchers and AGA Medical LLC and its affiliated 
companies (located in the U.S. and other countries), representatives designees 
that provide services related to the device and/or this study as permitted by law. 
 
5. 
Once my health information has been disclosed to a third party, privacy laws may 
no longer protect it from further disclosure.  However, the Researchers and AGA 
Medical LLC agree to protect my health information by using  and disclosing it 
only as permitted by me in this Authorization and the Informed Consent.  Also, no 
publication about the research will reveal my identity without my specific written 
permission.  These limitations continue even if I revoke (take back) this 
Authorization. 
 
6. 
Please note that: 
• 
You do not have to sign this Authorization, but if you do not, you will not 
 
be allowed to participate in the research. 
• 
You may change your mind and revoke this authorization at any time. To  
 
 
revoke this Authorization, you must write to {name and contact  
 
 
 
information}.  However, if you revoke this Authorization, you will no  
 
 
longer be allowed to participate in the research.  Also, if you revoke this  
 
 
Authorization, the information already obtained by the Researchers and  
 
 
AGA Medical LLC may be used and disclosed as permitted by the   
 
          Authorization and the Informed Consent. 
• 
While the research is in progress, you will not be allowed to see your  
 
 
health information that is created or collected in the course of the   
 
 
research.  After the research is finished, however, you may see this  
 
 
information as described in the {add hospital/clinical study site name  
 
 
here}’s Notice of Information practices.  
 
7. 
This Authorization does not have an expiration (ending) date. 
 
8. 
You will be given a copy of this Authorization after you have signed it. 
 
 
Print Name of Patient: 
Signature of Patient / Legally Authorized Representative: 
Date: 
 
 
Signature of Witness: 
Date: 

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CONFIDENTIAL AND PROPRIETARY 
© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
8.  IRB INFORMATION 
AGA requests waiver of the requirements under 21 CFR 812.35(b) for submitting certification of 
IRB approval to the FDA prior to the beginning the investigation at a particular center.  In lieu of 
this requirement AGA Medical will submit an IRB/Investigator list update in six-month intervals. 
 
9. 
OTHER INSTITUTIONS 
There are no other institutions which are part of this clinical study other than the investigative 
sites, the Sponsor’s independent contractor performing the economic healthcare analysis and 
designated core labs.

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
10.  ADDITIONAL RECORDS AND REPORTS 
The investigator and sponsor are responsible for maintaining the following accurate, complete, 
and current records relating to the investigation: 
 
RECORDS 
MAINTAINED BY 
INVESTIGATOR 
MAINTAINED BY 
SPONSOR 
All correspondence with another 
investigator, an IRB, the sponsor, a monitor, 
or the FDA  
X 
X 
Shipments, receipts, and disposition of the 
ACPs 
Packing lists, device 
accountability logs  
Records of  shipment and 
disposition of devices, 
copies of signed packing 
lists 
ACP administration and use 
Device accountability logs and 
CRFs 
Copies of site’s device 
accountability log and 
CRFs 
Records of each subject’s case history and 
exposure to the ACP 
CRFs and source 
documentation 
 
Informed consent or documentation the 
device was used without consent 
X 
Documentation if the 
device was used without 
consent 
The clinical Protocol and amendments, if 
any, and documentation of deviations from 
protocol 
X 
X 
Adverse events and complaints 
Adverse event CRFs and 
product incident reports along 
with IRB notifications and 
acknowledgement, if 
applicable 
Adverse event CRFs and 
product incident reports 
along with IRB 
notifications and 
acknowledgement, if 
applicable 
Signed Investigator agreements, financial 
disclosures, and mutual non-disclosure 
agreements 
X 
X 
Any other FDA required records 
X 
X 
 
The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents.  Study correspondence will be defined as documents 
pertaining to global study issues affecting the rights, safety, welfare, or scientific 
soundness of the study. 
 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
10.1 
DOCUMENTING STUDY CORRESPONDENCE 
Document phone conversations and file in the Regulatory Binder.  Written hard copy 
correspondence from AGA Medical should also be filed in the Regulatory Binder. 
 
10.2 
RECORD RETENTION 
Records are subject to FDA inspection and must be retained by Investigators for a period of 
two years after the latter of the following dates: 
• 
The date on which the investigation is terminated or completed 
• 
The date the records are no longer required for purposes of supporting an application 
to the FDA to market the device 
REPORTS 
INVESTIGATOR 
SPONSOR 
Unanticipated Adverse Device 
Effects  
To IRB and AGA Medical 
To the FDA, all IRBs, and all Investigators 
within ten (10) working days after receiving 
notice of the event 
Withdrawal of IRB Approval 
To AGA Medical within five (5) 
working days 
All IRBs and all Investigators will be notified 
within five (5) working days 
Withdrawal of FDA approval 
 
All IRBs and all Investigators will be notified 
within five (5) working days 
Progress reports  
To  IRB and AGA Medical annually 
To FDA and IRBs annually 
Deviations from the 
Investigation Plan  
IRB notification and 
acknowledgement (If applicable) 
FDA if deviation affects the scientific 
soundness of the Investigational Plan 
Informed consent  
Use of device without consent must 
be reported to AGA and IRB within 
five (5) days 
To the FDA within five (5) days working 
days of receipt of a device implant without 
informed consent 
Final Reports  
 
Investigators submit a final report to 
AGA Medical and the IRB within 
three (3) months after termination or 
completion of a study or the 
Investigator’s part in a study 
A Final Report will be sent to the FDA, all 
IRBs and Investigators within six (6) months 
after completion or termination 
Other reports that may be 
requested by AGA or the IRB 
Other reports that may be requested 
by AGA or the IRB 
Reports that may be requested by IRB or 
FDA 
Current Investigator List 
 
Current Investigator List to the FDA every 
six (6) months following study initiation 
Recall and device disposition 
 
FDA and all IRBs will be notified within 30 
working days of the reasons for any request 
that an Investigator return, repair, or dispose 
of any devices 
Other  
 
Investigators provide accurate, 
complete and current information 
about any aspect of the investigation 
AGA Medical provides accurate, complete 
and current information about any aspect of 
the investigation upon request of the IRB or 

ACP Investigational Plan 
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CONFIDENTIAL AND PROPRIETARY 
© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
 
The investigator must notify AGA Medical LLC prior to deleting any records relating to the ACP 
clinical trial.  Sites will be notified when records no longer need to be retained. 
 
10.3 
RECORD CUSTODY 
Record custody may be transferred to any other person who will accept responsibility.  The 
FDA will be notified of this transfer no later than ten days after the transfer occurs. 
 
10.4 
REPORTS 
Investigators and sponsors are responsible for preparing and submitting the following 
complete, accurate, and timely reports; 
 
These reports are subject to FDA inspection and the retention requirements. 
 
IRB Records 
 
Each reviewing IRB must maintain the following records: 
• 
All pertinent correspondence relating to the investigation 
• 
All records of membership and affiliations 
• 
Meeting minutes 
 
 
 
upon request of the IRB or FDA 
FDA 

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© 2012 –AGA Medical LLC: All rights reserved.  No portion of this work may be reproduced in whole or in part without the 
express written permission of AGA Medical LLC. 
APPENDIX: A - TRANSESOPHAGEAL ECHOCARDIOGRAPHY (TEE) PROTOCOL 
 
(ALL views to be provided in the following sequence): 
 
 
I. TEE Scanning Protocol (abbreviations listed at end of protocol) 
The following TEE protocol is recommended to ensure uniformity across clinical study sites. 
TEE studies are to be performed at baseline, during the procedure, at the 45 day and 6 month 
follow-up visits. The TEE study should image the Left Atrium (LA) and Left Atrial Appendage 
(LAA) in multiple planes (i.e., 0°- ~110°). The purpose of the TEE is to obtain information 
regarding: a) LA/LAA thrombus; b) LAA ostium measurements; c) length distal to the LAA 
ostium; d) Flow into the LAA and e) to assess for procedural complications, such as device 
migration, pericardial effusion, etc. 
 
II. Adjustment of the ultrasound instrument: 
a. Adjust transmission power (gain) to minimize/eliminate “blooming” of specular reflectors. 
b. Adjust the time gain compensation in such way that the image exhibits uniform 
brightness. 
c. Adjust the color Doppler gain below the point where random color noise appears. 
d. Set pulse repetition frequency with Nyquist velocity for CFD at ~35-45 cm/sec. 
e. Use a velocity variance map with a “medium” color filter; set color tissue priority at a 
level that avoids overlay of color signals onto tissue structures. 
f. Perform TEE at 5-7.5 MHz, with all other settings as mentioned above. 
g. Perform both longitudinal and transverse plane sweeps to ensure full coverage of 
LA/LAA. 
h. Record 3-5 consecutive beats for all cine-loop images; record at least 3-5 consecutive 
beats for all Doppler velocity tracings – record these as still frames (provide 2-3 still 
frames) at 100mm/s sweep speed.  
i. Ensure that the ECG is recorded for all cine-loops and still-frame images. 
 
III. TEE imaging study to be obtained in the following views: 
a. The 5-chamber view (Omniplane 0°) with the aortic valve in the center of the screen and 
the LA in the right upper corner. 
• Standard 2D imaging 
• Zoom mode of LA and LAA; place color flow Doppler (CFD) around device to 
document communication between LA and LAA.  (Post procedure only) 
• Zoom mode of LA and LAA; align Pulse Wave (PW) Doppler sample volume to 
record LAA-LA blood flow.  The PW sample should be placed 0.5 to 1 cm from the 
ostium into the LAA. 
• 2D imaging of LV at mid-papillary muscle level (short axis), from gastric view.   
b. The high LA/LAA view (Omniplane ~60°)  
Optional views (these may be difficult to obtain in some subjects): 
• Zoom mode of LA and LAA; place CFD around device to document communication 

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between LA and LAA.  (Post procedure only)  
• LA/LAA views; align PW Doppler sample volume to record LAA-LA blood flow.  The 
PW sample should be placed 0.5 to 1 cm from the ostium into the LAA. 
c. The longitudinal imaging plane (Omniplane ~80-110°) with LA/LAA in field of view. 
• Zoom mode of LA and LAA; place CFD around device to document communication 
between LA and LAA. (Post procedure only) 
• Zoom image of LA-LAA; align PW Doppler sample volume to record LAA blood flow.  
The PW sample should be placed 0.5 to 1 cm from the ostium into the LAA. 
 
IV. Technical Notes for Completion of Echocardiographic Studies 
 
a. Study subjects are to be identified only by study site and study subject number. This 
information will be entered in the ultrasound system patient data section in adherence to 
applicable privacy laws. No subject names should be displayed in the submitted studies. 
 
b. Two-dimensional imaging to be performed in harmonic mode; the ECG tracing should 
be displayed on all images (still frames and cine-loops), clearly showing P wave/QRS 
morphology during the echocardiographic study. Avoid recording extrasystolic (PVC) 
beats. 
 
c. For all spectral Doppler velocities, please use a display speed of 100 mm/sec, and 
optimize the velocity profile by moving the baseline up or down and showing the 
maximal velocity obtained at the top of the scale. 
 
d. Clinical sites should retain a digital copy of the echocardiographic study in DICOM and 
the study should be analyzed locally. The Echocardiography Core Laboratory WILL 
NOT return submitted studies. An echocardiographic analysis WILL NOT be provided 
by the Echocardiography Core Laboratory to the clinical sites. The Echocardiography 
Core Laboratory Report will only be used for the purposes of the ACP study and NOT 
for diagnosis and/or clinical management of subjects enrolled in the ACP study. 
 
V. Variables to be recorded by the study sites 
a. Thrombus in the LA and/or LAA 
b. LAA ostium measurements 
c. Length distal to the LAA ostium 
d. Spontaneous Echo Contrast (SEC) in the LA 
e. Thrombus in the RA and/or RAA 
f. Spontaneous Echo Contrast (SEC) in the RA 
g. LAA-LA communication/flow (see E below) 
h. Left Ventricular Ejection Fraction (LVEF) 
i. Presence, location, and size of any aortic plaques 
j. Mitral or aortic valve stenosis or regurgitation 

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k. In addition the following data points must also be documented: presence of  
1. Atrial septal defect  
2. Patent foramen ovale 
3. Prosthetic valve 
4. Intracardiac thrombus 
5. Atrial septal device 
 
VI. Measurements to be analyzed by the Echocardiography Core Lab 
a. Thrombus in the LA and/or LAA 
b. LAA ostium measurements 
c. Length distal to the LAA ostium 
d. Thrombus in the RA and/or RAA 
e. Spontaneous Echo Contrast (SEC) in the LA 
f. Presence, location and size of any aortic plaque 
g. LAA-LA communication/flow (see VII below) 
 
VII. Assessment of Flow in Left Atrial Appendage 
a. None - No color flow jet in or out of the LAA  
b. Small leak -  ≤ 3 mm diameter jet by color flow Doppler or multiple leaks which are 
cumulatively ≤  3 mm diameter jet by color flow Doppler 
c. Large leak - > 3 mm diameter jet by color flow Doppler or multiple leaks which are 
cumulatively > 3 mm diameter jet by color flow Doppler 

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APPENDIX: B - TRANSTHORACIC ECHOCARDIOGRAM (TTE) PROTOCOL 
 
With the subjects in the left lateral position, standard transthoracic imaging should be 
obtained in the parasternal long-axis, parasternal short-axis, apical 4-chamber, apical 2-
chamber and apical 3-chamber views.  For the evaluation of left ventricular systolic 
function a sweep of the entire chamber from base to apex should be imaged from the 
parasternal short axis view.   Evaluation of all 4 valves should include color flow 
Doppler, continuous and pulse wave Doppler interrogation.  With the subjects lying 
supine, the atrial septum should be evaluated in the subcostal long axis view by both 2D 
imaging alone and with color flow Doppler. 
 
Any post procedure complication such as pericardial effusion must be documented. 
 
 
 

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APPENDIX: C - AMERICAN HEART ASSOCIATION RECOMMENDATIONS 
FOR PROPHYLAXIS 
 
 

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APPENDIX: D- CLINICAL INVESTIGATIONAL PLAN CHANGES DUE TO 
ENROLLMENT DISCONTINUATION 
 
 
AGA Medical/St. Jude Medical has made the decision to discontinue further 
enrollments in the AMPLATZER Cardiac Plug (ACP) IDE trial.  This decision was 
not a consequence of a safety or efficacy issue with the device or the study.  All 
device subjects should continue to be followed per the protocol with the 
modifications noted below. 
 
The following sections of the protocol are being changed due to the 
discontinuation of enrollment in the trial. 
 
1.5 DURATION OF THE INVESTIGATION AND SAMPLE SIZE 
 
A total of 97 subjects were enrolled in the trial at 17 centers.  Safety data 
collected will be summarized in a final report.  No additional subjects or centers 
will be added to the study.  
 
2.12  FOLLOW-UP REQUIREMENTS 
 
#3 From:  For subjects randomized to control arm and those subjects who are 
randomized to device arm but do not undergo an implant attempt, follow-up 
windows are calculated based on the day of randomization. For subjects who 
undergo an implant attempt and/or receive the device, follow-up windows are 
calculated from the date of procedure.  Subjects who are on warfarin should 
maintain an INR between 2-3 INR levels must be documented on an INR log. 
To:  Control subjects should be discontinued (exited) from the trial.   
To:  Device subjects who underwent an implant attempt, however did not receive 
the ACP device, should be discontinued (exited) from the trial. 
To:  Device subjects will have office visits through 2-years post-implant, and then 
telephone visits annually through 5 years post-implant.  Once the subject has 
completed the 5 year telephone  follow-up visit they should be discontinued 
(exited) from the trial. 
 
#10 From:  As part of the health economic and quality of life sub-study, hospital 
bills of enrolled subjects will be collected up to 2 years or until the study is 
completed. 
To:  The health economic and quality of life sub-study is being stopped. The 
collection of hospital bills is discontinued.  The hospital bills collected for the 
index procedure will be analyzed. 
 

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2.12.1 ASSESSMENT AND FOLLOW-UP SCHEDULE; SUBJECTS WHO 
RECEIVE THE DEVICE 
From: 
 
To: 
The following changes have been made to the assessment and follow-up table: 
• The quality of life assessments have been removed. 
• Added a note that monthly INR logs are only required for subjects that 
remain on warfarin. 
 
 
Procedure 
Pre-discharge  
(+ 1 day) 
45 days  
(+/-5 days) 
3 Month (+/- 10 days) 
Post OAC 
Discontinuation 
Phone Visit 8 
6 months 
(+/- 30 days)
12 months  
(+/-30 days) 
18 months 
(+/-60 days)  
2 years 
(+/- 60 days ) 
Annually thereafter 
(+/- 60 days) 
phone visit 4 
Physical Exam 
 
X 
X 
 
X 
X 
X 
X 
 
Neurological Symptoms Interview 
 
 
X 
 
X 
X 
X 
X 
X 5 
Urine Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
12 lead Electrocardiogram  
 
X 
X 
 
X 
X 
X 
X 
 
2-D Color Flow 
 Doppler Transthoracic 
 Echo (TTE) 
 
X 
 
 
 
X 6 
 
X 6 
 
Transesophageal Echocardiogram 
(TEE)  
X 
 
X 
 
 X  
X 6 
 
X 6 
 
MRI of head/brain 7 
 
 
 
 
 
X 
 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessment 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR Assessment 3 
 
 
 
 
 
 
 
 
 
Quality of Life  Assessment(s) 
 
 
 
 
 
X 
 
X 
 

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Procedure 
Pre-discharge  
(+ 1 day) 
45 days  
(+/-5 days) 
3 Month (+/- 10 days) 
Post OAC 
Discontinuation 
Phone Visit 8 
6 months 
(+/- 30 days)
12 months  
(+/-30 days) 
18 months 
(+/-60 days)  
2 years 
(+/- 60 days ) 
Annually thereafter 
(+/- 60 days) 
phone visit 4 
Physical Exam 
 
X 
X 
 
X 
X 
X 
X 
 
Neurological Symptoms Interview 
 
 
X 
 
X 
X 
X 
X 
X 5 
Urine Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
12 lead Electrocardiogram  
 
X 
X 
 
X 
X 
X 
X 
 
2-D Color Flow 
 Doppler Transthoracic 
 Echo (TTE) 
 
X 
 
 
 
X 
 
X 6 
 
Transesophageal Echocardiogram 
(TEE)  
X 
 
X 
 
 X6  
X 6 
 
X 6 
 
MRI of head/brain 7 
 
 
 
 
 
X 
 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessment 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR Assessment 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1Urine pregnancy test must be done within 24 hours prior to the procedure (for female 
subjects of childbearing potential) 
2Review and record all and any changes to antiarrhythmic and antiplatelet medications 
3INR must be tested within 24 hours prior to the procedure (for those subjects on 
warfarin).  Post procedure- INR testing should commence 2-3 days after the initiation of 
warfarin therapy and be tested frequently until a stable dose / INR has been achieved 
and then at least every 4 weeks subsequently. Subjects are recommended to maintain a 
target INR between 2-3 while they are on warfarin (Monthly INR logs are not required 
once the subject stops taking warfarin) 
5If during a telephone visit, an SAE is reported or a response of Yes or Don’t know to 
any question on the Neurological Symptoms Interview is elicited an in-person interim 
office visit is required 
6Refer to flowchart above 
7MRI must include FLAIR, DWI, ADC maps, and GRE among other sequences. If subject 
is medically contraindicated to MRI, a CT of the head must be performed. If 
asymptomatic cerebral hemorrhage is detected through imaging, please note that there 
are no standardized clinical guidelines or treatment recommendation for the use of 
antithrombotic therapy based on MR Imaging findings. Subjects should be managed per 
institutional or investigator standard of care.  
8 This phone visit must be performed 3 months after a subject stops taking OAC (Note: 
OAC must be discontinued once no flow or ≤3mm jet into the LAA (via TEE) has been 
demonstrated 
One week equals 7 days. One month = 30 days. One year= 365 days 
2.15.3 Study Design 
 
The study as designed was intended to determine the difference in efficacy and 
safety between the device and control arm (subjects treated with OMT). 
 
There were three primary endpoints and hypotheses intended to be evaluated in 
the ACP clinical trial; these will no longer be analyzed as specified in the original 
trial protocol, rather, will be summarized as below:   
  
1. From:  An efficacy endpoint which compares the 2-year event rates of 
ischemic stroke and peripheral thromboembolism.  This is a non-inferiority 
analysis where the device will be deemed efficacious if the risk ratio is < 1.75 or 
the risk difference in two years event rates is < 2.87.  
 
To:  This objective will not be analyzed as specified above.  A summary of 
ischemic strokes and peripheral thromboembolism reported through 2 years  of 
follow-up will be provided using descriptive statistics.   
 
2. From:  A long-term safety endpoint which compares long-term composite rates 
of all-cause mortality and major bleed.  This is a superiority analysis where the 

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device will be deemed safe if the safety event rate in the device arm is proven 
superior to the safety event rate in the control arm (OMT). 
 
To:  This objective will not be analyzed as specified above.  A summary of all-
cause mortality and major bleeds reported through 2 years of follow-up will be 
provided using descriptive statistics.   
 
3. From: An acute safety (short-term) endpoint which compares the rate of device 
or procedure related serious adverse events against a performance goal (PG). If 
this rate is less than 5%, the device is considered to have met the acute safety 
endpoint.  
 
To:  This objective will not be analyzed as specified.  A summary of the device or 
procedure related serious adverse events reported through hospital discharge 
will be provided using descriptive statistics.   
 
2.15.4 Analysis of Secondary Endpoints 
 
From:  Three comparisons for secondary endpoints will be made between OMT 
control group and the device group at the end of the trial.  Secondary endpoints 
include: rate of transient ischemic attacks, asymptomatic intracerebral or 
intraventricular hemorrhage, atrial fibrillation status, device or procedure related 
adverse events, in-hospital procedure success, Day 45 clinical success, long-
term clinical success, technical success and complete closure. 
 
To:  The following secondary endpoints will not be analyzed: rate of transient 
ischemic attacks, asymptomatic intracerebral or intraventricular hemorrhage, 
atrial fibrillation status, device or procedure related adverse events, in-hospital 
procedure success, Day 45 clinical success, long-term clinical success, technical 
success and complete closure. 
 
2.15.6 Endpoints and Labeling 
 
From:  The following primary and secondary endpoints will be included in product 
labeling for the ACP device.   
• Primary Effectiveness Endpoint 
• Primary Safety Endpoint 
• Secondary Endpoints 
 
To:  The endpoints will no longer be analyzed and hence no labeling claims are 
intended to be made. 
 
2.15.7 Primary Analysis 
 

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From:  Intent-to-treat analysis- Subjects are considered enrolled in the ACP 
clinical trial after informed consent and HIPAA authorization form or any other 
applicable permission form required by law has been signed and the subject has 
been randomized.  All primary endpoint analyses will be based on the “intent-to-
treat” principle.  Specifically, subjects will be considered part of the intent-to-treat 
analysis population as long as they are randomized into the study, with no 
adjustment made for whether the device was implanted, compliance with 
treatment, or events occurring after randomization. 
 
To: All device subjects will be summarized in a final report.  Descriptive statistics 
will be used to summarize the analysis of all primary endpoints. 
 
2.15.8 Secondary Analysis 
 
From:  In addition to the intent-to-treat analysis, secondary analyses will be 
performed on the three following analysis populations (two per protocol analyses 
and one as-treated). 
 
To: The per-protocol analysis and the as treated analysis will not be performed. 
 
2.15.9 Other Analyses 
 
From:  The following other analyses were planned:  Subgroup analysis, Adverse 
Events Categorization, Residual Flow in LAA, Primary Effectiveness Component 
Analysis, Poolability Analysis, Center Effect, Analysis of Demographics, CHADS2 
Score Distribution, Time within therapeutic range (TTR) for INR subjects assigned 
to warfarin, Effect of Learning Curve, Handling of Missing Data, and Worst-case 
analysis. 
 
To:  The other analyses will not be performed due to the limited sample size and 
because control subjects will be discontinued (exited) from the trial. 
 
2.16.2 DATA SAFETY MONITORING BOARD AND CLINICAL EVENTS 
COMMITTEE 
 
From:  Both an independent Data Safety Monitoring Board (DSMB) and Clinical 
Events Committee (CEC) will be utilized to regularly review study progress with 
regard to safety. The CEC will be blinded to subject’s treatment assignment. 
Members of these boards cannot be investigators on the ACP Clinical Trial.  
Board membership includes: cardiologists, neurologists, and biostatisticians.  
The primary responsibilities of the DSMB and CEC include: 
• Review and refine adverse event definitions as necessary during the 
conduct of the clinical investigation 

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• Review and adjudicate adverse events and primary endpoints as they 
occur over the course of the clinical investigation 
• Review and validate the subject sample (i.e., review inclusion/exclusion 
deviations and other protocol deviations) 
• Provide oversight for issues affecting general subject welfare 
• Recommend premature study termination 
 
 
To: The Data Safety Monitoring Board (DSMB) will continue to review and 
adjudicate all adverse events and oversee safety of the trial.  As blinding is no 
longer necessary to prevent bias, the Clinical Events Committee will no longer 
review events, and their responsibilities will be absorbed by the DSMB. 
 
2.16.5 BLOOD WORK CORE LAB 
 
From: An independent core lab will be utilized to perform baseline hematology 
and coagulation tests (as described in section 2.9).  Members of the Blood Work 
Core Lab will have no affiliation with the ACP Clinical Trial.  
 
To: This independent core lab will be closed as all of the baseline coagulation 
samples have been analyzed. 
 
2.29 ECONOMIC AND QUALITY OF LIFE SUB-STUDY 
 
From:  In conjunction with the pivotal phase of clinical study, the costs and 
benefits of treatment will be evaluated through an economic and quality of life 
analysis.  Medical resource use, cost and health-related quality of life within the 
trial period will be compared between treatment groups.  If ACP therapy is found 
to be effective, its long term cost-effectiveness analysis will be assessed.  The 
economic and quality of life analysis will be fully integrated into the clinical trial, 
with a common informed consent form and collection of subject reported 
resource use in the case report form. Hospital bills reporting hospital care for 
study subjects during the study period will also be collected at least through 2 
years and until the study is completed. 
 
To:  The health economic sub-study will be stopped.  Hospital bills were collected 
for all index procedures.  No additional hospital bills or quality of life 
questionnaires will be collected.