Clinical trial NCT00738894
Conditions: Stroke Transient Ischemic Attack
Keywords: cryptogenic stroke transient ischemic attack TIA PFO Patent foramen ovale HELEX Septal Occluder PFO Occluder
Sponsor: W.L.Gore & Associates
Start date: 2008-12-10; Completion date: 2020-05-11
Enrollment: 664 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine if patent foramen ovale (PFO) closure with the GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder plus antiplatelet medical management is safe and effective and reduces the risk of recurrent stroke or imaging-confirmed transient ischemic attack (TIA) when compared to antiplatelet medical management alone in patients with a PFO and history of cryptogenic stroke or imaging-confirmed TIA.

A co-primary objective is to demonstrate that medical management plus closure with the study device reduces the risk of new brain infarct compared to medical management alone.

Detailed description:

Arms: arm 1: Antiplatelet medical therapy alone arm 2: PFO closure with study septal occluder device plus antiplatelet medical therapy
Interventions: intervention 1: Septal Occluder Device intervention 2: Antiplatelet Medical Therapy
Intervention descriptions: intervention 1: PFO closure with study septal occluder device intervention 2: Investigator's choice of one of three regimen options specified in protocol

Protocol documents:
Prot_000.pdf: 
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CONFIDENTIAL INFORMATION 
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 Nothing herein is to be disclosed in any way without the prior express written permission of W.L. Gore & 
Associates, Inc. 
 
 
 
 
 
 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  
and Antiplatelet Medical Management for Reduction of Recurrent Stroke or 
Imaging-Confirmed TIA in Patients with Patent Foramen Ovale (PFO) 
 
 
 
The Gore REDUCE Clinical Study 
 
 
 
 
 
                   
 
 
      
 
 
 
 
 
 
 
 
W.L. Gore & Associates, Inc. 
Medical Products Division 
4250 West Kiltie Lane 
Flagstaff, AZ  86001 USA 
Telephone: (01) 1-800-437-8181 
Facsimile: (01) 1-623-234-5730 
 
 
 
 
 
 
 
Protocol Number: HLX 06-03 
Amendment [3]: 15-JAN-2016 
Amendment [2]: 15-MAY-2012 
Amendment [1]: 01-DEC-2009 
Original Protocol: 07-APR-2008 


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ii 
 
 
SIGNATURE PAGE 
 
Device:  
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  
 
Title: GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  and Antiplatelet 
Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients with 
Patent Foramen Ovale (PFO) – The Gore REDUCE Clinical Study 
 
Protocol Version:  Amendment No. 3, January 15, 2016 
 
 
I, the undersigned, have read and understood the specified Protocol and agree with the contents.  The 
Protocol, the Clinical Study Agreement, and any additional information provided by the Sponsor will 
serve as a basis for cooperation in the study. 
 
Investigator:  Please complete the following.  Sign and date the bottom of the page and return the 
original to the Clinical Study Manager at W. L. Gore & Associates.  Retain a copy with the Protocol at the 
study site. 
 
Name and Title (print):  
 
 
 
Address:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone: 
 
      _________________________  
___ 
 
Fax: 
 
 
 
 
 
Please sign and date this page. 
 
Signature: _________________________                         Date: __________________ 
 
 


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iii 
 
 
Study Summary 
 
Please refer to the main protocol for comprehensive descriptions of study entrance criteria and 
endpoints.  
 
Study Title 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  and 
Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-
Confirmed TIA in Patients with Patent Foramen Ovale (PFO) – The Gore REDUCE 
Clinical Study 
Sponsor 
W.L. Gore & Associates, Inc.  
Medical Products Division 
4250 West Kiltie Lane 
Flagstaff, AZ 86001  USA 
US Telephone: (011) 800-437-8181 
US Facsimile: (011) 623-234-5730 
Study Number 
HLX 06-03 
IDE Number 
G070185 
Reimbursement 
Code 
B-4 
Study Objective 
Demonstrate that patent foramen ovale (PFO) closure with the GORE® HELEX® 
Septal Occluder / GORE® CARDIOFORM Septal Occluder  plus antiplatelet 
medical management is safe and effective and reduces the risk of recurrent stroke 
or imaging-confirmed transient ischemic attack (TIA) when compared to antiplatelet 
medical management alone in patients with a PFO and history of cryptogenic stroke 
or imaging-confirmed TIA. 
 
A co-primary objective is to demonstrate that medical management plus closure 
with the study device reduces the risk of new brain infarct compared to medical 
management alone. 
Study Design 
 
Overview 
HLX 06-03 is a prospective, randomized, multicenter, multinational clinical trial.  
Approximately 664 subjects will be randomized to either the test or control arm 
using a 2:1 randomization scheme.  A maximum of eighty (80) Investigational Sites 
in the United States, Canada and Europe will participate in the study with no per-
site subject limit.   
The anticipated accrual rate is approximately 10 subjects per month for a total 
accrual period of approximately 60-66 months.  Randomized subjects will be 
followed for 60 months with follow-up evaluations at 1, 6, 12, 18, 24, 36, 48, and 60 
months.  
Study Endpoints  
Co-Primary Endpoint 1: freedom from recurrent ischemic stroke or imaging-
confirmed TIA through at least 24 months post-randomization.   
 


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iv 
 
 
Co-primary Endpoint 2: incidence of subjects with new brain infarct or clinical 
findings of ischemic stroke from screening through 24 months or last follow-up visit, 
whichever occurs first. 
Secondary endpoints: 
Safety: 
 
Adverse events (AEs) directly related to the device, procedure, and/or 
antiplatelet medical therapy 
Efficacy: 
 
Assessment of PFO closure in test (device) arm subjects by transthoracic 
echocardiography (TTE) or transesophageal echocardiography (TEE) 
Additional secondary endpoints: 
 
Clinical Success–  
 
Test Arm - defined as the composite of Device Success, PFO 
closure, and absence of a recurrent stroke or imaging-confirmed TIA 
at 24 months post-procedure 
 
Control Arm - defined as the freedom from a recurrent stroke or 
imaging-confirmed TIA at 24 months post-randomization 
 
Overall Survival – time from randomization to death from any cause or last 
known contact 
 
Time to any stroke/TIA 
 
Device Success – the proportion of test arm subjects with successful 
implant and retention after procedure of the GORE® HELEX® Septal 
Occluder / GORE® CARDIOFORM Septal Occluder   
Statistical Hypotheses 
This study is designed to test the null hypothesis that the hazard of a recurrent 
stroke or imaging-confirmed TIA in subjects treated with antiplatelet medical 
management and percutaneous PFO closure is equal to or higher than subjects 
treated with antiplatelet medical management alone.  The alternative hypothesis is 
that the hazard of a recurrent neurologic embolic event is lower in subjects treated 
with percutaneous PFO closure plus antiplatelet medical management compared to 
antiplatelet medical management alone.  In statistical terms: 
 
 
t
all
for
t
HR
H
t
all
for
t
HR
H
C
T
A
C
T
O
0.1
)
(
:
0.1
)
(
:
/
/


 
 
where: 
HRT/C = hazard ratio comparing the test (T) arm (PFO closure) to the control (C) 
arm (antiplatelet medical management only). 
 
In addition, this study will test the null hypothesis that the incidence of brain infarct 
at 24 months in subjects treated with percutaneous PFO closure plus antiplatelet 
medical management is equal to or higher than subjects treated with antiplatelet 
medical management alone. The alternative hypothesis is that the brain infarct 
incidence is lower in subjects treated with percutaneous PFO closure plus 
antiplatelet medical management compared to antiplatelet medical management 
alone. In statistical terms: 
𝐻0:  𝑃𝐶−𝑃𝑇≤0
𝐻1:  𝑃𝐶−𝑃𝑇> 0 


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v 
 
 
 
where: 
PC = true proportion of subjects with incident brain infarct in the control group 
PT = true proportion of subjects with incident brain infarct in the test group 
 
 


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vi 
 
 
Subject 
Population 
(study entrance 
criteria) 
 
 
 
 
 
 
 
 
Major Inclusion Criteria 
 
Patient has presence of cryptogenic, ischemic stroke, or transient ischemic 
attack (TIA), of presumed embolic etiology, verified by a neurologist within 
180 days prior to randomization. 
o Patient has a diagnosis of ischemic stroke (clinical symptoms 
persisting ≥24 hours).   
o Patient has a diagnosis of TIA (clinical symptoms persisting <24 
hours) must have MRI evidence of infarction to qualify for inclusion.  
 
Presence of Patent Foramen Ovale (PFO), as determined initially by 
positive bubble study utilizing transesophageal echocardiography (TEE), 
demonstrating spontaneous right-to-left shunting or right-to-left shunting 
during Valsalva maneuver.  
 
Absence of an identifiable source of thrombo-embolism in the systemic 
circulation. 
 
Patient has no evidence of hypercoagulable state, which requires 
anticoagulation therapy.  
 
Age range: 18 - 60 years 
 
Major Exclusion Criteria 
 
Other co-morbidities including, but not limited to, mural thrombus, dilated 
cardiomyopathy, atrial fibrillation/flutter, cardiac prosthetics (valves), mitral 
valve stenosis, aortic dissection, significant atherosclerosis, vasculitis, pre-
existing neurologic disorders, multiple sclerosis, arteriovenous 
malformations, prior intracranial hemorrhage, severe CNS disease, severe 
disability related to prior stroke, and autoimmune disorders that would 
increase the risk of mortality or morbidity above what is typical for the 
treatment. 
 
Previous Myocardial Infarction 
 
Active infection that cannot be treated successfully prior to randomization.  
 
Sensitivity or contraindication to all proposed medical treatments. 
 
Patient is pregnant, lactating, or intent on becoming pregnant through 24-
months after randomization.  
 
Patient is unwilling or unable to sign informed consent. 
 
Patient expresses foreseen difficulties complying with study compliance and 
follow-up schedule. 
 
Indications outside the parameters accepted for placement of the GORE® 
HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder, 
including extensive congenital cardiac anomalies and defect diameters 
considered too large for closure with the device. 
 
Atrial septal anatomy that is expected to necessitate placement of more 
than one device. 
 
Need for concomitant procedure(s) that may confound detection of adverse 
events related to device placement. 


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vii 
 
 
Contact Information 
 
Principal 
Investigators 
Scott Eric Kasner, MD, FAHA 
Neurologist  
Philadelphia, Pennsylvania 
 
 
 
 
Lars Thomassen, MD   
Neurologist 
Bergen, Norway 
 
 
 
John F. Rhodes, MD  
Cardiologist  
Miami, Florida 
 
 
 
 
Lars Søndergaard, MD  
Cardiologist 
Copenhagen, Denmark 
 
 
 
Contract 
Research 
Organization 
United States, Canada and Europe:  
 
  
 
 
 
 
 


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Study Entry 
Ischemic Stroke 
or Imaging-
Confirmed TIA 
MRI  
PFO + 
Absence of 
identifiable 
source of 
thrombo-
embolism  
Screening 
Within 180 days prior to 
randomization 
1° Endpoint 1: freedom from a stroke or imaging-confirmed TIA 
through at least 24-months.  
1° Endpoint 2: incidence of subjects with new brain infarct or 
clinical findings of ischemic stroke from screening through 24 
months or last follow-up visit, whichever occurs first. 
 
Randomize to a 
treatment arm if 
patient meets 
inclusion / 
exclusion 
criteria 
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Test (Device) Arm 
Control (Medical) 
Arm 
All available subjects have 
MRI at 24 months post-
randomization 
          Subjects followed until first stroke or imaging-
confirmed TIA, or 60-month follow-up, whichever 
occurs first. 
Subjects followed until first stroke or imaging-confirmed 
TIA or 60-month  
follow-up, whichever occurs first. 



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TABLE OF CONTENTS 
STUDY SUMMARY ..................................................................................................................................... III 
1. 
INTRODUCTION ............................................................................................................................. 1 
1.1. 
BACKGROUND ....................................................................................................................... 1 
1.2. 
SUMMARY OF CLINICAL EXPERIENCE WITH  GORE® HELEX® SEPTAL OCCLUDER ................... 5 
1.3. 
DEVICE DESCRIPTION ............................................................................................................ 7 
1.3.1. 
GORE® HELEX® Septal Occluder ......................................................................... 7 
1.3.2. 
GORE® Delivery System........................................................................................ 7 
1.3.3. 
GORE® HELEX® Septal Occluder Package Configuration .................................... 8 
1.3.4. 
GORE® CARDIOFORM Septal Occluder .............................................................. 9 
1.3.5. 
GORE® CARDIOFORM Septal Occluder  Delivery System .................................. 9 
2. 
STUDY DESIGN AND STATISTICAL CONSIDERATIONS ......................................................... 11 
2.1. 
STUDY OBJECTIVES ............................................................................................................ 11 
2.2. 
STUDY DESIGN OVERVIEW .................................................................................................. 11 
2.3. 
PRIMARY ENDPOINTS .......................................................................................................... 11 
2.4. 
SECONDARY ENDPOINTS ..................................................................................................... 12 
2.5. 
PRIMARY STUDY HYPOTHESES ............................................................................................ 13 
2.6. 
SAMPLE SIZE DETERMINATION ............................................................................................. 13 
2.6.1. 
Sample Size Assumptions ................................................................................... 13 
2.6.2. 
Randomization and Enrollment ............................................................................ 14 
2.6.3. 
Sample Size Calculations .................................................................................... 14 
2.6.4. 
Power Calculations for Brain Infarct Hypothesis Test ......................................... 15 
2.7. 
RANDOMIZATION SCHEME .................................................................................................... 16 
2.8. 
STATISTICAL ANALYSIS OF PRIMARY ENDPOINTS .................................................................. 16 
2.9. 
INTERIM ANALYSES ............................................................................................................. 17 
2.10. 
STATISTICAL ANALYSIS OF SECONDARY ENDPOINTS ............................................................. 17 
2.11. 
HYPOTHESIS TESTING STRUCTURE ...................................................................................... 17 
2.12. 
EVALUATION OF SEPTAL OCCLUDER DEVICE POOLABILITY .................................................... 18 
3. 
CLINICAL STUDY PLAN .............................................................................................................. 20 
3.1. 
ETHICAL CONSIDERATIONS .................................................................................................. 20 
3.2. 
STUDY INITIATION ................................................................................................................ 20 
3.3. 
SUBJECT POPULATION......................................................................................................... 20 
3.4. 
INCLUSION/EXCLUSION CRITERIA ......................................................................................... 20 
3.4.1. 
General Inclusion Criteria .................................................................................... 20 
3.4.2. 
General Exclusion Criteria ................................................................................... 21 
3.5. 
SCREENING EVALUATION AND CONSENT .............................................................................. 22 
3.6. 
SCREEN FAILURES .............................................................................................................. 25 
3.7. 
RANDOMIZATION AND ENROLLMENT ..................................................................................... 25 
3.8. 
TREATMENT GROUPS .......................................................................................................... 25 
3.9. 
INITIATION AND ADMINISTRATION OF ANTIPLATELET THERAPY FOR ALL SUBJECTS .................. 28 
3.10. 
PFO CLOSURE ................................................................................................................... 28 
3.10.1. 
Pre-Procedure Evaluation – Within 72 hours of PFO Closure .......................... 28 
3.10.2. 
Subject Preparation ........................................................................................... 28 
3.10.3. 
Pre-medication ................................................................................................... 28 
3.10.4. 
Procedure .......................................................................................................... 29 
3.10.5. 
Post-Device Placement Echocardiogram .......................................................... 29 
3.10.6. 
Access Site Management .................................................................................. 30 
3.10.7. 
Post-Procedural Care ........................................................................................ 30 
3.11. 
EARLY POST-PROCEDURE EVALUATIONS – 4-72 HOURS POST PFO CLOSURE ...................... 30 
3.12. 
FOLLOW-UP EVALUATIONS – TEST ARM ............................................................................... 30 
3.13. 
FOLLOW-UP TIME ALLOWANCES – TEST ARM ....................................................................... 32 
3.14. 
FOLLOW-UP EVALUATIONS – CONTROL ARM ......................................................................... 33 
3.15. 
FOLLOW-UP TIME ALLOWANCES – CONTROL ARM ................................................................. 34 


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3.16. 
TREATMENT CHANGES POST-RANDOMIZATION ..................................................................... 34 
3.17. 
STUDY FAILURES ................................................................................................................ 34 
3.18. 
SUBJECT WITHDRAWAL OR DISCONTINUATION FROM THE CLINICAL STUDY ............................ 35 
3.19. 
IMAGING ANALYSIS .............................................................................................................. 35 
3.19.1. 
MRI / CT ............................................................................................................. 35 
3.19.2. 
Echocardiography .............................................................................................. 36 
3.20. 
DATA SAFETY MONITORING BOARD ..................................................................................... 36 
3.21. 
CLINICAL EVENTS COMMITTEE ............................................................................................. 37 
4. 
ADVERSE EVENTS ...................................................................................................................... 38 
4.1. 
ANTICIPATED ADVERSE EVENTS........................................................................................... 38 
4.2. 
SERIOUS ADVERSE DEVICE EFFECTS / SERIOUS ADVERSE EVENTS ....................................... 40 
5. 
DATA COLLECTION AND EVALUATION ................................................................................... 42 
5.1. 
PROTOCOL DEVIATIONS AND VIOLATIONS ............................................................................. 43 
5.1.1. 
Protocol Violations ............................................................................................... 44 
6. 
RISK ANALYSIS ........................................................................................................................... 45 
6.1. 
MINIMIZATION OF RISKS ....................................................................................................... 47 
6.2. 
EXPECTED BENEFITS ........................................................................................................... 47 
7. 
INVESTIGATOR RESPONSIBILITIES ......................................................................................... 48 
7.1. 
SPECIFIC INVESTIGATOR RESPONSIBILITIES .......................................................................... 48 
7.1.1. 
Subject Informed Consent ................................................................................... 48 
7.1.2. 
Compliance .......................................................................................................... 49 
7.1.3. 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  Use 49 
7.1.4. 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  Disposal
 
49 
7.1.5. 
Occluder Explant.................................................................................................. 49 
7.1.6. 
Investigator Records ............................................................................................ 49 
7.1.7. 
Investigator Reports ............................................................................................. 50 
8. 
SPONSOR AND MONITOR RESPONSIBILITIES ....................................................................... 51 
8.1. 
SPONSOR RESPONSIBILITIES ............................................................................................... 51 
8.2. 
MONITOR RESPONSIBILITIES ................................................................................................ 51 
8.2.1. 
Pre-investigation Site Visit ................................................................................... 52 
8.2.2. 
Periodic Site Visits ............................................................................................... 52 
8.2.3. 
Clinical Monitor Reports ....................................................................................... 53 
9. 
STEERING COMMITTEE AND PUBLICATION OF RESULTS ................................................... 54 
 
 


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1. 
Introduction 
1.1. Background 
In the United States (U.S.), stroke is been recognized as a leading cause of both death and 
disability (CDC 2001, Rosamond 2007).  Approximately 700,000 individuals experience new or 
recurrent strokes annually, which translates to an estimated socioeconomic impact of more 
than $67 billion in lost productivity and total health care costs (Rosamond 2007).  
Approximately 87% of all strokes are ischemic, resulting from a blockage in a blood vessel.  
Even after extensive investigation, up to 40% of all ischemic strokes have no clear 
pathogenesis and are considered cryptogenic (Halperin 2002).  
 
The historical treatment for cryptogenic stroke is medical therapy, including antiplatelet and/or 
anticoagulation medication.  These regimens, however, can increase the risk of bleeding 
complications and may not prevent recurrent ischemic neurological events (McBride 1994, 
Stone 1996).  Thus, research has turned to identifying potential etiologies of ischemic stroke 
having no detectable thromboembolic source.  
 
Increasingly, attention has been focused on the potential relationship between Patent 
Foramen Ovale (PFO) and cryptogenic stroke, when there is no other detected 
thromboembolic source.  Studies of cryptogenic stroke patients have found that those with 
PFO are younger and less likely to have traditional risk factors for stroke than those without 
PFO, suggesting a different stroke mechanism within this subset (Lamy 2002).  Proposed 
mechanisms of PFO-induced stroke include embolism from the peripheral venous system 
through the PFO and genesis of thromboembolism directly from the endocardial surface of the 
atrial septum [Halperin 2002].  Although rare, additional documented cases of 
thromboembolism have been observed within a PFO (Caes 1995, Falk 1997).   
 
The frequency of PFO in patients with presumed normal hearts has been estimated at 
approximately 25%, based on autopsy studies (Hagen 1984).  Controlled studies in the current 
literature consistently report statistically higher prevalence of PFO among cryptogenic stroke 
populations (between 40-75%) compared to (between 5-30%) non-cryptogenic stroke 
populations (Lechat 1988, Webster 1988, Di Tullio 1992, Itoh 1994, Job 1994, Chant 2001, 
Chen 1991, and Homma 2002).  These findings suggest that embolization through the PFO 
may provide a plausible etiology of stroke in some patients.  Nevertheless, a causal 
relationship between PFO and cryptogenic stroke remains open to debate, since other studies 
have reported statistically insignificant differences in the occurrence of PFO in patients with 
cryptogenic stroke versus control populations (Petty 2006, Meissner 2006). 
 
Contributing to this uncertainty, the extent of increased risk of recurrent embolic events for 
cryptogenic stroke patients with a PFO remains unclear compared to cryptogenic stroke 
patients without a PFO.  Recurrent-event rates for patients with and without a PFO reported in 
the literature vary from 0% to 15% and include many confounding factors (Mas 1995, De 
Castro 2000, Mas 2001, Homma 2002, and Messe 2004).  Further, several of these studies 
found similar recurrent stroke rates in patients regardless of the presence of a PFO (Mas 
2001, Homma 2002, and De Castro 2000).   
 
For example, the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), reported on 
265 patients (42.1%) with cryptogenic stroke and 365 patients (57.9%) with strokes of known 


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etiology.  The average annual risks of death or subsequent stroke in the entire cohort among 
patients with and without PFO were 7.4% and 7.7%, respectively, and 7.15% and 6.35% 
among patients with and without PFO in the cryptogenic stroke subset (Homma 2002).   
 
Although a direct association of PFO with cryptogenic stroke or its recurrence has yet to be 
validated, additional existing evidence suggests a combination of PFO and any one of various 
synergistic factors may exacerbate the risk of stroke.  Such features include increased shunt 
through the PFO and the presence of an atrial septal aneurysm.  Other evidence suggests that 
certain features of the PFO, atrial septal aneurysm and degree of shunting, as well as multiple 
cerebral infarcts/TIA, Valsalva preceding the presenting event, and age also may contribute to 
increased stroke risk (Webster 1988, Cabanes 1993, Hausmann 1995, Stone 1996, and De 
Castro 2000).  As before, consensus on each of these factors also still is lacking.  
 
With regard to the morphological characteristics of the PFO and the atrial endocardium, De 
Castro, et al. (2000) found that “high-risk” patients with both right-to-left shunting at rest and 
increased septal mobility had significantly higher risk  of recurrent stroke at three years 
compared to PFO patients with no shunting at rest (12.5% versus 4.3%; p=0.05).  Additionally, 
presence of an atrial septal aneurysm accompanying a PFO has been associated with higher 
stroke risk in several studies (Cabanes 1993, Mas 1995, De Castro 2000, and Mas 2001).  
Although Mas, et al. (2001) did not find an increased risk of recurrent stroke for patients with 
PFO only, they did report increased risk for patients with PFO plus an atrial-septal aneurysm 
(4-year recurrent-event rate of 2.3% for patients with PFO, 15.2% for patients with PFO and 
atrial-septal aneurysm, and 4.2% for patients with neither of these cardiac abnormalities).  In 
the PICSS analysis (Homma 2002) and prospective studies by Martin, et al. (2002) and 
Harrer, et al. (2006), however, presence of an atrial-septal aneurysm was not associated with 
increased incidence of recurrent embolic events after either medical treatment or closure of 
the PFO with a device (p > 0.05).   
 
Finally, with regard to age, the PICSS study revealed that stroke recurrence was not 
dependent on presence of a PFO in patients younger than 55 (p=0.15) or in patients 55 to 64 
years old (p=0.48).  In contrast, patients with a PFO who were older than 65 years were 4.14 
times more likely to experience a recurrent stroke than those without a PFO (p=0.01).  Other 
studies have indicated, however, that young cryptogenic stroke patients with a PFO are at 
increased risk (Lechat 1988, Ranoux 1993) and recurrence rates of up to 15% in patients 
younger than 50 years remain a serious concern (Sievert 2004).  
 
To summarize, several plausible etiologies and risk factors for cryptogenic stroke have been 
considered.  However, associated data still are inconclusive as to whether a difference in 
recurrent embolic event rates exists between cryptogenic stroke patients with and without a 
PFO, as well as with or without other putative risk factors.  Based on available data, many 
physicians already have accepted a causal relationship between PFO and stroke, particularly 
in younger patients (Ranoux 1993, Bogousslavsky 1996).  Indeed, many consider 
transcatheter/percutaneous closure the treatment of choice for these patients in light of the 
risks associated with medical therapy, i.e., lifelong anticoagulation and surgical PFO closure 
(Sievert 2004).  In addition, various studies have been, or currently are, underway to 
determine if transcatheter closure can further reduce the risk of recurrent embolic events for 
cryptogenic stroke patients with a PFO.  Although these studies are not randomized, controlled 
multicenter trials, the data are promising and suggest that a reduction in recurrent-events 
occurs after PFO closure. 


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In a primary example of risk reduction following PFO closure, Schuchlenz, et al. (2005) studied 
280 consecutive patients with cryptogenic cerebrovascular events and PFO.  The annual 
recurrence rates of patients treated with medical therapy (13% for patients treated with platelet 
inhibitors, 5.6% for those on oral anticoagulation) and for those treated with device closure 
(0.6%) were statistically different (p < 0.001).  In this study, PFO diameters > 4 mm and 
multiple previous cerebral vascular accidents (CVAs) also were found to be independent 
predictors of recurrent stroke.   
 
Similarly, Windecker, et al. (2004) compared risk of recurrent events in 308 patients with 
cryptogenic stroke and PFO who were treated either medically or with percutaneous PFO 
closure.  At four years of follow-up, percutaneous PFO closure resulted in a nonsignificant 
trend (p=0.08) toward risk reduction of recurrent stroke or TIA compared with medical 
treatment (7.8% versus 22.2%, respectively).  Further, patients with more than one 
cerebrovascular event at baseline and those with complete PFO occlusion were at significantly 
lower risk for recurrent stroke or TIA when compared with medically treated patients (7.3% 
versus 33.2%, p=0.01).  
 
Although limited by uncontrolled data and baseline differences, a meta-analysis (Khairy, et al., 
2003) of ten studies of transcatheter closure (1355 patients) and six studies of medical therapy 
(895 patients) demonstrated that transcatheter closure of patent foramen ovale may prevent a 
substantial proportion of cryptogenic strokes.  Overall, the one-year rate of recurrent 
neurologic thromboembolism with transcatheter intervention was 0% to 4.9%, while medical 
management was associated with one-year recurrence rates of 3.8% to 12.0%.  
 
A recently published study (Harrer, et al. 2006), however, did not show a difference in 
recurrent-event rates among 124 patients with cryptogenic stroke and PFO who were treated 
either medically or had PFO closure (34 transcatheter, 7 surgical).  Annual stroke recurrence 
rates were generally low and comparable among all groups (2.9% percutaneous closure, 2.1% 
medical closure, 0% surgical closure, 2.2% no therapy).  Of the two patients who experienced 
recurrent events after transcatheter closure, both were found to have residual shunts.  
 
Recurrent-event rates after transcatheter closure of PFOs in non-controlled studies have 
ranged between 0-6%.  In initial and intermediate reports from the AGA U.S. Multicenter 
Clinical Trial, of a total of 94 patients, no recurrent thromboembolic complications were 
reported following implantation of the Amplatzer® PFO occluder (Hong 2003, Du 2002, and 
Bruch 2002).  In a prospective study, (Braun, et al. 2002), 276 patients underwent PFO 
closure using the PFO Star device.  The mean follow-up time was 15.1 months.  During the 
follow-up period, only six patients (1.7%) had recurrent events, all of which were TIAs 
occurring within the first six months after implantation.  Martin, et al. (2002) also conducted a 
prospective study to investigate immediate and long-term outcomes of 110 patients who, after 
paradoxical embolism, underwent percutaneous PFO closure with either a Sideris Button or 
CardioSEAL® occluder.  An annual risk of recurrence of 0.9% based on a mean follow-up of 
2.3 years was reported.   
 
Other studies have reported embolic recurrence rates following percutaneous PFO closure of 
3.2% with mean follow-up of 2.6 years (Hung 2000); 3.4% with mean follow-up of 1.6 years 
(Windecker 2000); and 0.0% with mean follow-up of 8.4 months (Bridges 1992).  Differences 
in the outcomes of these PFO closure studies may be due to factors specific to the devices 


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used, e.g. thrombus formation, closure rates, and device complications or to patient variability, 
atrial-septal aneurysm (ASA), size of shunt, multiple cerebral infarcts/TIA, and patient age.  
Randomized multicenter clinical trials with appropriate rigorous patient selection need to be 
conducted to provide definitive objective data to clarify the relationship between presence of a 
PFO in cryptogenic stroke patients and increased risk of recurrent embolic events.  Even with 
these considerations, current data suggest that transcatheter closure of PFO has the potential 
for reducing the rate of recurrent ischemic events. 
 
In the United States, three additional clinical trials comparing PFO closure to medical 
management for recurrent stroke prevention are in various stages: the CLOSURE-I study 
sponsored by NMT Medical; the RESPECT trial sponsored by St. Jude Medical Corp.; and the 
CARDIA trial sponsored by CARDIA medical.  Each of these clinical trials have faced, major 
enrollment issues and the consensus among the medical community is that enrollment 
difficulties stem from patient and physician bias toward closure. Also, it has been suggested 
that patients with significant concern for a paradoxical event are often unwilling to risk 
randomization to the medical treatment control arm.   
 
Further complicating slow enrollment in these studies are the low risk of recurrent embolic 
events (generally < 4%) and the consequent large numbers of patients required for statistically 
powering studies.  If strokes alone (excluding TIAs) are included in the primary endpoint to 
reduce confounding factors, annual risk of recurrent embolic events is even less, generally < 
2%, and an even larger number of patients is required.  For patients being treated with 
antiaggregants or anticoagulants, Bogousslavsky, et al. (1996) reported an average annual 
recurrence rate of 1.9% for stroke alone and 3.8% for stroke and TIA.  For patients with a PFO 
and no atrial septal aneurysm, Mas, et al. (2001) reported that the risk of stroke alone at two 
years was 1.8%, while the risk of either stroke or TIA was 4.6%.  In the Mas study, presence of 
an atrial septal aneurysm in PFO patients also increased the risk of recurrent events.  The risk 
of stroke at two years was 4.0% while the risk of either stroke or TIA was 8.0% in that group. 
 
The study design described in the Clinical Study Plan (Section 4.0 of this document) 
addresses the difficulties encountered in other studies in several ways.  Patients will be 
enrolled into the study from European countries where device availability outside of trials is 
less of an obstacle to enrollment than in the U.S. and patients are more willing to participate in 
randomized trials.  The study design employs a 2:1, device (test) arm to medical treatment 
(control) arm, randomization scheme.  Because this study allows more patients in the device 
treatment arm, it provides incentive for patients to be randomized.  Finally, a comparison of 
screening Magnetic Resonance Images (MRIs) or Computed Tomographs (CTs) with end-of-
study MRIs or CTs will yield more definitive information on the nature and etiology of recurrent 
embolic events in the study population.   
 
The original closure device selected for this trial is the GORE® HELEX® Septal Occluder, 
manufactured by W. L. Gore & Associates, Inc.  It is comprised of an implantable prosthesis 
(Occluder) and a catheter delivery system.  The Occluder is designed to be soft, atraumatic to 
surrounding tissue, and to conform to septal anatomy in order to provide safe and effective 
PFO closure.  The safety and efficacy of the GORE® HELEX® Septal Occluder for closing 
small to medium atrial septal defects (ASDs) has been demonstrated in U.S. studies (Zahn 
2001, Latson 2006, and Jones 2007).  The excellent closure rates and few complications 
provide the rationale for use of the GORE® HELEX® Septal Occluder in the present study.   
 


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In Europe, nearly a decade of experience regarding the safety and efficacy of PFO closure 
with the GORE® HELEX® Septal Occluder has been reported in the literature (Sievert 2001, 
Krumsdorf 2004, Wahl 2005, Billinger 2006, and Schrale 2007).  Based on information 
available to date, the GORE® HELEX® Septal Occluder represents an ideal device for use in a 
study of the association between PFO closure and recurrent stroke reduction because of its 
low rate of mild clinical complications and established efficacy for defect closure. 
 
During the course of the Gore REDUCE Clinical Study, W.L. Gore & Associates, Inc. 
developed a new septal defect occluder. As with the GORE® HELEX® Septal Occluder, the 
GORE® CARDIOFORM Septal Occluder  provides a soft, atraumatic, conformable option for 
the closure of patent foramen ovale. Initial experience with the device, through its development 
and observations from its initial clinical use, demonstrate that this device is easier to use than 
the GORE® HELEX® Septal Occluder.  It additionally is thought to provide quicker closure of 
the defect than the GORE® HELEX® Septal Occluder, while maintaining a similar safety profile. 
Thus, upon its availability, this device will be used as the device of choice within the test arm 
of the study. 
 
1.2. Summary of Clinical Experience with  GORE® HELEX® Septal Occluder 
Considerable clinical experience has been gained with the GORE® HELEX® Septal Occluder 
since it became commercially available in Europe in June 1999 and in the US in August 2006.  
Published data demonstrate that the GORE® HELEX® Septal Occluder provides a reliable and 
safe system for occlusion of small and moderate ASDs and PFOs with minimal risk of major 
complications (Sievert 2001, 2002, Pedra 2003, Billinger 2006, Jones 2007).   
 
FDA-reviewed studies leading to approval of the GORE® HELEX® Septal Occluder for closure 
of ASDs included the GORE Feasibility study (two-center, single-arm), the GORE Pivotal 
study (multicenter, surgical control arm, nonrandomized), and the GORE Continued Access 
study (multicenter, single-arm, prospective), with a total of 388 patients receiving a device.  
The clinical success outcomes from the GORE Pivotal study satisfied the primary, 
noninferiority hypothesis (p <0.001; two-sample binomial proportions test with noninferiority 
margin = 10%).  The Composite Clinical Success of the Continued Access study, defined as 
no major adverse events or repeat procedures and clinical closure success at 12 months, was 
92.6%.  To date, portions of these data have been presented in the peer-reviewed literature 
(Vincent 2003, Latson 2006, and Jones 2007). 
 
In Europe, the GORE® HELEX® Septal Occluder is indicated for closure of both ASDs and 
PFOs.  Over 3000 devices have been sold.  Several peer-reviewed articles have discussed 
the safety and efficacy of the GORE® HELEX® Septal Occluder for transcatheter closure of 
PFOs (Sievert 2001, Krumsdorf 2001, 2004, Wahl 2005, and Billinger 2006).  Billinger, et al. 
(2006) demonstrated the feasibility and safety of the GORE® HELEX® Septal Occluder for 
transcatheter PFO closure in a large series of patients (128) receiving the HELEX® device.  
Their follow-up included evaluations of residual right-to-left shunt, device-related adverse 
events, and recurrent embolic events.  Right-to-left shunt was resolved completely in 90% of 
the patients, a result similar to occlusion rates reported for other septal occluders (Wahl 2001, 
Beitzke 2001, Martin 2002, and Braun 2002).  Furthermore, there were no reported strokes 
and only one reported TIA (0.8% recurrence) after a mean follow-up of 21 months.  This mean 
recurrence rate of 0.9% per year compares favorably with recurrence rates of up to 3.4% per 
year observed in closure studies utilizing other devices (Windecker 2000, Beitzke 2001, Martin 
2002, Braun 2002, and Wahl 2005).   


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Wahl, et al. (2005) also reported on effectiveness and safety of several septal occluder 
devices, including the HELEX® device, for transcatheter PFO closure in patients with 
cryptogenic stroke.  In this study, there were no complications for patients receiving a HELEX® 
implant, the rate of residual shunt for the HELEX® device was 5% (the lowest of all of devices 
tested, e.g. compared to 9%, the next lowest rate).  The rate of recurrent embolic events, 0%, 
was among the lowest of all devices tested. 
 
In an earlier study, Sievert, et al. (2001), seven types of septal occluders were implanted in 
281 patients; 33 received HELEX® Septal Occluders.  In the HELEX® device group, no 
adverse events were reported.  During mean follow-up of 12 months, the average annual 
embolic recurrence rate was 3.3% across all devices, but 0% for patients who received 
HELEX Septal Occluders. 
 
Thrombus formation on atrial septal occluders generally is rare, but is a potential clinical 
complication that could cause an embolic event.  The expanded polytetrafluoroethylene 
(ePTFE) material used in the GORE® HELEX® Septal Occluder is less thrombogenic than 
most other materials across a multitude of implanted medical devices (vascular patches, stent-
grafts, surgical patches, etc).  This low thrombogenicity also has been demonstrated in the 
GORE® HELEX® Septal Occluder.  To date, there has been only one documented report of 
thrombus formation associated with a GORE® HELEX® Septal Occluder (Krumsdorf 2004).  In 
that study, thrombus formation was evaluated on nine different types of septal occluders 
implanted in a total of 1000 patients, 161 of whom received a HELEX® device.  The rate of 
thrombus formation for the HELEX® device was 0.8% (one patient), compared to rates as high 
as 7% for other occluders.   
 
To conclude, multiple studies reported in the scientific literature provide many examples and 
data that have implicated PFO as a contributing factor to increased risk of ischemic embolic 
event.  This putative correlation is supported further by the reduction of recurrent events in 
patients receiving transcatheter closure of PFO compared to controls.  Clinical experience with 
the GORE® HELEX® Septal and the GORE® CARDIOFORM Septal Occluder  illustrate these 
devices’ potential for demonstrating a reduction of recurrent ischemic embolic events.  With 
the Gore REDUCE Clinical Study, W.L. Gore & Associates will provide the clinical basis to 
support this claim by demonstrating that transcatheter closure of PFO with the GORE® 
HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  reduces the risk of 
recurrent stroke or TIA while maintaining a minimal complication rate.   


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1.3. Device Description 
1.3.1. 
GORE® HELEX® Septal Occluder 
The approved GORE® HELEX® Septal Occluder is comprised of an implantable 
prosthesis and a catheter delivery system (control catheter, delivery catheter, and 
mandrel).   
 
The implanted portion of the GORE®HELEX® Septal Occluder is helical in shape 
when stretched and supported by the delivery system, but resumes a low-profile 
shape when fully deployed in the heart (Figure 2). The Occluder is comprised of a 
hydrophilic, expanded polytetrafluoroethylene (ePTFE) material supported by a 
nickel-titanium (nitinol), supporting wire frame.  The ePTFE material is supported by 
the nitinol frame and spaced by distal, central, and proximal nitinol eyelets. 
 
 
 
 
The GORE® HELEX® Septal Occluder implantable device is supplied in five nominal 
diameters of 15 mm, 20 mm, 25 mm, 30 mm, or 35 mm.  The GORE® HELEX® Septal 
Occluder is deployed from a 10-French (Fr) outer diameter delivery system. 
 
 
Figure 2: The GORE® HELEX® Septal Occluder 
 
1.3.2. 
GORE® Delivery System 
The GORE® Catheter Delivery System is a catheter assembly composed of three 
primary components:   
 
Delivery Catheter: Delivers the Occluder to the treatment site. 
 
Control Catheter: Advances/retracts the Occluder at the treatment site. 
 
Mandrel: Supports the nitinol frame and the locking mechanism of the Occluder. 
 
The control catheter is equipped with a white retrieval cord to retrieve the Occluder if 
necessary.  A red retrieval cord cap on the proximal end of the control catheter 
secures the retrieval cord until Occluder release.  The mandrel provides mechanical 
support to the Occluder frame during deployment.  In conjunction with the control 
catheter, the mandrel is used to guide and form the Occluder during deployment. 
 


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The catheter components are arranged coaxially within one another at the distal tip of 
the catheter.  Proximal to the distal tip of the catheter, the control catheter is slotted to 
allow the mandrel to bifurcate out and run parallel to the control catheter.  The 
mandrel runs parallel to the control catheter within the delivery catheter for the 
remaining distance to the y-arm (Figure 3).   
 
 
 
Figure 3: The GORE® HELEX® Septal Occluder Catheter Delivery System 
 
1.3.3. 
GORE® HELEX® Septal Occluder Package Configuration 
The packaging configuration contains a holding tray, ethylene oxide gas compatible 
pouches, and a carton, all labeled appropriately.  The tray is packaged within the dual 
pouches, and the pouches are packaged within the carton.  The carton and the outer 
package are labeled appropriately and Instructions for Use are included.  The 
packaging configuration is validated to provide an appropriate sterile barrier. 
 
The GORE® HELEX® Septal Occluder and catheter delivery system arrive within the 
tray in a fully deployed state (Figure 4).   
 
 
Figure 4: Tray with GORE® HELEX® Septal Occluder 
 


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1.3.4. 
GORE® CARDIOFORM Septal Occluder   
The GORE® CARDIOFORM Septal Occluder  consists of an implantable occluder 
and a catheter delivery system. The occluder is comprised of five platinum-filled 
nickel-titanium (Nitinol) wires, which form a frame covered with expanded 
polytetrafluoroethylene (ePTFE). The ePTFE is treated with a hydrophilic coating to 
facilitate echocardiographic imaging of the occluder and surrounding tissue during 
implantation. When fully deployed, the occluder assumes a double-disc configuration 
(Figure 5) to prevent shunting of blood between the right and left atria.  
 
The occluder is configured in nominal diameters of 15, 20, 25, and 30mm.  The 
occluder is delivered using conventional catheter delivery techniques and may be 
delivered with the aid of a 0.035" guidewire, or smaller, if necessary.   
 
 
Figure 5: GORE® CARDIOFORM Septal Occluder  
 
1.3.5. 
GORE® CARDIOFORM Septal Occluder  Delivery System 
The delivery system consists of a 75 cm working length 10 Fr (O.D.) delivery catheter, 
a control catheter, and a mandrel coupled to a handle (Figure 6). The handle 
facilitates loading, deployment, and locking of the occluder. The handle also allows 
repositioning and retrieval of the occluder via the retrieval cord, if necessary.  
 
The catheter delivery system for the GORE® CARDIOFORM Septal Occluder  is a 
catheter and handle assembly composed of four primary components:  
 
Delivery Catheter: Delivers the occluder to the treatment site. 
 
Control Catheter: Advances/retracts the occluder at the treatment site. 
 
Mandrel: Supports the Nitinol frame and the locking mechanism of the occluder. 
 
Handle: Facilitates simple push/pull motions for occluder loading, deployment, 
and locking. 
 


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The catheter components are arranged coaxially and are coupled to the handle 
mechanism. The handle moves the catheter components separately or in 
combination to facilitate simple push/pull motions for occluder loading, deployment, 
and locking.  The retrieval cord attaches the proximal eyelet of the occluder to the 
control catheter and facilitates occluder retrieval after lock release, if necessary.  A 
flexible flushing port is attached to the handle to permit convenient device flushing 
prior to implant.  
 
 
Figure 6: GORE® CARDIOFORM Septal Occluder  Handle Delivery System 


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2. 
Study Design and Statistical Considerations 
2.1. Study Objectives 
The primary objective of this study is to demonstrate that antiplatelet medical management 
plus PFO closure with the GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal 
Occluder  reduces the risk of a recurrent stroke or imaging-confirmed TIA compared to 
antiplatelet medical management alone in patients with a patent foramen ovale (PFO) and 
history of cryptogenic stroke or imaging-confirmed TIA.   
 
A co-primary objective is to demonstrate that medical management plus closure with the study 
device reduces the risk of new brain infarct compared to medical management alone. 
 
A secondary objective of this study is to evaluate the safety and efficacy of the GORE® 
HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder for the transcatheter 
closure of PFO. 
 
2.2. Study Design Overview 
The Gore REDUCE Clinical Study is a prospective, randomized, multinational, multicenter 
evaluation comparing antiplatelet medical management (control arm) to PFO closure plus 
antiplatelet medical management with the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder  (test arm) for the reduction of recurrent stroke or imaging-
confirmed TIA or new brain infarct in subjects with a PFO and history of cryptogenic stroke or 
imaging-confirmed TIA. 
 
A total of 664 eligible subjects will be randomized to either the test or control arm using a 2:1 
randomization scheme.  A maximum of eighty (80) investigational sites in the United States, 
Canada, and Europe will participate in the study with no per-site subject limit.  The anticipated 
accrual rate is approximately 10 subjects per month for a total accrual period of approximately 
60-66 months. 
 
Randomized subjects will be followed for up to five (5) years.  For the control arm, follow-up 
intervals will be calculated from the date of randomization.  For the test arm, follow-up intervals 
will be calculated from the date of the transcatheter closure procedure.  All subjects will 
receive follow-up evaluations at 1, 6, 12, 18, 24, 36, 48, and 60 months.  Test arm subjects will 
receive an additional follow-up evaluation at early post-procedure (within 4 to 72 hours 
following the transcatheter closure procedure).  
 
2.3. Primary Endpoints 
Co-Primary Endpoint 1 is freedom from a recurrent stroke or imaging-confirmed TIA through at 
least 24 months post-randomization.  For this study, a recurrent stroke or imaging-
confirmed TIA event is defined as the first occurrence, post-randomization, of one of the 
following: 
 
Clinical finding of ischemic stroke that may be associated with MRI evidence of a new 
relevant brain infarction.  For this study, an ischemic stroke is defined as a neurological 
deficit, presumed due to ischemia, persisting longer than 24 hours or until death. 


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 
Clinical finding of TIA that also has MRI evidence of a new relevant brain infarction.  For 
this study, a TIA is defined as a transient neurological deficit, presumed due to ischemia, 
persisting less than 24 hours. 
 
Clinical findings of stroke/TIA may include:  
 
Sudden numbness or weakness of the face, arm or leg (especially on one side of the 
body)  
 
Sudden confusion, trouble speaking or understanding speech  
 
Sudden trouble seeing in one or both eyes  
 
Sudden trouble walking, dizziness, loss of balance or coordination  
 
Sudden severe headache with no known cause  
 
Co-Primary Endpoint 1 will be calculated as the time from randomization to the first recurrent 
event.  Subjects free from a recurrent event will be censored at the date of last known contact. 
 
All deaths and suspected recurrent stroke/TIA events will be reviewed and adjudicated by a 
Clinical Events Committee (CEC).  In the event of subject death, all possible efforts will be 
made to obtain relevant records from the hospital or the subject’s primary care physician, 
including a death certificate or autopsy report, to determine the cause of death. 
Co-primary Endpoint 2 is the incidence of subjects with new brain infarct or stroke from 
screening through 24 months or last follow-up visit, whichever occurs first, hereinafter referred 
to as brain infarct. A responder is defined as any subject with at least one new T2 
hyperintense MRI lesion with diameter ≥ 3 mm from screening or clinical findings of ischemic 
stroke, through 24 months or last follow-up visit, whichever occurs first. It will be calculated as 
a subject-based binomial proportion. 
 
2.4. Secondary Endpoints 
Safety Endpoints will include the proportion of subjects who experience adverse events 
(AEs) that are determined to be related to device, procedure, and/or antiplatelet medical 
management.  This will include specific adverse events and groups of adverse events such as 
all-cause adverse events, device-related events, procedure-related events, antiplatelet 
medical therapy-related events, and any serious adverse events. 
 
The safety endpoints may also be analyzed using time-to-event methods to estimate the 
percentage of subjects free from the event at time points of interest, such as 30 days and 24 
months post-randomization (or post-procedure for the test arm). 
 
Efficacy Endpoints will evaluate the success of the device in achieving PFO closure in 
subjects randomized to the test arm.  PFO closure success will be measured by assessing the 
degree of residual right-to-left shunt after device implant.  Time points for the assessment of 
PFO closure include early post-procedure, 1 month, 12 months, and 24 months. 
 
Additional Secondary Endpoints will include: 
1. Clinical Success –  


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a. Test Arm - defined as the composite of Device Success, PFO closure, and absence of 
a recurrent stroke or imaging-confirmed TIA at 24 months post-procedure 
b. Control Arm - defined as the freedom from a recurrent stroke or imaging-confirmed 
TIA at 24 months post-randomization 
2. Overall Survival – defined as time from randomization to death from any cause or last 
known contact 
3. Time to any stroke/TIA – defined as time from randomization to first occurrence of stroke 
or TIA 
4. Device Success – defined as the proportion of device arm subjects with successful 
implant and retention of the device after procedure (test arm only) 
 
2.5. Primary Study Hypotheses 
This study is designed to test the null hypothesis that the hazard of a recurrent stroke or 
imaging-confirmed TIA in subjects treated with percutaneous PFO closure plus antiplatelet 
medical management is equal to or higher than subjects treated with antiplatelet medical 
management alone.  The alternative hypothesis is that the hazard of a recurrent 
stroke/imaging-confirmed TIA is lower in subjects treated with percutaneous PFO closure plus 
antiplatelet medical management compared to antiplatelet medical management alone.  In 
statistical terms:
  
t
all
for
t
HR
H
t
all
for
t
HR
H
C
T
A
C
T
O
0.1
)
(
:
0.1
)
(
:
/
/


 
where: 
HRT/C = hazard ratio comparing the test (T) arm (PFO closure) to the control (C) arm 
(antiplatelet medical management only). 
In addition, this study will test the null hypothesis that the incidence of brain infarct at 24 
months in subjects treated with percutaneous PFO closure plus antiplatelet medical 
management is equal to or higher than subjects treated with antiplatelet medical management 
alone. The alternative hypothesis is that the brain infarct incidence is lower in subjects treated 
with percutaneous PFO closure plus antiplatelet medical management compared to 
antiplatelet medical management alone. In statistical terms: 
𝐻0:  𝑃𝐶−𝑃𝑇≤0
𝐻1:  𝑃𝐶−𝑃𝑇> 0 
where: 
PC = true proportion of subjects with incident brain infarct in the control group 
PT = true proportion of subjects with incident brain infarct in the test group 
 
2.6. Sample Size Determination 
2.6.1. 
Sample Size Assumptions 
Based on literature available at the study’s initiation (see Section 1.0 - Introduction), 
the proportion of PFO patients free from a recurrent stroke or imaging-confirmed TIA 
at 24 months after initial, cryptogenic stroke or imaging-confirmed TIA is assumed to 
be approximately 92%, with a range of 86% to 94%.  Antiplatelet medical 
management plus PFO closure will be considered superior to antiplatelet medical 
management alone if there is at least a 55% reduction in the hazard of a recurrent 
stroke or imaging-confirmed TIA.  


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At the time this study was designed, Co-primary Endpoint 2 was considered a 
secondary endpoint and was not relevant to the sample size assumptions. 
2.6.2. 
Randomization and Enrollment  
Subjects will be randomized in a 2:1 allocation ratio with the greater proportion of 
subjects randomized to the test arm.  Enrollment of 120 to 140 subjects per year is 
anticipated, for a total enrollment period of 60-66 months (5 to 5.5 years).   
2.6.3. 
 
 
 
 
 
    
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7. Randomization Scheme 
Patients who meet the study eligibility criteria will be randomized to one of the two study 
treatment arms.  Randomization will be weighted 2:1 in favor of the test arm. 
 
2.8. Statistical Analysis of Primary Endpoints 
The primary endpoint analyses will be performed when the last subject enrolled completes 24 
months of follow-up.   
 
Co-primary Endpoint 1, freedom from a recurrent event, will be compared between treatment 
groups using an unadjusted log-rank test and presented using Kaplan-Meier methods. All 
follow-up data through 5 years will be included on subjects continuing follow-up past the 24-
month evaluation. As part of a simultaneous test with the brain infarct co-primary endpoint 
hypothesis a multiplicity-adjusted p-value for the hazard ratio test of 0.025 or less will be 
considered evidence to reject the freedom from recurrent event null hypothesis. 
 
The analysis sample will consist of randomized subjects with valid MRI core lab data at 
screening and an appropriate follow-up, where follow-up will be at 24 months or immediately 
following a recurrent event (suspected stroke or TIA), whichever occurs first, as well as 
randomized subjects who experience a confirmed recurrent event through 24 months 
regardless of MRI data status. Responders are subjects who show one or more new 
infarction(s) on MRI since screening or experience a confirmed recurrent event. 
Nonresponders are subjects who do not show new infarction on MRI since screening and do 
not experience a confirmed recurrent event. 
 
The primary analysis will be a two-sample comparison of the binomial proportion of subjects 
with brain infarct between the two treatment groups. Each binomial proportion will be 
calculated as the count of responders divided by the count of evaluable subjects (sum of the 
responder and nonresponder counts). 
The hypothesis will be tested using a two-sample binomial proportions test: 
𝑧=
𝑝𝐶−𝑝𝑇
√𝑝𝐶(1 −𝑝𝐶)
𝑛𝐶
+ 𝑝𝑇(1 −𝑝𝑇)
𝑛𝑇
  
where: 


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pC = observed brain infarct proportion in control group 
nC = number of evaluable subjects in control group 
pT = observed brain infarct proportion in test group 
nT = number of evaluable subjects in test group 
The test statistic z is assumed to have a standard Normal distribution. The significance level 
for this test will be set at a 1-sided  = 0.025 , but the p-value will be adjusted for multiplicity 
with the 1-sided  = 0.025 test performed simultaneously on the primary endpoint. Therefore, 
pC −pT > 0 and a multiplicity-adjusted p-value  0.025 will result in rejection of the null 
hypothesis in favor of the alternative hypothesis and a conclusion that the test treatment 
reduces the rate of brain infarct compared to the control treatment. The 1-sided multiplicity-
adjusted p-value and unadjusted 2-sided 95% confidence interval for the difference in 
proportions will be reported. 
 
2.9. Interim Analyses 
The original protocol specified that, in addition to standard study monitoring, an interim 
analysis will be performed after approximately 50% of the total expected recurrent stroke or 
imaging-confirmed TIA events have occurred. This milestone event had not occurred as of the 
completion of full enrollment in February 2015. Under the plan described herein, the original 
interim analysis plan no longer serves its purpose and is rescinded. 
A new interim analysis that does not involve any statistical hypothesis testing is anticipated to 
occur around April 2016. No analyses that would require alpha spending are planned for this 
interim analysis. 
 
2.10. Statistical Analysis of Secondary Endpoints 
The secondary endpoint analysis will be performed in conjunction with the primary endpoint 
analysis.  Statistical methods for testing multiple endpoints will be utilized in the comparison of 
secondary endpoints across test and control to preserve the overall Type I error rate. 
 
 
 
 
 
 
 
p 
 
 
 
 
 


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Based on the final analysis of correlation between the two endpoints and the unadjusted p-
values obtained from the two test statistics, the appropriate adjusted p-values will be compared 
to the overall 1-sided  = 0.025 for the experiment. 
2.12. Evaluation of Septal Occluder Device Poolability 
It is expected that shortly after approximately one-third of the subjects have been enrolled, the 
new study device (GORE® CARDIOFORM Septal Occluder ) will become available and will be 
used as the device of choice within the test arm of the study. As a regulatory requirement, an 
assessment of poolability will be conducted for the two study device subgroups in the test arm. 
The statistical plan for this assessment will consist of two stages: baseline homogeneity and 
primary outcome comparability. 
 
For baseline homogeneity, the two test device subgroups will be compared on the following six 
baseline demographic and predictor covariates: age, gender, qualifying cerebrovascular event, 
balloon-sized PFO diameter, PFO tunnel length, and presence of atrial septal aneurysm. 
These subgroup comparisons will use the two-sample t-test, chi-square test, or Fisher’s Exact 
test, depending on the distribution of the covariate. 
 
For primary outcome comparability, covariate-by-device interactions will be assessed using 
Cox proportional hazards regression models where main effects for device and the covariate 
and the covariate-by-device interaction term will be regressed on the 24-month freedom from 
recurrent stroke or imaging-confirmed TIA primary endpoint; this will be performed individually 
for each of the six baseline covariates. Statistically significant interactions will be assessed 


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graphically for the nature of the interaction (quantitative vs. qualitative). Qualitative interactions 
(difference in direction of device effect across levels of covariate) will suggest differences 
between the device subgroups, leading to analyses performed separately for each device 
subgroup. A similar approach will be used for brain infarct comparability, but using a logistic 
regression model for this binary endpoint. 
 
Finally, device subgroup and any baseline covariates deemed to be different between device 
subgroups will be included as main effects in a Cox regression model on the primary endpoint. 
If the device subgroup term is statistically significant and the observed hazard reduction (test 
vs. control) for either of the device subgroups is less than the hypothesized 55%, then the 
device subgroups will not be considered outcome comparable, leading to analyses performed 
separately for each device subgroup. A similar approach will be used for brain infarct 
comparability, but using a logistic regression model for this binary endpoint. 
 
A significance level of =0.15 will be used for these poolability tests, without correction for 
multiplicity. Since this evaluation plan calls for a minimum of 13 significance tests per 
endpoint, the overall Type-I error rate per endpoint for this analysis may exceed 1 − (1 − 
0.15)13 = 0.88. 
 


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3. 
Clinical Study Plan 
3.1. Ethical Considerations 
The clinical study will be conducted in accordance with the applicable national regulatory 
requirements, the US Investigational Device Exemption (IDE) regulations (21 CFR § 812) and 
the current European ISO standard, as required.  In addition, the clinical study will comply with 
the ethical principles of the Declaration of Helsinki.   
3.2. Study Initiation 
Initiation of the clinical study can begin following: 
 
FDA approval of the Investigational Device Exemption (IDE), and  
 
Sponsor receipt of notification of the investigational site Institutional Review Board (IRB) 
or Ethics Committee (EC) approval, and  
 
Sponsor’s receipt of an executed Clinical Study Agreement (CSA) or Clinical Trial Letter of 
Agreement (CTLA) for the investigational site.   
 
3.3. Subject Population 
Subjects will be enrolled at a maximum of eighty (80) investigational sites in the United States, 
Canada and Europe.  All potential subjects must have been diagnosed with cryptogenic stroke 
or imaging-confirmed TIA and the presence of a PFO and be at risk for recurrent stroke or TIA 
event. 
 
Eligible subjects will be randomized to a treatment arm in a 2:1 fashion (device-to-antiplatelet 
medical therapy).  This randomization will result in approximately 443 in the test (device) arm 
and 221 subjects in the control (antiplatelet medical therapy) arm. 
 
3.4. Inclusion/Exclusion Criteria 
3.4.1. 
General Inclusion Criteria 
The criteria listed below shall be used to determine whether a patient is eligible for 
entry into the trial.  The patient must meet all inclusion criteria to be enrolled in the 
study.  In other words, all inclusion criteria must be answered “yes” for the patient to 
be eligible for the study. 
1. 
Patient has had a cryptogenic, ischemic stroke, or transient ischemic attack 
(TIA), of presumed embolic etiology, verified by a neurologist within 180 days 
prior to randomization, meeting either criteria a or b: 
a) 
Patient has a diagnosis of ischemic stroke (clinical symptoms persisting 
≥24 hours).   
    OR 
b) 
Patient has a diagnosis of TIA (clinical symptoms persisting <24 hours) 
and has MRI evidence of infarction. For MRI-incompatible patients (i.e., 
patients that are claustrophobic and/or have implants that are 
contraindicated for MR) a CT scan of the brain will be accepted. 
2. 
Patient is diagnosed with a patent foramen ovale (PFO), confirmation of which is 
achieved by transesophageal echocardiography (TEE) with bubble study 
demonstrating spontaneous right-to-left shunting or right-to-left shunting during 
Valsalva maneuver. 


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3. 
There is an absence of an identifiable source of thromboembolism in the 
systemic arterial circulation. 
4. 
Patient is at least 18 years and less than 60 years of age (subjects cannot have 
reached their 60th birthday prior to randomization/enrollment). 
5. 
Patient has vascular imaging that rules out other potential sources of cerebral 
thromboembolism (e.g., dissection of the aorta or neck vessels, carotid stenosis 
> 50% and/or presence of ulcerated plaques, or intracranial stenosis > 50%). 
6. 
Patient has no evidence of hypercoagulable state, which requires 
anticoagulation therapy.  This determination will be based on the evaluation of, 
at a minimum: platelet count, Prothrombin Time (PT) or International Normalized 
Ratio (INR), Activated Partial Thromboplastin Time (aPTT), and 
Antiphospholipid Antibodies.  All test results are to be evaluated based on the 
laboratory normals established at the institution.  A thorough history of 
thromboembolic events in first degree family members must be obtained for all 
patients.  For patients who have a first degree family member with such an 
event prior to age 55, or whose family history is unknown, the following 
additional tests are required and must be interpreted as normal:  Factor V 
Leiden mutation, Prothrombin Gene G20210A mutation, protein C, protein S, 
and Antithrombin III.   
7. 
Patient is willing and capable of complying with the study protocol requirements, 
including the specified follow-up period, and can be contacted by telephone. 
8. 
Patient or patient’s legal representative (or person designated acceptable under 
local Ethics Committee requirements) is willing to provide written informed 
consent prior to enrollment in study. 
 
3.4.2. 
General Exclusion Criteria 
All exclusion criteria must be answered “no” for subject inclusion in the study.  
1. 
Patient has a life expectancy of less than one year. 
2. 
Patient is experiencing severe disability, defined as modified Rankin Scale 
(mRS) score greater than or equal to 3, at the time of randomization. 
3. 
Patient has neurological deficits not due to stroke that may affect the patient’s 
neurologic assessments. 
4. 
Patient has other potential source(s) of cardio-embolism, for example: atrial 
fibrillation (AFib) or atrial flutter (AFlu), prosthetic heart valve, severe native 
valve disease, left ventricular ejection fraction of <40%, severe ventricular wall 
motion abnormalities (akinesis, severe hypokinesis), intracardiac thrombus, 
mitral valve stenosis, prior cardiac surgery, other major congenital cardiac 
abnormality. 
5. 
Patient has had a prior myocardial infarction.  
6. 
Patient has uncontrolled diabetes mellitus at the time of randomization, in the 
opinion of the investigator. 
7. 
Patient has pulmonary hypertension (mean pulmonary artery pressure >25 
mmHg). 
8. 
Patient has uncontrolled systemic hypertension at the time of screening, in the 
opinion of the investigator.   
9. 
Patient presented with a lacunar stroke syndrome (e.g., small deep infarction 
<1.5 cm in diameter and/or a typical lacunar syndrome such as pure motor 
hemiparesis, pure sensory stroke, clumsy hand-dysarthria syndrome, or ataxic-
hemiparesis syndrome). 


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10. Patient has intracranial pathology that makes the patient inappropriate for study 
participation based on discretion of the Investigator (e.g., brain tumor other than 
meningioma, arterio-venous malformation (AVM) or cerebral hemorrhage, 
cerebral venous sinus thrombosis on CT or MRI, or cerebral aneurysm > 7 mm). 
11. Patient has active autoimmune disease (e.g., lupus erythematosus disseminata, 
rheumatoid arthritis, polyarteritis nodosa, primary cerebral vasculitis). 
12. Patient has active infection that cannot be treated successfully prior to 
randomization.  
13. Patient abuses alcohol and/or drugs [e.g., on average >5 units or drinks (60 
grams) of alcohol/day] or abuses alcohol and/or drugs in the opinion of the 
Investigator. 
14. Patient is pregnant, lactating, or intent on becoming pregnant through 24-
months after randomization. 
15. Patient has contraindication to study medications, including antiplatelet therapy. 
16. Patient requires chronic anticoagulation therapy that cannot be discontinued 
prior to randomization, in the opinion of the Investigator. Testing for 
prothrombotic disorders may be performed at the discretion of the treating 
physicians but is not required for this study.  
17. Patient is currently participating in another clinical device or drug trial that has 
not completed its primary endpoint or that will clinically confound the current 
study endpoints or does not permit subjects to participate in other studies.  
Typically, subjects that are involved in the long-term surveillance phase of a 
clinical study are eligible. 
18. Patient has other anatomic or co-morbid conditions that could, in the 
Investigator’s opinion, limit the patient’s ability to participate in the study or to 
comply with follow-up requirements, or impact the scientific soundness of the 
study results. 
19. Patient has a known sensitivity to contrast media that cannot be controlled 
adequately with pre-medication. 
20. Patient has had any major surgical procedure within 30 days preceding 
randomization. 
21. Patient plans to have a major elective surgical procedure within 30 days after 
randomization or within 30 days of a PFO closure procedure.  
22. Patient has the need for any concomitant procedure, based on the results of the 
screening evaluations, during the PFO closure procedure that may confound 
detection of device-related adverse events. 
23. In the opinion of the Investigator, patient has anatomic criteria identified during 
the screening evaluation and/or the screening transesophageal echocardiogram 
(TEE) that are unfavorable for successful placement of the GORE® HELEX® 
Septal Occluder / GORE® CARDIOFORM Septal Occluder  or the patient has 
contraindications for device placement, which may include: 
 
Inability to accommodate a 10 Fr delivery catheter 
 
The need for trans-septal puncture 
 
Requires placement of more than one device 
 
PFO estimated to be too large for successful device placement 
 
Device would impinge on cardiac structure(s) 
 
Anatomy would likely prevent discs from apposing the septal tissue.  
 
3.5. Screening Evaluation and Consent 


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Informed consent must be obtained prior to performing study-related screening tests or 
procedures that are not standard of care.   
 
Patients will be screened by a Neurologist Investigator or designee for initial study eligibility.  
Patients who meet the initial criteria for entry (i.e., previous cryptogenic stroke or imaging-
confirmed TIA and the presence of PFO with right-to-left shunting) will be informed of his/her 
potential eligibility.  An Investigator or designee will discuss the clinical study with the patient 
including risks, benefits, and required follow-up procedures before obtaining informed consent.  
(See Appendix F for the Informed Consent Form template.)   
 
The patient will be required to read and sign an Informed Consent Form prior to completing 
study-related tests and procedures.  A legal representative (or legal guardian or person 
designated acceptable under local Ethics Committee requirements) may provide consent if the 
patient is unable to do so.  Patients with a signed Informed Consent will be scheduled for 
screening evaluation.   
 
Patients who consent will complete the screening tests and procedures (e.g. vascular imaging, 
neurologic assessments, ECG, and blood tests) within 180 days of the qualifying stroke or TIA 
and prior to final determination of study entrance (e.g., meeting all inclusion and exclusion 
criteria) by the Investigator.   
 
The following will be included in the overall screening evaluation: 
 
Initial eligibility assessment, to include confirmation of  
o previous cryptogenic stroke or imaging-confirmed TIA  
 
All patients must have a brain MRI obtained for future comparison.   
 
For patients with a diagnosis of TIA, MRI must be positive for 
infarction. 
 
For patients with CT evidence of infarction a MRI must also be obtained as 
part of the baseline screening assessments. 
 
For MRI-incompatible patients only (i.e., patients that are 
claustrophobic and/or have metal implants that are contraindicated 
for MR) a CT scan of the brain will be accepted. 
o presence of a patent foramen ovale (PFO) with positive bubble study utilizing 
transesophageal echocardiography TEE demonstrating  spontaneous right-to-left 
shunting or right-to-left shunting during Valsalva maneuver 
o absence of left atrial appendage thrombus or other mural thrombus during the TEE 
 
Physical examination 
 
MRA, MRI, CTA, duplex color Doppler, carotid ultrasound,  transcranial Doppler (TCD), or 
conventional angiography of the head, neck, and aortic arch (aortic arch may also be 
evaluated by TEE) 
 
ECG  
 
Obtain patient demographics 
 
Record patient’s medical history 
 
Neurologic assessments performed by the Neurologist Investigator, or  designee, qualified 
to score NIHSS and modified Rankin Scales, to include all of the following 


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o Modified Rankin Scale (mRS) 
o National Institute of Health Stroke Scale (NIHSS), and 
o Supplemental neurologic examination (captures assessments not gathered by the 
NIHSS and should be performed by a Neurologist Investigator only) 
 
Blood pressure  
 
Laboratory Evaluations 
o Blood drawn for determination of hypercoagulable state by the Investigator, to 
include, but not limited to: 
 
Platelet count 
 
Prothrombin Time (PT) or International Normalized Ratio (INR) 
 
Activated Partial Thromboplastin Time (aPTT) 
 
Antiphospholipid Antibodies 
 
Additional testing for patients who have a first degree family member with a 
history of thromboembolic events prior to age 55, or whose family history is 
unknown: 
 
Factor V Leiden Mutation 
 
Prothrombin Gene G20210A Mutation 
 
Protein C 
 
Protein S 
 
Antithrombin III   
o Pregnancy test (if applicable) 
 
The MRI scan must include Fluid Attenuated Inversion Recovery (FLAIR) sequencing and 
diffusion-weighted images (transverse and coronal planes, with 5 mm or thinner section 
thicknesses recommended, and no gaps) of the brain to detect and record any evidence of 
clinical and/or silent lesions.  This MRI will serve as the screening image for later comparison 
with a follow-up image at 24 months or recurrent event, whichever occurs first.  For MRI-
incompatible patients (i.e., patients that are claustrophobic and/or have metal implants that are 
contraindicated for MR) a CT scan of the brain will be accepted.  An independent Core Lab will 
be utilized to compare all MRI and CT screening scans with recurrent event or 24-month scans 
for determination of endpoints.   
 
In addition, a vascular examination of the head, neck, and aortic arch must have been 
performed using one or more of the following diagnostic tools: magnetic resonance 
angiography (MRA), magnetic resonance imaging (MRI), computed tomography angiography 
(CTA), duplex color Doppler, carotid ultrasound, transcranial Doppler (TCD) ultrasound, and/or 
conventional angiography to rule out other potential sources of emboli in the systemic 
circulation.  Transesophageal echocardiography (TEE) may also be used for the evaluation of 
the aortic arch. 
 


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3.6. Screen Failures 
Patients who consent to participate in the study, but who are not randomized to treatment, or 
who withdraw consent prior to randomization will be considered screen failures and will not 
be followed in this study.  Screen failures will be entered in the Electronic Data Capture (EDC) 
system.   
 
3.7. Randomization and Enrollment 
Upon completion of screening tests and confirmation of study eligibility, consented patients will 
be randomized to a treatment arm.  Using the EDC database approved by the Sponsor, the 
patient will be assigned to a treatment arm in the study.  Patients will have a 2-in-3 chance of 
being randomized to the test (device) arm.   
 
Because of the inclusion criteria of prior cryptogenic stroke, patients may have already initiated 
antiplatelet medical therapy prior to randomization.  All patients will be instructed to continue 
antiplatelet medical therapy or begin antiplatelet medical therapy, according to the regimen 
prescribed in this protocol and upon instruction of their Neurologist Investigator.   
 
For all patients randomized, if the subject has already initiated antiplatelet medical therapy 
prior to randomization, treatment should continue based on the antiplatelet regimen prescribed 
in this protocol (see Section 3.9 – Initiation and Administration of Antiplatelet Therapy).  If 
antiplatelet medical therapy is not in progress or a regimen change is required, treatment 
should commence promptly (within 48 hours of randomization).   
 
Patients randomized to the test (device) arm must be treated (have a PFO closure attempt) 
within 90 days of randomization.   
 
Patients are considered “subjects” enrolled in the study following randomization to a 
treatment arm.  A patient is considered enrolled into the clinical study when: 
 
he/she signs the consent form, and 
 
he/she completes all required screening tests and evaluations, and 
 
he/she meets inclusion/exclusion criteria, and  
 
he/she is randomized to a treatment arm. 
 
3.8. Treatment Groups 
The Schedules of Events for each treatment group, both test and control arms, are presented 
in Table 1: Test Arm Schedule of Events and Table 2: Control Arm Schedule of Events. 


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Table 1: Test Arm Schedule of Events 
 
 
 
Procedure 
 
 
 
 
 
 
 
 
  
Screening 
 
Pre 
(within 
72 
hours) 
Procedure 
Early 
Post 
(4-72 
hours) 
Month 
1 
Month 
6 
 
Month 
12 
Month 
18 
Month 24 
/ 
Endpoint  
Event 
Month 
36 
and 
48 
Month 
60 
Unsched. 
Visit 
Demographics 
X 
RANDOMIZE 
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Physical Exam (BP, HR, 
height/weight) 
X 
  
  
X 
X 
X 
X 
X 
X 
o 
o 
o 
ECG 
X 
X 
  
X 
X 
X 
X 
X 
X 
o 
o 
o 
Brain MRI 
X  
  
  
  
  
  
  
  
X 
o 
o 
o 
Vascular Imaging of head, 
neck, and aortic arch 
X 
  
  
  
  
  
  
  
  
  
  
  
TEE with bubble study & 
Valsalva 
X  
  
X^ 
  
  
  
  
  
X 
o 
o 
o 
TTE with bubble study  
  
  
  
X 
X 
o 
X 
o 
  
o 
o 
o 
Fluoroscopy (required for Gore 
Septal  subjects ONLY) 
  
  
  
 o 
o 
o 
X 
o 
o 
o 
o 
o 
Neurological Assessments  
X 
X 
  
X 
X 
X 
X 
X 
X 
o 
o 
o 
Stroke-free Questionnaire 
  
  
  
  
  
  
  
  
  
X 
X 
o 
Blood work 
X 
o 
  
  
  
  
  
  
  
  
  
  
Hypercoaguable Blood work 
X* 
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Test 
X** 
o 
  
  
  
  
  
  
  
  
  
  
Antiplatelet study medication 
X 
X~ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-procedure Medication 
  
  
X 
X** 
  
  
  
  
  
  
  
  
  
Post-device Placement 
Medication 
  
  
  
  
X 
  
  
  
  
  
  
  
  
Concomitant Mediation 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* If SOC at site or if patient has a 1st degree family history of embolic event prior to age 55 
 
 
 
^ or ICE 
 
 
 
** If applicable 
 
 
 
 
 
 
 
 
 
o at discretion of investigator 
 
~ Start protocol-specific antiplatelet regimen within 48 hours of randomization 
 
 
 
 
 
 
 
 


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Table 2: Control Arm Schedule of Events 
  
Screening 
 
Month 
1 
Month 
6 
Month 
12 
Month 
18 
Month 24 / 
Endpoint  
Event  
Month 
36 and 
48 
Month 
60 
Unscheduled 
Visit 
Demographics 
X 
RANDOMIZE 
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
Physical Exam (BP, HR, 
height/weight) 
X 
X 
X 
X 
X 
X 
o 
o 
o 
ECG 
X 
X 
X 
X 
X 
X 
o 
o 
o 
Brain MRI 
X  
  
  
  
  
X 
o 
o 
o 
Vascular Imaging of head, 
neck, and aortic arch 
X 
  
  
  
  
  
  
  
  
TEE with bubble study & 
Valsalva 
X  
  
  
  
  
  
  
  
  
Neurological Assessments 
X 
X 
X 
X 
X 
X 
o 
o 
o 
Stroke-free Questionnaire 
  
  
  
  
  
  
X 
X 
o 
Blood work 
X 
  
  
  
  
  
  
  
  
Hypercoaguable Blood work 
X* 
  
  
  
  
  
  
  
  
Pregnancy Test 
X** 
  
  
  
  
  
  
  
  
Antiplatelet Study Medication 
X 
X~ 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* If SOC at site or if patient has a 1st degree family history of embolic event prior to age 55 
 
 
 
 
** If applicable 
 
 
 
 
 
 
 
 
 
 
~ Start protocol-specific antiplatelet regimen within 48 hours of randomization 
 
 
 
 
 
o at discretion of investigator 
 
 
 
 
 
 
 
 
 
 
 


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3.9. Initiation and Administration of Antiplatelet Therapy for All Subjects 
Investigators will prescribe the same or similar antiplatelet medical therapy regimens for all 
subjects, test and control, participating in the study at their site, based on their best medical 
judgment.   
 
All subjects will receive an antiplatelet therapy regimen throughout the course of the study, 
whether randomized to the test (device plus antiplatelet medical therapy) arm or control 
(antiplatelet medical therapy alone) arm.  Investigators will choose one of the options listed 
below. Use of more than one of the options below is not permitted according to this protocol:  
 
Aspirin alone.  A dosage between 75 - 325 mg once daily. 
 
Aggrenox™ or generic equivalent.  A total daily dosage of 50-100 mg of aspirin and 
225-400 mg of dipyridamole.  
 
Clopidogrel (Plavix®) or generic equivalent.  A dosage of 75 mg once daily. 
 
All subjects will be maintained on one of these antiplatelet medication options, as prescribed, 
through study completion.   
 
If applicable, subjects should be instructed to continue taking antihypertensive medications to 
minimize hypertension and fluctuations in blood pressure.   
 
If for any reason a subject is noncompliant with the antiplatelet therapy, or must change 
antiplatelet medications, change medical therapy, or can no longer tolerate antiplatelet 
medication, record the reason on the appropriate CRF and continue to follow all subjects per 
protocol. 
 
3.10. PFO Closure  
3.10.1. Pre-Procedure Evaluation – Within 72 hours of PFO Closure  
Within 72 hours prior to the transcatheter PFO closure procedure, a neurologic 
examination will be performed to assess the subject’s neurological status.   
 
The following assessments will be performed within 72 hours prior to the PFO-closure 
procedure (pre-procedure): 
 
NIHSS, supplemental neurologic examination, and modified Rankin Scale 
 
Antiplatelet study medication and pre-medication 
 
Concomitant medications  
 
ECG  
 
Pregnancy test (if applicable) 
 
3.10.2. Subject Preparation 
If applicable, subjects should be instructed to continue taking antihypertensive 
medications to minimize hypertension and fluctuations in blood pressure.   
3.10.3. Pre-medication  


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To minimize the risk of neurological embolic events related to thrombosis during the 
transcatheter procedure, subjects should remain on the antiplatelet medical therapy 
regime chosen by the investigator at randomization until time of scheduled procedure.  
Pre-procedural antiplatelet therapy is recommended per the institutional standard of 
care or physician discretion.   
 
3.10.4. Procedure 
Subjects will undergo percutaneous transcatheter PFO closure with the GORE® 
HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  (or alternative 
closure method if closure with the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder  cannot be achieved).  The procedure starts upon 
venous cannulation and the procedure ends upon removal of the final catheter.  
Procedure start and stop times will be recorded for this study. 
 
Anesthesia times, whether general anesthesia or conscious sedation, and 
fluoroscopy times will be recorded during the procedure.  Anesthesia starts when the 
subject is intubated and stops when the subject is extubated.  Sedation starts at the 
time of intravenous (IV) administration and stops when the subject becomes 
responsive (or termination of subject monitoring).  Fluoroscopy time is the total 
fluoroscopy exposure time recorded during the procedure. 
 
The Investigator should follow the Instructions for Use (IFU) of the GORE® HELEX® 
Septal Occluder / GORE® CARDIOFORM Septal Occluder  (see Appendix E: 
Instructions for Use) when performing this procedure.  (Note: Protamine is not to be 
given to reverse heparin).   
Subjects who have a delivery attempt with the GORE® HELEX® Septal Occluder /  
GORE® CARDIOFORM Septal Occluder  but whose PFO cannot be closed with the 
device (e.g., closed with an alternative occluder device, surgery, or no closure) will be 
considered technical failures.  Subjects who are technical failures will remain in the 
study and should be followed per the protocol based on the original treatment 
assignment received (reference Section 3.16 Treatment Changes Post-
Randomization). 
 
3.10.5. Post-Device Placement Echocardiogram 
Post-device-placement echocardiograms [TEE or intracardiac echocardiography 
(ICE)] should be performed in the catheterization laboratory during the original 
procedure and in accordance with the Echocardiographic Core Laboratory (Echo 
Core Lab) guidelines to check for complications and possible residual shunting.  
Following device placement, the Investigator should evaluate the subject for the 
presence of any residual shunting using bubble contrast. 
 


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3.10.6. Access Site Management 
Closure of the femoral venous puncture site should be performed per hospital 
standards.  Access site hemostasis may be achieved by manual compression, or by 
utilizing alternative methods, such as a suture closure device.  
 
3.10.7. Post-Procedural Care 
Subjects will be monitored in the recovery room (per the investigational site’s 
standard post-treatment procedures) until stable. 
 
Subjects are to be provided with Clopidogrel (Plavix), 75 mg daily for three days post-
procedure. No additional antiplatelet therapy should be provided during this time 
period. Subjects should continue their prescribed antiplatelet regimen, as specified in 
section 3.9, through at least 24 months post-randomization.  Subjects will be 
encouraged to stay on their prescribed medication throughout the five (5) year follow-
up period.   
 
Antibiotic therapy may be administered at the discretion of the Investigator. 
 
3.11. Early Post-procedure Evaluations – 4-72 Hours Post PFO Closure 
Prior to leaving the hospital, typically within 4 to 72 hours after treatment, test arm subjects will 
be evaluated for concomitant medications, adverse events (AEs), and device-related or 
procedure-related events.  The following evaluations will be performed at the early post-
procedure visit: 
 
Physical examination 
 
ECG 
 
Transthoracic echocardiogram (TTE) with bubble study 
 
Fluoroscopy examination without contrast may be performed at the discretion of the 
Investigator.   
 
NIHSS, supplemental neurologic examination, and modified Rankin Scale  
 
Antiplatelet study medication 
 
Concomitant medications 
 
3.12. Follow-up Evaluations – Test Arm 
The follow-up schedule for enrolled test arm subjects is presented in Table 3.  All test subjects 
will be required to return for regular follow-up visits with their Neurologist Investigator 
through 24 months (see Table 4: Follow-Up Contact Requirements).   
 
Table 3: Test Arm Follow-up Schedule 
Subject Population 
Follow-up Schedule 
Subjects Randomized to Test Arm 
and who have a: 
 
Successful GORE® HELEX® Septal 
Occluder / GORE® CARDIOFORM 
Septal Occluder  implant 
Follow-up at Months 1, 6, 12, 18, 24, 36, 48, and 60 post-
procedure 


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Subject Population 
Follow-up Schedule 
Successful alternative transcatheter 
occluder device implant 
Follow-up at Months 1, 6, 12, 18, 24, 36, 48, and 60 post-
procedure 
Subjects with no occluder implanted 
Follow-up at Months 1, 6, 12, 18, 24, 36, 48, and 60 post-
procedure 
Subjects with surgical PFO closure 
Follow-up at Months 1, 6, 12, 18, 24, 36, 48, and 60 post-
procedure 
 
Table 4:  Test Arm Follow-up Contact Requirements 
Interval 
Contact 
Month 1 
Neurology, Cardiology 
Month 6 
Neurology, Cardiology** 
Month 12 
Neurology, Cardiology 
Month 18 
Neurology, Cardiology** 
Month 24 
Neurology, Cardiology 
Year 3 
Neurology (phone), Cardiology** 
Year 4 
Neurology (phone), Cardiology** 
Year 5 
Neurology (phone), Cardiology** 
** Cardiology Visit– may be scheduled at the discretion of an Investigator 
 
All test arm subjects will be evaluated at 24 months by MRI for changes in brain lesions.  Test 
arm subjects also will be evaluated by TEE for residual leak status at 24 months. 
 
In addition, all test arm subjects will then be followed through five (5) years post-procedure or 
until recurrent stroke/imaging-confirmed TIA, whichever occurs first.  Follow-up, occurring 
annually during Years 3, 4, and 5, will be conducted by telephone.  The Investigator may 
request that a subject schedule an office appointment with his/her Neurologist or Cardiologist 
Investigator at any time the Investigator deems necessary. 
 
An MRI scan of the brain with Fluid Attenuated Inversion Recovery (FLAIR) sequencing 
and diffusion-weighted images (transverse and coronal planes, with 5 mm or thinner sections 
recommended, and no gaps) is required for all subjects following the clinical diagnosis of a 
stroke or TIA.  Additionally, subjects who have not experienced a recurrent stroke or imaging-
confirmed TIA will complete the MRI evaluation at the 24-month follow-up visit.  This image will 
be evaluated by the MRI Core Lab and compared with the screening image.  Subjects who are 
free from stroke or imaging-confirmed TIA at the 24-month follow-up visit but have a 
subsequent clinical diagnosis of stroke or TIA through five years should have an MRI for 
imaging-confirmation of the event. 
 
At each Neurology follow-up visit through 24 months (see Table 1: Test Arm Schedule of 
Events), all subjects will undergo: 
 
Physical examination  
 
ECG 
 
NIH Stroke Scale, supplemental neurologic examination, and modified Rankin Scale 
(mRS) 
 
MRI – required for all subjects at 24 months 
 
Antiplatelet study medication  


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 
Concomitant medications  
 
Adverse events (device- or medical therapy-related events as applicable, see Appendix 
J: Site Requirements for Adverse Event Reporting.)   
 
All test arm subjects will be asked to return for a follow-up visit with their Cardiologist 
Investigator at select intervals (see Table 4: Test Arm Follow-up Contact Requirements).   
 
At Cardiology follow-up visits through 24 months, test arm subjects will undergo:  
 
TTE – with bubble study.  If TTE is inconclusive, or if otherwise indicated, TEE and/or 
angiography must be performed.   
 
TEE – with bubble study.  Required for all subjects at 24 months 
 
Fluoroscopy examination without contrast is required at the 12-month follow-up visit for all 
test arm subjects implanted with the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder .  Fluoroscopy examination may be performed at any 
other interval at the discretion of the Investigator.   
 
The Investigator will perform follow-up evaluations of each subject.  A complete schedule of 
subject follow-up events is presented in Table 1: Test Arm Schedule of Events.  The 
Investigator will remain responsible for subject follow-up and data integrity.  The Investigator 
may request that a subject schedule a visit for additional follow-up at any time they deem 
necessary. 
 
3.13. Follow-up Time Allowances – Test Arm 
Follow-up visits will be scheduled at appointed times after the date of treatment.  The Sponsor 
recognizes that subjects may not be able to return for follow-up visits on the exact date 
required.  Thus, periods during which each visit is allowed, (i.e., “window”), are described 
below (Table 5). 
 
Table 5.  Schedule of Test Arm Subject Follow-up and Associated Visit Windows 
Follow-up 
Visit Window 
Time Interval During which Visit Must Occur 
Early Post-
procedure 
Typically 4-72 hours post PFO closure procedure, but must be 
completed prior to leaving the hospital, out-patient facility, or 
surgical-center 
1 month 
1 month ± 2 weeks post PFO closure procedure 
6 months 
6 months ± 1 month post PFO closure procedure 
12 months 
12 months ± 2 months post PFO closure procedure 
18 months 
18 months ± 2 months post PFO closure procedure 
24 months 
24 months ± 2 months post PFO closure procedure 
Year 3 
36 months ± 2 months post PFO closure procedure 
Year 4 
48 months ± 2 months post PFO closure procedure 
Year 5 
60 months ± 4 months post PFO closure procedure 
 


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3.14. Follow-up Evaluations – Control Arm 
Subjects randomized to the control arm will be followed by the Neurologist at months 1, 6, 12, 
18, 24, 36, 48, and 60.  
 
All control arm subjects will be required to return for regular follow-up visits through 24 months 
with their Neurologist Investigator (refer to Table 6: Control Arm Follow-up Contact 
Requirements).  
 
Table 6: Control Arm Follow-up Contact Requirements 
Interval 
Contact 
Month 1 
Neurology 
Month 6 
Neurology 
Month 12 
Neurology 
Month 18 
Neurology 
Month 24 
Neurology 
Year 3 
Neurology (phone) 
Year 4 
Neurology (phone) 
Year 5 
Neurology (phone) 
 
All control arm subjects will be evaluated at 24 months by MRI for changes in brain lesions.   
 
All control arm subjects will be followed through five (5) years post-randomization or until 
recurrent stroke/imaging-confirmed TIA, whichever occurs first.  Follow-up will be conducted 
annually during Years 3, 4, and 5.  The Neurologist Investigator may request that a subject 
schedule an office appointment with his/her Neurologist or Cardiologist Investigator at any time 
the Investigator deems necessary. 
 
An MRI scan of the brain with Fluid Attenuated Inversion Recovery (FLAIR) sequencing 
and diffusion-weighted images (transverse and coronal planes, with 5 mm thinner sections 
recommended, and no gaps) is required of all subjects following the clinical diagnosis of 
stroke or TIA.  Additionally, subjects who have not experienced a recurrent stroke or TIA will 
complete the MRI evaluation at the 24-month follow-up visit.  This image will be evaluated by 
the MRI Core Lab and compared with the screening image.  Subjects who are free from stroke 
or imaging-confirmed TIA at the 24-month follow-up visit but have a subsequent clinical 
diagnosis of stroke or TIA through five years should have an MRI for imaging-confirmation of 
the event. 
 
At each Neurology follow-up visit through 24 months (see Table 2: Control Arm Schedule of 
Events), all subjects will undergo: 
 
Physical examination  
 
ECG 
 
NIH Stroke Scale, supplemental neurologic examination, and modified Rankin Scale 
(mRS) 
 
MRI – required for all subjects at 24 months 
 
Antiplatelet study medication compliance 
 
Concomitant medications  


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 
Adverse events (medical therapy-related events as applicable, see Appendix J: Site 
Requirements for Adverse Event Reporting.)   
 
The Investigator will perform follow-up evaluations of each subject.  A complete schedule of 
subject follow-up events is presented in Table 2: Control Arm Schedule of Events.  The 
Investigator will remain responsible for subject follow-up and data integrity.  The Investigator 
may request that a subject schedule a visit for additional follow-up at any time they deem 
necessary. 
3.15. Follow-up Time Allowances – Control Arm 
Follow-up visits will be scheduled at appointed times after the date of treatment.  The Sponsor 
recognizes that subjects may not be able to return for follow-up visits on the exact date 
required.  Thus, periods during which each visit is allowed, (i.e., “windows”), are described 
below (Table 7). 
 
Table 7.  Schedule of Control Arm Subject Follow-up and Visit Windows 
Follow-up Visit Window 
Time Interval During which Visit Must Occur 
1 month 
1 month ± 2 weeks post randomization 
6 months 
6 months ± 1 month post randomization 
12 months 
12 months ± 2 months post randomization 
18 months 
18 months ± 2 months post randomization 
24 months 
24 months ± 2 months post randomization 
Year 3 
36 months ± 2 months post randomization 
Year 4 
48 months ± 2 months post randomization 
Year 5 
60 months ± 4 months post randomization 
 
3.16. Treatment Changes Post-Randomization 
If a subject is randomized to a treatment arm, but receives the alternative treatment during the 
course of the study, every effort should be made to follow those subjects according to their 
original treatment arm schedule. 
 
If a subject in the control arm receives PFO closure during the course of the study the 
Intervention CRF should be completed to document the procedure.  Additional follow-up visits 
may be conducted per standard of care at the given investigational site. 
 
3.17. Study Failures 
All enrolled subjects will be followed per protocol until recurrent stroke or imaging-confirmed 
TIA or through 24 months, whichever occurs first, for the endpoint evaluation and through five 
(5) years for long-term follow-up.  Any randomized subject who experiences recurrent stroke 
or imaging-confirmed TIA at any time, whether in the test (device) or control (medical therapy) 
arms, will be considered a study failure.  Confirmation of the embolic event by MRI is 
required.  No further follow-up will be required beyond confirmation of the embolic event. 


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3.18. Subject Withdrawal or Discontinuation from the Clinical Study 
The Investigator should encourage subjects to return for the required follow-up visits.  These 
measures are important as the clinical study objectives may not be realized if a large number 
of subjects are lost to follow-up (LTF).   
 
A subject may withdraw from the clinical study at any time and should notify the Investigator in 
this event.  If a subject refuses to return for the follow-up visits, the Investigator will attempt to 
obtain at least vital status and complete the Stroke-Free Questionnaire.  If the Stroke-Free 
Questionnaire suggests a possible event, then records and images will be requested for 
adjudication in the same manner as all suspected endpoints.  In the event of subject death, a 
death certificate or autopsy report should be obtained to confirm cause of death and reported 
on the Subject Completion / Discontinuation Form. 
 
A subject will be considered lost to follow-up and discontinued from the study when both of the 
following criteria have been met: the subject has missed two consecutive follow-up visits, and 
the Investigator has documented three failed attempts to contact the subject.  One of the three 
documented attempts must include a certified (traceable) letter.  The Investigator will ensure 
that the appropriate CRF (Study Completion / Discontinuation Form) is completed, 
documenting the subject’s discontinuation (i.e., lost to follow-up) from the clinical study.  If a 
subject is considered lost to follow-up, the Investigator will attempt to obtain vital status and 
complete the Stroke-Free Questionnaire annually from the point of last contact.  Any 
information collected after the time of discontinuation should be captured in the study 
database under an Unscheduled visit.   
 
The Investigator may also withdraw the subject from the clinical study at any time based on 
the Investigator’s medical judgment.   
 
The study Monitor will ensure that subject withdrawals are documented properly, discussed 
with the Investigator, and reported to the Sponsor (ISO 14155 – 1:2003, Section 9.1(j.).   
 
3.19. Imaging Analysis 
3.19.1. MRI / CT 
For all subjects, an independent MRI Core Laboratory will compare the screening 
MRI with the 24 month follow-up or recurrent event MRI for a determination of study 
imaging endpoints.   
 
Variables assessed by the MRI Core Laboratory will include: 
 
Screening lesion evaluation 
 
Change in focal lesion on follow-up scan 
 
MRI Guidelines are provided for reference for the MRI technician and MRI Core 
Laboratory at Appendix H: MRI Imaging Guidelines. 
 


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3.19.2. Echocardiography 
An independent Echocardiography Core Laboratory will conduct analyses of pre-
procedure/pre-treatment (required screening) echocardiography data for all (test and 
control) subjects, and procedure and follow-up echocardiography data for test 
(device) subjects only.   
 
Variables assessed by the Echocardiography Core Laboratory will include: 
 
Residual shunting, as determined by TEE with Valsalva maneuver and contrast 
bubble study  
 
Residual shunting, as determined by TTE ordered by an Investigator 
 
Thrombus on device 
 
Residual shunt will be evaluated based on maximum number of agitated saline or 
microbubble particles seen in the left atrial chamber in any single frame during first 
three cardiac cycles, during a resting state or during/after Valsalva maneuver.  The 
scale for measuring the significance of the shunt is as follows: 
 
 
   
Occluded = 0 particles 
Trivial or small = 1 – 5 particles 
Moderate = 6 – 25 particles 
Large = > 25 particles 
 
Echocardiography Guidelines are provided for reference by the echocardiographer 
and Echocardiography Core Laboratory at Appendix D – Echocardiography 
Imaging Guidelines.  
De-identified and appropriately labeled media (e.g., CDs, DICOM, videotape, or other 
format) of the required imaging evaluations should be forwarded to the appropriate 
Core Lab along with any technical worksheets and/or transmittal forms at the 
designated intervals (refer to Table 1: Test Arm Schedule of Events and Table 2: 
Control Arm Schedule of Events).   
 
All media should be forwarded to the Core Lab, in DICOM format, as soon as 
possible, but no later than 10 days following the Screening and Procedure 
Evaluations and no later than 30 days following all subsequent follow-up visits.   
 
3.20. Data Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be comprised of an 
interdisciplinary team of five individuals, four physicians and a biostatistician, who are not 
directly involved in the conduct of the study.   
 
The team shall include, at minimum, one stroke neurologist, one interventional cardiologist, 
and a biostatistician to assist with formulation of stopping rules and direction of interim 
analyses.   
 


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The members may be compensated for their participation in the DSMB, including 
reimbursement for reasonable travel expenses to attend meetings.  Members will not have any 
business or financial affiliation with the study sponsor, the core laboratories, or the study 
investigators.  
 
The DSMB is responsible for conducting periodic reviews of aggregate data on a prescribed 
schedule.  Based on the safety data, the DSMB will make recommendations to the Sponsor.  
Recommendations may include modifying the study, stopping the study, or continuing the 
study.  All final decisions regarding study modifications or study continuation, however, will 
rest with the Sponsor.  
 
3.21. Clinical Events Committee 
The independent Clinical Events Committee (CEC) will be comprised of at least three 
physicians who are not participating in the study and do not have any conflicts of interest with 
the study Sponsor.  The CEC will include representatives from at least three of the following 
specialties/disciplines: 
 
stroke neurology 
 
interventional cardiology 
 
echocardiography 
 
neuro-radiology 
 
Input from other disciplines shall be solicited, if required.  The members may be compensated 
for their involvement in the CEC including reimbursement for reasonable travel expenses to 
attend meetings.  
 
The committee will be responsible for: 
 
Review definitions of clinical endpoints in the study in conjunction with the Sponsor. 
 
Review and adjudication of adverse events that have the potential to be study endpoint 
events including death, stroke, or TIA; AND 
 
Subsequent classification of these adverse events as related to the study device, 
procedure, or medications. 
 


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4. 
Adverse Events 
This study will adhere to current ISO requirements and 21 CFR 812, regarding the definitions and 
reporting of adverse events (AEs).  Adverse events (AEs) are defined as any untoward medical 
occurrence in a subject.   
 
An adverse device effect (ADE) is an untoward and unintended response to a medical device.  
This includes ADEs resulting from insufficiencies or inadequacies in the Instructions for Use (IFU), 
the deployment of the device, or any response that is a result of a user error (in accordance with the 
current ISO standard) 
 
The severity of an AE or ADE will be rated as follows: 
 
Mild – subject is aware of event or symptom, but event/symptom is easily tolerated. 
 
Moderate -  subject experiences sufficient discomfort to interfere with or reduce their usual level 
of activity 
 
Severe – significant impairment of functioning; subject is unable to carry out usual activities  
 
Adverse events or adverse device effects are anticipated, but usually are not expected (i.e., not 
previously reported in relation to the study device; expected events are those that are referred to in 
the protocol, Investigator’s Brochure, consent form, or IFU when applicable). 
 
All AEs will be recorded on the appropriate internet case report form (CRF) and documented in the 
subject’s permanent medical record.  The CRFs to be used for data collection during the study are in 
Appendix B: Case Report Forms.  All AEs will be reported to the FDA, the IRBs and ECs, 
Competent Authorities per local requirements, participating Investigators, and/or safety monitoring 
boards via annual study progress updates.  (in accordance with the current ISO standard) 
 
4.1. Anticipated Adverse Events 
Study complications, whether device-, procedure-, or antiplatelet medical therapy-related, that 
may be anticipated in subjects undergoing PFO closure with the GORE® HELEX® Septal 
Occluder / GORE® CARDIOFORM Septal Occluder , another occluder, or in subjects being 
treated with study-specified medications (i.e., antiplatelets) are listed below and under Section 
6.0, Risk Analysis.  These complications are considered anticipated AEs. 
 
Access site complications 
o Emboli (air, tissue, or thrombotic emboli)  
o Groin hematoma, with or without surgical repair  
o Infection and pain at insertion site  
o Pseudoaneurysm, femoral  
o Retro-peritoneal bleeding 
o Thrombosis at access puncture site or remote site  
o Venous occlusion  
o Vessel dissection, perforation, or rupture  


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 
Allergic response 
o To a study medication 
o To nickel in the Occluder 
o To contrast media 
o To latex 
 
Arrhythmia  
 
Bleeding, hemorrhage, or bruising 
o Related to study (antiplatelet) medications  
o With or without transfusion 
 
Cerebral hemorrhage  
 
Chest pain or palpitations 
 
Death  
 
Effusion, pericardial or pleural, with or without drainage 
 
Headache, including  
o Migraine, with or without aura 
o Pain in the head or neck 
o Severe unilateral headache  
 
Hospitalization (in-patient) required to treat a complication 
 
Hypertension 
 
Hypotension  
 
Infection, with or without fever 
o Bacteremia 
o Septicemia 
 
Ischemic events 
o Cerebral ischemia  
o Cerebrovascular accident (CVA) 
o Myocardial infarction (MI) 
o Stroke  
o TIA with or without motor weakness  
 
Medications, study-related  
o Allergic responses  
 
Rash, itching, or papules 
o Excessive bruising 
o Gastro-intestinal problems 
 
stomach ache 
 
ulcer 
 
diarrhea 


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 
Occluder-related issues 
o Component detachment 
o Damage to delivery system or occluder during prep or delivery 
o Embolization 
o Erosion of cardiac tissue 
o Malposition  
o Migration  
o Perforation of a cardiac structure 
o Removal of the device post-implant 
o Thrombosis  
o Wire frame fracture  
 
Procedure-related issues 
o Brachial plexus stretch injury 
o Back pain resulting from lengthy procedures 
o Excessive radiation exposure during imaging  
o Sore throat (intubation / extubation / probe) 
 
Prolonged medication required to treat a complication 
 
Seizure   
 
The Investigator at each investigative site is ultimately responsible for reporting AEs to the 
Sponsor.  The Investigator is required to complete the appropriate CRF to report the 
occurrence of AEs.  The CRFs for a given visit must list all AEs that have occurred since the 
last documented visit.  
 
4.2. Serious Adverse Device Effects / Serious Adverse Events 
A SERIOUS adverse event (SAE) is an event that: 
 
Led to death,   
 
Led to a serious deterioration in the health of the subject that: 
o Resulted in a life-threatening illness or injury,  
o Resulted in a permanent impairment of a body structure or a body function 
o Resulted in in-patient hospitalization or prolongation of existing hospitalization 
o Resulted in a medical or surgical intervention to prevent permanent impairment of a 
body structure or a body function, or led to: 
 
Led to fetal distress, fetal death, or a congenital anomaly or birth defect. 
 
Any serious adverse event (SAE), whether considered to be related to the investigational 
product or not, whether foreseen or unforeseen, anticipated or unanticipated, must be reported 
by the Investigator to the Sponsor, the CRO (European sites only), the IRB or EC, and 
Competent Authorities if applicable.  A list of SAEs and their definitions are provided in 
Appendix I: Reportable Adverse Event Definitions to assist Investigators in determining 
when an adverse event becomes serious.  The European countries may require reporting 
these events as soon as possible, but in no event later than 10 working days after the 
Investigator first learns of the event.   


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A SERIOUS adverse device effect (SADE) is an effect that results in any of the 
consequences of characteristics of a SAE, or that might have led to death, or a serious 
deterioration in the health of a subject or any other person if suitable action had not been 
taken, or intervention had not been made, or if circumstances had been less opportune.  
These events must be reported by the Investigator to the Sponsor, the CRO (European sites 
only), the IRB or EC, and Competent Authorities if applicable, as soon as possible, but in no 
event later than 10 working days after the Investigator first learns of the event. 
 
Unanticipated adverse device effects (UADEs) means 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 previous identified in nature, severity, or degree of 
incidence in the Investigational Plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR § 
812.3(s) and 150(a)(1)).  These events are encompassed by the definition of serious adverse 
events (SAEs) and must be reported by the Investigator to the Sponsor, the CRO (European 
sites only), the IRB or EC, and Competent Authorities if applicable, as soon as possible, but 
in no event later than 10 working days after the Investigator first learns of the event. 
 
If applicable to local requirements of the reviewing IRB or EC, the Investigator must submit to 
the Sponsor and to the IRB or EC a report of any SADE, UADEs, and SAEs that occur during 
the clinical study, no later than 10 working days after the Investigator first learns of the 
event.  All SADEs and UADEs must be documented by the Investigator, including the date of 
onset, a complete description of the event, possible reason(s) for the event, severity, duration, 
actions taken and outcome.  Copies of all supporting documents should accompany the 
appropriate CRF, where applicable.   
 
Emergency contact information for the United States and European sites for the required 
reporting of SAEs/SADEs/UADEs can be found in Appendix J: Site Requirements for 
Adverse Event Reporting. 
 
The Sponsor will immediately conduct an evaluation of any event determined to be 
unanticipated (i.e., UADE) and report the results of the evaluation to the FDA, all IRBs and 
ECs, and participating Investigators within 10 working days after the Sponsor first receives 
notice of the effect by the investigative site (§812.46(b), 812.150(b)(1))   
 
If the event or effect is determined to present unreasonable risk to subjects, the Sponsor shall 
terminate all investigations or part of investigations presenting that risk as soon as possible, 
but no later than 5 working days after making the determination and no later than 15 days 
after first learning of the effect (21 CFR § 812.46(2). 
 


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5. 
Data Collection and Evaluation 
Data gathered during the course of the study will be documented through Electronic Data Capture 
(EDC) on internet case report forms (CRFs).  Missing, incomplete or inconsistent data will be 
requested from the Investigator and appropriate corrections will be made.  An audit trail will identify 
all changes and corrections to the electronic data.  The CRF completion schedule and submission is 
presented in Table 8 – CRF Completion Schedule. 
 
If necessary, sites will be provided with paper replicas of the CRFs for reference or for use as source 
documentation.  If for any reason a site is not able to enter data into the EDC system or the system 
is unavailable, paper case report forms are to be completed in lieu of data entry into the EDC 
system. 
 
All devices opened at the initial treatment or for a re-intervention procedure will be documented on 
the Device Accountability CRF, as well as the Device Accountability Log.   
 
Table 8: CRF Completion Schedule  
Interval 
CRFs to Submit 
Pre-Screening 
Subject Information (Form 0) 
Screening (Within 180 days prior 
to Randomization) 
 
Inclusion/Exclusion  (Form 1) 
Patient Demographics  (Form 2)  
Patient Medical History  (Form 3)  
Screening Evaluation (Form 4) 
MRI Brain Evaluation  (Form 5) 
Vascular Imaging Evaluation (Form 6) 
Echocardiographic Evaluation (Form 7) 
NIHSS Assessment (Form 8) 
Supplemental and Modified Rankin Scale Neurological Assessments  
(Form 9)  
Antiplatelet Study Medications (Form 13) 
Concomitant Medications  (Form 14) 
Randomization 
Patient Randomization (Form 10) 
Pre-Procedure (required for 
Device Arm only), within three 
days prior to procedure) 
Antiplatelet Study Medications (Form 13) 
Concomitant Medications  (Form 14) 
NIHSS and Neuro Assessments (Forms 7 and 8) 
Pre-Procedure Electrocardiogram (ECG) (Form 25) 
Procedure (required for Device 
Arm only) 
Echocardiographic Evaluation  (Form 7) 
Procedure Summary  (Form 11) 
Device Accountability  (Form 12) – for each GORE® HELEX® Septal 
Occluder / GORE® CARDIOFORM Septal Occluder  device opened 
Early Post-procedure (required 
for Device Arm only) 
 
Echocardiographic Evaluation  (Form 7) 
NIHSS and Neuro Assessment (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 
Month 1   
 
Echocardiographic Evaluation (required for Device Arm only) (Form 7)  
NIHSS and Neuro Assessment (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 
Month 6 
 
NIHSS and Neuro Assessment (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 
Month 12 
 
Echocardiographic Evaluation  (required for Device Arm only) (Form 7) 
NIHSS and Neuro Assessments (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 
Month 18 
 
NIHSS and Neuro Assessments (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 


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Interval 
CRFs to Submit 
Month 24 
 
MRI Brain Evaluation  (Form 5) 
Echocardiographic Evaluation  (required for Device Arm only)  (Form 7) 
NIHSS and Neuro Assessments (Form 8 and Form 9) 
Subject Follow-Up Evaluation  (Form 15) 
Months 36, 48, 60, or unscheduled  Subject Follow-Up Evaluation  (Form 15) 
Study Withdrawal or 
Discontinuation 
Study Completion / Discontinuation (Form 19) 
Event-Dependent Forms: 
CRFs to Submit 
If patient fails to meet 
Inclusion/Exclusion criteria, has 
recurrent event, or withdraws 
consent prior to randomization 
 
Inclusion/Exclusion  (Form 1) 
Patient Randomization (Form 10) 
Forms for any Screening Assessments performed 
If subject requires changes to 
study medications and/or 
concomitant medications 
Antiplatelet Study Medications (Form 13)  
Concomitant Medications  (Form 14) 
If subject discontinues antiplatelet 
medical therapy and starts 
warfarin 
Antiplatelet Study Medications (Form 13)  
Concomitant Medications  (Form 14) 
INR Log (Form 16) 
Adverse Event  (Form 17) – if applicable 
If subject experiences an adverse 
event after randomization 
Adverse Event  (Form 17) 
If subject experiences a recurrent 
stroke/TIA 
 
MRI Brain Evaluation  (Form 5) 
Echocardiographic Evaluation  (for subjects with device only)  (Form 7) 
NIHSS and Neuro Assessments (Form 8 and Form 9) 
Adverse Event  (Form 17) 
Study Completion / Discontinuation (Form 19) (for MRI confirmed 
events only) 
If subject is unable to participate in 
a follow-up visit, but is willing to 
have telephone contact  
Subject Follow-Up Evaluation  (Form 15) 
If subject has an Intervention 
(PFO closure outside of protocol-
required procedure) 
Echocardiographic Evaluation  (Form 7) 
PFO Intervention  (Form 18) 
If Protocol Deviation/Violation 
identified 
Protocol Deviation/Violation (Form 24) 
 
5.1. Protocol Deviations and Violations 
A protocol deviation occurs when, without significant consequences or impact on the study, 
the activities during a study depart from the IRB-approved or Ethics Committee-approved 
protocol.  For example, if a subject misses a visit window because he/she is traveling, this 
departure from the protocol does not have a serious impact on the scientific soundness of the 
clinical study or study data.   
 
The Investigator will report protocol deviations to the Sponsor by documenting the deviation on 
the Protocol Deviation CRF (Form 24) and, if required, to the local reviewing IRB or EC.  The 
Sponsor will determine the effect of the protocol deviation on the scientific soundness of the 
clinical study and subject safety and determine if additional reports are required. 
 


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5.1.1. 
Protocol Violations 
A protocol violation is defined as a divergence from the protocol that materially:  
(a) reduces the quality or completeness of the data, 
(b) renders the informed consent document inaccurate, or 
(c) impacts a subject’s safety, rights or welfare. 
 
Examples of protocol violations may include, but are not limited to: 
 
Inadequate or delinquent informed consent 
 
Inclusion/exclusion criteria not met 
 
Unreported serious adverse events (SAEs) 
 
Incorrect or missing tests that may impact the primary endpoint 
 
Multiple visits missed or outside permissible windows (and not reported as a lost 
to follow-up) 
 
Materially inadequate record-keeping 
 
Intentional deviation from protocol, good clinical practices (GCP), or regulations 
by study personnel 
 
The Investigator will report protocol violations within five (5) days to the Sponsor by 
documenting the deviation on the Protocol Deviation CRF (Form 24) and, if required, 
to the local reviewing IRB or EC.  The Sponsor will determine the effect of the 
protocol violation on the scientific soundness of the clinical study and subject safety 
and determine if additional reports are required. 
 


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6. 
Risk Analysis  
The purpose of this study is to assess the safety and effectiveness of the GORE® HELEX® Septal 
Occluder / GORE® CARDIOFORM Septal Occluder  when used in conjunction with antiplatelet 
therapy to close PFOs in subjects who are at high risk for recurrent embolic (stroke or TIA) events.  
 
The adverse events listed here are considered anticipated adverse events because they have been 
known to occur with the use of occluder devices or during the administration of the study 
medications.  An adverse event that is anticipated or foreseen does not preclude the event from 
being a serious adverse event (SAE or SADE). 
 
Complications associated with the use of the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder  or the study medications may be related to the device, the 
procedure, or medical (antiplatelet) therapy and may include, but are not limited to:  
 
Access site complications 
o Emboli (air, tissue, or thrombotic emboli)  
o Groin hematoma, with or without surgical repair  
o Infection and pain at insertion site  
o Pseudoaneurysm, femoral  
o Retro-peritoneal bleeding 
o Thrombosis at access puncture site or remote site  
o Venous occlusion  
o Vessel dissection, perforation, or rupture  
 
Allergic response 
o To a study medication 
o To nickel in the Occluder 
o To contrast media 
o To latex 
 
Arrhythmia  
 
Bleeding, hemorrhage, or bruising 
o Related to study (antiplatelet) medications  
o With or without transfusion 
 
Cerebral hemorrhage  
 
Chest pain or palpitations 
 
Death  
 
Effusion, pericardial or pleural, with or without drainage 
 
Headache, including  
o Migraine, with or without aura 
o Pain in the head or neck 
o Severe unilateral headache  
 
Hospitalization (in-patient) required to treat a complication 
 
Hypertension 
 
Hypotension  


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 
Infection, with or without fever 
o Bacteremia 
o Septicemia 
 
Ischemic events 
o Cerebral ischemia  
o Cerebrovascular accident (CVA) 
o Myocardial infarction (MI) 
o Stroke  
o TIA with or without motor weakness  
 
Medications, study-related  
o Allergic responses  
 
Rash, itching, or papules 
o Excessive bruising 
o Gastro-intestinal problems 
 
stomach ache 
 
ulcer 
 
diarrhea 
 
Occluder-related issues 
o Component detachment 
o Damage to delivery system or occluder during prep or delivery 
o Embolization 
o Erosion of cardiac tissue 
o Malposition  
o Migration  
o Perforation of a cardiac structure 
o Removal of the device post-implant 
o Thrombosis  
o Wire frame fracture  
 
Procedure-related issues 
o Brachial plexus stretch injury 
o Back pain resulting from lengthy procedures 
o Excessive radiation exposure during imaging  
o Sore throat (intubation / extubation / probe) 
 
Prolonged medication required to treat a complication 
 
Seizure   
 


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6.1. Minimization of Risks 
Potential risks associated with the use of the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder  or the study medications may be minimized by the following 
activities: 
 
Investigator and staff training will be conducted to share information regarding design of 
the device, its application, and preliminary clinical results from any pre-clinical and clinical 
studies. 
 
Investigators will be reminded of the importance of complex anatomies when using the 
device. 
 
Investigators will be reminded of the importance of monitoring subjects on antiplatelet 
medications 
 
An evaluation will be completed by the Investigator for each subject against the 
inclusion/exclusion criteria before study entry to ensure the subject’s medical and anatomical 
status is appropriate.  Procedural angiography will be used to assess the morphology of the 
heart and the characteristics of the PFO. 
 
Antiplatelet therapy will be administered to reduce the risk of thrombosis. 
Procedural anticoagulation therapy will be administered to reduce thromboembolic risk.  
(Note: Protamine is not to be given to reverse heparin).  Subjects will be assessed at 
discharge and periodically during the follow-up period.   
 
Evaluations will include, but will not be limited to, physical examination performed by the 
Neurologist Investigator and/or the Cardiologist Investigator , neurologic assessments, and 
transthoracic or transesophageal echocardiography (TTE or TEE). 
 
The Investigator or designee will evaluate the subject for device-related events or AEs related 
to the procedure or medical treatment. 
 
Data submitted from the investigative sites will be monitored.  An initiation site visit and interim 
site visit(s) will be conducted as appropriate to evaluate protocol compliance, accuracy, and 
subject safety. 
 
Safety data obtained during the clinical study will be shared with the Investigators to aid 
understanding of the device and potential complications associated with its use. 
 
All echos performed will be reviewed by the Echocardiography Core Laboratory to evaluate 
the heart and any residual shunting across the PFO. 
 
A DSMB and CEC will be utilized to further mitigate risk to subjects during the study.  
 
6.2. Expected Benefits  
A major expected benefit from the use of the GORE® HELEX® Septal Occluder / GORE® 
CARDIOFORM Septal Occluder  is the reduction of risk from recurrent embolic (stroke or TIA) 
events when compared with antiplatelet medical therapy alone.   


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7. 
Investigator Responsibilities 
The Investigator is responsible for ensuring the clinical study is conducted according to the Clinical 
Study Agreement (CSA) or Clinical Trial Letter of Agreement (CTLA), the study protocol, all 
conditions of the FDA and IRB or EC approvals and applicable FDA and European regulations.   
 
Written confirmation of IRB or EC approval must be provided to the Sponsor before the start of the 
clinical study.  A copy of the current curriculum vitae (CV) for the Investigator and any Sub-
Investigators with information concerning their prior experience will be provided to the Sponsor at 
the beginning of the study and may be updated periodically on the request of the Sponsor.   
 
The Investigator is responsible for protecting the rights, safety, and welfare of subjects under the 
Investigator’s care and for the control of devices under investigation.  The Investigator or trained 
designee is also responsible for ensuring that informed consent is properly obtained.  (CFR § 812 
Subpart E and current ISO standard) 
 
7.1. Specific Investigator Responsibilities 
7.1.1. 
Subject Informed Consent 
Each potential subject that meets the inclusion/exclusion criteria for this clinical study 
will be informed of the requirements for participating in the clinical study.  Subjects will 
be provided with a copy of the Informed Consent Form and an opportunity to discuss 
any questions with the Investigator.   
 
Subjects will be informed that their medical records will be subject to review by the 
Sponsor, its representatives and the regulatory authorities (i.e., the FDA and 
European regulatory authorities), and will be asked to sign an Authorization for the 
Use and Disclosure of Protected Health Information.  Subjects will be informed that 
they may refuse to participate in this clinical study without loss of benefits to which 
they are otherwise entitled, and that if they choose to participate, they may withdraw 
at any time without prejudice to future care.  Once a subject agrees to the study 
requirements, the Informed Consent Form and Authorization for the Use and 
Disclosure of Protected Health Information must be signed and dated by the subject 
or subject’s guardian or legal representative and Investigator (or Investigator’s 
designee).   
 
The original signed Informed Consent Form for each subject will be retained by the 
investigative site and is subject to review by the regulatory authorities, the Sponsor, 
and its representatives.  A copy of the signed Informed Consent Form will be 
provided to the subject.  The Sponsor’s representatives will review a copy of the 
signed Informed Consent Form.  A copy of the Sponsor’s Informed Consent Form 
template is provided in Appendix F: Informed Consent Template. 
 
The Investigator or trained designee will be required to obtain informed consent from 
the subject, the subject’s legal representative, or a person designated acceptable by 
local Ethics Committee requirements, as appropriate.  
 


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7.1.2. 
Compliance 
The Investigator will adhere to the signed Clinical Study Agreement (CSA), the clinical 
study protocol, all applicable FDA or European regulations, and any conditions of 
approval imposed by the FDA or IRB or EC or European Regulatory Bodies. 
 
7.1.3. 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  Use 
The Investigator will ensure that patients meeting the study entrance criteria, 
specifically confirmation of the presence of a PFO, and who become subjects 
enrolled in this clinical study, will have access to the GORE® HELEX® Septal 
Occluder / GORE®CARDIOFORM Septal Occluder  for PFO closure.  The 
Investigator will not supply a study device or device component to any person not 
authorized to participate in the clinical study or to any other person who does not 
have legal access to the device.   
 
7.1.4. 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder  
Disposal 
Upon completion or termination either of the clinical study or the Investigator’s 
participation in the clinical study, or at the Sponsor’s request, the Investigator will 
return any remaining supply of the device(s) or dispose of the device(s) as directed by 
the Sponsor, including devices that are opened but not used. 
 
7.1.5. 
Occluder Explant 
In the event that an Occluder must be explanted or there is an opportunity to retrieve 
a device secondary to autopsy, the device should be returned to W.L. Gore and 
Associates for pathological and mechanical analyses. Ideally, the Occluder and 1-2 
cm of native tissue would be excised and returned in 10% neutral buffered Formalin.  
If possible, physical damage to the device should be avoided.  Operative photographs 
and clinical/pathological impressions are helpful and appreciated.  
 
Instructions for obtaining a return kit and processing explanted devices are provided 
in Appendix C – Device Explant and Return Procedure.   
 
7.1.6. 
Investigator Records 
The Investigator will maintain complete, accurate and current study records.  Records 
will be maintained during the clinical study and for a minimum of two (2) years after 
the latter of the date on which the study is terminated or completed, or the date the 
records are no longer required to support FDA approval of the new indication for the 
device.   
 
Clinical study records will not be disposed of or custody of the records will not be 
transferred without prior Sponsor approval.  Investigator records will include the 
following: 
1. 
All correspondence with another Investigator, the IRB, the EC, the Sponsor, 
DSMB, a monitor, FDA, a European regulatory body, or a study subject. 


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2. 
Accountability records of receipt, use and disposition of all devices including the 
type and quantity of devices received, the dates of their receipt, and the lot 
numbers.  In addition, the names of all persons who received, used or disposed 
of each device must be recorded. 
3. 
Subject records that include the subject’s case history and exposure to the 
device.  This information will be documented on standardized CRFs provided by 
the Sponsor.  Other subject records that should be retained by the Investigator 
include the signed informed consent and supporting documents, e.g., 
catheterization reports, diagnostic tests, and laboratory reports. 
4. 
Documentation of device use without informed consent.  In the event of such an 
occurrence, the IRB or EC and Sponsor must be notified within five (5) 
working days.  The Investigator must provide a written concurrence from a 
physician who is not participating in the clinical study explaining why informed 
consent was not obtained. 
5. 
A copy of the study protocol and all amendments. 
6. 
Reports and information pertaining to ADEs, SADEs, SAEs, and UADEs. 
7. 
All information pertaining to IRB or EC review and approval of the clinical study.  
This includes a copy of the IRB or EC approval, the IRB- or EC-approved 
Informed Consent Form, and a certification stating that the IRB or EC is in 
compliance with FDA regulations and applicable European regulations. 
8. 
An original signed Clinical Study Agreement (CSA) or Clinical Trial Letter of 
Agreement (CTLA). 
9. 
Any other records as required by the FDA, European regulatory requirements, 
and the Sponsor. 
 
7.1.7. 
Investigator Reports 
The Investigator will prepare and submit the following reports:  
1. 
CRFs documenting any SAE/SADE occurrence will be submitted to the IRB or 
EC and Sponsor no later than 10 working days after the Investigator is notified.  
The Sponsor will submit a report to the FDA and, if applicable, to the 
appropriate Competent Authority in the European countries, no later than 10 
working days after receipt of notification from the site. 
2. 
Information pertaining to withdrawal of IRB or EC approval will be submitted to 
the Sponsor within five (5) working days after the Investigator has been 
notified of the withdrawal. 
3. 
Progress reports documenting the procedure, AEs and follow-up data 
concerning individual subjects will be submitted to the Sponsor on standardized 
CRFs.  The Investigator may also be required to submit progress reports to the 
IRB or EC and to the Sponsor summarizing the Investigator’s experience during 
the study. 
4. 
Information concerning deviations/violations from the clinical study plan will be 
reported.  The Investigator will notify the Sponsor, and when applicable, the 
reviewing IRB or EC, of any violation of the clinical study no later than five (5) 
working days after the violation occurred (refer to Section 5.1 for definitions).  
 


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8. 
Sponsor and Monitor Responsibilities 
8.1. Sponsor Responsibilities 
The Sponsor will be responsible for ensuring the Investigators have the necessary skills, 
training, and information to properly conduct the clinical study.  The Sponsor will ensure proper 
monitoring of the clinical study, ensure IRB or EC approval is obtained, and provide 
information to the Investigators, the reviewing IRBs or ECs, and the FDA and Regulatory 
Bodies concerning the progress and new information about the clinical study.   
 
The Sponsor will conduct the clinical study in accordance with applicable national regulatory 
requirements. In addition, the clinical study will comply with the ethical principles of the 
Declaration of Helsinki.   
 
The Sponsor of this study is: 
 
W.L. Gore & Associates, Inc. 
Medical Products Division 
4250 West Kiltie Lane  
Flagstaff, AZ  86001 USA 
US Telephone: 800.437.8181 
US Facsimile: 928.864.4952 
Outside US Telephone: 011.928.779.2771 
Outside US Facsimile:  011.928.864.4952 
 
8.2. Monitor Responsibilities 
The Clinical Monitor is qualified by training and experience to oversee the progress of the 
study and will ensure that the Investigators and their staff understand and adhere to both the 
regulatory requirements and the study protocol.  In addition, the Clinical Monitor and Clinical 
Study Managers will assist in resolution of any problems that may arise during the study.   
 
The Sponsor’s Clinical Monitor may work with a Contract Research Organization (CRO) to 
assist in investigative site monitoring for this study.  The CRO will be managed and 
coordinated by the Sponsor’s Clinical Monitor and/or designee. 
 
The Sponsor’s Clinical Study Managers or designees for this study can be contacted at the 
following: 
 
W.L. Gore & Associates, Inc. 
Clinical Research 
4250 West Kiltie Lane 
Flagstaff, AZ  86001   USA 
Telephone: (011) 800-437-8181 
Facsimile: (011) 623-234-5730 
E-mail: REDUCE@wlgore.com 
 
 


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8.2.1. 
Pre-investigation Site Visit 
A pre-investigation visit will be made to each investigative site at or before study 
initiation to assure that each Investigator and his/her staff understand the protocol, 
the Investigator’s obligations, and have adequate time, subject population, facilities, 
and staff support to properly perform the study.   
 
Topics to be discussed will include: 
1. 
FDA or European regulations pertaining to the clinical study, including 
obligations of Investigators and inspection procedures by FDA or European 
regulatory bodies, and the Sponsor. (21 CFR § 812 Subpart C and current ISO 
standard) 
2. 
IRB or EC approval, continuing annual review and approval, and documentation 
to be provided. 
3. 
Adequacy of subject population, facilities, and support staff. 
4. 
The Investigator's availability and commitment to the clinical study. 
5. 
Identification of the Clinical Coordinator. 
6. 
Training of Investigators and coordinators to ensure site understanding of 
responsibilities and FDA or European regulations pertaining to the clinical study 
and the protocol. 
7. 
Informed consent requirements for each subject participating in the clinical 
study.  Written informed consent must be obtained using the Informed Consent 
Form approved by the reviewing IRB or EC, FDA, and Sponsor. 
8. 
Record keeping requirements including documentation, traceability and 
inventory control for device accountability. 
9. 
Completion and timely submission of CRFs. 
10. Administrative, AEs, ADEs, SADEs, SAEs, UADEs and other reports and time 
frames. 
 
8.2.2. 
Periodic Site Visits 
Periodic site visits will occur as necessary to ensure continuing adequacy of facilities, 
adherence to the clinical study, maintenance of proper records, adherence to 
regulations that pertain to the conduct of the clinical study, and the timely submission 
of accurate records to the Sponsor, as well as a review of the CRFs and source 
documentation for the duration of the study.  Other visits will occur as necessary 
depending on subject enrollment and problems encountered.  Periodic site visits may 
include: 
 
Informed consent form review for completion and accuracy 
 
A review of subject CRFs, source documents pertinent to the data requested on 
the forms, subject enrollment log, compliance with Eligibility criteria, review of 
adverse events, verification of attendance at study visits, and records of receipt 
and disposition of the device.  (in accordance with the current ISO standard) 
 
Resolution of missing, incomplete, and/or inconsistent data. 
 
Confirmation of continued compliance with the IDE regulations and adherence to 
the clinical study, including adequate documentation of any deviations from the 
protocol. 
 
Verification of continued adequacy of the facilities and staff support. 


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8.2.3. 
Clinical Monitor Reports 
The Sponsor’s Clinical Monitor(s) or Sponsor’s designee will prepare a written report 
for the Sponsor following investigative site visits.  A summary of the report will be 
given to the Investigator at each site.  Reports will include specific information 
regarding the site visit, including staff members contacted, records reviewed, subject 
enrollment and general progress of the study, status of any problems identified and 
any corrective action recommended. 
 
 
 


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9. 
Steering committee and publication of results 
The REDUCE Steering Committee is a multidisciplinary group of sponsor representatives and study 
principal investigators who collectively have the scientific, medical, and clinical trial management 
experience to conduct and evaluate the Gore REDUCE Clinical Study.  The Committee will serve as 
liaison to the REDUCE Data and Safety Monitoring Board (DSMB) and Gore study management on 
issues of study design, conduct, and analysis.  The REDUCE Steering Committee consists of the 
four National Principle Investigators and two representatives from the sponsor.  Publication of the 
manuscript reporting the main results will be authored by the Steering Committee on behalf of all 
REDUCE study investigators.   

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Statistical Analysis Plan 
 
GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder and Antiplatelet 
Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in 
Patients with Patent Foramen Ovale (PFO) 
 
The Gore REDUCE Clinical Study 
 
 
Protocol #: HLX 06-03 
SAP Version: Revision #1 15-JAN-2016 
 
 


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Table of Contents 
 
1.0 
Introduction ........................................................................................................................... 3 
2.0 
Study Design .......................................................................................................................... 3 
2.1 
Objectives .......................................................................................................................... 3 
2.2 
Design Summary ................................................................................................................ 3 
2.3 
Randomization and Enrollment .......................................................................................... 4 
2.4 
Study Treatment Arms ....................................................................................................... 4 
2.5 
Study Endpoints ................................................................................................................. 4 
2.6 
Statistical Hypotheses ........................................................................................................ 5 
2.7 
Sample Size Determination ................................................................................................ 6 
3.0 
Study Data Collection ............................................................................................................. 9 
3.1 
Study Data Collection Intervals ........................................................................................... 9 
3.2 
Study Interval Windows ..................................................................................................... 9 
3.3 
Data and Safety Monitoring Board ................................................................................... 10 
3.4 
Clinical Events Committee ................................................................................................ 10 
3.5 
Site Enrollment Restrictions ............................................................................................. 10 
3.6 
Core Labs ......................................................................................................................... 10 
4.0 
Statistical Analyses and Methods ......................................................................................... 11 
4.1 
Analysis Sets .................................................................................................................... 11 
4.2 
Timing of Analyses ........................................................................................................... 12 
4.3 
Primary Endpoints ............................................................................................................ 12 
4.4 
Secondary Endpoints ........................................................................................................ 13 
4.5 
Hypothesis Testing Structure ............................................................................................ 13 
4.6 
Adverse Events ................................................................................................................. 14 
4.7 
Comparison of Baseline Data ............................................................................................ 14 
4.8 
Subgroup Analysis of Primary Endpoints........................................................................... 15 
4.9 
Poolability of Investigative Sites ....................................................................................... 15 
4.10 
Additional Analyses .......................................................................................................... 15 
4.11 
Interim Analyses .............................................................................................................. 16 
5.0 
Analysis Specifications ......................................................................................................... 16 
5.1 
SAS Analysis Dataset Specifications .................................................................................. 16 
5.2 
Statistical Output Specifications ....................................................................................... 16 
5.3 
Verification Level for Statistical Output ............................................................................ 17 
6.0 
References ........................................................................................................................... 17 
7.0 
Revision History ................................................................................................................... 17 
 
 


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1.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analyses planned to address the 
objectives of the REDUCE clinical trial. It details the analyses that will be performed to accomplish 
these objectives. This SAP defines variables and identifies methods and algorithms used to populate 
the tables, figures, and listings that are included in reports for this study. 
2.0 Study Design 
2.1 
Objectives 
2.1.1 
Primary Objectives 
The primary objective of this study is to demonstrate that antiplatelet medical management plus 
PFO closure with the GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder (study 
device) reduces the risk of a recurrent stroke or imaging-confirmed TIA compared to antiplatelet 
medical management alone in patients with a patent foramen ovale (PFO) and history of cryptogenic 
stroke or imaging-confirmed TIA. 
A co-primary objective is to demonstrate that medical management plus closure with the study 
device reduces the risk of new brain infarct compared to medical management alone. 
2.1.2 
Secondary Objectives 
Evaluate the safety and efficacy of the study device for the transcatheter closure of PFO. 
2.2 
Design Summary 
The Gore REDUCE Clinical Study is a prospective, randomized, multinational, multicenter evaluation 
comparing antiplatelet medical management without PFO closure (control arm) to PFO closure with 
the study device plus antiplatelet medical management (test arm) for the reduction of recurrent 
stroke or imaging-confirmed TIA or new brain infarct in subjects with a PFO and history of 
cryptogenic stroke or imaging-confirmed TIA. 
A total of 664 eligible subjects will be randomized to either the test or control arm using a 2:1 
randomization scheme. A maximum of 80 investigational sites in the United States, Canada, and 
Europe will participate in the study with no per-site subject limit. The anticipated accrual rate is 
approximately 10 subjects per month for a total accrual period of approximately 60-66 months. 
Randomized subjects will be followed for up to five (5) years. For the control arm, follow-up 
intervals will be calculated from the date of randomization. For the test arm, follow-up intervals will 
be calculated from the date of the transcatheter closure procedure. All subjects will receive follow-
up evaluations at 1, 6, 12, 18, 24, 36, 48, and 60 months. Test arm subjects will receive an additional 
follow-up evaluation at early post-procedure (within 4 to 72 hours following the transcatheter 
closure procedure). 


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2.3 
Randomization and Enrollment 
A patient is considered an enrolled subject in the study upon randomization to one of the two 
treatment arms, Test or Control. Randomization will be weighted 2:1 in favor of the test arm. The 
randomization plan does not stratify by site or any other baseline variables. 
2.4 
Study Treatment Arms 
2.4.1 
Test Arm and Test Device 
The test arm will consist of enrolled subjects who were determined by the randomization process to 
receive the test treatment regimen, which consists of prompt antiplatelet medical therapy and PFO 
closure with the test device within 90 days of randomization. At the start of enrollment in December 
2008, the test device was the GORE® HELEX® Septal Occluder; with Protocol Amendment 2, dated 
May 15, 2012, the test device was changed to the GORE® CARDIOFORM Septal Occluder. 
2.4.2 
Control Arm 
The control arm will consist of enrolled subjects who were determined by the randomization 
process to receive the control treatment regimen, which consists of prompt antiplatelet medical 
therapy alone, with no closure of the PFO. 
2.5 
Study Endpoints 
2.5.1 
Primary Endpoints 
Co-primary Endpoint 1 is freedom from a recurrent stroke or imaging-confirmed TIA through at least 
24 months post-randomization. For this study, a recurrent stroke or imaging-confirmed TIA event is 
defined as the first occurrence, post-randomization, of one of the following: 
x 
Clinical finding of ischemic stroke that may be associated with MRI evidence of a new relevant 
brain infarction. For this study, an ischemic stroke is defined as a neurological deficit, presumed 
due to ischemia, persisting longer than 24 hours or until death. 
x 
Clinical finding of TIA that also has MRI evidence of a new relevant brain infarction. For this 
study, a TIA is defined as a transient neurological deficit, presumed due to ischemia, persisting 
less than 24 hours. 
Co-primary Endpoint 1 will be calculated as the time from randomization to the first recurrent 
event. Subjects free from a recurrent event will be censored at the date of last known contact. 
All deaths and suspected recurrent stroke/TIA events will be reviewed and adjudicated by a Clinical 
Events Committee (CEC). In the event of subject death, all possible efforts will be made to obtain 
relevant records from the hospital or the subject’s primary care physician, including a death 
certificate or autopsy report, to determine the cause of death. 
Co-primary Endpoint 2 is the incidence of subjects with new brain infarct or stroke from screening 
through 24 months or last follow-up visit, whichever occurs first, hereinafter referred to as brain 
infarct. A responder is defined as any subject with at least one new T2 hyperintense MRI lesion with 
diameter t 3 mm from screening or clinical findings of ischemic stroke, through 24 months or last 
follow-up visit, whichever occurs first. It will be calculated as a subject-based binomial proportion. 


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2.5.2 
Secondary Endpoints 
Safety Endpoints will include the proportion of subjects who experience adverse events (AEs) that 
are determined to be related to device, procedure, and/or antiplatelet medical management. This 
will include specific adverse events and groups of adverse events such as all-cause adverse events, 
device-related events, procedure-related events, antiplatelet medical therapy-related events, and 
any serious adverse events. 
The safety endpoints may also be analyzed using time-to-event methods to estimate the percentage 
of subjects free from the event at time points of interest, such as 30 days and 24 months post-
randomization (or post-procedure for the test arm). 
Efficacy Endpoints will evaluate the success of the device in achieving PFO closure in subjects 
randomized to the test arm. PFO closure success will be measured by assessing the degree of 
residual right-to-left shunt after device implant. Time points for the assessment of PFO closure 
include early post-procedure, 1 month, 12 months, and 24 months. 
Additional Secondary Endpoints will include: 
1. Clinical Success –  
a. Test Arm – defined as the composite of Device Success, PFO closure, and absence of a 
recurrent stroke or imaging-confirmed TIA at 24 months post-procedure 
b. Control Arm – defined as the freedom from a recurrent stroke or imaging-confirmed TIA at 
24 months post-randomization 
2. Overall Survival – defined as time from randomization to death from any cause or last known 
contact 
3. Time to any stroke/TIA – defined as time from randomization to first occurrence of stroke or 
TIA 
4. Device Success – defined as the proportion of device arm subjects with successful implant and 
retention of the device after procedure (test arm only) 
2.6 
Statistical Hypotheses 
This study is designed to test the null hypothesis that the hazard of a recurrent stroke or imaging-
confirmed TIA in subjects treated with percutaneous PFO closure plus antiplatelet medical 
management is equal to or higher than subjects treated with antiplatelet medical management 
alone. The alternative hypothesis is that the hazard of a recurrent stroke/imaging-confirmed TIA is 
lower in subjects treated with percutaneous PFO closure plus antiplatelet medical management 
compared to antiplatelet medical management alone. In statistical terms:
 
 
⨇଴: ܪ்ܴ஼
⁄ (ݐ) ≥1.0݂݋ݎ݈݈ܽݐ
⨇ଵ: ܪ்ܴ஼
⁄ (ݐ) < 1.0݂݋ݎ݈݈ܽݐ 
where HRT/C is the hazard ratio comparing the test (T) arm to the control (C) arm. 
In addition, this study will test the null hypothesis that the incidence of brain infarct at 24 months in 
subjects treated with percutaneous PFO closure plus antiplatelet medical management is equal to or 
higher than subjects treated with antiplatelet medical management alone. The alternative 
hypothesis is that the brain infarct incidence is lower in subjects treated with percutaneous PFO 


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closure plus antiplatelet medical management compared to antiplatelet medical management 
alone. In statistical terms: 
⨇଴:ܲ஼−்ܲ≤0
⨇ଵ:ܲ஼−்ܲ> 0 
where: 
PC = true proportion of subjects with incident brain infarct in the control group 
PT = true proportion of subjects with incident brain infarct in the test group 
2.7 
Sample Size Determination 
2.7.1 
Sample Size Assumptions 
Based on literature available at the study’s initiation (see Section 1.0 of the study protocol), the 
proportion of PFO patients free from a recurrent stroke or imaging-confirmed TIA at 24 months after 
initial, cryptogenic stroke or imaging-confirmed TIA is assumed to be approximately 92%, with a 
range of 86% to 94%. For the purposes of determining sample size for adequate power, a 55% 
reduction in the hazard of a recurrent stroke or imaging-confirmed TIA is considered a clinically 
relevant benefit. 
At the time this study was designed, Co-primary Endpoint 2 was considered a secondary endpoint 
and was not relevant to the sample size assumptions. 
2.7.2 
Randomization and Enrollment 
Subjects will be randomized in a 2:1 allocation ratio with the greater proportion of subjects 
randomized to the test arm. Enrollment of 120 to 140 subjects per year is anticipated, for a total 
enrollment period of 60-66 months (5 to 5.5 years). 
 
 
 
 
    
 
    
 
 
 
 
 
 
 
 
 
 


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%
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.0 Study Data Collection 
3.1 
Study Data Collection Intervals 
Refer to Section 5, Data Collection And Evaluation, in the protocol. 
3.2 
Study Interval Windows 
For Test Arm subjects, all follow-up intervals are calculated from the day of the PFO closure 
procedure. 
Schedule of Test Arm Subject Follow-up and Visit Windows 
Follow-up 
Visit Interval 
Follow-up Visit Interval Window 
Early Post-
procedure 
Typically 4-72 hours post-PFO closure procedure, 
but must be completed prior to leaving the 
hospital, out-patient facility, or surgical center 
1 month
1 month (30 days) ± 2 weeks (14 days) 
6 months
6 months (182 days) ± 1 month (30 days) 
12 months 
12 months (365 days) ± 2 months (60 days)
18 months 
18 months (547 days) ± 2 months (60 days)
24 months 
24 months (730 days) ± 2 months (60 days)
Year 3
36 months (1,095 days) ± 2 months (60 days) 
Year 4
48 months (1,460 days) ± 2 months (60 days) 
Year 5
60 months (1,825 days) ± 4 months (120 days) 
 
For Control Arm subjects, all follow-up intervals are calculated from the day of randomization. 
Schedule of Control Arm Subject Follow-up and Visit Windows 
Follow-up 
Visit Interval 
Follow-up Visit Interval Window 
1 month
1 month (30 days) ± 2 weeks (14 days) 
6 months
6 months (182 days) ± 1 month (30 days) 
12 months 
12 months (365 days) ± 2 months (60 days)
18 months 
18 months (547 days) ± 2 months (60 days)
24 months 
24 months (730 days) ± 2 months (60 days)
Year 3
36 months (1,095 days) ± 2 months (60 days) 
Year 4
48 months (1,460 days) ± 2 months (60 days) 
Year 5
60 months (1,825 days) ± 4 months (120 days) 
 


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3.3 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be comprised of an interdisciplinary 
team of five individuals, four physicians and a biostatistician, who are not directly involved in the 
conduct of the study. 
The team shall include, at minimum, one stroke neurologist, one interventional cardiologist, and a 
biostatistician to assist with formulation of stopping rules and direction of interim analyses. 
The members may be compensated for their participation in the DSMB, including reimbursement 
for reasonable travel expenses to attend meetings. Members will not have any business or financial 
affiliation with the study sponsor, the core laboratories, or the study investigators. 
The DSMB is responsible for conducting periodic reviews of aggregate data on a prescribed 
schedule. Based on the safety data, the DSMB will make recommendations to the Sponsor. 
Recommendations may include modifying the study, stopping the study, or continuing the study. All 
final decisions regarding study modifications or study continuation, however, will rest with the 
Sponsor. 
3.4 
Clinical Events Committee 
The independent Clinical Events Committee (CEC) will be comprised of at least three physicians who 
are not participating in the study and do not have any conflicts of interest with the study Sponsor. 
The CEC will include representatives from at least three of the following specialties/disciplines: 
x 
stroke neurology 
x 
interventional cardiology 
x 
echocardiography 
x 
neuroradiology 
 
Input from other disciplines will be solicited, if required. The members may be compensated for 
their involvement in the CEC including reimbursement for reasonable travel expenses to attend 
meetings. 
The committee will be responsible for: 
x 
Review of definitions of clinical endpoints in the study in conjunction with the Sponsor. 
x 
Review and adjudication of adverse events that have the potential to be study endpoint events, 
including death, stroke, and TIA; AND 
x 
Subsequent classification of these adverse events as related to the study device, procedure, or 
medications. 
3.5 
Site Enrollment Restrictions 
There is no per-site subject enrollment limit specified for this study. 
3.6 
Core Labs 
An independent MRI Core Laboratory will provide centralized assessment of study endpoints from 
protocol-required MRI and CT imagery. Three board-certified radiologists with specific neurological 


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imaging expertise will be responsible for the review of all MRI and CT images. The principal 
measures provided by this core lab are detection of new brain infarct from screening to 24 months 
for the brain infarct endpoint, and detection of brain infarct for the recurrent event endpoint, 
especially regarding confirmation of a TIA as a recurrent event. The core lab readers are blinded to 
treatment in their image assessments. 
Similarly, an independent Echocardiography Core Laboratory will provide centralized assessment of 
study endpoints from protocol-required echocardiography imagery, principally to confirm the 
presence of PFO in all subjects and to assess PFO closure status at follow-up for test subjects. Three 
board-certified cardiologists with expertise in echocardiography will be responsible for the review of 
all echocardiograms. 
Refer to Section 3.19, Imaging Analysis, in the protocol. 
4.0 Statistical Analyses and Methods 
4.1 
Analysis Sets 
The co-primary endpoints will be analyzed under several different analysis set definitions, as 
described below. The primary analysis set for testing of the co-primary endpoints is the intent-to-
treat analysis set. 
4.1.1 
Intent-To-Treat (ITT) Analysis Set (Primary Analysis Set) 
The ITT analysis set is defined as all enrolled subjects (randomized to treatment) and will be 
analyzed by treatment assigned at randomization, regardless of whether or not the correct 
treatment was administered. 
4.1.2 
Per-Protocol Analysis Set 
For per-protocol analysis, only subjects who were randomized and treated according to protocol will 
be analyzed by treatment assigned at randomization. Specifically, subjects randomized to test who 
received antiplatelet medical therapy and PFO closure with the test device, and subjects randomized 
to control who received antiplatelet medical therapy and no PFO closure by any means, will be 
included in the analysis. 
4.1.3 
As-Treated Analysis Set 
For as-treated analysis, subjects who were randomized and treated will be analyzed by treatment 
received, regardless of treatment assigned at randomization. Specifically, randomized subjects who 
received antiplatelet medical therapy and PFO closure by any means (test device, alternative device, 
surgery) will be analyzed in the “PFO Closure” group, and randomized subjects who received 
antiplatelet medical therapy and no PFO closure by any means will be analyzed in the “No PFO 
Closure” group. 


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4.2 
Timing of Analyses 
4.2.1 
Primary Endpoint Analysis 
The primary endpoint analysis will be performed when the last subject enrolled completes 24 
months of follow-up. 
4.2.2 
Interim Analyses 
The original protocol specified that, in addition to standard study monitoring, an interim analysis will 
be performed after approximately 50% of the total expected recurrent stroke or imaging-confirmed 
TIA events have occurred. This milestone event had not occurred as of the completion of full 
enrollment in February 2015. Under the plan described herein, the original interim analysis plan no 
longer serves its purpose and is rescinded. 
4.3 
Primary Endpoints 
4.3.1 
Freedom From Recurrent Event 
Co-primary Endpoint 1, freedom from a recurrent event, will be compared between treatment 
groups using an unadjusted log-rank test and presented using Kaplan-Meier methods. All follow-up 
data through 5 years will be included on subjects continuing follow-up past the 24-month 
evaluation. As part of a simultaneous test with the brain infarct co-primary endpoint hypothesis 
(described in sections 4.3.2 and 4.5 below) a multiplicity-adjusted p-value for the hazard ratio test of 
0.025 or less will be considered evidence to reject the freedom from recurrent event null 
hypothesis. 
4.3.2 
Brain Infarct 
The analysis sample for Co-primary Endpoint 2, brain infarct, will consist of randomized subjects 
with valid MRI Core Lab data at screening and an appropriate follow-up, where follow-up will be at 
24 months or immediately following a recurrent event (suspected stroke or TIA), whichever occurs 
first, as well as randomized subjects who experience a confirmed recurrent event through 24 
months regardless of MRI data status. Responders are subjects who show one or more new 
infarction(s) on MRI since screening or experience a confirmed recurrent event. Nonresponders are 
subjects who do not show new infarction on MRI since screening and do not experience a confirmed 
recurrent event. 
The primary analysis will be a two-sample comparison of the binomial proportion of subjects with 
brain infarct between the two treatment groups. Each binomial proportion will be calculated as the 
count of responders divided by the count of evaluable subjects (sum of the responder and 
nonresponder counts). 
 
 


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The hypothesis will be tested using a two-sample binomial proportions test: 
ݖ=
݌஼−݌்
ට݌஼(1 −݌஼)
݊஼
+ ݌்(1 −݌்)
்݊
  
where: 
pC = observed brain infarct proportion in control group 
nC = number of evaluable subjects in control group 
pT = observed brain infarct proportion in test group 
nT = number of evaluable subjects in test group 
The test statistic z is assumed to have a standard Normal distribution. The significance level for this 
test will be set at a 1-sided D = 0.025, but the p-value will be adjusted for multiplicity with the 1-
sided D = 0.025 test performed simultaneously on the primary endpoint. Therefore, pC −pT >
0 and a multiplicity-adjusted p-value d 0.025 will result in rejection of the null hypothesis in favor of 
the alternative hypothesis and a conclusion that the test treatment reduces the rate of brain infarct 
compared to the control treatment. The 1-sided multiplicity-adjusted p-value and unadjusted 2-
sided 95% confidence interval for the difference in proportions will be reported. 
4.4 
Secondary Endpoints 
The secondary endpoint analysis will be performed in conjunction with the primary endpoint 
analysis. Statistical methods for testing multiple endpoints will be utilized in the comparison of 
secondary endpoints across test and control to preserve the overall Type I error rate. 
 
 
 
 
 
 
−
 
p
 
 
r
 
 
 
 
H0RE 
  
 
H0RE 
 
 
 
H0RE 
  
  
0BI   
 
  
 
 


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Based on the final analysis of correlation between the two endpoints and the unadjusted p-values 
obtained from the two test statistics, the appropriate adjusted p-values will be compared to the 
overall 1-sided D = 0.025 for the experiment. 
4.6 
Adverse Events 
All site-reported AEs will be MedDRA coded and grouped by MedDRA System/Organ Class (SOC) and 
by MedDRA Preferred Term within SOC. AEs will also be grouped by seriousness (SAE vs. nonserious 
AE), primary relationship (device, procedure, antiplatelet medication, unrelated, and unknown) and 
timing of onset (procedure, pre- and postdischarge). AEs will be summarized as rates given by 
subject-based binomial proportions. The numerator will be the count of subjects who experienced 
one or more episodes of the AE of interest in the time period of interest. The denominator will be 
the count of subjects free of the AE of interest through the time period of interest and with 
sufficient clinical follow-up for the time period of interest, plus the count of subjects in the 
numerator. Unless otherwise specified for a particular endpoint measure, all enrolled subjects in the 
analysis set of interest will be considered evaluable and will contribute to the denominator. 
4.7 
Comparison of Baseline Data 
Subject demographics, clinical history, risk factors, and screening PFO characteristics will be 
summarized for all subjects using descriptive statistics for continuous variables (mean, standard 
deviation, number of observations, minimum and maximum) and discrete variables (percentage and 
count/sample). These measures will be compared between the test group and the control group 
using test methods appropriate for the measures, for example, two-sample t- or Wilcoxon rank-sum 
tests for continuous measures and chi-square or Fisher’s exact tests for discrete measures. 


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4.8 
Subgroup Analysis of Primary Endpoints 
In addition to the overall analysis, the two co-primary endpoints will also each be analyzed 
controlling for region, defined as enrolled at a site within the United States (US) or enrolled at a site 
outside of the United States (OUS). 
4.9 
Poolability of Investigative Sites 
The data from all investigative sites will be pooled based on the assumption of clinical comparability: 
the sites used a common protocol; the sponsor adequately monitored the study to assure protocol 
compliance; and the data gathering and validation mechanisms were the same across all study sites. 
Analyses to justify pooling will include the following: 
x 
The primary endpoint will be presented by site: Kaplan-Meier estimates of freedom from 
recurrent event will be presented for the two treatment groups.  
x 
An assessment of the poolability of the sites using a Cox regression model of recurrent event 
outcome with coefficient terms for treatment group (test, control), site, and treatment 
group-by-site interaction. Statistical significance of the interaction term will be used to make 
inferences on site homogeneity. Sites with fewer than five subjects will be combined based 
on geographic region (US versus OUS). 
x 
If the sites are found to be significantly heterogeneous with respect to the primary 
endpoint, additional analyses will be conducted to assess differences between sites in 
baseline and procedural variables that might explain differences in primary outcome. 
Similar analyses to justify pooling for the brain infarct endpoint will be performed using a logistic 
regression model. 
4.10 
Additional Analyses 
Additional subgroup analyses may be performed based on variables identified to be significant 
predictors (p-value < 0.05) in multivariate analyses. 
Sensitivity analyses of the recurrent event and brain infarct co-primary endpoints will be conducted 
and will include, at a minimum, a “worst-case” analysis (subjects who withdraw or are lost to follow-
up considered recurrent events in the test group and censored in the control group), a “best-case” 
analysis (subjects who withdraw or are lost to follow-up considered censored in the test group and 
recurrent events in the control group), and, if necessary, a tipping point analysis (threshold of 
successes vs. failures between the treatment groups at which the primary test conclusion changes). 
4.10.1 Evaluation of Septal Occluder Device Poolability 
It is expected that shortly after approximately one-third of the subjects have been enrolled, the new 
study device (GORE® CARDIOFORM Septal Occluder) will become available and will be used as the 
device of choice within the test arm of the study. As a regulatory requirement, an assessment of 
poolability will be conducted for the two study device subgroups in the test arm. The statistical plan 
for this assessment will consist of two stages: baseline homogeneity and primary outcome 
comparability. 


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For baseline homogeneity, the two test device subgroups will be compared on the following six 
baseline demographic and predictor covariates: age, gender, qualifying cerebrovascular event, 
balloon-sized PFO diameter, PFO tunnel length, and presence of atrial septal aneurysm. These 
subgroup comparisons will use the two-sample t-test, chi-square test, or Fisher’s Exact test, 
depending on the distribution of the covariate. 
For primary outcome comparability, covariate-by-device interactions will be assessed using Cox 
proportional hazards regression models where main effects for device and the covariate and the 
covariate-by-device interaction term will be regressed on the 24-month freedom from recurrent 
stroke or imaging-confirmed TIA primary endpoint; this will be performed individually for each of 
the six baseline covariates. Statistically significant interactions will be assessed graphically for the 
nature of the interaction (quantitative vs. qualitative). Qualitative interactions (difference in 
direction of device effect across levels of covariate) will suggest differences between the device 
subgroups, leading to analyses performed separately for each device subgroup. A similar approach 
will be used for brain infarct comparability, but using a logistic regression model for this binary 
endpoint. 
Finally, device subgroup and any baseline covariates deemed to be different between device 
subgroups will be included as main effects in a Cox regression model on the primary endpoint. If the 
device subgroup term is statistically significant and the observed hazard reduction (test vs. control) 
for either of the device subgroups is less than the hypothesized 55%, then the device subgroups will 
not be considered outcome comparable, leading to analyses performed separately for each device 
subgroup. Again, a similar approach will be used for the binary brain infarct endpoint, but using a 
logistic regression model instead of a Cox regression model. 
A significance level of D=0.15 will be used for these poolability tests, without correction for 
multiplicity. Since this evaluation plan calls for a minimum of 13 significance tests per endpoint, the 
overall Type-I error rate per endpoint for these analyses may exceed 1 − (1 − 0.15)13 = 0.88. 
4.11 
Interim Analyses 
No interim analyses involving formal statistical testing of the study hypotheses are planned. 
5.0 Analysis Specifications 
5.1 
SAS Analysis Dataset Specifications 
A specifications document is created for each analysis data set and contains, at a minimum: 
x 
Dataset name 
x 
Variable name 
x 
Format 
x 
Label 
x 
Study database input field(s) and/or calculation logic 
5.2 
Statistical Output Specifications 
A specifications document is created for each statistical output (Table, Listing, or Figure) and 
contains, at a minimum: 


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x 
Title and footnote information 
x 
Column headers 
x 
General appearance of each cell (for tables and listings) 
x 
If the output includes a figure, either an example figure or a detailed description of the 
figure is included in this section 
x 
Variables, procedures, and/or calculation logic used in the statistical output  
x 
Change log section 
5.3 
Verification Level for Statistical Output 
Verification levels for statistical output are defined per MD111325. The minimum required 
verification levels for statistical output in this study are as follows: 
x 
All Analysis Datasets – Level 1 
x 
All Tables – Level 1 
x 
All Figures – Level 2 
x 
All Listings – Level 2 
x 
Ad Hoc or Post Hoc analyses – Level 3 
 
 
 
 
 
 
 
 
 
 
 
7.0 Revision History 
 
Log of Changes Made to the Statistical Analysis Plan 
Version Date
Initiated By
Summary of Change
15-JAN-2016 
Bryan Randall
Initial Version (Revision #1)