A Multicenter Trial of Endoscopic Radiofrequency Ablation for High-grade and Low-grade Intraepithelial Squamous Neoplasia Using the Barrx™ Flex Radiofrequency Ablation System
Phase: NA
Conditions: Esophageal Squamous Cell Neoplasia (ESCN)
Sponsor: Medtronic - MITG

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  REACH:  A multicenter trial of endoscopic 
radiofrequency ablation for macroscopically flat 
type high-grade and medium-grade 
intraepithelial squamous neoplasia using the 
Barrx™ Flex Radiofrequency Ablation System 
Clinical Investigation Plan Identifier COVB3050540 
Study Product Name Barrx™ Flex Radiofrequency Ablation System 
Sponsor/Local Sponsor US Sponsor 
 
Director Global Clinical Affairs, Early Technologies 
Medtronic, Minimally Invasive Therapies Groups 
 
 
 
 
 
 
 
Clinical Project Manager | Clinical Affairs 
Medtronic, Minimally Invasive Therapies Groups 
 
  
 
 
China Sponsor 
Medtronic MITG, Greater China 
 
 
 
 
 
Document Version 7.0, 15-Mar-2018 

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Lead Investigator(s) 
 
Cancer Institute and Hospital 
Chinese Academy of Medical Sciences (CICAMS) 
Beijing, People’s Republic of China 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
 
 

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1. Investigator Statement 
Study product Name 
Barrx™ Flex Radiofrequency Ablation System 
Sponsor 
Medtronic, Minimally Invasive Therapies Groups, Early 
Technologies 
Clinical Investigation Plan Identifier 
COVB3050540 
Version Number/Date  
 Version 7.0/15-Mar-2018 
I have read the protocol, including all appendices, and I agree that it contains all necessary details for 
me and my staff to conduct this study as described. I will conduct this study as outlined herein and 
will make a reasonable effort to complete the study within the time designated. 
I agree to comply with Declaration of Helsinki, ISO 14155:2011 (Clinical Investigation of Medical 
Devices for Human Subjects – Good Clinical Practice), and China regulations. I agree to ensure that the 
confidential information contained in this document will not be used for any purpose other than the 
evaluation and conduct of the clinical investigation without the prior written consent of Medtronic. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Medtronic. I will discuss this material with them to ensure that they are fully 
informed about the products and the study. 
Investigator’s Signature: 
 
Investigator’s Name: 
 
Institution: 
 
Date:  
 
 
 
 
 
 
 
 
 

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Table of Contents  
 
1. 
Investigator Statement ...................................................................................................... 3 
Table of Contents ...................................................................................................................... 4 
2. 
Glossary .............................................................................................................................. 7 
3. 
Synopsis ............................................................................................................................. 9 
4. 
Introduction ..................................................................................................................... 14 
4.1. Background ........................................................................................................................... 14 
4.2. Purpose ................................................................................................................................. 16 
5. 
Objectives and Endpoints ................................................................................................. 17 
5.1. Objectives ............................................................................................................................. 17 
5.1.1.  Primary Objective(s) ........................................................................................................ 17 
5.2. Endpoints .............................................................................................................................. 17 
5.2.1.  Primary Endpoint ............................................................................................................ 17 
5.2.2.  Secondary Endpoint(s) .................................................................................................... 18 
6. 
Study Design .................................................................................................................... 18 
6.1. Duration ................................................................................................................................ 18 
6.2. Rationale ............................................................................................................................... 19 
7. 
Product Description.......................................................................................................... 20 
7.1. General ................................................................................................................................. 20 
7.2. The Barrx™ Circumferential Radiofrequency Ablation System .................................................... 20 
7.3. The Barrx™ Focal Radiofrequency Ablation System .................................................................. 21 
7.4. Regulatory Approval in China .................................................................................................. 21 
7.5. Product Training Requirements ............................................................................................... 21 
7.6. Study Supplies and Device Accountability ................................................................................ 21 
8. 
Selection of Subjects ........................................................................................................ 22 
8.1. Study Population .................................................................................................................... 22 
8.2. Subject Enrollment ................................................................................................................. 22 
8.3. Inclusion Criteria .................................................................................................................... 22 
8.4. Exclusion Criteria ................................................................................................................... 24 

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9. 
Study Procedures ............................................................................................................. 25 
9.1. Schedule of Events ................................................................................................................. 25 
9.1.1. 
Tissue Specimen Processing and Histopathological Interpretation ........................................ 27 
9.2. Subject Screening .................................................................................................................. 28 
9.3. Subject Consent ..................................................................................................................... 29 
9.4. Treatment Assignment ........................................................................................................... 29 
9.4.1. 
Treatment Phase .............................................................................................................. 29 
9.4.2. 
Follow-up Phase ............................................................................................................... 36 
9.4.3. 
Escape treatment: Endoscopic (EMR or ESD) or Non-Endoscopic Therapy during Treatment or 
Follow-up Phase ............................................................................................................................ 37 
9.5. Assessment of Efficacy ........................................................................................................... 39 
9.6. Assessment of Safety ............................................................................................................. 39 
9.7. Recording Data ...................................................................................................................... 39 
9.8. Deviation Handling ................................................................................................................. 40 
9.9. Subject Withdrawal or Discontinuation .................................................................................... 40 
9.10. 
Definitions ....................................................................................................................... 41 
10. 
Risks and Benefits ......................................................................................................... 42 
10.1. 
Potential Risks .................................................................................................................. 42 
10.2. 
Potential Benefits ............................................................................................................. 43 
10.3. 
Risk-Benefit Rationale ....................................................................................................... 43 
11. 
Adverse Events and Device Deficiencies ....................................................................... 43 
11.1. 
Definitions/Classifications .................................................................................................. 43 
Adverse Event (AE) .................................................................................................................... 43 
Serious Adverse Event (SAE) .......................................................................................................... 43 
Adverse Device Effect (ADE) .......................................................................................................... 44 
Serious Adverse Device Effect (SADE) ............................................................................................. 44 
Adverse Event Severity Classification .............................................................................................. 44 
Adverse Event Relationship Classification ........................................................................................ 45 
Adverse Event Outcome Classification ............................................................................................. 47 
11.2. 
Reporting of Adverse Events ............................................................................................. 47 
Notification to Authorities............................................................................................................... 48 
11.3. 
Device Deficiencies ........................................................................................................... 49 

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12. 
Data Review Committees .............................................................................................. 49 
Independent Medical Advisors ........................................................................................................ 49 
13. 
Statistical Design and Methods ..................................................................................... 49 
13.1. 
General Principles ............................................................................................................. 49 
13.2. 
Sample Size Determination ............................................................................................... 50 
13.3. 
Analysis Populations ......................................................................................................... 50 
13.4. 
Effectiveness Analysis ....................................................................................................... 50 
13.5. 
Safety Analysis ................................................................................................................. 50 
13.6. 
Additional Analyses........................................................................................................... 51 
14. 
Ethics ............................................................................................................................. 51 
14.1. 
Statement(s) of Compliance .............................................................................................. 51 
14.2. 
Protocol Compliance ......................................................................................................... 52 
15. 
Study Administration ..................................................................................................... 52 
15.1. 
Monitoring ....................................................................................................................... 52 
15.2. 
Data Management ............................................................................................................ 53 
15.3. 
Direct Access to Source Data/Documents ........................................................................... 53 
15.4. 
Confidentiality .................................................................................................................. 53 
15.5. 
Liability ............................................................................................................................ 54 
15.6. 
CIP Amendments ............................................................................................................. 54 
15.7. 
Record Retention ............................................................................................................. 54 
15.8. 
Publication and Use of Information .................................................................................... 55 
15.9. 
Suspension or Early Termination ....................................................................................... 56 
16. 
References ..................................................................................................................... 56 
17. 
Appendices .................................................................................................................... 60 
18. 
Version History .............................................................................................................. 61 
 
 
 

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3. Synopsis 
Title 
A multicenter trial of endoscopic radiofrequency ablation for 
macroscopically flat type high-grade and medium-grade 
intraepithelial squamous neoplasia using the Barrx™ Flex 
Radiofrequency Ablation System 
Clinical Study Type 
Prospective, multi-center, non-blinded, single-arm (non-randomized) 
post-market study 
Product Name 
Barrx™ Flex Radiofrequency Ablation System 
Sponsor  
Medtronic, Minimally Invasive Therapies Groups, Early Technologies 
Local Sponsor 
Medtronic 
MITG, Greater China 
  
 
Indication under 
investigation  
Esophageal squamous cell neoplasia (ESCN) 
Investigation Purpose 
To measure the effectiveness and durability of the Barrx™ Flex 
Radiofrequency Ablation System in the eradication of diseased 
epithelium at 12 months post-treatment and up to 5 years in subjects 
with early flat-type -defined as type 0-IIb lesions on White Light 
Endoscopy (WLE) and Lugol’s chromoendoscopy- esophageal 
squamous cell neoplasia (ESCN), defined as moderate-grade 
squamous intraepithelial neoplasia (MGIN) or high-grade squamous 
intraepithelial neoplasia (HGIN). 
 
Product Status 
The Barrx™ Flex Radiofrequency Ablation System obtained China Food 
and Drug Administration (CFDA) approval in January 2015 for use in 
China.   The Barrx Flex System is indicated for the clinical treatment of 
lesions limited to the mucosa in the gastrointestinal tract, specifically 
flat intraepithelial neoplasia and Barrett’s esophagus. 
Primary Objective(s) 
The primary objective is to measure the effectiveness of the Barrx™ 
Flex Radiofrequency Ablation System in the eradication of diseased 
epithelium at 12 months post-treatment in subjects with early flat-
type -defined as type 0-IIb lesions on White Light Endoscopy (WLE) 
and Lugol’s chromoendoscopy- esophageal squamous cell neoplasia 
(ESCN), defined as moderate-grade squamous intraepithelial 
neoplasia (MGIN) or high-grade squamous intraepithelial neoplasia 
(HGIN). 

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Secondary Objective(s) 
The secondary objectives are to assess safety, to measure durability 
of complete response during long-term follow-up, and to measure 
overall ESCC progression and associated mortality after treatment 
Study Design 
Multicenter, prospective cohort clinical trial in greater China. 
Patients will be followed-up for up to 5 years post initial RFA. 
Sample Size 
Up to 100 subjects will be included in the cohort, in up to 10 clinical 
sites. This is excluding up to 50 “run-in” subjects, defined as up to 5 
patients for each endoscopist that is inexperienced with RFA or has 
had no onsite RFA training from CICAMS. 
Data from the run-in patients will be analyzed separately from the 
cohort.   
Inclusion/Exclusion Criteria 
Inclusion Criteria 

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1. 
Patient is 18-85 years of age 
2. 
Patient has evidence of ESCN, within the last 3 months, 
patient demonstrated a new diagnosis or a reconfirmed 
diagnosis of squamous MGIN or HGIN of the esophagus  
3. 
On endoscopic examination, subject has at least one USL 
that measures at least 3 cm in at least one dimension and is 
greater than ¼ of the esophageal circumference and has 
MGIN or HGIN on biopsy, confirmed by central pathologist 
4. 
All lesions in the esophagus are completely flat (Paris type 0-
IIb), both on WLE and Lugol’s chromoendoscopy 
5. 
The maximum allowable linear length of “USL-bearing 
esophagus” is 12 cm 
6. 
Baseline endoscopic ultrasound (EUS) (if applicable) shows 
no exclusionary findings for the trial 
7. 
Computed tomography (CT) scan of chest and upper third of 
the abdomen (if applicable) shows no exclusionary findings 
for the trial 
8. 
Based on the judgment of the study endoscopist, the patient 
is eligible for treatment, and follow-up endoscopy and 
biopsy as required by the protocol 
9. 
EMR or ESD occurred > 3 months before enrollment, 
patients may be eligible for the study if procedure was 
curative (negative margins and no risk of lymph node 
involvement) and the patient has no other findings 
concerning for cancer 
10. The subject is willing to provide written, informed consent 
to participate in this clinical study and understands the 
responsibilities of trial participation 
Exclusion Criteria 
1. 
Patient has esophageal squamous cell carcinoma (ESCC) 
2. 
Any non-flat  (Paris type 0-I, 0-IIa, 0-IIc, 0-III) abnormalities 
anywhere in the esophagus 
3. 
Any abnormalities under WLE, Lugol’s or NBI that are 
suspicious for ESCC anywhere in the esophagus (e.g. ‘pink 
sign’ USL, defined as a color change after Lugol’s staining: 
initially whitish yellow and pink 2-3 minutes later) 
4. 
Any USL with MGIN or worse on biopsy outside the 
treatment area 
5. 
Esophageal stricture preventing passage of a therapeutic 
endoscope 
6. 
Prior endoscopic mucosal resection (EMR) or endoscopic 
submucosal dissection (ESD) which occurred < 3 months 
before enrollment.  

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7. 
Any esophageal dilation in the past 12 months 
8. 
Any history of a non-squamous cell cancer of the esophagus, 
or any history of a squamous cell cancer of the esophagus 
(any stage)  
9. 
Any previous ablative therapy within the esophagus 
(photodynamic therapy, multipolar electrical coagulation, 
argon plasma coagulation, laser treatment, cryoablation, or 
other) or any radiation therapy to the esophagus. 
10. Previous esophageal surgery, except fundoplication without 
complications (i.e., no slippage, dysphagia, etc.) 
11.  Evidence of esophageal varices detected within last 6 
months or at initial RFA procedure 
12. Patient has active reflux esophagitis grade C or D. 
13. Evidence of eosinophilic esophagitis on endoscopy and/or 
histology 
14. Inner diameter of the esophagus measuring less than 18mm 
15. Report of uncontrolled coagulopathy with international 
normalized ratio (INR) > 2 or platelet count <75,000 platelets 
per µL (note: a complete blood count is not required for all 
subjects in this study) 
16. Patient is using anti-thrombotic agents that cannot be 
discontinued 7 days before and after therapeutic sessions 
17. Patient has an implantable pacing device (examples: 
automated implantable cardioverter defibrillator, 
neurostimulator, cardiac pacemaker) and has not received 
clearance for enrollment in this study by specialist 
responsible for the pacing device 
18. Patient has life expectancy less than 5 years 
19. Patient suffers from psychiatric or other illness and/or has a 
known history of unresolved drug or alcohol dependency 
that would limit ability to comprehend or follow instructions 
related to informed consent, post- treatment instructions, or 
follow-up guidelines 
20. Patient is considered to be part of a vulnerable population  
(e.g. prisoners or those without sufficient mental capacity) 
21. The subject has participated in an investigational drug or 
device research study within 30 days of enrollment that 
would interfere with this study 
22. Patient is pregnant or has plans to become pregnant in the 
ensuing 12 months (confirmation of non-pregnant status in 
women of child-bearing age and ability required with urine 
or blood test to be eligible) 
Study Procedures and 
Assessments 
Subject’s duration of involvement expected to be up to 60 months. 
The overall study duration expected to last a total of 6 years. 

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First 12 months will be indicated as “treatment phase”. 
Subject eligibility will be documented at a Baseline Qualifying Exam 
(BQE) as part of regular care.  Eligible subjects will be consented and 
will undergo primary circumferential radiofrequency ablation 
(12J/cm2 applied once with no cleaning of coagulum) within three 
months after BQE.  All subjects will return 3, 6 and 9 months later for 
a repeat standardized chromoendoscopy. Flat USLs found within the 
previously treated area will be biopsied and treated again with RFA. 
Patients with ESCC in biopsies, non-flat visible lesions or lesions 
otherwise suspicious for ESCC (exceedance of initial inclusion criteria) 
found during follow-up will undergo escape treatment (see section 
9.4.3 for description). If subsequent pathology assessment shows 
progression, defined as ESCC in any biopsy/resection specimen will be 
considered a failure of the primary endpoint. All subjects will return at 
12 months after the primary RFA for biopsy to evaluate the primary 
endpoint of “complete response.”  
Subsequent study duration after 12 months until 60 months will be 
defined as “follow-up phase.” 
Patients with a complete response at 12 months will directly enter the 
follow-up phase, whereas patients with residual ESCN at 12 months 
(“treatment failures”) will undergo escape treatment per 
investigator’s discretion under the hospital standards of care.  
The follow-up phase consists of yearly Lugol’s endoscopies with 
biopsies. If any flat USL will be found in TA, additional RFA treatment 
will be performed. If subsequent biopsies show MGIN or worse, an 
extra FU endoscopy will be performed within 3 months. A maximum 
of 4 consecutive RFA sessions are allowed and if CR won’t be re-
established thereafter, escape-treatment will be indicated. Escape 
treatment is directly indicated for patients with ESCC in biopsies, non-
flat lesions and lesions otherwise suspicious for ESCC (in line with the 
treatment phase) in TA. 
Escape treatment may consist of endoscopic mucosal resection 
(EMR), endoscopic submucosal dissection (ESD), or non-endoscopic 
therapy such as surgery, radiotherapy or chemotherapy, at the 
discretion of the physician under the hospital standard of care. As 
long as pathology indicates endoscopic treatment (i.e.: sm1 disease, 
well/moderate differentiation, no lymphovascular infiltration and 

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negative vertical resection margins), trial participation will be 
continued.  
All patients, regardless of failure of the primary endpoint or use of 
escape treatment during the trial, will be followed to study 
termination to assess secondary endpoints. A patient that has not 
been withdrawn or otherwise disqualified from the study, will have 
completed the study when the patient has finished all follow-up visits 
and the study has been terminated. 
Safety Assessments 
Adverse events will be reported by number, severity, and relationship 
to the study procedures and devices. 
 Statistics 
The primary study hypothesis is that 80% of treated subjects will have 
a complete response at 12 months after the initial treatment session 
(per protocol analysis). Descriptive statistics will be used to 
summarize primary and secondary endpoints along with 95% 
confidence intervals or precisions as appropriate.   
4. Introduction  
4.1. Background  
Esophageal cancer is the 9th most common cancer and the 6th most common cause of cancer death 
world-wide, with 442,000 new cases and 440,000 deaths in 2013 (1).   
The incidence rate of esophageal cancer varies widely by region, with highest rates found in Eastern and 
Central Asia and Eastern and Southern Africa (1, 2).  In China in 2011, esophageal cancer was the 4th 
leading cause of cancer death among both men and women, behind lung, liver, and stomach cancer (3). 
In high-risk areas of Central Asia and North-Central China, esophageal squamous cell carcinoma (ESCC) 
represents 90% of esophageal cancer cases, compared to approximately 26% among Caucasians in the 
United States where esophageal adenocarcinoma is more common (2). 
Risk factors for the development of ESCC include alcohol consumption, tobacco use, very hot drinks, and 
exposure to certain carcinogens found in salted vegetables and preserved fish (4, 5). 
ESCC develops from the epithelial cells that line the esophagus.  The precursor lesion to ESCC is 
esophageal squamous intraepithelial neoplasia (6, 7), also known as esophageal squamous cell neoplasia 
(ESCN), which is defined histologically as nuclear atypia (enlargement, pleomorphism and 
hyperchromasia), loss of normal cellular polarity, and abnormal tissue maturation (6). 

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Intraepithelial neoplasia is graded according to the proportion of the epithelial thickness that contains 
neoplasia (6). Lesions are categorized as either low-grade intraepithelial neoplasia (LGIN) or high-grade 
intraepithelial neoplasia (HGIN) depending on the extent of the neoplasia within the epithelium.  In 
China where the incidence of ESCC is high, many pathologists adhere to a three-tier classification for 
intraepithelial squamous neoplasia, as shown below. 
Table 1.  Three-tier Classification for Intraepithelial Squamous Neoplasia 
Class 
Description 
LGIN 
Intraepithelial neoplasia confined to the lowest third of the epithelium 
(mild dysplasia) 
MGIN 
Intraepithelial neoplasia involving the lower two thirds of the epithelium 
(moderate dysplasia) 
HGIN 
Intraepithelial neoplasia involving all thirds of the epithelium 
(severe dysplasia) 
 
Follow-up studies in China have shown that the rate of progression to ESCC differs significantly between 
the grades of intraepithelial neoplasia.  At 3.5 years and 13.5 years, respectively, the progression rates 
were 5% and 24%, respectively for LGIN; 27% and 50% for MGIN; and 65% and 74% for HGIN (8, 9). 
Once diagnosed, the prognosis for ESCC is often quite poor and depends on the stage of disease at 
diagnosis.  Worldwide 5-year survival rates (2001-2007) have been estimated at 37%, 18%, and 3% for 
localized, regional, and distant disease, respectively (7, 10). 
Thus, early screening and endoscopic treatment of MGIN and HGIN before the progression to ESCC may 
improve outcomes (11). 
Management of ESCN commences with an extensive staging work-up, which typically includes 
chromoendoscopy, multiple biopsies of the esophagus with targeting of unstained lesions (USLs) on 
chromoendoscopy and any irregularities of the mucosa, endoscopic resection (ER) of any mucosal 
irregularity, and in some cases endoscopic ultrasound and computed tomography (CT) to rule out deeply 
invading lesions or metastatic cancer (12). Review of all histopathology is performed to determine the 
grade of neoplasia and the depth of invasion, when applicable.  
Based on neoplastic progression rates, LGIN is generally managed with endoscopic surveillance and 
biopsies. Given the higher risk of progression to ESCC, patients with MGIN and HGIN are typically offered 
therapy.  These therapies have consisted of wide-field endoscopic mucosal resection (EMR) or 

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endoscopic submucosal dissection (ESD), focal ablation, and surgical esophagectomy.  Each intervention 
has specific risks and benefits that have been reported in the literature.  
For wide-field EMR, resecting more than a 4 cm length of the esophagus or involving more than 50% of 
the inner circumference has a very high stricture rate, and the procedure is technically demanding.  In 
addition, recurrence has been reported in up to 26% of cases (13).  
ESD allows en bloc removal of neoplastic tissue regardless of length (13, 14).  However, post-procedural 
side effects remain a challenge; strictures have been reported to complicate more than 90% of cases of 
esophageal ESD involving the entire lumen circumference, with resultant dysphagia requiring multiple 
sessions of dilations, with decrease in patients’ quality of life.  This procedure is even more technically 
demanding, requiring a high level of expertise, especially for large lesions. In addition, a long learning 
period is required to successfully perform ESD, and therefore this procedure can only be performed in 
high capacity institutions (15, 16).   
Both EMR and ESD enable en bloc resection of neoplasia and allow for a pathological assessment to 
evaluate the curability (13-16).   
Surgical esophagectomy is curative for ESCN, but the operative mortality at high-volume centers 
remains 3% or higher and the morbidity of the resulting gastric pull-up is substantial.  Morbidity and 
mortality rates may even be higher for cases located in the upper 2/3 of the esophagus (17). 
Radiofrequency ablation (RFA) is an endoscopically guided procedure which uniformly removes the 
diseased squamous epithelium without the need for removing the entire organ, as in surgery (11, 18, 
19).  RFA has been shown to safely, effectively, and durably eradicate early neoplasia in Barrett’s 
esophagus, the precursor of esophageal adenocarcinoma (20-22). Several studies have demonstrated 
the potential of RFA to treat early ESCN as well (11, 19, 23-25).  In a retrospective analysis of 65 patients 
with flat-type ESCN, RFA was also shown to provide similar effectiveness to ESD in the short-term 
treatment of ESCN, but with fewer adverse events, especially in lesions extending more than ¾ of the 
circumference (26). 
This clinical study will assess (i) the effectiveness of radiofrequency ablation (RFA) using the Barrx™ Flex 
Radiofrequency Ablation System in the eradication of diseased epithelium at 12 months post-treatment, 
and (ii) the durability of established eradication of disease during 5 years of follow-up, in subjects with 
early ESCN, defined as MGIN or HGIN.   
4.2. Purpose 
To measure the effectiveness and durability of the Barrx™ Flex Radiofrequency Ablation System in the 
eradication of diseased epithelium at 12 months post-treatment and up to 5 years in subjects with early 
flat-type -defined as type 0-IIb lesions on White Light Endoscopy (WLE) and Lugol’s chromoendoscopy- 

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esophageal squamous cell neoplasia (ESCN), defined as moderate-grade squamous intraepithelial 
neoplasia (MGIN) or high-grade squamous intraepithelial neoplasia (HGIN).  
5. Objectives and Endpoints 
5.1. Objectives 
5.1.1. 
Primary Objective(s) 
The primary objective is to measure the effectiveness of the Barrx™ Flex Radiofrequency Ablation 
System in the eradication of diseased epithelium at 12 months post-treatment in subjects with 
macroscopically flat-type – defined as Paris type 0-IIb on white light endoscopy (WLE) and Lugol’s 
endoscopy- early esophageal squamous cell neoplasia (ESCN), defined as moderate-grade squamous 
intraepithelial neoplasia (MGIN) or high-grade squamous intraepithelial neoplasia (HGIN). 
5.1.2. 
Secondary Objective(s) 
The secondary objectives are to assess safety, to measure durability of complete response during long-
term follow-up, and to measure overall ESCC progression and associated mortality after treatment.  
5.2. Endpoints 
5.2.1. 
Primary Endpoint 
The percentage of subjects with “complete response (CR),” defined as complete eradication of 
squamous histological abnormalities (MGIN or worse) within the treatment area (TA) at 12 months after 
the initial treatment session (per protocol analysis). Patients who show ESCC in biopsies or resection 
samples are defined as failures for this endpoint, even if subsequent biopsies at 12 months indicate CR. 
The primary study hypothesis is that 80% of treated subjects will have a complete response.  
 
 
Patients 
All 100 patients who are included in the cohort will be assessed for the primary endpoint. The run-in 
patients will not be included for the primary endpoint analysis. 
 
Biopsies 
Only biopsies obtained from the original USL bearing portion of the esophagus (the treatment area) will 
be used in the analysis for the primary endpoint analysis.  MGIN or worse noted in any biopsy from 
outside this region are not considered failures of ablation for the purposes of the primary endpoints. 

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5.2.2. 
Secondary Endpoint(s) 
1. The percentage of subjects with a sustained CR during long-term follow-up, defined as patients 
with a CR at 12 months that sustained this absence of squamous abnormalities (MGIN or 
worse) during all subsequent FU endoscopies through 60 months. 
2. Proportion of patients with CR after primary RFA, defined as absence of MGIN or worse in any 
of the biopsies from the treatment area, at the three month visit. 
3. Proportion of patients demonstrating progression within the treatment area (TA), defined as 
detection of ESCC in biopsy or resection specimen at any time within the first 12 months. 
4. Occurrence of serious adverse device effects (SADE) after RFA treatment. 
5. Proportions of “run-in” subjects, are defined as the first 5 subjects enrolled per endoscopist 
that is inexperienced with RFA or has had no RFA onsite training from CICAMS, with a CR at 3 
and 12 months after the initial treatment session, and with sustained CR during follow-up. 
6. Proportion of patients with CR at 12 months who subsequently developed recurrent disease in 
TA, defined as MGIN or HGIN for patients with MGIN at baseline, and MGIN or HGIN for 
patients with HGIN at baseline.  
7. Proportion of patients with CR at 12 months who subsequently developed progressive disease 
in TA, defined as ESCC in biopsy or resection specimen.  
8. Durability after reiterative RFA, defined as proportion of patients with a CR at 12 months who 
sustain or re-establish CR upon reiterative RFA treatment sessions during FU. 
9. Durability after additional endoscopic treatment, defined as proportion of patients with CR at 
12 months who sustain or re-establish CR upon endoscopic treatment (RFA and eventually in 
combination with EMR or ESD) during FU. 
10. Esophageal squamous cell cancer mortality. 
11. Proportion of patients demonstrating MGIN or worse outside the TA during treatment phase or 
follow-up. 
6. Study Design  
This clinical study will evaluate a subject population having macroscopically flat type (type 0-IIb) 
esophageal lesions with histological evidence of MGIN or HGIN in biopsy specimens obtained from the 
esophagus.  
6.1. Duration 
Enrollment of up to 100 subjects is expected to take 12 months.  Subject’s duration of involvement in 
the study is expected to be up to 60 months (estimated based on primary RFA plus 12 months of 
treatment phase and 48 months of follow-up). The overall study is expected to last a total of 6 years if 
enrollment is completed in a timely manner. 

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6.2. Rationale  
This study design is a prospective, multi-center, non-blinded, single-arm (non-randomized), post-market 
study.  This study design was selected given the desire to evaluate treatment efficacy (RFA) on a disease 
state (ESCN) with generally well understood natural history. Two recently published reports have 
evaluated the Barrx™ Flex Radiofrequency Ablation System for the eradication of ESCN (11, 18).  
Bergman et al. 2011 reported on 29 subjects (18 MGIN, 10 HGIN, and 1 ESCC) treated with 
circumferential RFA followed by focal RFA every 3 months until the complete histological eradication of 
MGIN or worse.  Two energy applications were administered at 10 J/cm2 or 12 J/cm2, with and without 
cleaning of the coagulum between passes.  The primary endpoint was complete response at 12 months, 
defined as the histological absence of MGIN, HGIN, or ESCC.  The rate of complete response was 86% at 
3 months after the primary RFA session and 97% at 12 months after the primary RFA session (11).  Four 
strictures (14%) were reported, all dilated to resolution.  The authors concluded that RFA was associated 
with a high rate of histological complete response for the eradication of ESCN with no neoplastic 
progression (11).  Because the stricture rate was slightly higher than typically reported in studies 
assessing RFA for the treatment of Barrett’s Esophagus, the authors concluded that technique and dose 
may contribute to stricture formation and proposed further evaluation of dosimetry to preserve the 
high rate of complete response while reducing the stricture rate (11). 
The authors continued the study to a total enrollment of 96 subjects (45 MGIN, 42 HGIN, and 9 ESCC).  
In that analysis, the complete response rate was 73% after 3 months (1 RFA session) and 84% after 12 
months.  The stricture rate was 21%.  However, when using a circumferential RFA dose of 12J/cm2 with 
one application and no cleaning of the coagulum, the stricture rate was only 6%, with complete 
response rates of 65% and 82% at 3 months and 12 months respectively. This regimen had additional 
benefit of procedural simplicity. However, only a total of 17 patients were treated with this regimen 
(18). 
Although preliminary, results for the long-term follow-up of this study will be shortly discussed. 
Sustained CR during 5 years follow-up was observed in 86% (67/78 patients). Recurrence occurred in 9% 
(7/78 patients, MGIN 5, HGIN 1). 5 were managed with RFA, one with ESD. Progression of baseline 
disease occurred in another 5% (4/78 patients; HGIN (n=1), sm-ESCC (n=3)); all were treated with ESD. 
Two progressor lesions were normally stained after Lugol’s and with repeatedly negative biopsies, and 
were therefore left untreated. Later both lesions were considered suspicious for cancer and escape 
treatment was performed, with pathology assessment for one case showed submucosal cancer buried 
under normal epithelial cells. Pathology assessment for the second case is pending. 
However, protocol violations during follow-up occurred in the majority of patients (59%) resulting in 
prolonged follow-up intervals, lesions left untreated or no adequate follow-up after detection of 
recurrent or progressive disease. This might have interfered with the results, and those might have been 
better with strict follow-up protocols. 

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The 12 patients with residual ESCN suffered a poorer prognosis. Fifty-eight percent (7/12 patients) 
developed progressive disease and were treated with either ESD (n=2) or non-endoscopic treatment 
(n=5), suggesting that RFA failures should directly be managed with an alternative treatment like EMR or 
ESD. 
Therefore, to further assess the safety, effectiveness, and durability of the Barrx™ Flex Radiofrequency 
Ablation System for the eradication of ESCN, the current study will employ methods similar to the 2 
studies reported above but with a consistent primary RFA dose of 12 J/cm2 with one application and no 
cleaning of the coagulum, and with subsequent 5-years follow-up according to strict study protocols.   
7. Product Description 
7.1. General 
The Barrx™ Flex Radiofrequency Ablation System uses radiofrequency (RF) energy to coagulate (ablate) 
the thin layer of diseased squamous epithelium of the esophagus.  RF is used for the purpose of 
coagulation and ablation in many other target tissue sites.  The heat generated by RF delivery results in 
tissue vaporization or coagulation.  Specific to the esophagus, the study device has been evaluated 
extensively in the treatment of Barrett’s esophagus, a glandular metaplastic disease of the esophagus 
related to gastroesophageal reflux disease. 
There are two Barrx™ Flex Radiofrequency Ablation Systems, each with a specific role in the treatment 
of diseased esophageal epithelium. 
Each part of the Barrx™ Flex Radiofrequency Ablation System is assembled in a Medtronic 
manufacturing facility. Each part of the process from the raw materials to the finished device is diligently 
controlled to ensure the quality and effectiveness of each product.  
7.2. The Barrx™ Circumferential Radiofrequency Ablation System 
The Barrx™ Circumferential Radiofrequency Ablation System includes an energy generator (Model 
1190A-115A), ablation catheters (Model 32041-18, 32041-22, 32041-25, 32041-28, 32041-31), and sizing 
balloons (Model 3441C). The circumferential ablation catheters will be used for independent treatment 
or main treatment.  The energy generator is used to inflate a sizing balloon positioned within the 
esophageal body, in order to measure the inner diameter of the targeted portion of the esophagus.  
Upon determination of the inner diameter size (mm), an appropriately sized ablation catheter is 
selected for ablation.  The ablation catheter has a balloon at its distal end, wrapped with an electrode 
having tightly spaced bipolar electrode bands.  The generator inflates this ablation catheter within the 
esophagus and delivers the controlled amount of RF energy to achieve the desired ablation effect.  At 

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the recommended energy density and number of applications, the maximum depth of ablation in 
previous studies is the muscularis mucosae. 
7.3. The Barrx™ Focal Radiofrequency Ablation System  
The Barrx™ Focal Radiofrequency Ablation System (Model 90-9100, 90-9200, 90-9300: additional models 
may be used for the study after CFDA approval is obtained) consists of a similar energy generator and a 
cap-based electrode that is mounted on the distal end of an endoscope. The focal ablation catheters will 
be used for supplementary topical treatment. This device is introduced with the endoscope to provide 
more focally targeted ablation of small areas of disease, either primary or secondary therapy.  The 
Barrx™ Focal Radiofrequency Ablation System is substantially equivalent to the Barrx™ Circumferential 
Radiofrequency Ablation System in terms of energy delivery and ablation depth, having the same 
electrode design.  The difference is that the surface area is smaller, allowing more focal selective 
ablation of residual diseased tissue, and this device is attached to the endoscope, rather than to a 
balloon catheter. 
7.4. Regulatory Approval in China 
The Barrx™ Flex Radiofrequency Ablation System obtained CFDA approval in January 2015 for the 
following indication for use:   The Barrx Flex System is indicated for the clinical treatment of lesions 
limited to the mucosa in the gastrointestinal tract, specifically flat intraepithelial neoplasia and Barrett’s 
esophagus. 
In this proposed clinical trial, the Barrx Flex RFA Generator will be utilized in accordance with the 
indications for use in the labeling for the device.  All study device catheters are single use, disposable 
medical devices.  See the Clinical Evaluation Report, REG-0023 and REG-0022 for additional information.  
7.5. Product Training Requirements 
Each Investigator participating in the clinical trial and the associated clinical study staff will receive 
training on the clinical protocol, IRB-approved ICF and additional training materials as per the study 
training plan, as well as hands-on training in the use of the Barrx™ Flex Radiofrequency Ablation System 
for the treatment of ESCN. All endoscopies will be observed by an expert from CICAMS. The tissue 
specimen review and histopathological interpretation will be centralized at CICAMS by expert 
pathologists who are the process developers, hence do not require additional training. 
7.6. Study Supplies and Device Accountability 
The Barrx™ Flex Radiofrequency Ablation System will be provided to each site upon Sponsor collection 
and approval of all required regulatory documentation.  Up to 8 catheters per patient (including both 

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balloon catheters and focal catheters) may be used during the study protocol (including both treatment 
phase and follow-up phase).  This number may be exceeded depending on extent of disease during 
follow-up and the number of energy applications needed per session. The device should be stored in a 
secure (locked) area under the appropriate storage conditions.  The study devices shall be used 
according to the CIP. Access should be limited to designated study staff only.  Device accountability logs 
will be provided to the site.  It is the site’s responsibility to document the receipt date, device 
identification, disposition of the product (per subject use including date, including amount used, amount 
remaining, etc.), transfer (if applicable) and return of all unopened expired or malfunctions study 
devices.  
8. Selection of Subjects 
8.1. Study Population 
The study cohort will be subjects with early ESCN, defined as MGIN or HGIN. 
8.2. Subject Enrollment 
Up to 100 subjects are planned for enrollment in the primary analysis cohort. With up to 10 sites and 1-2 
endoscopists at each site, up to 50 ‘run-in’ patients will be included in this study. Run-in patients are 
defined as up to 5 patients for each endoscopist that is inexperienced with RFA or has had no RFA onsite 
training from CICAMS. Data from the run-in patients will be analyzed separately from the cohort.  
 
Patients shall be reviewed according to the following inclusion and exclusion criteria.  An answer of “no” 
to any inclusion criterion or an answer of “yes” to any exclusion criterion disqualifies a subject from 
participating in this study.  Complete the Eligibility CRF. 
Definitive eligibility can only be assured during the primary RFA endoscopy, e.g. if a severe stricture or a 
non-flat abnormality is present, patient is not eligible. Therefore, the subject is considered as enrolled 
after insertion of the RFA catheter. 
8.3. Inclusion Criteria 
1. 
Patient is 18-85 years of age 
2. 
Patient has evidence of ESCN, within the last 3 months, patient demonstrated a new diagnosis 
or a reconfirmed diagnosis of squamous MGIN and/or HGIN of the esophagus  
3. 
On endoscopic examination, subject has at least one USL that measures at least 3 cm in at least 
one dimension and greater than ¼ of the esophageal circumference and has MGIN or HGIN on 
biopsy, confirmed by central pathologist 

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4. 
All lesions in the esophagus are completely flat (Paris type 0-IIb), both on WLE and Lugol’s 
chromoendoscopy 
5. 
The maximum allowable linear length of “USL-bearing esophagus” is 12 cm 
6. 
Baseline endoscopic ultrasound (EUS) (if applicable) shows no exclusionary findings for the trial 
7. 
Computed Tomography (CT) scan of chest and upper third of the abdomen (if applicable) shows 
no exclusionary findings for the trial 
8. 
Based on the judgment of the study endoscopist, the patient is eligible for treatment, follow-up 
endoscopy, and biopsy as required by the protocol 
9. 
EMR or ESD occurred > 3 months before enrollment, patients may be eligible for the study if 
procedure was curative (negative margins and no risk of lymph node involvement) and the 
patient has no other findings concerning for cancer 
10. The subject is willing to provide written, informed consent to participate in this clinical study 
and understands the responsibilities of trial participation 

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8.4. Exclusion Criteria 
1. 
Patient has  esophageal squamous cell carcinoma (ESCC) 
2. 
Any non-flat  (Paris type 0-I, 0-IIa, 0-IIc, 0-III) abnormalities anywhere in the esophagus 
3. 
Any abnormalities under WLE, Lugol’s chromoendoscopy or NBI that are suspicious for ESCC 
anywhere in the esophagus (e.g. ‘pink sign’ USL, defined as a color change after Lugol’s staining: 
initially whitish yellow and pink 2-3 minutes later) 
4. 
Any USL with MGIN or worse on biopsy outside the treatment area 
5. 
Esophageal stricture preventing passage of a therapeutic endoscope 
6. 
Prior endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) which 
occurred < 3 months before enrollment  
7. 
Any esophageal dilation in the past 12 months 
8. 
Any history of a non-squamous cell cancer of the esophagus, or any history of a squamous cell 
cancer of the esophagus (any stage)  
9. 
Any previous ablative therapy within the esophagus (photodynamic therapy, multipolar 
electrical coagulation, argon plasma coagulation, laser treatment, or other) or any radiation 
therapy to the esophagus 
10. Previous esophageal surgery, except fundoplication without complications (i.e., no slippage, 
dysphagia, etc.) 
11. Evidence of esophageal varices detected within last 6 months or at initial RFA procedure 
12. Patient has active reflux esophagitis grade C or D 
13. Evidence of eosinophilic esophagitis on endoscopy and/or histology 
14. Inner diameter of the esophagus measuring <18 mm 
15. Report of uncontrolled coagulopathy with international normalized ratio (INR) > 2 or platelet 
count <75,000 platelets per µL (note: a complete blood count is not required for all subjects in 
this study) 
16. Patient is using anti-thrombotic agents that cannot be discontinued 7 days before and after 
therapeutic sessions 
17. Patient has an implantable pacing device (examples: automated implantable cardioverter 
defibrillator, neurostimulator, cardiac pacemaker) and has not received clearance for 
enrollment in this study by specialist responsible for the pacing device 
18. Patient has life expectancy less than 5 years 
19. Patient suffers from psychiatric or other illness and/or has a known history of unresolved drug 
or alcohol dependency that would limit ability to comprehend or follow instructions related to 
informed consent, post- treatment instructions, or follow-up guidelines 
20. Patient is considered to be part of a vulnerable population (e.g. prisoners or those without 
sufficient mental capacity) 
21. The subject has participated in an investigational drug or device research study within 30 days 
of enrollment that would interfere with this study 
22. Patient is pregnant or has plans to become pregnant in the ensuing 12 months (confirmation of 
non-pregnant status in women of child-bearing age and ability required with urine or blood test 
to be eligible) 
 

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2 Only recurrent or progressive disease during FU will be assessed by a second expert pathologist. This 
includes biopsies indicating recurrent or progressive disease, and eventual EMR/ESD/surgery specimens. 
3 If persistent after 4 additional RFA sessions 
4 Study completion is defined as when all follow-up visits have been completed, all data has been 
entered, reviewed, monitored, and database has been locked.  
 
9.1.1. 
Tissue Specimen Processing and Histopathological 
Interpretation 
In order to ensure uniform tissue specimen preparation, staining technique, and histopathological 
evaluation, all study tissue specimen processing using the same laboratory practices.  All slides will be 
stained with hematoxylin and eosin. 
All baseline tissue specimens obtained from the esophagus will be independently reviewed by two 
expert GI pathologists at the lead study site (CICAMS) to confirm eligibility per the inclusion and 
exclusion criteria.  Eventual discrepant results will be resolved by joint reading. All results are entered on 
the pathology CRF. 
All biopsies obtained after the initial RFA procedure at any time of the study will also be reviewed by the 
lead study site pathologist. This includes biopsies from all USLs, biopsies from a normal staining post-
RFA esophagus to confirm CR, and any new USL or lesion outside the treated area (TA). All results are 
entered onto the pathology CRF.  
All biopsies obtained at the 12 month primary endpoint, and all pathology specimens for recurrent or 
progressive disease (including biopsies and EMR/ESD/surgical specimens, if applicable) will be 
independently read by two expert gastrointestinal (GI) pathologists at the lead study site with results 
entered on a CRF.  Any discordance between reviewer results will be resolved with a non-blinded 
consensus review between the pathologists. 
For histopathological interpretation for specimens obtained at baseline or follow-up sessions, as 
described above, each specimen from each slide will be read out as follows according to the worst cell 
type observed: 
1. 
Squamous epithelium without intra-epithelial neoplasia 
2. 
Glandular (gastric or intestinal metaplasia) +/- normal squamous epithelium 
3. 
Squamous epithelium with low-grade intra-epithelial neoplasia 
4. 
Squamous epithelium with moderate-grade intra-epithelial neoplasia 
5. 
Squamous epithelium with high-grade intra-epithelial neoplasia 
6. 
Invasive squamous cell carcinoma (depth and grade determined if possible, given limitations 
of biopsy method versus EMR or ESD) 
In a biopsy fragment where multiple grades of intraepithelial neoplasia co-exist, the highest grade will 
represent the diagnosis for that biopsy fragment.  The final subject diagnosis is represented by the worst 

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histological grade of any fragment for that biopsy session.  The study site data will be recorded on a case 
report form that will include all individual biopsy diagnoses, all lesion diagnoses, and the final subject 
diagnosis for the individual endoscopy session. 
9.2. Subject Screening  
If a possibly eligible patient is detected during a regular care endoscopy, a member of the research team 
will enter those subjects into the provided screening log.  If the endoscopy fulfills all BQE requirements 
listed below, this endoscopy is mentioned as the BQE. Additional tests like EUS or CT will be performed if 
clinically indicated. More detailed eligibility criteria will be assessed by reviewing medical records and 
subject history.   
Baseline Qualifying Endoscopy (BQE)  
It is permissible for a site to have performed the baseline qualifying endoscopy prior to a 
particular subject’s enrollment as standard of care, provided the time interval was less than 3 
months and at least 1 week prior to primary RFA and all steps as outlined below were 
completed.  Otherwise, the baseline qualifying endoscopy will be performed prospectively. 
1. Start WLE to document landmarks and to check all selection criteria that can be assessed 
endoscopically (e.g. appearance of the lesion, strictures, presence of varices, eosinophilic 
esophagitis, reflux esophagitis, etc.) 
2. Upper endoscopy using Lugol’s solution ~1.25% is performed to identify all diseased squamous 
epithelium of the esophageal body.  The only allowable lesions are type 0-IIb. 
3. Confirmation of at least one flat (type 0-IIb) USL with a minimum diameter greater than or equal 
to 3 cm in at least one dimension and greater than 1/4 of esophageal circumference (including a 
USL mosaic where the entire lesion is at least 3 cm in one dimension). At least one biopsy from 
at least one such a ‘qualifying USL’ must demonstrate MGIN or HGIN, and no biopsy can 
demonstrate ESCC. 
4. Confirm that no abnormalities under WLE or Lugol’s chromoendoscopy are suspicious for ESCC 
anywhere in the esophagus (e.g. any non-flat [Paris type 0-I, 0-IIa, 0-IIc, 0-III] abnormalities; ‘pink 
sign’ USL, defined as a color change after Lugol’s staining: initially whitish yellow and pink 2-3 
minutes later). No lesions suspicious for ESCC may exist in the esophagus. 
5. Confirmation that the total linear length of the esophagus containing USLs is 12 cm or less is 
required. This area (plus one additional centimeter proximal and distal) defines the Treatment 
Area (TA) that will be treated with RFA at the primary RFA session.  Only flat type (type 0-IIb) 
USLs containing LGIN or less may be present outside the TA. 
6. Only one continuous TA is permitted per subject, and may by definition include any number of 
individual USLs.  For example, two 4 cm TAs may not be created to treat two separate areas of 
USLs. 
7. The location of the USLs and targeted TA will be documented by obtaining video recordings and 
still images (with high-resolution endoscopy (optional) and Lugol’s staining) of the entire TA at 1 
cm intervals. The insertion depth of the endoscope at the proximal and distal margins will be 
documented in the CRF. Locations of individual USLs are described in the CRF. 
8. Biopsies from the BQE and USLs are obtained using standardized localization technique as 
described in section 10.4.1 and are processed per instructions in section 10.1.1 : 

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o Biopsies are obtained first from the distal portion of the esophagus, working 
proximally so as to minimize obscuring subsequent biopsy targets with blood 
from the biopsy sites. 
o The maximum number of biopsy specimens per specimen jar is 2 
 
Targeted biopsies are obtained from each USL and each USL should 
have a unique jar(s) for its biopsies. 
9.3. Subject Consent 
If the subject is deemed eligible after BQE and medical record reviewing, the research team member 
may then approach the potential subject to discuss participation in the study, including background of 
the proposed study, inclusion and exclusion criteria, the benefits and risks of the procedures and the 
follow-up requirements.  If the study is of interest to the subject, the informed consent form (ICF) will be 
discussed and presented.  The subject must sign the ICF prior to enrollment.  This form must have prior 
approval of institutional review board (IRB)/ ethics committee (EC) for all participating sites.  Failure to 
obtain informed consent will render the subject ineligible for the study.  
Patients will be approached to obtain written informed consent prior to any study specific procedures 
being performed.  The purpose of the study and the benefits and risks of the procedures will be 
explained to the subject in their local language.  The consent process must be documented accordingly 
in the medical record.  Patients who agree to study participation must sign an IRB/EC-approved ICF.  
Subjects will be informed that their participation in this study is voluntary and they may refuse to 
participate or discontinue from the study at any time.  Subjects will be given the opportunity to ask the 
investigator questions so that they are adequately informed about the research.  A copy of the signed 
informed consent must be provided to the subject and the informed consent process will be 
documented in source documents. 
If new information becomes available that may affect a subject’s decision to continue to take part in the 
study, this information will be discussed with the subject by the investigator. 
Subjects will be assured that they may withdraw from the study at any time for any reason. 
9.4. Treatment Assignment 
9.4.1. 
Treatment Phase 
Patient History 
After the subject signs the ICF, the Patient History CRF is completed for that subject. 

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Baseline Qualifying Tests 
Results from the subject’s BQE including pathology review and baseline staging tests (EUS and/or CT 
where applicable) are entered onto the Baseline Qualifying CRF. Afterwards, definitive eligibility will be 
assessed by completing the Eligibility CRF. 
Primary Radiofrequency Ablation 
If the subject is found to be eligible for the study after BQE, central review of the BQE pathology results 
and reviewing medical records, he or she will proceed to the primary ablation session within 1 week - 3 
months after BQE. Primary RFA will be observed by an expert from CICAMS. 
1. Start WLE to document landmarks and to check all selection criteria that can be assessed 
endoscopically (e.g. appearance of the lesion, confirmed absence of non-flat lesions, strictures, 
presence of varices, eosinophilic esophagitis, reflux esophagitis, etc.) 
2. Lugol’s staining and assessment of all endoscopic selection criteria 
3. Assessment of definitive eligibility of the subject. 
4. Marking on the estimated TA with electrocoagulation (preference is not to use APC for this). 
5.  Measuring will be performed. If the inner diameter of the esophagus is less than 18mm, the 
patient is ineligible for the study. 
6. Primary RFA is performed with the Barrx™ Circumferential Radiofrequency Ablation System.  
The ablation zone must encompass the entire TA. The energy density setting is 12 J/cm2, applied 
once, using the default power set by the RF generator according to catheter size, with no 
cleaning of coagulum. 
7. Beginning proximally, the electrode is deployed so that the proximal margin of the electrode is 
aligned with the proximal marker.  The balloon is automatically inflated and ablation energy is 
delivered. 
8. After automated deflation of the balloon, air is insufflated by the endoscope and the catheter 
carefully advanced distally avoiding denuding of the ablated mucosa.  The proximal margin of 
the electrode is aligned with the distal margin of the first ablation zone minimizing overlap 
between zones.  Ablation is performed. 
9. These steps are repeated until the ablation overlaps the distal markings. 
10. Tattoos are placed in at least 2 quadrants at the most proximal and distal extent of TA (providing 
at least 1 cm margin between proximal tattoo and most proximal USL, and at least 1 cm margin 
between distal tattoo and most distal USL). 
All data from the RFA procedure are entered onto the Endoscopy CRF.  
 
3, 6, 9 months (from primary RFA, +/- 4 weeks) Follow-up Endoscopy, Biopsy, and 
Additional RFA 
After baseline treatment, patient will return for standardized endoscopies at 3, 6 and 9 months, (from 
primary RFA, +/- 4 weeks), to endoscopically assess the TA for USLs using Lugol’s iodine. All endoscopies 
in the treatment phase will be observed by an expert from CICAMS. The following two treatment 
scenarios are possible based on the presence or absence of USLs. For every endoscopy, the Endoscopy 
CRF, the Table of findings CRF and the Pathology CRF will be completed. 

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Scenario #1: No USLs are present 
At the 3 months FU visit, (from primary RFA, +/- 4 weeks), biopsy sampling of TA will be performed to 
confirm absence of occult MGIN or worse:  Using a maximum capacity forceps or larger (for example, 
Boston Scientific Radial Jaw 3 or 4) and commencing at the most proximal extent of the original USL-
bearing portion of the esophagus and tattoos as reference points, 2 biopsy specimens are obtained for 
every 2 cm segment of the original USL-bearing esophageal segment.  The most distal biopsies are 
obtained 1 cm above the distal Tattoo.  All fragments from a particular 2 cm level are placed in the same 
pathology specimen container and labeled as to their location (cm from the incisors).  In this manner, 
the portion of the esophagus that originally contained USLs is well-sampled (tissue at baseline that was 
both USL and non-USL), with the allowance of focusing some biopsies at each level in certain areas 
based on original USL location (referring to baseline imaging and CRF’s). Re-tattoos will be performed if 
necessary. 
Example:  Baseline USL-bearing portion of the esophagus is 30-36 cm (therefore, TA 29-37 cm).  A total of 
6 biopsies would be obtained (approximately two fragments each at 30-32, 32-34, and 34-36).  Biopsies 
of the 1 cm “safety zone” at either end of TA are not obtained in any biopsy session. 
At the 6 and 9 months FU visit, (from primary RFA, +/- 4 weeks), no biopsies will be performed from 
normally stained TA. 
No RFA is applied in “Scenario #1: no USLs are present.”  
In the very unlikely scenario that any biopsy subsequently shows MGIN+ despite a normally stained 
esophagus, the entire TA is treated once again with circumferential or focal RFA (to ensure complete 
treatment of any occult neoplasia.)   
Scenario #2: USLs are present in the TA 
If there are residual flat USLs within the original TA, the investigator records the extent of the USLs 
(length, diameter, location) and obtains biopsies of each USL starting distally and moving proximally as 
follows: 
For each two centimeters in length, 1 level of biopsies will be performed. The number of biopsies per 
level depends on the circumferential extent of the USL as follows:  
o <25% of circumference: 1 biopsy per level 
o 25 – 49% of circumference: 2 biopsies per level 
o 50 – 74% of circumference: 3 biopsies per level 
o ≥75% of circumference: 4 biopsies per level. 
Example: for a USL of 3 centimeter in length covering 60% of circumference, 2 levels with 3 biopsies per 
level will be performed, summing up to a total of 6 biopsies. 
Each set of unique USL samples are placed in individual containers, and labeled as to their location. If 3 
or more biopsies are obtained from a single USL, use multiple jars for that USL with a maximum of 2 
biopsies per jar.  The investigator designates the staining characteristic of each tissue area prior to 
biopsy, and enters this information on the Table of findings CRF.  It is presumed that biopsies from USLs 
are unstained, while biopsies from the non-USL TA are “stained”.  The CRF also contains information 
about each specimen/USL location. 

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Treatment of USL 
In general, all residual flat USLs during follow-up will be treated with RFA.  
USLs that are deemed clearly reactive can be biopsied without need for additional treatment. Clearly 
reactive USLs will be defined as any USL with stain code III (lightly stained) that is deemed as non-
suspicious for ESCN and reactive after RFA on both WLE and NBI by the Investigator. If a USL will be 
deemed reactive and therefore left untreated, and if subsequent biopsies do show MGIN or worse, the 
USL will then be treated on the next endoscopy, independent of the endoscopic appearance. 
If subsequent biopsies show cancer, patients is defined as progressor will be considered a failure for the 
primary endpoint and he will be offered escape treatment (see section 9.4.3. for description), at the 
discretion of the physician under the hospital standard of care.  
If an indication for additional RFA exists, the investigator will determine whether to provide secondary 
RFA with the circumferential or focal device, based on the extent of disease: 
• 
If lesions involve more than 3/4 of the circumference, circumferential RFA will be used 
• 
If lesions involve less than 3/4 of the circumference, focal RFA will be used 
o It is presumed that all secondary RFA procedures will be performed with the focal 
device, and this presumption is reflected in Figure 1. 
If focal RFA is selected, it is important to note that the effect of Lugol’s may significantly wane during the 
biopsy procedures therefore it may be necessary to reapply the Lugol’s in order to target the remaining 
USLs.  Or simply use the biopsy sites for targeting.  Each USL is treated so that the ablation effect 
overlaps at least 5 mm onto the normal staining esophageal mucosa surrounding the USL.  The energy 
density setting is 12 J/cm2 and the power density setting is 40 W/cm2.  Each USL is ablated 3x without 
changing the position of the catheter.  Upon completing focal RFA of USL(s), biopsies are obtained from 
the TA avoiding all acute RFA sites.  Two biopsy fragments are obtained from every 2 cm of the original 
USL-bearing esophagus that was not treated at this session (see Figure 1). 
Example:  TA from 30-40, USL bearing esophagus 31-39.  One USL at 3 months from 31-32.  Sample USL, 
then RFA USL.  Then obtain 2 biopsy fragments from every 2 cm starting at 33-35, 35-37, and 37-39 cm.  
The area of the USL is avoided (31-33 cm). 
In the unlikely event that circumferential RFA is selected for a follow-up RFA, the entire extent of 
original TA is treated, using same technique as at the primary RFA session.   
If necessary, a maximum of four RFA sessions will be performed in total for each patient in this study. If 
USLs with MGIN or worse in the TA persist after four sessions, the subject is considered a failure for the 
primary endpoint. Such patients will undergo escape treatment. 
Scenario #3: Lesions Suspicious for ESCC Are Present in the TA 
If any non-flat USL (Paris type 0-I, 0-IIa, 0-IIc, 0-III) is detected, independent of its staining 
characteristics upon Lugol’s staining, or WLE, NBI or Lugol’s chromoendoscopy show a lesion 
suspicious for ESCC (e.g. ‘pink sign’ USL, defined as a color change after Lugol’s staining: initially 
whitish yellow and pink 2-3 minutes later), or if previous biopsies from this lesion showed ESCC, 
subject will be managed with escape treatment (see section 9.4.3 for description), at the discretion of 
the physician under hospital standard of care depending on the lesion type. If histology is needed before 

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escape treatment, a keyhole biopsy should be performed, but the Investigator can perform escape 
treatment if deemed necessary, regardless of the biopsy result. The patient will be considered a failure 
for the primary efficacy endpoint only if escape treatment histology shows progression to ESCC. If 
histology does not show ESCC, the patient will return in 3 months from escape treatment for possible 
RFA and will be eligible for success in the primary endpoint. For continuation on trial, please refer to 
section 9.4.3. 
Scenario #4: USLs are present outside the TA 
If any new USL(s) is (are) detected outside the TA during follow-up prior to 12 months, it is biopsied and 
the biopsy fragments are placed in a separate container and labeled as to their location.  This finding 
does not alter the plan for RFA inside TA for that particular procedure, and the USL outside the TA is 
treated according the standard practice under hospital standard of care.    
During all endoscopies, re-tattoos will be performed if necessary. If clinically indicated, extra 
endoscopies can always be performed. 
12 Months Follow-up Endoscopy 
No RFA is provided to any subject at the 12-month primary endpoint biopsy visit. 
For the biopsy methodology for the primary endpoint: 
1. 
If there are no USLs within the TA, see Section 10.4, “Scenario #1:  No USLs are present” 
2. 
If there are one or more persistent USLs within the TA, see Section 10.4, “Scenario #2: USLs 
are present” 
If there are any USLs discovered outside the original USL bearing esophagus, these may be biopsied or 
resected, but must be submitted in separate containers are not considered in the primary endpoint 
analysis.  
Patients with a CR at 12 months will enter the follow-up phase as described in figure 2 and section 9.4.2. 
Patients with residual ESCN at 12 months will be defined as treatment failures, and will undergo escape 
treatment within 3 months (+/- 4 weeks). If CR will be re-established after escape treatment, patients 
will stay in the trial and will be followed-up and treated if necessary, according to figure 2. If non-
endoscopic treatment is performed at 12 months, or if pathology indicates non-endoscopic treatment, 
patients won’t be treated and/or followed-up according to the study protocol, but will still be followed-
up until 5 years after baseline to assess secondary endpoints. 
 

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9.4.2. 
Follow-up Phase 
All subjects with a CR at 12 months will immediately enter follow-up phase. All patients with residual 
ESCN at 12 months who achieve CR upon endoscopic escape treatment will also enter the follow-up 
phase. All patients who progress to ESCC and require escape treatment during the trial, including non-
endoscopic, will enter the follow-up phase regardless of primary endpoint failure to assess secondary 
endpoints. All endoscopies in the follow-up phase will be observed by an expert from CICAMS. 
Follow-up procedures include (fig 2): 
Annual follow-up endoscopy visit: 
• 
upper endoscopy 
• 
re-tattoo the TA, as necessary 
• 
stain the esophagus with Lugol’s solution 
• 
map the entire esophagus for USLs 
For TA:  
i. If no USLs in TA, perform biopsies of TA (2 biopsy specimens are obtained for 
every 2cm segment of the original USL-bearing esophageal segment) 
ii. If unstained lesion (USLs) are found in the TA, each lesion will be biopsied (as 
described in section 9.4.1, scenario #2). In addition, 2 biopsy specimens are 
obtained for every 2cm segment of the original USL-bearing esophageal 
segment that does not now contain USLs. All flat USLs will be treated with RFA. 
One exception needs to be addressed in line with the treatment phase: clearly 
reactive USLs may be biopsied and left untreated.  
iii. Any non-flat lesion or lesion suspicious for ESCC (e.g. ‘pink sign’) in TA will be 
treated with escape treatment (see section 9.4.3 for description), at the 
discretion of the physician under hospital standard of care.   
iv. Subsequent follow-up will be determined by pathology results: 
1. If biopsies show LGIN or less: next follow-up endoscopy will occur in a 
year.  
2. If any biopsies are found to have MGIN or HGIN, endoscopy with RFA 
will be repeated at 3 month intervals until resolution of MGIN or HGIN is 
demonstrated. If patient still harbors MGIN or HGIN after a maximum of 
4 consecutive 3-monthly RFA sessions, escape treatment will be 
performed.  
3. If ESCC is found in any biopsy, the patient will be treated with escape 
treatment. 
Outside the TA: 
v. If no USLs, biopsies will not be necessary 
vi. If USLs are found outside the TA, each lesion should be biopsied and treated per 
investigator’s discretion. 

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1. If any biopsies from outside the TA are found to be MGIN or worse, 
patient will be treated and followed-up at the discretion of the 
physician under hospital standard of care.  
 
• 
Central pathology review of biopsies for all biopsies or resection specimens during FU, 
with independent reading from two pathologists in case of recurrent or progressive 
disease. 
• 
Safety assessment 
If clinically indicated, Investigator may always perform extra endoscopies in addition to figure 2. 
 
9.4.3. 
Escape treatment: Endoscopic (EMR or ESD) or Non-
Endoscopic Therapy during Treatment or Follow-up Phase 
Several indications for escape treatment exist: 
• 
Any non-flat lesion (Paris type 0-I, 0-IIa, 0-IIc, 0-III) during treatment or 
follow-up phase  
• 
Any abnormality under WLE or Lugol’s chromoendoscopy that is 
suspicious for ESCC (e.g. ‘pink sign’ USL, defined as a color change after 
Lugol’s staining: initially whitish yellow and pink 2-3 minutes later) 
• 
ESCC in biopsies during treatment or follow-up phase (defined as 
progression of disease) 
• 
Presence of MGIN or worse in any biopsies from TA at the 12 months 
endoscopy 
• 
Persistent MGIN or worse during follow-up phase despite a maximum of 
4 consecutive 3-monthly RFA sessions  
• 
If clinically indicated per Investigator’s discretion 
Escape treatment can be performed endoscopically (EMR or ESD), or non-endoscopically (surgery, 
radiotherapy or chemotherapy) per investigator’s discretion under the hospital’s standards of care. All 
patients, regardless of treatment used or failure of the primary endpoint, will be followed to study 
termination for assessment of secondary endpoints: 
• 
Patients who undergo non-endoscopic therapy will be considered a 
failure for the primary endpoint, but will be tracked through the 5-year 
follow-up to assess secondary endpoints. 
• 
For patients who undergo endoscopic treatment, final pathology is 
required: 
o If the disease stage is eligible for endoscopic escape treatment 
(i.e.: good to moderate differentiation and negative vertical 
resection margins and m1/m2/m3/sm1 disease and without 
lymphovascular infiltration), further treatment and/or follow-up 
endoscopies after the escape treatment will occur according to 

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Discharge Instructions after RFA Procedures 
• Liquid acetaminophen with narcotic per oral as needed for pain 
• Liquid antacid, lidocaine, and sucralfate slurry or Almagate Suspension for first 5 
days, as needed  
• Liquid diet for 3 days, then soft diet for 4 days, then normalize 
• At the direction of the physician, anti-thrombotic agents should be avoided for 7 
days before and after any RFA procedure. 
• All patients commence proton pump inhibitor (PPI) medication (esomeprazole 
40 mg bid) after the Primary RFA to allow restoration of a normal epithelium.  
Patients will continue PPI after each RFA session until endoscopy and biopsy 
demonstrate no further MGIN+ and no need for further RFA. 
• Contact physician for any vomiting, shortness of breath, pain not controlled on 
medication, fever, or bleeding. 
• Subject is educated to not eat very hot foods including soups, and not drink very 
hot liquids as such behavior can delay healing and potentially promote stricture 
formation and prolonged pain.  Subject is instructed to not eat or drink anything 
in which they are unable to comfortably place their finger for at least 10 
seconds prior to ingesting. 
9.5. Assessment of Efficacy 
The primary effectiveness will be measured as the percentage of subjects with complete response 
within the treatment area. The response rates and 95% confidence intervals will be summarized. Run-in 
subjects will be summarized separately. 
9.6. Assessment of Safety 
For safety analyses, adverse events will be summarized using frequency counts and percentages. 
Descriptive statistics will be provided by event type, severity and relationship to study procedures and 
devices. Event rates along with 95% confidence intervals will be provided based on subject or event. 
Individual listings of adverse events, including event type, start date, duration, severity, and device-
relatedness will be provided as appropriate. 
9.7. Recording Data 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. All data recorded on the eCRF will be supported by a source document. Examples of 
source data are hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 

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or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
This study will utilize electronic Case Report Forms (eCRFs). The study CRF is the primary data collection 
instrument for the study. All data requested on the CRF must be recorded. All missing data must be 
explained.   
9.8. Deviation Handling 
The investigator must notify Medtronic and the reviewing IRB of any deviation from the protocol when 
specific to the protection of the life or physical well-being of a subject in an emergency. Such notice must 
be given as soon as possible, but in no event later than 5 working days after the emergency has occurred. 
Except in such an emergency, prior written approval by Medtronic and the site IRB/EC is required for 
changes in or deviations from the plan. All deviations will be reported per the site’s IRB/EC deviation 
policy. Should any deviations from the protocol occur, these will be reviewed by Medtronic for their 
clinical significance. If the event is performed without written approval from all parties, the investigator 
may be terminated from the study. Corrective and preventive actions and principal investigator 
disqualification will be included in the Clinical Study Management Plan. If further escalation is needed, it 
may result in Corrective and Preventive Action (CAPA), suspension, or termination. When conducting 
clinical research, an investigator must comply with all applicable rules and regulations.  The falsification 
of information, actions determined to fraudulent or criminal in nature, failure to comply with 
investigator’s responsibilities, failure to appropriately fulfill all study-related responsibilities or failure to 
disclose relevant financial interests may lead to the investigator being disqualified. If it is determined that 
there is investigator fraud, or strong evidence of fraud, the course of action may include, but is not limited 
to: potential exclusion from analyses, site closure, notification of the responsible IRB/EC of the actions to 
be taken, notification of key stakeholders and/or study team of the actions to be taken, notification of 
appropriate regulatory authority(ies) and/or restrictions on future participation in clinical studies. 
Protocol deviations identified by the Monitor during a monitoring visit should be discussed with the 
Principal Investigator/ Study staff involved at the time of discovery. Protocol non-compliance will be 
documented accordingly and communicated again in writing to the site within the follow-up letter. 
Monitors will also escalate the deviations significant in nature to the study manager (or designee), as soon 
as possible. 
9.9. Subject Withdrawal or Discontinuation  
Any subject who wishes to withdraw from this investigation on his/her own accord and for whatever 
reason is entitled to do so without obligation and prejudice to further treatment.  In addition, the 

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Principal Investigator or study endoscopist may decide for reasons of medical prudence, to withdraw a 
subject. 
In either event, the Principal Investigator or study endoscopist will clearly document the date and 
reason(s) for the subject’s withdrawal from this investigation on the Study Exit CRF and should indicate 
whether or not he considers it related to the device. 
Every attempt will be made to contact subjects who are noncompliant.  Subjects will be considered “Lost 
to Follow-up” once the following steps have been taken: 
1. 
Two phone calls should be made to the subject.  Each attempt should be clearly documented in 
the source documents and the response or lack thereof should be captured.   
2. 
If there is no response to the phone calls, then an official letter should be written to the 
subject.  A copy of the letter should be retained in the subject’s source document. 
3. 
Additionally, the site should attempt to reach out to the subject’s general practitioner to 
determine the status of the subject. 
4. 
After a period of four (4) weeks, after all of the above steps have been taken, the subject will be 
considered “Lost to Follow-up”.  The sponsor should be notified and the Study Exit CRF should 
be completed.   
 
All patients, regardless of failure of the primary endpoint or use of escape treatment during the trial, will 
be followed to study termination to assess secondary endpoints. A patient that has not been withdrawn 
or otherwise disqualified from the study, will have completed the study when the patient has finished all 
follow-up visits and the study has been terminated. 
9.10. Definitions 
-CR = complete response 
Absence of MGIN or worse in biopsies from TA at a single endoscopy. 
- Escape treatment 
Escape treatment is indicated for lesions with (i) ESCC in biopsies, (ii) non-flat lesions, or (iii) lesions 
otherwise suspicious for ESCC (e.g. pink-sign positive lesions). Escape treatment will be performed by 
investigator’s distinction and per hospital’s standards of care. Subsequent pathology assessment 
determines whether patient is defined as progressor and failure for the efficacy endpoint. 
- Progressive disease 
This term is applicable during the whole study. Progressive disease is defined as ESCC in any biopsy or 
resection specimen. Progressive disease on biopsy will always be treated with escape treatment. 

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Patients with progressive disease within the first 12 months are a failure for the primary efficacy 
endpoint, whereas progression patients in subsequent 4 years of follow-up are a failure for the 
durability endpoint. Progressive disease can be classified into 2 categories based on pathology: 
• 
Eligible for endoscopic treatment, if all of the following characteristics 
are met: good to moderate differentiation, negative vertical resection 
margins, m1/m2/m3/sm1 disease and without lymphovascular 
infiltration. 
• 
Exceeding the limits for endoscopic treatment, if any of the following 
characteristics was found: poor differentiation, positive vertical 
resection margins, sm-2 or sm-3 invasion or lymphovascular invasion. 
 
- Treatment failure 
This term is applicable to the first 12 months of study. All patients with residual ESCN at the 12 months 
endoscopy, and patients who progressed to ESCC before 12 months, will be defined as treatment 
failures. 
- Sustained CR 
This term is applicable during follow-up, to all patients that were not defined as treatment failures at 12 
months. Sustained CR is defined as sustained eradication of MGIN or worse in biopsies from TA, during 
all FU endoscopies until 60 months. 
- Recurrent disease 
This term is applicable during follow-up, to all patients that were not defined as treatment failures at 12 
months. Recurrent disease is defined as flat (Paris type 0-IIb) USLs with MGIN or HGIN in biopsies from 
TA during FU, independent of baseline pathology. Recurrent disease will be treated with RFA initially, or 
escape treatment if persistent, as described in section 9.4.3 
10. Risks and Benefits 
10.1. Potential Risks 
Potential risks of the use of the Barrx™ Flex Radiofrequency Ablation System for treatment of ESCN have 
been evaluated in Clinical Evaluation Reports for the Barrx™ Circumferential Radiofrequency Ablation 
System (REG-0023, Revision C, August 12, 2014), the Barrx™ Focal Radiofrequency Ablation System 
(REG-0022, Revision B, December 6, 2013), and the product Instructions for Use (Ref 32041-18, 32041-
22, 32041-25, 32041-28, 32041-31, 3441C; Version 717-0050-01 B and Ref 90-9100, 90-9200, 90-9300; 
Version 717-0053-01 B). 

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10.2. Potential Benefits 
Potential benefits to the subject include the potential for complete eradication of ESCN, which has been 
reported in the literature with rates between 50% and 100% (11, 18, 19, 23-25, 27, 28). 
10.3. Risk-Benefit Rationale 
As described in the Clinical Evaluation Reports referenced above, risk analyses for the Barrx™ 
Circumferential Radiofrequency Ablation System and the Barrx™ Focal Radiofrequency Ablation System 
was conducted in compliance with ISO 14971‐Risk Management for Medical Devices.  The overall 
evaluation of the residual system risks found no unacceptable design or process hazards of significant 
impact to the safety and reliability of the Barrx™ Radiofrequency Ablation System.  The residual risks 
have been rated as either broadly acceptable or as low as possible. 
11. Adverse Events and Device Deficiencies 
11.1. Definitions/Classifications 
Adverse Events 
Adverse event (AE) definitions used in this study are based on ISO 14155:2011 (Clinical Investigation of 
Medical Devices for Human Subjects -- Good Clinical Practice).  Adverse events will be collected starting 
from enrollment into the study. 
Adverse Event (AE) 
An Adverse Event is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device.  
NOTE 1 This definition includes events related to the investigational medical device or the comparator. 
NOTE 2 This definition includes events related to the procedures involved. 
NOTE 3 For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
Serious Adverse Event (SAE) 
A Serious Adverse Event is an adverse event that has 
a) Led to death, 
b) Led to serious deterioration in the health of the subject, that either resulted in 
1) A life-threatening illness or injury, or 

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2) A permanent impairment of a body structure or a body function, or 
3) In-patient or prolonged hospitalization, or 
4) Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the clinical 
investigational plan, without serious deterioration in health, is not considered a serious adverse event. 
Adverse Device Effect (ADE) 
An Adverse Device Effect is an adverse event related to the use of an investigational medical device.  
NOTE 1 This definition includes adverse events resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation, or any malfunction of the investigational 
medical device. 
NOTE 2 This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
Serious Adverse Device Effect (SADE) 
 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Unanticipated Serious Adverse Device Effect (USADE) 
An Unanticipated Serious Adverse Device Effect (USADE) is defined as serious adverse device effect 
which by its nature, incidence, severity or outcome has not been identified in the current version of the 
risk analysis report.   
 
Adverse Event Severity Classification 
Severity will be defined according to the following criteria: 
Mild 
Awareness of event, but easily tolerated 
Moderate 
Discomfort enough to cause some interference with activities of daily living (ADL) 

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Severe 
Incapacitating, with an inability to perform ADL 
 
An AE can be classified as severe and not deemed a SAE.  Similarly, a SAE is not automatically severe in 
nature. 
 
Adverse Event Relationship Classification 
Causality assessments define the relationship between the use of the medical device (including the 
medical-surgical procedure) and the occurrence of each adverse event.  During causality assessment 
activity, clinical judgment shall be used and the relevant documents, such as the Clinical Evaluation 
Report and the Risk Management Report shall be consulted, as all the foreseeable serious adverse 
events and the potential risks are listed and assessed there. The presence of confounding factors, such 
as concomitant medication/treatment, the natural history of the underlying disease, other concurrent 
illness or risk factors shall also be considered. 
Each AE and SAE will be classified according to five different levels of causality. The sponsor and the 
investigators will use the following definitions to assess the relationship of the serious adverse event to 
the investigational medical device or procedures: 
 
 
 

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• 
Not related:  relationship to the device or procedures can be excluded when: 
o the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures 
o the event has no temporal relationship with the use of the investigational device or the 
procedures; 
o the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
o the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
o the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
o the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
o the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
o harms to the subject are not clearly due to use error; 
o In order to establish the non-relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious event. 
• 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
• 
Possible:  the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
• 
Probable:  the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably be explained by another cause, but additional information may be 
obtained. 
• 
Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
o the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
o the event has a temporal relationship with investigational device use/application or 
procedures; 
o the event involves a body-site or organ that 
 
the investigational device or procedures are applied to; 
 
the investigational device or procedures have an effect on; 
o the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
o the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 

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o other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
o harm to the subject is due to error in use; 
o the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
o In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
The sponsor and the investigators will distinguish between the serious adverse events related to the 
device and those related to the procedures (any procedure specific to the clinical investigation). An 
adverse event can be related both to procedures and the device. Complications of procedures are 
considered not related if the said procedures would have been applied to the patients also in the 
absence of device use/application. 
In some particular cases the event may be not adequately assessed because information is insufficient 
or contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators 
will make the maximum effort to define and categorize the event and avoid these situations. Where the 
sponsor remains uncertain about classifying the serious event, it should not exclude the relatedness and 
classify the event as “possible”.  
Adverse Event Outcome Classification 
Outcome of the event will be defined according to the following:  
• 
Resolved: The event has fully resolved at the end of the study. 
• 
Resolved with sequelae: The event has resolved, but retained pathological conditions resulting 
from the prior disease or injury. 
• 
Continuing: The event is ongoing at the end of the study. 
• 
Death: This event is determined to be the cause of death. 
11.2. Reporting of Adverse Events 
Assessment of the occurrence of an AE will be based on changes in the subject’s physical examination, 
laboratory results and/or signs and symptoms.  Adverse events will be monitored until a subject 
completes the study.  Medical care will be provided, as defined in the informed consent, for any AE 
related to study participation.  Adverse events will be collected on an AE CRF and applicable source 
documentation.  To the extent possible, the event to be recorded and reported is the event diagnosis as 
opposed to event symptoms (e.g., fever, chills, nausea and vomiting in the presence of a clinically 
diagnosed infection is to be reported as infection only).  For the purposes of this protocol, only those 
AEs occurring after enrollment will be recorded. 

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• 
Events will be reviewed by sponsor or designee to determine any reporting obligations to National 
Competent Authorities and IRB/EC.   
• 
According to the CFDA Notice No. 766-2008, Provisions of Adverse Events Surveillance and Revaluation of 
Medical Device (Trial),  
1)        Death events should be reported to the local provincial technical institution of medical device 
adverse events surveillance within 5 working days; 
2) Events led to serious injury or potentially led to serious injury or death, should be reported to the local 
provincial technical institution of medical device adverse events surveillance within 15 working days. 
Any Adverse Event will be recorded on the Adverse Event CRF. 
11.3. Device Deficiencies  
A device deficiency is an inadequacy of a medical device related to its identity, quality, durability, 
reliability, safety, or performance, such as malfunction, misuse or use error and inadequate labeling. 
All device deficiencies will be documented on the Device Complaint CRF (1 for each Device Deficiency), 
and the device should be returned to the Sponsor for analysis, if possible.  Instructions for returning the 
device will be provided.  Device deficiencies should also be documented in the subject’s medical record. 
 Device Deficiencies that led to an AE are reported on the AE CRF and the Device Complaint CRF.   
12. Data Review Committees  
Independent Medical Advisors 
The Sponsor will utilize Independent Medical Advisor(s) to provide an independent medical review and 
adjudication of pre-specified adverse events in support of protocol defined endpoint data. The 
Independent Medical Advisor(s) will be qualified, board-certified physicians. 
During the review of adverse events or overall study utility, efficacy, and safety data, the Independent 
Medical Advisor(s) will be blinded to the investigational site. 
13. Statistical Design and Methods 
13.1. General Principles 
In general, descriptive statistics will be used to summarize study outcomes. For continuous variables, the 
number of available observations, mean, standard deviation, median, minimum and maximum values 
will be provided.  For categorical variables, frequency and percentage will be used. Unless otherwise 
specified, statistical assessments will be based on two-sided tests at an alpha level of 0.05, which include 
Student-t or Wilcoxon rank-sum test for continuous variables, and Chi-square or Fisher’s exact test for 

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categorical variables. Other statistical methods may be used as appropriate. Statistical analysis will be 
performed using SAS Version 9.2 or higher (SAS Institute Inc., Cary, NC) or other valid statistical 
software.  
13.2. Sample Size Determination 
The proposed sample size of up to 100 subjects is considered adequate for the study objective. From 
published data, a complete response rate of 80%-90% of the RFA treatment is expected at 12 months 
post-treatment for the subject population (18).  With 100 study subjects, a precision (half 95% CI width) 
of 6%-8% will be achieved for estimating the primary endpoint of complete response rate. For safety, a 
sample of 100 subjects will have greater than a 99% chance to detect a rare event of 5% incidence or an 
85% chance to detect a rare event of 2% incidence. The NIH defines an acceptable dropout rate at 20% 
or less.  However, over 70% of all high-quality clinical studies in China had a dropout rate lower than 
10%.  For example, the dropout rate at CICAMS was 3% in a previous ESCN study.  
13.3. Analysis Populations 
The primary analysis will be based on a per-protocol basis. Subjects who enrolled into the study (a 
patient is defined as enrolled after introduction of RFA catheter at primary RFA), and had valid study 
outcomes with no major protocol violations will be included in the analysis. Only the 100 cohort patients 
will be included for primary analysis. 
Additional analyses based on subsets of the study subjects or combining run-in subjects may be 
performed to provide further support to the study results.    
All enrolled study subjects will be included in the safety analysis. 
13.4. Effectiveness Analysis 
The primary effectiveness will be measured as the percentage of subjects with complete response 
within the treatment area. The response rates and 95% confidence intervals will be summarized. Run-in 
subjects will be summarized separately.   
13.5. Safety Analysis 
For safety analyses, adverse events will be summarized using frequency counts and percentages. 
Descriptive statistics will be provided by event type, severity and relationship to study procedures and 
devices. Event rates along with 95% confidence intervals will be provided based on subject or event. 
Individual listings of adverse events, including event type, start date, duration, severity, and device-
relatedness will be provided as appropriate. 

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Safety will be closely monitored during the course of the study. If the incidence of severe or serious 
adverse events is higher than expected (stricture/stenosis requiring dilation >10%, any mucosal 
laceration requiring intervention, any perforation, any bleed or infection requiring intervention, or any 
other severe or serious unexpected adverse event), or a statistically significant trend is observed, the 
medical advisors will notify the sponsor, review all available data, and make a recommendation 
regarding continuation of the study. 
13.6. Additional Analyses 
Subgroup analysis will be performed for potential confounding factors such as study center, age, gender, 
use of escape treatment, and disease severity (moderate vs. high grade).  A multivariate analysis will be 
conducted to further examine the predictors of compete response. Potential predictive factors to be 
considered will include but not limited to: age, gender, and grade (MGIN vs. HGIN).  
The number and proportion of subjects eligible for and compliant with each follow-up examination will 
be presented. Subjects who withdraw from the study will be tabulated with reasons for withdrawal. 
Sensitivity analysis for discontinuations or missing data will be conducted to assess the robustness of 
study results which may include last observation carried forward, multiple imputations, and tipping 
point analysis, as appropriate.   
For study monitoring and learning curve evaluations, summary data will be provided for the primary and 
secondary endpoints between the first half of subjects enrolled versus the second half of subjects 
enrolled for each site and overall. Furthermore, CR-rates at 3 and 12 months for the run-in cases will be 
analyzed. 
Additionally, interim data summaries may be performed, as needed, for requirements related to 
abstract submission, IRB requests, or Independent Medical Advisor requests. Considering the feasibility 
nature of the study, no multiplicity adjustment is considered. Efficacy and safety will be specifically 
assessed after enrollment of up to 50 patients. 
Any departure or deviation from these planned statistical methodologies will be documented and 
discussed in the Statistical Analysis Plan (SAP) that will include the statistical rationale for divergence.  
14. Ethics 
14.1. Statement(s) of Compliance  
This clinical investigation will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, ISO 14155:2011 (Clinical Investigation of Medical Devices for Human 
Subjects – Good Clinical Practice), and any regional or national regulations, as appropriate. The 
principles of the Declaration of Helsinki have all been implemented by means of the 

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patient informed consent process, EC approval, study training, clinical study registration, 
preclinical testing, risk benefit assessment, and publication policy. Pediatric, legally 
incompetent, or other vulnerable subjects are not eligible for the study. 
The clinical investigation will not begin until all necessary approvals/favorable opinions are obtained 
from the appropriate EC/IRBs or regulatory authority, as appropriate.  Should an EC/IRB or regulatory 
authority impose any additional requirements, they will be followed.   
Information regarding the study and study data will be made available via publication on clintrials.gov.  
Additionally, the results of this study will be submitted for publication in an appropriate journal. 
14.2. Protocol Compliance 
No changes to the protocol will be permitted without the written approval from the Sponsor and the 
IRB/EC.  The investigator must notify the Sponsor and the reviewing IRB/EC of any deviation from the 
Investigational Plan when specific to the protection of the life or physical well-being of a subject in an 
emergency.  Such notice must be given as soon as possible, but in no event later than 5 working days 
after the emergency has occurred.  Except in such an emergency, prior written approval by the Sponsor 
and the site IRB/EC is required for changes in or deviations from the Plan.  All deviations will be reported 
per the site’s IRB/EC deviation policy.  Should any deviations from the Investigational Plan occur, these 
will be reviewed by the Sponsor for their clinical significance.  If the event is performed without written 
approval from all parties, the investigator may be terminated from the study. 
15. Study Administration 
15.1. Monitoring  
Site visits will be conducted by an authorized Sponsor representative to inspect study data, subjects’ 
medical records, and CRFs in accordance with the respective local and national government regulations 
and guidelines (if applicable).  The Study Investigator and the investigating site will permit authorized 
clinical research personnel and clinical monitors from the Sponsor and/or designee(s) employed by the 
Sponsor to review completed CRFs, IRB decisions, and Investigator, clinical site records, and facilities 
relevant to this study at regular intervals throughout the study per the monitoring plan.  Additionally, 
subject charts and clinical records will be requested and reviewed so that protocol adherence and 
source documentation can be verified.  The accuracy and quality of the data obtained from the 
investigator and maintained by the Sponsor will be confirmed through a structured program of clinical 
field auditing and internal review detailed in the monitoring plan.  In instances where data protection 
regulations prohibit the direct examination of hospital records by the study Sponsor or designee(s), the 
Investigator will cooperate in a system of source data verification with the Sponsor.  Monitoring may be 
performed with in person visits or remotely, when applicable.  

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To ensure the rights, safety, and welfare of study subjects are being maintained, the monitor will review 
training records to ensure all study staff are trained on the study protocol and use of the study devices.  
If the monitor discovers that an investigator is not complying with the signed Investigator Agreement, 
the investigational plan, applicable laws, or any conditions of approval imposed by the reviewing IRB or 
Competent Authority, the monitor will report to the Sponsor and take such steps necessary to promptly 
secure compliance.  If compliance cannot be secured, device shipments to the investigator may be 
discontinued and the investigator’s participation in the investigation terminated.  The monitor shall also 
require such an investigator to dispose of or return the device, unless this action would jeopardize the 
rights, safety, or welfare of a subject.  
15.2. Data Management 
This study will utilize an electronic database and eCRF.  All data requested on the CRF are considered 
required.  Data points not collected and/or recorded will be considered deviations unless otherwise 
specified.  The Principal Investigator must ensure the accuracy and completeness of the recorded data 
and then provide his/her signature on the appropriate CRFs.  The Investigator’s electronic signature for 
specific CRFs will be documented in compliance with local regulations.  Changes to data previously 
submitted to the sponsor will require a new electronic signature by the Investigator to 
acknowledge/approve the changes. 
Visual and/or computer data review will be performed to identify possible data discrepancies.  Manual 
and/or automatic queries will be created in the Oracle remote data capture (RDC) system and will be 
issued to the site for appropriate response.  The site staff will be responsible for resolving all queries in 
the database. 
15.3. Direct Access to Source Data/Documents  
The investigator must agree to the inspection of study-related records by the Regulatory 
Authority/Sponsor representatives, and must allow direct access to source documents to the Regulatory 
Authority/Sponsor representatives/EC representatives. 
15.4. Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
Subject names will be kept confidential.  Only the subject number and initials will be recorded in the 
CRF, and if the subject name appears on any other document, it must be obliterated.  In cases were the 
local low does not allow using the subject initials, an identifying number will be assigned.  

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A Subject Log will be maintained in a secure locked location by the Investigator to enable tracing of 
specific case study numbers to subjects, in the event required. 
Study findings stored on a computer will be stored in accordance with local data protection laws.  The 
subjects will be informed in writing that representatives of the sponsor, IRBs, or Regulatory Authorities 
may inspect their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws.  
Subjects will also be informed that information regarding the study that does not include subject 
identifiers will be posted on clinicaltrials.gov. 
If the results of the trial are published, the subject’s identity will remain confidential.  
The investigator will maintain a list to enable subjects’ records to be identified. 
15.5. Liability 
Medicine is not an exact science and no guarantees can be made as to the results. The procedure to be 
followed in this study may involve risks and discomforts, as with any procedure. All the risks of being 
treated with the Barrx™ Flex Radiofrequency Ablation System are the same whether in clinical trials or 
not. Nevertheless, study related insurance will be available. 
 
The sponsor shall be responsible for any medical expense and will provide compensation for injury or 
death resulting from participation in the study.   However, it shall be excluded from the sponsor’s 
responsibility if the injury or death is in a result of medical institute or the investigator’s fault. 
In the event of physical injury or physical illness resulting from participation in this study, any medical 
treatment that is needed will be provided. The expense of any relevant medical treatment for physical 
injury or physical illness resulting from participation in this study will be reimbursed by Medtronic.   
15.6. CIP Amendments 
Changes or clarifications to the protocol may be described in a formal protocol amendment as needed, 
including a summary of changes and a rationale for the changes.  Changes to the CIP will not be 
implemented until all necessary approvals/favorable opinions are obtained from the appropriate 
IRB/ECs or regulatory authority, as appropriate.     
15.7. Record Retention 
The investigator will maintain the records of the study including all pertinent correspondence, the study 
protocol with any/all amendments, all correspondence with and approval from the IEC, the clinical trial 

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agreement, the Investigator Agreement, device accountability records, individual subject records, and 
signed ICFs. Subject files and other source data must be kept for a period of not less than 2 years after 
the latter of the following two dates:  the date on which this investigation is terminated or completed, 
or the date that the records are no longer required for purposes of supporting a premarket application.  
Records may need to be maintained by the Principal Investigator for a longer duration if national 
regulations require or if agreed to in writing with the Sponsor.  All data and documents should be made 
available if requested by relevant authorities. The sponsor must keep study records for no less than 15 
years. 
 
15.8. Publication and Use of Information 
The Medtronic Publication and Authorship Policy is aligned with the International Committee of Medical 
Journal Editors (ICMJE) recommendations (www.icmje.org). The Sponsor will seek to publish, in 
appropriate peer-reviewed journals and scientific conferences, results of clinical studies where human 
subjects are involved, regardless of outcome. While study results are owned by the Sponsor, all data on 
which a publication is based will be made available to all authors as required for their participation in 
the publication process. Furthermore, data may be published or used by study investigators provided 
that such publication or use is in accordance with this protocol, the Medtronic Publication and 
Authorship Policy, and the Clinical Investigation Agreement. Investigators must submit a copy of all 
manuscripts and/or abstracts to the Sponsor for review and comment 30 days prior to planned 
submission. Medtronic acknowledges that its right to review and comment shall relate solely to the 
proprietary, licensing, and/or confidential rights Medtronic may have in such proposed publication, 
rather than whether such results and/or opinions are favorable to Medtronic.   
The publication of substudies, post-hoc analyses, regional results, or single-center experiences based on 
multicenter clinical studies should not precede that of the primary multicenter publication, and should 
cite the primary publication whenever possible, as required by specific journal and scientific meeting 
guidelines.  
Medtronic involvement in a publication (e.g., funding of the study; sponsor of the study; collection, 
analysis, and interpretation of data; professional writing assistance) must be disclosed according to 
journal-specific policies, submission requirements, and prevailing editorial standards, in addition to 
those specified by International Committee of Medical Journal Editors. Authors must ensure that an 
acknowledgement/disclosure statement is included in the body of the manuscript for Medtronic to 
review for accuracy. All authors must also disclose financial or personal affiliations that could be 
considered conflicts of interest as per journal/conference requirements. 

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To enable health care providers, payers, and patients access to the wealth of Medtronic’s research, 
Medtronic will report its scientific data in accordance with the principles outlined in the Guidance 
Document on Registration and Reporting Results of Company-Sponsored Clinical Trials Under FDAAA 
2007 (Title VIII).   
15.9. Suspension or Early Termination 
The Sponsor reserves the right to discontinue the study at any stage, with suitable written notice to all 
investigators; all reviewing institutional review boards (IRBs) or ethic committees (ECs).  Similarly, 
investigators may withdraw from the study at any time, subject to providing written notification to the 
Sponsor 30 days prior to the date they intend to withdraw.  However, the Sponsor and investigators will 
be bound by their obligation to complete the follow-up of subjects already participating in the study.  
The subjects must be followed according to the clinical protocol, and information obtained during 
subject follow-up shall be reported to the Sponsor on the appropriate CRF. 
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ablation in Barrett's esophagus with dysplasia. The New England journal of medicine. 
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van Vilsteren FG, Alvarez Herrero L, Pouw RE, ten Kate FJ, Visser M, Seldenrijk CA, et al. 
Radiofrequency ablation for the endoscopic eradication of esophageal squamous high grade 
intraepithelial neoplasia and mucosal squamous cell carcinoma. Endoscopy. 2011;43(4):282-90. 
doi: 10.1055/s-0030-1256309. PubMed PMID: 21455869. 
25. 
Haidry RJ, Butt MA, Dunn J, Banks M, Gupta A, Smart H, et al. Radiofrequency ablation for early 
oesophageal squamous neoplasia: outcomes form United Kingdom registry. World journal of 
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24106401; PubMed Central PMCID: PMC3785622. 
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Wang WL, Chang IW, Chen CC, Chang CY, Mo LR, Lin JT, et al. Radiofrequency Ablation Versus 
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COVB3050540 (REACH) Clinical Investigation Plan  
 
 
 
Version 7.0 
15-Mar-2018 
Page 62 of 62 
 
Medtronic Confidential 
This document is electronically controlled  
 
056-F275, v3.0 Clinical Investigation Plan Template 
 
 
 
 
• 
Clarified Table 2. Study Schedule and 
Assignments 
• 
Discharge instruction (Page 30): added 
“or Almagate Suspension”  
4.0 
• 
Clinical Project Manager information 
change 
• 
Medical device model number corrected 
• 
Follow-up extension added 
• 
Additional secondary endpoints added 
• 
Clarified failures for the primary endpoint 
• 
Edited Table 2 and Figure 1 
• 
Added Figure 2 
• 
DSMB removed 
• 
Added +/- 4 weeks window to all visits 
post initial RFA procedure 
 MD, PhD 
Director, Global Medical Affairs 
 
Director, Global Clinical Affairs 
 
5.0 
• 
Local sponsor information change 
• 
Number of sites changed from 5 to up to 
10 
• 
Exclusion criteria revised to include 
patients who have had EMR > 3 months 
prior. 
• 
BQE changed to 1 week from 2 weeks 
prior to RFA 
 
Director, Global Medical Affairs 
 
 
Director, Global Clinical Affairs 
 
 
6.0 
• 
Exclusion criteria # 6 revised to exclude 
patients who have had EMR or ESD <3 
months prior.  
• 
Inclusion criteria #9 revised to include 
“EMR or ESD occurred > 3 months 
before enrollment, patients may be 
eligible for the study if procedure was 
curative (negative margins and no risk of 
lymph node involvement) and the patient 
has no other findings concerning for 
cancer.” 
• 
Included 5 satellite sites of CICAMS 
• 
Run-in patients defined as up to 5 
patients for each endoscopist that is 
inexperienced with RFA or has had no 
RFA onsite training from CICAMS. 
 
Director, Global Clinical Affairs 
 
 
7.0 
• 
Remove reference to 5 satellite sites of 
CICAMS  
 
 
Director, Global Clinical Affairs 
Clinical Research 
Specialist