A Randomized Study of Biologic Scaffolds And Esophageal Healing Following Endoscopic Resection
Phase: NA
Conditions: Barretts Esophagus With High Grade Dysplasia, Barrett Adenocarcinoma
Sponsor: Mayo Clinic

 
 
A Randomized Study of Biologic Scaffolds and 
Esophageal Healing Following Endoscopic 
Resection 
 
NCT03240679 
 
August 22, 2016 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 1 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
 
 
A RANDOMIZED STUDY OF BIOLOGIC SCAFFOLDS AND 
ESOPHAGEAL HEALING FOLLOWING ENDOSCOPIC 
RESECTION 
 
 
 
Principal Investigator 
 
 
Kenneth K. Wang, MD 
Russ and Kathy Professor of Gastroenterology Research 
Mayo Clinic 
Division of Gastroenterology and Hepatology  
200 Frist St SW, Rochester MN 55905 
507-284-2174 
 
Study Product: 
Extracellular matrix-urinary bladder matrix, ACell 
MatriStem Surgical Matrix  
Protocol Number: (IRBe) 
16-006909 
 
 
 
 
 
Initial version: 8-22-16 Version (1.0)  
 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 2 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
Table of Contents 
STUDY SUMMARY ................................................................................................................................5 
1 
INTRODUCTION ...........................................................................................................................6 
1.1 
BACKGROUND ...................................................................................................................................... 6 
1.2 
INVESTIGATIONAL DEVICE ................................................................................................................... 6 
1.3 
PRECLINICAL DATA ............................................................................................................................. 7 
1.4 
CLINICAL DATA TO DATE .................................................................................................................... 7 
1.5 
STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO) ................................................ 7 
1.5.1 
Study Rationale ....................................................................................................................7 
1.5.2 
Anticipated Risks .................................................................................................................8 
1.5.3 
Potential Benefits ................................................................ Error! Bookmark not defined. 
1.6 
ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION ................................................................ 8 
2 
STUDY OBJECTIVES ....................................................................................................................8 
3 
STUDY DESIGN .............................................................................................................................9 
3.1 
GENERAL DESIGN ................................................................................................................................ 9 
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................. 10 
3.3 
SECONDARY STUDY ENDPOINTS ........................................................................................................ 10 
3.4 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 11 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL .............................................. 11 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 11 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................... 12 
4.4.1 
When and How to Withdraw Subjects ................................................................................. 12 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ....................................................... 12 
5 
STUDY DEVICE ......................................................................................................................... 12 
5.1 
DESCRIPTION ..................................................................................................................................... 12 
5.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................... 12 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE ....................... 13 
5.4 
SUBJECT COMPLIANCE MONITORING ................................................................................................. 13 
5.5 
PRIOR AND CONCOMITANT THERAPY ................................................................................................ 13 
5.6 
PACKAGING AND LABELING ............................................................................................................... 14 
5.7 
MASKING/BLINDING OF STUDY ......................................................................................................... 14 
5.8 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN .......................................................................... 14 
5.8.1 
Receipt of Investigational Devices ...................................................................................... 14 
5.8.2 
Storage ............................................................................................................................ 14 
5.8.3 
Distribution of Study Device .............................................................................................. 14 
5.8.4 
Return or Destruction of Study Device ................................................................................ 14 
6 
STUDY PROCEDURES............................................................................................................... 15 
6.1 
VISIT 1 ............................................................................................................................................... 15 
6.2 
VISIT 2 ............................................................................................................................................... 15 
6.3 
VISIT 3. ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN .................................................................................................................. 16 
7.1 
SAMPLE SIZE DETERMINATION .......................................................................................................... 16 
7.2 
STATISTICAL METHODS ..................................................................................................................... 16 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................................... 17 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................ 17 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 3 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
8.1 
DEFINITIONS ...................................................................................................................................... 17 
8.2 
RECORDING OF ADVERSE EVENTS ..................................................................................................... 20 
8.3 
INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS AND UNANTICIPATED 
PROBLEMS ........................................................................................................................................................ 20 
8.3.1 
Investigator Reporting, Notifying Mayo IRB ........................................................................ 21 
8.3.2 
Investigator Reporting: Notifying the FDA .......................................................................... 21 
8.4 
UNBLINDING PROCEDURES (BREAKING THE BLIND) (AS NECESSARY IF THE STUDY IS BLINDED) ....... 22 
8.5 
STOPPING RULES ................................................................................................................................ 23 
8.6 
MEDICAL MONITORING ..................................................................................................................... 23 
8.6.1 
Internal Data and Safety Monitoring Board .......................... Error! Bookmark not defined. 
8.6.2 
Independent Data and Safety Monitoring Board .................... Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................... 23 
9.1 
CONFIDENTIALITY.............................................................................................................................. 23 
9.2 
SOURCE DOCUMENTS......................................................................................................................... 23 
9.3 
CASE REPORT FORMS ........................................................................................................................ 24 
9.4 
RECORDS RETENTION ........................................................................................................................ 24 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................... 25 
10.1 
STUDY MONITORING PLAN ................................................................................................................ 25 
10.2 
AUDITING AND INSPECTING ............................................................................................................... 25 
11 
ETHICAL CONSIDERATIONS .................................................................................................. 25 
12 
STUDY FINANCES ..................................................................................................................... 26 
12.1 
FUNDING SOURCE .............................................................................................................................. 26 
12.2 
CONFLICT OF INTEREST ...................................................................................................................... 26 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................... ERROR! BOOKMARK NOT DEFINED. 
13 
PUBLICATION PLAN ................................................................................................................ 26 
14 
REFERENCES ............................................................................................................................ 26 
15 
ATTACHMENTS .............................................................. ERROR! BOOKMARK NOT DEFINED. 
 
 
 
 
 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 4 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
 
 
ECM 
Extracellular matrix 
EMR 
Endoscopic mucosal resection 
EGD 
Esophagogastroduodenoscopy 
BE 
Barrett’s esophagus 
 
 
 
 
 
 
 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 5 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
Study Summary 
Title 
A Randomized Study of the Use of Biologic Scaffolds in 
Constructive Healing Following Endoscopic Resection 
Running Title 
Biologic Scaffold Study 
IRB Protocol 
Number 
16-006909 
Phase 
Device Feasibility trial 
Methodology 
Randomized study 
Overall Study 
Duration 
1 year 
Subject 
Participation 
Duration 
12-16 weeks 
Objectives 
This study is being done to assess the efficacy of ECM products in 
promoting constructive healing as determined by the ability of the 
resection site to lift during follow-up. 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
18 and older 
Male or female 
Able to provide consent 
Impending endoscopy that may require initial EMR evaluation of 
esophageal lesions 
Study Device 
The Acell MatriStem Surgical Matrix will cover the defect site 
following mucosal resection using endoscopy clips or X-tac 
Duration of 
Exposure 
The device will remain attached to the esophagus and integrate with 
native tissue over time 
Reference therapy 
There is no reference treatment for comparison 
Statistical 
Methodology 
Univariate descriptive statistics and frequency distributions will be 
calculated, as appropriate for all variables 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 6 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures.  
1.1 
Background 
 
The relatively recent introduction of endoscopic resection techniques (endoscopic mucosal 
resection [EMR] and endoscopic submucosal dissection [ESD]) have enabled endoscopists to 
excise larger amounts of tissue for accurate staging, and often curative treatment of early 
esophageal adenocarcinoma. These techniques have largely supplanted esophagectomy for 
small esophageal cancers which carries significant risks of morbidity and mortality. 
 
One limitation of endoscopic resection, however, is the risk of esophageal stricture formation 
at the site of resection as a result of the inflammatory healing process that ensues after deep 
mucosal injury. The esophagus has limited regenerative ability and the default response is 
volume replacement of the defect with fibrosis.1 Esophageal stricture can significantly impact 
a patient’s quality of life and often requires treatment via multiple endoscopies for sequential 
pneumatic dilations, which carry risk of perforation. It has been reported that the risk of 
stricture formation is directly proportional to the size of the resection defect. Patients with 
mucosal defects greater than 75% of the esophageal circumference carry a significantly 
greater risk of stricture formation2, and in patients with full circumferential resection the risk 
may be as high as 88%.3, 4 Hence, extensive endoscopic resection typically give endoscopists 
pause. However, this risk of stricture is often justified by the need to excise the lesions en 
bloc to ensure accurate determination of depth of invasion and also to ensure the complete 
removal of the lesion. 
 
Various interventions have been described in an effort to prevent stricture formation, 
including intralesional and systemic steroids, preventative balloon dilation, and prophylactic 
covered stent, but results are conflicting.5 Currently, most endoscopists limit EMR to 
anticipated defects of 2 cm in diameter or 50% esophageal circumference in an effort to 
prevent stricture formation.  
 
1.2 
Investigational Device 
 
Extracellular matrix (ECM) products such as MatriStem® Surgical Matrix produced by Acell 
(Columbia, MD )are approved by the US Food and Drug Administration (FDA) to aid in the 
healing of wounds like those created by EMR. ECM are composed of collagen and natural 
proteins that provide a re-absorbable scaffold for tissue remodeling have been investigated in 
preclinical as well as clinical pilot studies and found to facilitate constructive healing 
following EMR, meaning formation of site-specific functional tissue. Meanwhile, the 
inflammatory pathway that leads to stricture formation is diverted. 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 7 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
1.3 
Preclinical Data 
 
ECM are the result of minimally processing (i.e., decellularizing) biological tissue (e.g., 
porcine bladder), during which antigenic cellular components are removed while important 
proteins (e.g, glycosaminoglycans) and an ultrastructure consisting of collagen, fibronectin 
and basement membrane are preserved.1, 6 These components retain their bioactivity in the 
host, and provide an environment that promotes cell adhesion and proliferation.7 ECM 
scaffold degradation begins to occur rapidly after placement,8, 9 reducing the potential for a 
chronic inflammatory process or foreign body reaction (as described with synthetic 
biomaterials10), and releasing cryptic peptides, including various cytokines and growth 
factors such as vascular endothelial growth factor and basic fibroblast growth.11 These 
peptides have been shown to exert chemotactic and mitogenic effects on stem and progenitor 
cells in vitro that contribute to the constructive remodeling process.12-14 ECM biologic 
scaffolds made of porcine-derived small intestinal submucosa have been successfully 
implanted without a keratonocyte layer in animal models. They were effective in reducing 
esophageal stricture after EMR, while facilitating constructive nonstenotic healing response 
with formation of all layers of the esophageal wall in a preclinical dog model.15 
1.4 
Clinical Data to Date 
 
Observations on the use of ECM in the human esophagus have been reported in several 
series. Scaffolds from porcine urinary bladder were used to treat five BE patients with high-
grade dysplasia/ esophageal adenocarcinoma and long-segment BE (8 to 13cm) following 
ESD.8 The scaffold was applied using a temporary stent that was removed within 9-17 days, 
allowing scaffold integration with the underlying muscular wall of the esophagus. Complete 
epithelialization and formation of a new submucosal layer was appreciated during follow-up. 
All patients required transient postoperative dilation for mild stricture formation in areas not 
covered by ECM, but were able to then tolerate a normal diet without recurrence of disease 
during 4-24 month follow-up. No other significant complications were reported. ECM 
scaffold degradation was noted to occur in vivo rapidly without any evidence of residual 
xenogeneic tissue. Using a similar approach, three additional patients were subjected to 
endoscopic, circumferential en bloc resection of Barrett’s with HGD, followed by 
fundoplication.16 One patient with incomplete ECM coverage developed an easily dilated 
stricture, whereas the remaining 2 patients who had complete ECM coverage did not. To 
date, no randomized clinical trials exist comparing the use of ECM in humans following 
EMR vs. the current standard of care (i.e., observation).  
1.5 
Study Rationale and Risk Analysis (Risks to Benefits Ratio) 
1.5.1 Study Rationale 
 
Data for alternative strategies to prevent stricture formation remain equivocal. The 
application of ECM, however, appears promising based on preclinical and clinical data, and 
ECM are FDA approved for use in wound healing. No randomized clinical trials exist.  
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 8 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
As an initial step towards assessing the utility of ECM in stricture prevention, we seek to 
assess the role of ECM in promoting constructive healing following endoscopic resection of 
esophageal lesions. This will be determined by the ability of a lesion to “lift” with saline 
injection during routine endoscopic follow-up. The importance of lift was first reported by 
Uno et al. in colonic lesions.17 Inability to lift with fluid injection is suggestive of 
submucosal tumor invasion, but a false-positive nonlift sign may occur after biopsy as a 
result of the ensuing inflammatory healing process. We hypothesize that the use of ECM in 
patients undergoing EMR will mitigate this inflammatory process and promote a more 
constructive model of healing with reformation of the esophageal wall layers as evidenced by 
a lift sign. Patients receiving ECM will be compared to patients undergoing EMR without 
application of ECM. 
 
Data from this study may be used to support larger studies investigating the role of ECM in 
preventing stricture formation in patients undergoing more extensive endoscopic resections 
via EMR or ESD. 
1.5.2 Anticipated Risks and Benefits 
 
The study adds minimal risks to procedures that patients are already scheduled to undergo 
(EMR). A potential risk of ECM is injury during application to the resection site. We propose 
the use of endoscopic clips or X-tac to carefully attach each corner of the square ECM 
material to healthy esophageal tissue surrounding the defect site. This will be carried out by 
an endoscopist with expertise in esophageal disease and endoscopic therapy. The potential 
benefit of this includes mitigation of the ensuing inflammatory process. Patients undergoing 
endoscopic resection return for routine endoscopic follow-up in 8-12 weeks. Injection with 
saline at this time is safe and will be performed by an experienced endoscopist. Saline is 
typically resorbed by the tissue within minutes of injection. 
1.6 
Anticipated Duration of the Clinical Investigation 
 
Screening and enrollment will be performed at the time of consent for their endoscopy and 
anticipated resection. In eligible patients randomized to ECM placement, the endoscopy will 
require an additional 5-10 minutes for application of ECM. Follow-up will occur per standard 
of care in all patients undergoing EMR, that is endoscopy in 8-12 weeks or sooner for patient 
symptoms (e.g., dysphagia). 
 
2 Study Objectives 
 
2.1 Primary Objective 
 
To assess the efficacy of ECM products in promoting constructive healing as determined by 
the ability of the resection site to lift during follow-up  
 
2.2 Secondary Objective 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 9 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
To assess the efficacy of ECM products in promoting constructive healing as determined by 
endoscopic inspection via white light and electron chromoendoscopy.  
 
3 Study Design 
3.1 
General Design 
 
This is a randomized study on the efficacy of ECM in promoting constructive healing 
following endoscopic resection (EMR). 20 patients anticipated to undergo endoscopic 
resection will be recruited in the outpatient setting from the Barrett’s Esophagus Unit. Prior 
to endoscopy, patients will complete a standardized questionnaire (Mayo Dysphagia 
Questionnaire) and the physician will use the Mellow-Pinkas scale to assess baseline 
dysphagia. Patients with lesions that lift and are amenable to cap-assisted EMR will be 
randomized to receive ECM to the defect site vs. standard of care. All patients should be on 
standard of care double dose proton-pump inhibitor therapy (Omeprazole 40mg PO daily or 
the equivalent); if this has not been initiated they will be provided a prescription . 
 
In both groups, patients will be brought back for repeat standard of care clinic and 
endoscopic assessments in 12-16 weeks, or sooner if needed. A clinical dysphagia 
assessment will be performed with repeat of the above questionnaires. Endoscopy will 
involve inspection of the wound site, and images in white-light and electron 
chromoendoscopy will be taken for blinded evaluation later. Submucosal saline injection at 
the wound site will be performed to determine its ability to lift.   
 
Any patients receiving esophageal dilations will be noted. Patients requiring esophagectomy 
will be excluded from the primary objective of the study but their surgical specimen at the 
site of endoscopic resection will be evaluated for evidence of constructive healing.  
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 10 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
 
 
 
 
3.2 
Primary Study Endpoints 
 
The primary endpoint will be efficacy of ECM in promoting mucosal lift with fluid injection 
after healing from prior EMR.  
3.3 
Secondary Study Endpoints 
 
Secondary endpoints include efficacy of ECM in preventing symptomatic esophageal 
stricture formation requiring dilation, preventing dysphagia as determined by questionnaires, 
and mitigating formation of post-resection scarring as determined by blinded comparison of 
Screening 
Endoscopy with 
EMR 
Randomization 
Treatment Group 1 
(ECM + Standard of care) 
Treatment Group 2 
(Standard of care) 
Follow-up 
endoscopy in 8-12 
weeks 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 11 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
pre- and post-resection images (taken using white-light endoscopy and electron 
chromoendoscopy). 
 
 
3.4 
Primary Safety Endpoints 
 
Primary safety endpoints include overall survival, incidence of all serious adverse events 
including unanticipated adverse device effects, incidence of technical and device failures and 
malfunctions, and quality of life as measured by the above dysphagia questionnaires.  
 
4 Subject Selection, Enrollment and Withdrawal 
 
Patients will be recruited from the Barrett’s Esophagus clinic where patients with Barrett’s 
esophagus, esophageal cancer, and/or esophageal nodules are referred for consideration of 
endoscopic evaluation and management. Patients with advanced esophageal cancer are 
typically not referred as they warrant chemoradiotherapy or palliative care, and are not 
candidates for endoscopic management. Thus, this clinic presents a selective population to 
screen from, and one we anticipate will be able to provide the proposed number of subjects 
for this study. It is estimated 75-100 patients with esophageal lesions undergoing EMR will 
be screened to ultimately meet study enrollment goals. 
4.1 
Inclusion Criteria 
 
• 18 and older 
• Male or female 
• Able to provide consent 
• Scheduled for standard of care endoscopy that may require initial EMR evaluation of 
esophageal lesions 
• Histological evidence of intestinal metaplasia with dysplasia or intramucosal 
carcinoma 
4.2 
Exclusion Criteria 
 
• Pregnant women 
• Age less than 18 
• Prior esophageal EMR or ESD in the same region  
• Anyone unable to provide informed consent  
• Medical co-morbidities precluding EGD evaluation 
• History of chemoradiotherapy to the neck/esophagus 
• Unable to stop anticoagulation therapy (non-steroid anti-inflammatory medications 
are permissible) 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 12 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be recruited from the endoscopic practice of the Principal Investigator and Co-
Investigator.  Patients will undergo screening for inclusion and exclusion criteria at the time 
of clinical consultation. 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Subjects will be withdrawn from the study if any adverse events related to EMR, or 
application of ECM occurs, including major bleeding, perforation, or infection. Patients will 
also be withdrawn if after EMR the patient proceeds to esophagectomy.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
An attempt will be made to collect follow-up data for withdrawn subjects, as well as patients 
who undergo esophageal surgery (i.e., surgical histology of the resection site). These patients 
will be called to collect this data.  
 
5 Study Device 
5.1 
Description 
 
ECM products such as those produced by Acell are approved by the FDA to aid in the 
healing of wound sites like those created by EMR. The product that will be used in this study 
is the A-cell Matristem, which is derived from porcine bladder (also known as urinary 
bladder matrix). Observations pertaining to this specific product have been reported in 
several clinical series, including use in patients undergoing esophageal surgery and hiatal 
hernia repair.18-20 
  
The device is supplied in sheets of varying sizes and thickness. Only one thickness will be 
used for all patients, whereas the smallest sized sheet that adequately covers the defect site 
will be selected and applied by the endoscopist. Identifying product information including 
serial, lot, and/or batch numbers will be recorded for each patient.  
 
5.2 
Method for Assigning Subjects to Treatment Groups 
 
Patients will be randomized using prepackaged envelopes to ECM or standard of care and 
stratified based on the size and number of EMR performed during the procedure. Thus, 
randomization will occur during the procedure immediately following resection.  
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 13 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
5.3 
Preparation and Administration/Implantation of Investigational Device 
 
The smallest sized version of material that adequately covers the defect site will be selected 
for application. Application will involve attachment of the corners of the material to healthy 
tissue surrounding the defect site using four standard endoscopic clips as depicted below. 
These clips are designed to slough following healing and rarely cause nuisance or 
complications to patients. X-tac is also a similar method but using screws instead. 
 
 
 
 
5.4 
Subject Compliance Monitoring 
 
Per endoscopic resection protocol, patients will be scheduled for follow-up in 12-16 weeks 
for repeat endoscopic assessment. Aside from continued use or initiation of proton pump 
inhibitor therapy (which will be assessed by patient history) there are no interim monitoring 
requirements for the patient. Patients lost to follow-up or referred for esophageal surgery will 
be excluded from analysis for the primary objective.  
 
5.5 
Prior and Concomitant Therapy 
 
No additional medications or therapies will be provided during this study beyond omeprazole 
40mg once daily or the equivalent which is recommended in all patients undergoing 
endoscopic resection. All prior or concomitant medical therapies can be continued during this 
study. 
 
 
 
ECM 
Clips 
Wound site 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 14 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
5.6 
Packaging and Labeling 
 
The ECM product will arrive in a sterile, airtight sleeve. Each sleeve will be inside of a 
sealed box. 
5.7 
Masking/Blinding of Study 
 
Patients will be randomized during the procedure based on our current understanding of risk 
factors for post-resection scarring and stricture formation. Thus, randomization will be 
primarily determined by the size of the defect and number of resections performed (during 
the initial endoscopy). 
 
5.8 
Receiving, Storage, Distribution and Return 
5.8.1 Receipt of Investigational Devices 
 
The ECM product is already stocked and stored in our lab located in the SMH Alfred Main 
endoscopy suite. Additional inventory will similarly be shipped directly from the 
manufacturer. At the initiation of the study, investigators will count and verify current 
inventory. This will be repeated whenever inventory is expanded. 
 
5.8.2 Storage 
 
The manufacturer instructions recommend storage in a clean, dry environment at a 
temperature of 15 – 35 C. Our laboratory temperature will be maintained within this range. 
Storage in our laboratory will also prevent unintended/unauthorized use. The product is 
sterilized and once opened must be used. 
 
5.8.3 Distribution of Study Device 
 
For patients randomized to receive ECM, the ECM will be prepared in the endoscopy suite 
for application. This will include notation of the manufacturer, catalog number, batch code, 
and serial number, in addition to details regarding the procedure (including patient 
information, procedure date and time). A running total number of devices in inventory will 
be maintained. Any products inadvertently damaged or not used will be noted. Inventory 
audits will be performed on a monthly basis.  
 
5.8.4 Return or Destruction of Study Device 
 
We will order clinical supply as needed and dispose of unused supply. We do not anticipate 
needing to return supplies. 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 15 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
6 Study Procedures 
6.1 
Visit 1 
 
Patients will be recruited from the Barrett’s Esophagus Clinic. Patients referred for 
endoscopic evaluation of Barrett’s esophagus with high grade dysplasia , esophageal nodules 
or early esophageal cancer and  are scheduled  for EMR, will be screened using inclusion and 
exclusion criteria outlined above. Patients meeting inclusion criteria will be consented for 
study inclusion and will be asked to complete the Mayo Dysphagia Questionnaire.  
6.2 
Visit 2 
 
Visit 2 refers to the procedure during which the patient will undergo planned EMR of the 
esophageal lesion. Visits 1&2 may take place on the same date. Patients will undergo 
endoscopy and those amenable to standard EMR will be randomized to receive ECM or 
receive standard of care (i.e., observation). ECM will be applied to patients in the manner 
described above. 
 
 
6.3 
Visit 3 
 
All patients will be scheduled to return in approximately 12-16 weeks (up to 6 months) 
following EMR for follow-up endoscopic evaluation. Patients will repeat the Mayo 
Dysphagia Questionnaire prior to endoscopy. During endoscopy, the EMR site will be 
inspected and multiple pictures will be taken in white-light as well as electron 
chromoendoscopy (i.e., narrow band imaging). Thereafter, standard submucosal saline 
injection of the healed EMR site will be performed, and the endoscopist will record whether 
no lift, a partial lift, or complete lift was observed. Symptomatic structuring will be treated 
with standard pneumatic dilation. 
 
 
Schedule of Events 
Study Activity 
Baseline* 
Procedure* 
 
Follow-up 
procedure (3-4 
months) 
 
 
 
 
Consent 
X 
 
 
History 
X 
 
X 
Physical Exam 
X 
X 
X 
Disease State Symptom Survey 
X 
 
X 
Concurrent Medications 
X 
X 
X 
Adverse Events 
 
X 
X 
Serious Adverse Events 
 
X 
X 
*Baseline and Procedure may be on the same date/visit. 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 16 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
A power analysis was performed for this two independent sample study with a dichotomous 
endpoint (presence of a saline lift during follow-up EGD). We assume 20% of patients 
receiving standard of care and no ECM will have a submucosal lift vs. 80% of patients 
receiving ECM will have submucosal lift. Using a power of 0.8, and alpha of 0.05, this 
equates to a sample size of 10 for each group for a total of 20 subjects.  
 
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate 
for all variables.  Baseline values for demographic, clinical, and outcome variables (primary 
and secondary) will be tabulated for the treatment groups.  These analyses will help identify 
potential confounding variables to be used as covariates in sensitivity analyses.  Distributions 
across subgroups used in randomization will be compared to assess whether the 
randomization was successful in equalizing distributions of these prognostic variables across 
treatment groups.  Putative prognostic variables that will be investigated through these 
descriptive analyses include variables such as presence of submucosal lift, esophageal 
caliber, need for esophageal dilation, and score on the Mayo Dysphagia Questionnaire.   
 
 
Handling of Missing Data 
 
Given the small number of patients and minimal follow-up time we do not anticipate missing 
data.  
 
 
Primary Hypothesis: To assess the efficacy of ECM products in promoting constructive 
healing as determined by the ability of the resection site to lift with saline injection during 
follow-up.  
 
A student unpaired t-test will be performed to compare the incidence of successful lift in the 
area of prior EMR among ECM and non-ECM groups. 
 
Secondary Hypothesis: Secondary endpoints include efficacy of ECM in preventing 
symptomatic esophageal stricture formation requiring dilation, preventing dysphagia as 
determined by questionnaires, and mitigating formation of post-resection scarring as 
determined by blinded comparison of pre- and post-resection images (taken using white-light 
endoscopy and electron chromoendoscopy). 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 17 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
Dysphagia questionnaire: student paired t-test will compare the pre and post treatment scores 
between both groups. 
Esophageal diameter: student paired t-test will compare the pre and post treatment sizes 
between groups. 
 
Interim Analysis 
 
As this is a small pilot study, we will not perform an interim analysis. Any serious adverse 
events will prompt immediate reevaluation of study methods. 
 
7.3 
Subject Population(s) for Analysis 
 
All-completed population:  Only subjects who completed ALL study related procedures and 
follow-up will be included (Per Protocol) maybe adjusted to subjects who completed the 
majority of the study visits and procedures. Patients lost to follow-up will be accounted for 
during calculation of the attrition rate. 
 
8 Safety and Adverse Events 
 
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form.  Records of these events will be maintained and reports submitted to the FDA 
and IRB according to the regulatory requirements.  Expected clinical adverse events and 
nonsignificant (not serious) clinical adverse events will not be reported. Expected clinical 
adverse events and anticipated adverse device effects are those listed in Section 1.5.2. 
 
8.1 
Definitions 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
IDE application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
 
Adverse Effect (Event) 
Any untoward medical occurrence in a subject involved in clinical study of an investigational 
device; regardless of the causal relationship of the problem with the device or, if applicable, 
other study related treatment(s). 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 18 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
Associated with the investigational device: There is a reasonable possibility that the 
adverse effect may have been caused by the investigational device. 
 
Life-threatening adverse effect: Any adverse effect that places the subject, in the view of 
the investigator, at immediate risk of death from the effect as it occurred.  It does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse effect: An adverse effect is considered “serious” if, in the view ofthe 
investigator, it results in any of the following outcomes:  
• death  
• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect. 
 
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or 
frequency of which is not consistent with the risk information in the clinical study protocol or 
elsewhere in the current IDE application. 
 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as an unanticipated adverse device effect unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances:  
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 19 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the local investigator should instruct each subject to report, to the local 
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The local investigator 
should notify the Mayo IRB of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to 
this study.  The IRB should also be notified if the local investigator should become aware of 
the development of problems, cancer or of a congenital anomaly in a subsequently conceived 
offspring of a subject that has participated in this study. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as 90 days following the last 
administration of study treatment.  
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 20 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Study subjects will be routinely 
questioned about adverse effects at study visits. Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event 
section of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
 
 
All adverse events occurring during the study period must be recorded.  All observed or 
volunteered adverse effects (serious or non-serious) and abnormal test findings, regardless of 
the treatment group if applicable or suspected causal relationship to the investigational device 
or if applicable other study treatment or diagnostic product(s) will be recorded in the 
subjects’ case history.  For all adverse effects sufficient information will be pursued and or 
obtained as to permit; an adequate determination of the outcome, an assessment of the casual 
relationship between the adverse effect and the investigational device or, if applicable other 
study treatment or diagnostic product.  The clinical course of each event should be followed 
until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up, to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be at least 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
 
Causality and severity assessment 
The investigator will promptly review documented adverse effects and abnormal test findings 
to determine 1) if the abnormal test finding should be classified as an adverse effect; 2) if 
there is a reasonable possibility that the adverse effect was caused by the investigational 
device or other study treatments; and 3) if the adverse effect meets the criteria for a serious 
adverse effect. 
If the investigator’s final determination of causality is “unknown and of questionable 
relationship to the investigational device or other study treatments,” the adverse effect will be 
classified as associated with the use of the investigational device or other study treatments for 
reporting purposes.  If the investigator’s final determination of causality is “unknown but not 
related to the investigational device or other study treatments,” this determination and the 
rationale for the determination will be documented in the respective subject’s case history. 
 
8.3 
Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The investigator will evaluate the event and determine the necessary 
follow-up and reporting required. 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 21 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
The investigator will promptly review documented Unanticipated Adverse Device Effects 
and as necessary shall report the results of such evaluation to FDA within 10 working days 
and Mayo IRB within 5 working days of initial notice of the effect.  Thereafter the sponsor-
investigator will submit such additional reports concerning the effect as requested. 
 
8.3.1 Investigator Reporting, Notifying Mayo IRB 
 
The investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs according 
to the Mayo IRB Policy and Procedures. 
 
Information collected on the adverse event worksheet (and entered in the research database):  
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research drug*:  
• If the adverse event was expected:  
• The severity of the adverse event: ** 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing 
treatment) 
• Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific reports need to 
be made to the IRB and FDA.  The investigator will sign and date the adverse event report 
when it is reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will be 
reported to the IRB. 
 
8.3.2 Investigator Reporting: Notifying the FDA 
 
. 
 
The investigator will report to the FDA all unanticipated adverse device effects according to 
the required reporting timelines, formats and regulations. 
 
The investigator will submit a completed FDA Form 3500A to the FDA’s Center for Devices 
and Radiological Health for any observed or reported adverse effect that is determined to be 
an unanticipated adverse device effect.  A copy of this completed form will be provided to 
the DSMB and all participating sub-investigators. 
 
The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, in 
no event, later than 10 working days after the investigator first receives notice of the adverse 
effect. 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 22 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
 
If the results of the investigator’s follow-up evaluation shows that an adverse effect that was 
initially determined to not constitute an unanticipated adverse device effect does, in fact, 
meet the requirements for reporting; the investigator will submit a completed FDA Form 
3500A as soon as possible, but in no event later than 10 working days, after the 
determination was made. 
 
For each submitted FDA Form 3500A, the investigator will identify all previously submitted 
reports that that addressed a similar adverse effect experience and will provide an analysis of 
the significance of newly reported adverse effect in light of any previous, similar report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the investigator will 
submit additional information concerning the reported adverse effect as requested by the 
FDA. 
 
 
Reporting Process 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
The contact information for submitting reports is: 
 
Food and Drug Administration 
Center for Devices and Radiological Health 
Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
 
Deviations from the investigational plan. 
 
The investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any deviation 
from the investigational plan to protect the life or physical well-being of a subject in an 
emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by 
the investigator is required for changes in or deviations from a plan, and if these changes or 
deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of 
human subjects, FDA and IRB notification in accordance with 21 CFR 812.35(a) also is 
required. 
 
8.4 
Unblinding Procedures (Breaking the Blind) (as necessary if the study is blinded) 
 
Unblinding will occur for any serious adverse event related to the ECM, or if execution of 
other therapies such as esophageal surgery, will be impacted by knowledge of the presence of 
ECM.  
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 23 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
8.5 
Stopping Rules 
 
Should an adverse event occur in any subject, further enrollment would be stopped 
immediately. 
 
8.6 
Medical Monitoring 
It is the responsibility of the investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as 
noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see Section 10 Auditing, Monitoring and Inspecting).  Medical monitoring 
will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
 
Source data comprise 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.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries 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. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents. 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 24 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
9.3 
Case Report Forms 
 
The study case report form (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.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries 
should be printed legibly in black ink.  If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  Do not obliterate, erase, or use “white-out” 
for errors.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it.  If the reason for the correction is not clear or needs additional 
explanation, neatly include the details to justify the correction. 
 
 
Data Management 
 
Data will be collected onto the CRF immediately during visits.  It will then be rapidly de-
identified and transferred to a secure computer based data base.   
 
 
Data Processing 
 
Data will be processed using electronic data management programs. 
 
 
Data Security and Confidentiality 
 
CRF will be kept in a lock drawer in a locked room at the St. Mary’s campus.  Electronic 
data will be de-identified, with the coding information for each patient kept on the CRF.  
Electronic data will be maintained on a secure server within encrypted data files. 
 
 
Data Quality Assurance 
 
Given the low number of patients, once all data has been collected, all CRF will be audited 
by an independent study team member to ensure that data transferred to the electronic 
database is accurate. 
 
 
Data Clarification Process 
 
Questions about data recording will be resolved by the principle investigator.  Notation of the 
question and its resolution will be made on the CRF and in the electronic database. 
9.4 
Records Retention 
 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 25 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
The investigator will maintain records and essential documents related to the conduct of the 
study.  These will include subject case histories and regulatory documents. 
 
 
The investigator will retain the specified records and reports for: 
1. Up to 2 years after the marketing application is approved for the drug; or, if a 
marketing application is not submitted or approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is discontinued and the FDA 
has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717,  
whichever is longer. 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
monitor, and government regulatory agencies, of all study related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as the investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be 
made in writing to the investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 26 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
and approval by the IRB for the study.  The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
 
12 Study Finances 
12.1 Funding Source 
This study will be funding through existing, internal sources. 
 
13 Publication Plan 
 
There are no publication requirements for this pilot study.  Decision to publish will be at the 
discretion of Dr. Kenneth Wang, the principle investigator. 
 
14 References 
 
1. 
Londono R, Badylak SF. Regenerative Medicine Strategies for Esophageal Repair. Tissue 
engineering. Part B, Reviews 2015;21:393-410. 
2. 
Katada C, Muto M, Manabe T, et al. Esophageal stenosis after endoscopic mucosal resection 
of superficial esophageal lesions. Gastrointest Endosc 2003;57:165-9. 
3. 
Konda VJ, Gonzalez Haba Ruiz M, Koons A, et al. Complete endoscopic mucosal resection 
is effective and durable treatment for Barrett's-associated neoplasia. Clin Gastroenterol 
Hepatol 2014;12:2002-10 e1-2. 
4. 
van Vilsteren FG, Pouw RE, Seewald S, et al. Stepwise radical endoscopic resection versus 
radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a 
multicentre randomised trial. Gut 2011;60:765-73. 
5. 
Barret M, Beye B, Leblanc S, et al. Systematic review: the prevention of oesophageal 
stricture after endoscopic resection. Alimentary pharmacology & therapeutics 2015;42:20-39. 
6. 
Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization 
processes. Biomaterials 2011;32:3233-43. 
7. 
Londono R, Badylak SF. Biologic scaffolds for regenerative medicine: mechanisms of in vivo 
remodeling. Annals of biomedical engineering 2015;43:577-92. 
8. 
Badylak SF, Hoppo T, Nieponice A, et al. Esophageal preservation in five male patients after 
endoscopic inner-layer circumferential resection in the setting of superficial cancer: a 
regenerative medicine approach with a biologic scaffold. Tissue Eng Part A 2011;17:1643-50. 
9. 
Record RD, Hillegonds D, Simmons C, et al. In vivo degradation of 14C-labeled small 
intestinal submucosa (SIS) when used for urinary bladder repair. Biomaterials 2001;22:2653-
9. 
10. 
Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Seminars in 
immunology 2008;20:86-100. 
11. 
Voytik-Harbin SL, Brightman AO, Kraine MR, et al. Identification of extractable growth factors 
from small intestinal submucosa. J Cell Biochem 1997;67:478-91. 
12. 
Badylak SF. Decellularized allogeneic and xenogeneic tissue as a bioscaffold for 
regenerative medicine: factors that influence the host response. Annals of biomedical 
engineering 2014;42:1517-27. 
13. 
Beattie AJ, Gilbert TW, Guyot JP, et al. Chemoattraction of progenitor cells by remodeling 
extracellular matrix scaffolds. Tissue engineering. Part A 2009;15:1119-25. 

BIOLOGIC SCAFFOLDS FOLLOWING ENDOSCOPIC RESECTION 
Version 2.0 
 
 
 
 
Page 27 of 27 
Kenneth K. Wang 
 
CONFIDENTIAL 
14. 
Reing JE, Zhang L, Myers-Irvin J, et al. Degradation products of extracellular matrix affect 
cell migration and proliferation. Tissue engineering. Part A 2009;15:605-14. 
15. 
Lopes MF, Cabrita A, Ilharco J, et al. Esophageal replacement in rat using porcine intestinal 
submucosa as a patch or a tube-shaped graft. Diseases of the esophagus : official journal of 
the International Society for Diseases of the Esophagus / I.S.D.E 2006;19:254-9. 
16. 
Hoppo T, Badylak SF, Jobe BA. A novel esophageal-preserving approach to treat high-grade 
dysplasia and superficial adenocarcinoma in the presence of chronic gastroesophageal reflux 
disease. World journal of surgery 2012;36:2390-3. 
17. 
Uno Y, Munakata A. The non-lifting sign of invasive colon cancer. Gastrointest Endosc 
1994;40:485-9. 
18. 
Nieponice A, Ciotola FF, Nachman F, et al. Patch esophagoplasty: esophageal 
reconstruction using biologic scaffolds. Ann Thorac Surg 2014;97:283-8. 
19. 
Reznichenko AA. Different biologic grafts for diaphragmatic crura reinforcement during 
laparoscopic repair of large hiatal hernia: A 6-Year single surgeon experience. Journal of 
Medical Implants and Surgery 2015. 
20. 
Reznichenko AA. Extracellular matrix scaffold in diaphragmatic crura reinforcement during 
laparoscopic repair of large hiatal hernia. Journal of Surgery & Transplantation Science 
2016;4:1018-1021.