Prospective Randomized Controlled Trial Describing the Recurrence Rate of Adenomas in Sessile or Flat Colonic Lesions 15mm or Larger Receiving Post-resection Site Treatment With Snare Tip Soft Coagulation or Argon Plasma Coagulation
Phase: NA
Conditions: Recurrence
Sponsor: Indiana University

September 3rd, 2020 
 
 
 
Prospective randomized controlled trial describing the recurrence rate of 
adenomas in sessile or flat colonic lesions 15mm or larger receiving post-
resection site treatment with snare tip soft coagulation or argon plasma 
coagulation 
 
NCT03654209 
 
 

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Prospective randomized controlled trial describing the recurrence rate of 
adenomas in sessile or flat colonic lesions 15mm or larger receiving post-
resection site treatment with snare tip soft coagulation or argon plasma 
coagulation  
 
Dr. Douglas Rex 
Indiana University Hospital 
Indianapolis, Indiana 46202 
Sub-Investigators: 
 
 
 
 
 
 
Dr. Nikhil Kumta 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. David Greenwald 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. Christopher DiMaio 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. Jerome D. Waye 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. Satish Nagula 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. Habeeb Salameh 
The Mount Sinai Hospital 
New York, New York 10029 
 
Dr. Mouen Khashab 
The Johns Hopkins Hospital 
Baltimore, Maryland 21287 
 
Dr. Kia Vosoughi 
The Johns Hopkins Hospital 
Baltimore, Maryland 21287 
 
Dr. Yervant Ichkhanian 
The Johns Hopkins Hospital 
Baltimore, Maryland 21287 
 
Dr. Stuart Gordon 
Dartmouth-Hitchcock Medical Center 
Lebanon, New Hampshire 03756 
 
Dr. Gregory B. Haber 
NYU Langone Medical Center 
New York, New York 10016 
 
Dr. Muhammad Hasan 
AdventHealth Orlando 
Orlando, FL 32803 
 
Dr. Amit Rastogi 
The University of Kansas Medical Center 
Kansas City, KS 66160 
 
Dr. Firas Al-Kawas 
Sibley Memorial Hospital 
Washington, D.C. 20016 
 
Dr. Matthew Moyer 
Penn State Health Milton S. Hershey Medical Center 
Hershey, PA 17033 
 
Dr. John M. Levenick 
Penn State Health Milton S. Hershey Medical Center 
Hershey, PA 17033 
 
Dr. Abraham Mathew 
Penn State Health Milton S. Hershey Medical Center 
Hershey, PA 17033 
 
Dr. Charles Dye 
Penn State Health Milton S. Hershey Medical Center 
Hershey, PA 17033 
 
Dr. Hadie Razjouyan 
Penn State Health Milton S. Hershey Medical Center 
Hershey, PA 17033 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
2.3 
Tertiary/Exploratory/Correlative Objectives 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
3.3 
Tertiary/ Exploratory/ Correlative Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events 
10.0 
Data Safety Monitoring 
11.0 
Study Withdrawal/Discontinuation 
12.0 
Statistical Considerations 
13.0 
Data Management 
14.0 
Privacy/Confidentiality Issues 
15.0 
Follow-up and Record Retention 
16.0 
References 
17.0 
Appendix 
 
 
Abbreviations 
 
AE 
Adverse Event 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
HIPAA Health Insurance Portability and Accountability Act  
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
US 
United States 
 
 
 
 

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1.0 
Background & Rationale 
Endoscopic resection of large benign lesions is the preferred treatment over surgical resection.  
Endoscopic mucosal resection (EMR) is associated with a lower risk and cost compared to 
surgical treatment.  However, it is important that patients undergo endoscopic follow-up after 
piecemeal EMR in approximately 6 months because there is an approximately 25% risk of 
recurrence of adenoma polyps 1. 
   
A randomized controlled trial in only 24 patients showed a significant reduction of the 
recurrence rate by treatment of the normal appearing perimeter of the EMR defect using the 
argon plasma coagulator 2. A recent non-randomized trial suggested a substantial reduction by 
treatment of the perimeter with the snare tip in the soft coagulation mode 3.   
 
In this study we are proposing a randomized controlled trial to test Argon Plasma Coagulation 
(APC) versus Snare Tip Soft Coagulation (STSC) vs no treatment.  In a previous trial of APC, 
the recurrence rate of the control arm was very high at 67%. With only 24 patients in the study 
the actual benefits of APC remain uncertain.  The previous study using STSC was a non-
randomized trial.  In this trial we hope to provide definitive evidence regarding the efficacy of 
APC and STSC vs control. 
 
2.0 
Objective(s) 
2.1 
Primary Objective 
To investigate the efficacy of APC or STSC in reducing the recurrence rate at the 
first follow-up after polypectomy of large colon polyps 

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Hypothesis: 
APC or STSC treatment of the perimeter of the EMR defect will reduce the 
recurrence rate of adenomas when compared to our control of no treatment.   
2.2 
Secondary Objective 
Time it takes to apply each respective treatment (APC or STSC) 
Number of complications for each randomization arm. Examples include 
bleeding, perforation, pain or post polypectomy syndrome. 
Cost analysis detailing the effectiveness of the treatment versus the cost of each 
therapeutic device (argon probe vs. snare). 
 
3.0 
Outcome Measures/Endpoints 
3.1 
Primary Outcome Measures 
Primary outcome is the recurrence rate of adenomas at the site of any qualifying, 
previously resected lesions at the first follow-up colonoscopy. At the first follow-
up the endoscopist will view the polypectomy scar with a high definition 
colonoscope under white light and NBI for any suspicious polyp tissue. The scar 
will be biopsied. All polyps noted as recurrent by the endoscopist at colonoscopy 
and/or by the pathologist based on histopathology will be considered a recurrent 
polyp. 
 
3.2 
Secondary Outcome Measures 
Time it takes to apply each treatment will be recorded by a research assistant 
during the index procedure using a stop watch. During the colonoscopy the 

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treatment time will be recorded as the time, after initial polyp resection, that the 
randomized treatment instrument comes into view until before clips are applied. 
Complications will be assessed during the follow-up call simply by asking the 
patients if they experienced any adverse events. We will use the following 
definitions to ascertain complications: 
Bleeding: severe bleeding event that required hospitalization, a blood transfusion, 
a colonoscopy, surgery, or any other invasive intervention to control bleeding, and 
that occurred after the patient left the endoscopy unit and within 30 days after 
completion of the colonoscopy 
Perforation: iatrogenic full thickness defect in the colon wall diagnosed within 
two weeks of the procedure 
Pain: Any pain perceived by the patient after they left the endoscopy unit and 
within 30 days after completion of the colonoscopy 
Post polypectomy syndrome: Abdominal pain, fever, leukocytosis and peritoneal 
inflammation in the absence of perforation within two weeks of the procedure 
Our cost analysis will then take all of these endpoints into account to report which 
method we found to be more affective. As stated, this will be based on the 
instrument cost, treatment time, polyp recurrence, and reported complications. 
 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
• 25 years and older 
• Ability to provide informed consent 

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• Undergoing colonoscopy for screening, surveillance, diagnostic reasons, or 
removal of a lesion 
 
4.2 
Exclusion Criteria 
• 
Pedunculated lesions 
• 
Inflammatory bowel disease 
• 
Inability to provide informed consent  
• 
Lesions less than 15mm in largest dimension 
 
5.0 
Study Design and procedures 
A member of the research team will approach a potential subject to discuss participation in the 
study, including background of the proposed study, inclusion and exclusion criteria, benefits and 
risks of the procedures and follow-up. If this is of interest to the subject, the informed consent 
document will be discussed and presented. The subject must sign the consent form prior to 
enrollment. This form will have prior approval of the study site's Institutional Review Board 
(IRB). Failure to obtain informed consent renders the subject ineligible for the study. 
 
Patients who have provided informed consented and are scheduled to undergo endoscopic 
mucosal resection (EMR) of lesions 15mm and larger will be enrolled in the study. During the 
procedure randomization will be performed by approved study staff once the colonoscopist 
confirms the eligibility (at least one sessile polyp greater than 15 mm in the largest dimension 
measured by the snare size). The three arms of randomization are STSC (80 W, Effect 5) vs APC 
(preferred settings) vs No Treatment of the perimeter of the EMR site. The randomization list, 

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which will include 645 randomized treatments, will be generated by our biostatistics department 
by George Eckert. These selections will then be printed and placed into sealed envelopes 
pertaining to the patient numbers and will be opened following confirmation that the patient is 
study eligible.  Randomization will occur on a per procedure basis. 
 
All randomized subjects will receive a 30-day post procedure follow-up phone call (+ 7 days) 
and be scheduled, as per the standard of care, to receive a standard follow-up colonoscopy 
procedure after the initial procedure. The follow-up window for the primary endpoint has been 
extended beyond 6 months due to procedure delays caused by the COVID-19 pandemic. We will 
measure the rate of recurrence by endoscopic visualization of the EMR site at the first follow-up 
using endoscopic magnification and electronic chromoendoscopy, as well as systematic biopsy 
of the scars. Additionally we will look for the presence of scarring and any clips retained. 
 
6.0 
Enrollment/Randomization 
All colonoscopies in the study will be performed by Dr. Douglas Rex or one of the Sub-
Investigators listed above.  Patients will be 25 and older and will be randomized to one of the 
aforementioned arms of the study. Blinding of the PI will be maintained until the end of the 
polypectomy procedure at the primary procedure. Further blinding is not possible due to the 
nature of the study. 
 
Screen failure: any patient enrolled in the study but not randomized because of not satisfying 
polyp size or other exclusion criteria discovered during the procedure. 
 

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7.0 
Study Calendar 
Index procedure will be the day of colonoscopy where one of the intervention arms or the control 
arm is administered. Patients will receive a follow-up phone call at 30-days (+ 7 days) to 
ascertain any complications as previously described. Patients will also receive a follow-up 
colonoscopy (standard of care for large polyp removal) where the polypectomy site is observed 
for any recurrence. 
 
Index procedure 
Follow-up phone 
call 
Follow-up colonoscopy 
Day 1 
Day 30 + 7 days 
Approximately Day 180 
Study 
Procedures 
Colonoscopy with one 
of the intervention arms 
or control 
Phone call to 
ascertain 
complications 
Colonoscopy to observe 
for recurrence at 
polypectomy site 
 
Lost to follow-up: All patients who are randomized to one of the interventions but fail to 
complete the required follow-up colonoscopy. Failure to contact at 30 days will not be 
considered lost to follow-up (complications information in such cases will be deemed acceptable 
if collected at the first follow-up but an accurate accounting of the number of such patients will 
be kept and reported to the DSMB). 
 
8.0 
Reportable Events 
All adverse events meeting prompt reporting criteria will be reported to the IRB within 5 
business days of the study team becoming aware of the event. An adverse event meeting prompt 

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reporting criteria for this study is defined as any event assessed by the PI, or appropriately 
trained and qualified designee, as (1) unexpected, (2) related or possibly related to study 
participation, AND (3) suggesting that the research places subjects or others at greater risk of 
harm than was previously known. The period for assessing AE’s will be from the point of 
inserting the colonoscope until 30 days after the index colonoscopy. 
 
9.0 
Data Safety Monitoring 
See Data and Safety Monitoring Board Charter for information about DSMB. Briefly, the data 
safety monitoring board comprises 4 members: Charles J. Kahi MD (Indiana University), 
Huiping XU PhD (Indiana Universtiy), Cyrus Piraka MD (Henry Ford Hospital), and Joseph B. 
Elmunzer MD (Chair), (Medical University of South Carolina). None of the board members are 
involved with the current study in any capacity. Additionally, Dr. Rex's research team will 
provide him up to date information regarding the status of patients and any reportable events. 
 
The data collected at sites other than IU will be de-identified before being sent to us. Each site 
will enter their data in to a secure web application (REDCap), which will then be accessed at the 
primary site. Only de-identified data from external sites will be added to the database (no HIPAA 
identifiers will be collected from external sites besides procedure dates and de-identified images 
of study lesions). Any other communication that is not patient related will be done over email or phone. 
Variables that will be transmitted from the other site include: 
• Information from the procedure to remove the large polyp 
 This includes information about meeting inclusion/exclusion criteria, procedure 
date, randomization envelope number/randomization treatment, age, gender, race, 

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ethnicity, whether a fellow was involved in the procedure (and which parts of 
procedure, if applicable), procedure times, study polyp characteristics, de-
identified study lesion images, resection times, information about the resection 
such as snare/ injection fluid usage and number of resected pieces, treatment 
times, other additional treatments used, clipping times, number/type of clips used, 
type of colonoscope used, Boston Bowel Preparation Score, whether fibrosis was 
present, whether there were any prior attempts at resection, information about 
procedural complications (if any), and study polyp pathology results 
• Information from the 30 day follow up call 
 This includes information about whether the follow-up phone call was made 
successfully, date subject was reached by phone, and whether patient reported 
experiencing adverse events (and if so, information about the adverse event). 
 Information from the first follow-up procedure 
 This includes information about the previous EMR site, date of follow-up 
procedure, pathology results from residual or recurrent polyp tissue found at 
previous EMR site (if applicable), and  pathology results from biopsies obtained 
from previous EMR site 
 
10.0 Study Withdrawal/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 Investigator may decide for reasons of medical prudence, to withdraw a subject. In 
either event, the Investigator will clearly document the date and reason(s) for the subject’s 

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withdrawal from this investigation in the CRF and should indicate whether or not he considers it 
was related to the study interventions. 
 
11.0 Statistical Considerations 
Assuming a 25% recurrence rate of the control arm, and a reduction to 10% in both of the 
treatment arms, we estimate that a sample size of 115 subjects per arm will be needed to 
demonstrate that APC and STSC are superior to no treatment for reduction of recurrence rate 
after EMR, based on 80% power and a two-sided 5% significance level for comparison of 
independent proportions with one interim analysis.  The no treatment arm will be used as our 
control. In order to account for drop-outs, an extra 35 patients will be enrolled into the study to 
ensure sufficient data will be included in the analysis.  Therefore, a sample size of 380 subjects 
will be enrolled in this study.  
 
Once a polyp has been identified and its size fits within the targeted range, each subject will be 
randomized in a 1:1:1 ratio using a computer generated randomization sequence. Enrollment into 
the study will be competitive with the possibility for each site outside of IU to randomize up to 
100 patients. Not all 645 randomization numbers generated will be used in the study. Instead 
each external site will continue to enroll until a total of 380 patients have been randomized 
study-wide with a potential to randomize up to 100 patients. Randomization numbers will be 
assigned as follows: IU will be assigned numbers 001 – 095 and 496 - 526; AdventHealth 
Orlando will be assigned 096 – 145 and 446 - 470; The Johns Hopkins Hospital will be assigned 
numbers 146 – 195; Dartmouth-Hitchcock Medical Center will be assigned numbers 196 – 245; 
NYU Langone Medical Center will assigned numbers 246 – 295 and 471 - 495; the Mount Sinai 

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Hospital will be assigned 296 – 345, Sibley Memorial Hospital will be assigned 346 – 395, the 
University of Kansas Medical Center will be assigned 396 – 445, and Penn State Health Milton 
S. Hershey Medical Center will be assigned 546 - 595. The proportion of subjects with 
recurrence will be compared between study arms using chi-square tests. The number of 
complications will be compared among treatment arms using negative binomial regression. 
Treatment times and costs will be compared between the APC and STSC arms using Wilcoxon 
Rank Sum tests. A 5% significance level will be used for all tests.  
Interim analysis and stopping rule: 
The interim analysis will be conducted after half of the subjects have completed the study, using 
an O’Brien-Fleming spending function with alpha levels 0.003 and 0.049 at the interim and final 
analyses. Any results will be considered significant at a p-value of <=0.003 at the interim 
analysis and the DSMB will make a decision about stopping the study based on those results. 
 
12.0 Statistical Data Management 
Primary data will be collected via case report forms. All paper charts pertaining to the patient 
will be kept under lock and key in coordinators office away from the endoscopy area. Each site 
will enter their data in to a secure web application (REDCap). Virtual data will be stored on an 
internal network drive with encryption and password security. Only approved personnel by the 
IRB will have access to the file storage.  This file will also not have any identifiable patient 
information.  A study log with the identifiable information will be kept in a separate folder to 
enable the investigators to assist in any research audit. No procedural data except the date of 
examination will be entered into this log.   

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The storage location on IU servers will be backed up automatically and continuously. Quality 
assurance steps will include built in range checks for age, procedure duration, lesion size, total 
resection time, treatment time, clipping time on REDCap and remote study site visits after 
completion of the study by 190 patients.   
 
Remote study site visit: 
Before interim analysis and after completion of the study by 190 patients, 10% of case report 
forms from each site will be verified with the site’s electronic medical system information via a 
video based call from the central data site (IU). Any patterns of systematic errors will trigger the 
verification of all case report forms for that particular site. 
13.0 References 
1. 
Zhan T, Hielscher T, Hahn F, et al. Risk Factors for Local Recurrence of Large, Flat 
Colorectal Polyps after Endoscopic Mucosal Resection. Digestion 2016;93:311-7. 
2. 
Brooker JC, Saunders BP, Shah SG, et al. Treatment with argon plasma coagulation 
reduces recurrence after piecemeal resection of large sessile colonic polyps: a 
randomized trial and recommendations. Gastrointest Endosc 2002;55:371-5. 
3. 
Tate DJ, Bahin FF, Desomer L, et al. Cold-forceps avulsion with adjuvant snare-tip soft 
coagulation (CAST) is an effective and safe strategy for the management of non-lifting 
large laterally spreading colonic lesions. Endoscopy 2018;50:52-62.