Safety of Endoscopic Resection of Large Colorectal Polyps: A Randomized Trial.
Phase: NA
Conditions: Colon Polyps
Sponsor: White River Junction Veterans Affairs Medical Center

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
 
 
 
 
 
NCT01936948 
 
 
 
 
Safety of endoscopic resection of large colorectal 
polyps: A randomized trial. 
 
 
Sponsor Protocol – version 9 
 
September 13, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
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Table of Contents 
 
1. ABSTRACT..................................................................................................................................................... 3 
2. SPECIFIC AIMS ............................................................................................................................................. 3 
3. RESEARCH PLAN ......................................................................................................................................... 4 
3.1. BACKGROUND AND SIGNIFICANCE ....................................................................................................................... 4 
3.1.1. Complications of endoscopic mucosal resection of large polyps................................................... 4 
3.1.2. Limitations of prior studies ............................................................................................................................ 5 
3.1.3. Electrocautery and complication risk ....................................................................................................... 6 
3.1.4. Clipping and complication risk ..................................................................................................................... 6 
3.2. RESEARCH DESIGN AND METHODS ...................................................................................................................... 7 
3.2.1. Design and patients ............................................................................................................................................ 7 
3.2.2. Inclusion and Exclusion criteria ................................................................................................................... 7 
3.2.3. Study screening procedures ........................................................................................................................... 8 
3.2.4. Patients on anticoagulation ........................................................................................................................... 9 
3.2.5. Allocation to treatment (Randomization process).............................................................................. 9 
3.2.6. Colonoscopy and endoscopic mucosal resection (EMR) .................................................................... 9 
3.2.7. Follow-up procedures .................................................................................................................................... 11 
3.2.8. Schedule of activities (Study table) ......................................................................................................... 11 
3.2.9. Study outcome evaluation............................................................................................................................ 11 
3.2.10. Statistical analysis ........................................................................................................................................ 14 
3.2.11. Timetables ........................................................................................................................................................ 16 
3.2.12. Research setting ............................................................................................................................................. 16 
3.3. DATA AND SAFETY MONITORING PLAN ............................................................................................................ 17 
3.3.1. Monitoring Plan ................................................................................................................................................ 17 
3.3.2. Data Safety Monitoring Board ................................................................................................................... 18 
4. GENDER/MINORITY MIX ...................................................................................................................... 19 
5. RISK ANALYSIS ......................................................................................................................................... 19 
5.1. ANTICIPATED RISKS ............................................................................................................................................. 19 
5.2. ADVERSE EVENT RECORDING AND REPORTING .............................................................................................. 19 
5.2.1. Adverse event definitions .............................................................................................................................. 19 
5.2.2  
Eliciting adverse effect information ................................................................................................... 20 
5.2.3  
Recording and assessment of adverse effects ................................................................................. 20 
5.2.4. Reporting of adverse effects to the responsible IRB ......................................................................... 21 
5.3. WITHDRAWAL OF SUBJECTS DUE TO ADVERSE EFFECTS ................................................................................ 21 
6. FDA RISK DETERMINATION ................................................................................................................ 22 
7. CONSENT PROCESS ................................................................................................................................. 22 
8. ADDITIONAL RECORDS AND REPORTS ........................................................................................... 23 
8.1. DATA HANDLING AND RECORD-KEEPING .......................................................................................................... 23 
8.2. RECORD MAINTENANCE AND RETENTION ......................................................................................................... 24 
9. FUNDING..................................................................................................................................................... 25 
APPENDIX 1. STUDY DESIGN ................................................................................................................... 26 
APPENDIX 2. STUDY TABLE ..................................................................................................................... 27 
REFERENCES .................................................................................................................................................. 28 
 
 
 
 
 

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1. ABSTRACT 
Background: The effectiveness of colonoscopy in reducing colorectal cancer mortality relies 
on the detection and removal of neoplastic polyps. Because the risk of prevalent cancer and 
of transition to cancer increases with polyp size, effective and safe resection of large polyps 
is particularly important. Large polyps ≥20mm are removed by so-called endoscopic 
mucosal resection (EMR) using electrocautery snares. Resection of these large polyps is 
associated with a risk of severe complications that may require hospitalization and additional 
interventions. The most common risk is delayed bleeding which is observed in 
approximately 2-9% of patients. A recent retrospective study suggests that closure of the 
large mucosal defect after resection may decrease the risk of delayed bleeding. However, 
significant uncertainty remains about the polypectomy techniques to optimizing resection 
and minimizing risk. Important aspects that may affect risk include clipping of the mucosal 
defect and electrocautery setting.   
Aims/Hypothesis: Our primary aim is to examine whether clip closure of the mucosal 
defect after endoscopic mucosal resection (EMR) of large polyps (≥20mm) will reduce the 
risk of delayed bleeding in a prospective randomized trial. In secondary analysis we will 
explore, whether electrocautery settings affect the risk of complications. We hypothesize 
that clip closure will reduce the risk of delayed bleeding. 
Methods: The study will include patients with a polyp ≥20 mm in size. Experienced 
endoscopists will follow a standardized resection protocol. Patients will be randomized in a 
2x2 factorial design to one of two electrocautery settings (Endocut versus low power 
coagulation; secondary comparison) and to either undergo or not undergo closing of the 
mucosal resection defect after resection. For the primary comparison (clip vs. no clip) the 
primary outcome will be incidence of delayed bleeding complications within 30 days 
following the procedure. We further plan to identify factors that may be associated with 
delayed bleeding. We are also interested in understanding recurrence of neoplastic polyps 
at first and second follow-up colonoscopy, defined as the presence of biopsy proven 
neoplastic tissue. 
Anticipated Results: The results of the study will help to determine whether clip closure of 
the mucosal defect after resection of large polyps is associated with a decreased delayed 
bleeding risk. The results will further help to understand whether there is a preferred 
electrocautery setting with a lower complication risk. The findings may therefore help to 
identify a safe resection practice and contribute to the development of resection standards 
for polypectomy. 
 
 
 
2. SPECIFIC AIMS 
 
Aim 1. The primary aim of the study is to compare the rate of delayed bleeding 
complications in patients undergoing endoscopic resection of large polyps between: 
A) Closing the mucosal defect after resection (Clip group) and 
B) Not closing the mucosal defect after resection (No clip group). 
 
Aim 2. The secondary aim of the study is to compare the rate of overall complications in 
patients undergoing endoscopic resection of large polyps between two cautery settings:  
A) Low power coagulation and 
B) Endocut. 

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Hypothesis: Specific endoscopic techniques are associated with a lower complication rate of 
endoscopic mucosal resection of large colorectal polyps.  
Additional secondary aims: The study further examines the rate of complete polyp 
resection, polyp recurrence, and factors that are associated with complete resection and 
recurrence during 5 years of follow-up. 
 
3. RESEARCH PLAN 
3.1. Background and Significance 
Colorectal cancer is the second most common cause of cancer death in the United States1. 
The effectiveness of colonoscopy in reducing the risk of dying from colorectal cancer relies 
on the detection and safe resection of neoplastic polyps to prevent incident cancers. Most 
polyps are small and can be easily removed using snare with or without electrocautery. 
Because the risk of prevalent cancer or transition to cancer increases with polyp size, 
effective and safe resection of large polyps is particularly important.  
Endoscopic mucosal resection (EMR) is evolving as the primary endoscopic technique to 
remove large non-pedunculated polyps. These flat or sessile polyps are defined as lateral 
spreading tumors with a low vertical axis that extend laterally along the luminal wall. Several 
mostly retrospective studies from Europe, the U.S. and Japan, have demonstrated a high 
“cure” rate, with results lending credence to the shift from surgical resection to endoscopic 
management of these lesions. Of concern, however, is 1) a fairly high overall complication 
rate of 8-26% in prospective studies2-6, and 2) the persistence of residual neoplasia on 
follow-up endoscopy ranging from 16% to 46%2, 5, 7.   
 
3.1.1. Complications of endoscopic mucosal resection of large polyps 
Severe complications that are associated with a standard screening colonoscopy, which 
may include resection of predominantly smaller polyps, are uncommon. Significant bleeding 
occurs in 0.2 to 0.5% of patients (defined as a 2gm drop in Hemoglobin), perforation of the 
colon in 0.05-0.10%, and post polypectomy syndrome in <0.5%8, 9.  
The risk of severe complications increases with polyp size. The incidences of complications 
associated with resection of large polyps are summarized in table 1. The most common 
complication is bleeding reported in 2 to 24% of polyp resections. Perforation occurred in 
approximately 1% of resections and postpolypectomy syndrome in 1-4% of patients. 
Postpolypectomy syndrome is caused by focal inflammation as a result of deep cautery 
injury to the serosal surface when resecting a polyp. Patients typically present with 
abdominal pain, fever, and leukocytosis. 
In addition to size, other factors that may affect complications. These include type of 
resection (piecemeal versus en-bloc), polyp location (right colon with a thinner wall than the 
left colon), age and comorbidities, especially those that affect clotting abilities (e.g. renal 
insufficiency, liver disease, use of anticoagulation). Studies that have examined variables, 
which may directly decrease the risk of complications associated with large polyp resection, 
are limited. 
 
 
 
 
 
 
 
 
 

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Table 1. Studies that examined complications related to EMR of large colon polyps.  
Study 
Design 
Patients
n 
Size 
Electro-
cautery  
Compli-
cations,  
overall 
Blee-
ding 
Perfo-
ration 
PPS 
Walsh  
199210 
Retrospective 
108 
≥10mm 
Unclear 
10.2% 
9.3% 
0.9% 
- 
Brooker 20022 
Prospective 
34 
≥15mm 
Low power 
coag 
26.5% 
23.5% 
0 
- 
Ahmad 
200211 
Retrospective 
29 
8-30mm 
Unclear 
24.1% 
24.1% 
0 
0 
Conio  
20043 
Prospective 
136 
≥ 20mm 
Blended  
14.7% 
- 
0 
3.7% 
Kaltenbach 
200712  
Retrospective 
125 
≥ 10mm 
Blended  
1.8% 
1.8% 
0 
0 
Arebi  
20077 
Retrospective 
161 
≥ 20mm 
Blended  
8.2% 
5.7% 
0 
- 
Luigiano 
200913 
Retrospective 
148 
≥ 20mm 
Unclear 
12.2% 
10.1% 
0.7% 
1.4% 
Swan  
20096 
Prospective 
174 
≥ 10mm 
Blended  
16.2% 
9.8% 
0 
- 
Ferrara 20104 
Prospective 
152 
≥15mm 
Blended  
18.4 
14.5% 
1.3% 
2.6% 
Moss  
20115 
Prospective 
464 
≥ 20mm 
Blended  
7.7% 
2.9% 
1.3% 
1.5% 
Gimeno-Garcia 
201214 
Retrospective 
1894 
≥ 10mm 
Unclear 
Na 
9.1% 
Na 
Na 
Buchner 2012 
15 
Retrospective 
249 
8-100mm Low power 
coag 
11.6% 
10.0% 
0.4% 
1.2% 
Qumseya & 
Wallace 
201216 
Retrospective 
525 
≥ 20mm 
Low power 
coag 
Na 
7.0% 
Na 
Na 
Liaquat & Rex 
201317  
Retrospective 
420 
≥ 20mm 
Low power 
coag 
Clip:  5.8%  
No clip: 12% 
3.1% 
8.8% 
0.5% 
1.2% 
PPS = postpolypectomy syndrome (synonymous for transmural burn syndrome) 
 
 
3.1.2. Limitations of prior studies  
Prior studies (table 1) 
Proposed study 
• Studies often included polyps of <20mm. Because of the 
association between size and complications, results from 
these studies do not reflect complications with resection 
of ≥20mm polyps. 
The study will only include 
patients with non-pedunculated 
≥20mm polyps. 
• Most studies were retrospective. Complications following 
within a 30-day window may go unnoticed (selection 
bias). There are few larger studies that evaluated 
complications prospectively. The risk of overall 
complications varied between 8% and 18%, with a 
bleeding risk between 3% and 14%. 
The design will be a 
prospective RCT. 

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• The follow-up interval was not always clear, which may 
also lead to underreporting of delayed complications. 
 
Complications will be assessed 
within 30 days following the 
procedure. 
• The definition of what was considered a complication 
was not always provided. 
 
Complications will be defined 
as clinical events following 
polyp resection, which require 
a visit to the ED, admission, or 
additional tests or procedures 
(see outcome measures).  
• The denominator of how complications were measured 
was not always clear. The incidence could be related to 
number of polyps or number of patients (a patient could 
have more than one polyp).  
We will calculate the incidence 
of complications per polyp and 
per patient. 
 
 
3.1.3. Electrocautery and complication risk 
Electrocautery snare resection represents the standard approach to resecting larger polyps. 
The principle of electrocautery snare resection relies on the application of an electrical 
current to the snare while closing the snare around the base of the polyp. Electrical energy 
is converted to heat energy by changing from a low frequency current (60Hz) to a high 
frequency current (>300,000Hz). 
Two types of currents can generally be distinguished, cutting current and coagulation 
current. Cutting current delivers a high frequency (density) and low voltage current, which 
results in high-energy intensity and allows swift “cuts” through tissue without deep thermal 
tissue injury. The flip side is that it does not provide sufficient cautery time to seal cut blood 
vessels and bleeding is therefore a concern.  
In contrast, coagulation current delivers a lower frequency (density) current. This current 
allows “sealing” of cut vessels and may prevent bleeding, but may cause deeper tissue 
injury and increase the risk for postpolypectomy syndrome and perforation. For polyp 
resection the so-called low power coagulation is used to resect polyps.  
Two minimize risk, cautery units provide a setting of cutting current alternating with 
coagulation current, also called blended current. Realizing that heat production is dependent 
on tissue resistance, some cautery units provide a special type of blended cautery setting 
(also called “Endocut” when used with the ERBE cautery unit, which will be used in the 
study). Endocut is a microprocessor-controlled current alternating between coagulation and 
cutting adjusted for tissue resistance. 
The rationale for assessing electrocautery current is very strong.  It is a fundamental aspect 
of polypectomy and not a single randomized trial has been done to address its effect on 
complications.  Endoscopists do polypectomy the way they were trained to do it.  It is not an 
issue that is settled. In the 2004 a survey by Singh et al found that 46% of US endoscopists 
used blended current and 46% use low power coagulation18.  Two retrospective studies 
found that low power coagulation causes delayed bleeding and blended current causes 
immediate bleeding19, 20. Thus the type of current used for polyp resection remains an 
important clinical question. 
 
3.1.4. Clipping and complication risk 
It is apparent that resection of a large polyp leaves behind a large mucosal defect. The 
mucosal ulcer that forms after polyp resection can take several weeks to heal. Bleeding 
complication typically occur within 7 to 10 days, requiring often admission, a repeat 

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colonoscopy to stop bleeding, and possible blood transfusions. To reduce the risk of 
bleeding it has been proposed to close the mucosal defect after polyp resection.  
To date, no randomized trial has examined whether clip application affects complications 
after large polyp resection. One recent study did not show a benefit21. Bleeding occurred in 
2% in either group. However, the study included patients with smaller polyps (mean size 
8mm) with a low expected bleeding risk. A recent retrospective study by Liaquat et al. 
showed that clip closure was associated with a significantly reduced risk of delayed bleeding 
(2% vs. 10%), and a reduced risk of overall complications (4% vs. 12%), when compared to 
historical controls22. Main limitations of the study include unmeasured factors that may have 
affected the outcome and performance of all resections by one expert colonoscopist. 
However, a third very recent retrospective study by Qumseya et al. reviewed their 
experience with 525 large colon polyp resection and did not find that clip closure was 
associated with delayed bleeding complications16. 
In clinical practice use of clips after polyp resection is largely dependent on endoscopist 
preference and availability. In preparation for this study informal evaluation of polyp 
resection practice showed that some endoscopists use clips, and others do not. The unclear 
benefit with using clips, the required technical skills to achieve clip closure of the mucosal 
defect, and the additional cost may prevent some from using clips routinely. 
Whether clip application prevents bleeding and other complications following resection of 
large polyps and may reduce overall cost of care remains an important clinical question: 
there is no established superior method, the issue arises daily, the potential impact on 
clinical practice from a definitive trial would be significant, both to establish an optimal 
approach and in terms of patient benefits. 
 
3.2. Research Design and Methods 
3.2.1. Design and patients  
General study design: The study will be designed as a multicenter multi-endoscopist 
randomized trial.  
A schematic diagram of the study design, procedures and stages is detailed in Figure 1, 
Appendix 3. 
Study participants: Potential study participants will include patients with a colonic non-
pedunculated polyp ≥ 20mm in size considered for endoscopic resection (see inclusion and 
exclusion criteria).  
 
Anticipated number of research subjects (see also sample size calculation): 
• 
Estimated number of participants for duration of entire study: Female: 470, Male: 550 
(several sites are VA Medical Centers)   
• 
Estimated total number at each site: ≥20  
 
3.2.2. Inclusion and Exclusion criteria 
Inclusion criteria:  
• 
Any patient ≥18 and ≤89 who presents for a colonoscopy and who does not have 
criteria for exclusion 
• 
Patients with a ≥20mm colon non-pedunculated polyp 

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Exclusion criteria: 
• 
Patients with known (biopsy proven) invasive carcinoma in a potential study polyp 
• 
Pedunculated polyps (as defined by Paris Classification type Ip or Isp)  
• 
Patients with ulcerated depressed lesions (as defined by Paris Classification type III) 
• 
Patients with inflammatory bowel disease 
• 
Patients who are receiving an emergency colonoscopy 
• 
Poor general health (ASA class>3) 
• 
Patients with coagulopathy with an elevated INR ≥1.5, or platelets <50 
• 
Poor bowel preparation 
• 
Pregnancy 
We will document patients who were referred for a resection of a large polyp, but were not 
consented. For these patients (not study subjects) we will record the reason for not 
consenting (e.g. did not elected to participate, patient met exclusion criteria, etc.), the 
patient’s age and gender. 
Similarly, we will collect information on reasons for exclusion of polyps (including size, 
morphology, and location). 
 
3.2.3. Study screening procedures 
To determine patient eligibility: 
• 
Review of the patient’s personal medical history  
• 
Review of medical records to verify patient inclusion and exclusion criteria (age, 
comorbid conditions, anticoagulation). 
To determine polyp eligibility: 
• 
Examining eligibility of a potential study polyp during the colonoscopy with respect to 
polyp inclusion and exclusion criteria (size, morphology).  
 
 
Potential study participants include patients with a ≥ 20mm non-pedunculated colorectal 
polyp (= study polyp). 
Identification of study participants: 
• 
Patients with a known ≥ 20mm polyp detected at a prior colonoscopy and referred for 
resection of this polyp.  
Patient characteristics (age), comorbidities (see exclusion criteria), and medications 
(exclusion of coagulopathy) will be reviewed prior to the procedure. The patient will 
be informed about potential study participation. If the patient agrees to participate 
and after informed consent is provided, the colonoscopy will be performed. Whether 
a polyp will meet inclusion criteria (size and morphology) will be determined during 
the colonoscopy. If the patient does not have a polyp that meets the inclusion 
criteria, the patient will not be included and considered a screen failure.  
 
An alternative subject identification may be applied at some centers with fewer referrals for 
polyp resection. Any patient who is scheduled for an elective colonoscopy will be provided 
with an information sheet that allows him/her to opt out to be considered for study 
enrollment. If the patient does not opt out and if an eligible study polyp is detected during the 
colonoscopy, the patient may be randomized to one of the four protocol arms (only if patient 
and polyp inclusion/exclusion criteria are met). The Polyp resection will be performed as 
determined by randomization. Following the procedure the patient will be informed about the 

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randomized approach to polyp resection and informed about potential participation in the 
study. Only after the patient provides informed consent, he/she will be included in the study 
(see Alternative Consent Process).  
 
3.2.4. Patients on anticoagulation 
Patients on anticoagulation medications will be managed according to the ASGE guideline23. 
According to the guideline, polypectomy is considered a high-risk procedure. All study 
procedures are elective procedures. In accordance with the guideline, the type of 
anticoagulation and the patient risk for a thromboembolic event will determine the decision 
on managing periprocedural anticoagulation.  
 
3.2.5. Allocation to treatment (Randomization process) 
Randomized will occur at the time of colonoscopy when a polyp has been identified as a 
study polyp using computer generated randomization. Patients will be randomized following 
a 2 x 2 factorial design to: (i) Endocut vs. low power coagulation after inspection of the polyp 
and decision to resect the polyp, and (i) clipping vs. no clipping of the mucosal defect after 
resection.  
Patients will hence be randomized to one of four groups:  
A) Endocut and clipping,  
B) Endocut and no clipping,  
C) Low power coagulation and clipping, and  
D) Low power coagulation and no clipping.  
Should a patient have more than one study polyp, all polyps will be resected in the same 
way (per patient randomization). The primary comparison will be between clip and no clip 
application. The comparison between cautery currents is secondary and exploratory.  
 
Breaking the blind:  The study is not blinded. 
 
Treatment adherence/study compliance: The primary intervention (one-time clip 
placement) does not require adherence to the intervention. Participants will therefore not be 
excluded because of non-compliance.  
The major outcome of interest will be assessed after 30 days following the intervention by a 
phone call. We expect that such short interval will allow an almost complete follow-up. 
Secondary outcomes of interests include polyp recurrence during longer-term follow-up. We 
will collect data on all follow-up procedures that are performed as per standard of care (not 
as a study intervention).  
 
3.2.6. Colonoscopy and endoscopic mucosal resection (EMR) 
Patients will have undergone colonoscopy prep as it is standard at each center, typically a 
polyethylene glycol lavage with 4–6 L until clear rectal fluid is evacuated. Periprocedural 
antithrombotic mediations will be managed according to ASGE guidelines23. All exams will 
be performed using high-definition colonoscopes with digital chromoendoscopy capability 
(e.g. Olympus 180 or 190 series or Pentax). Sedation will be provided as per standard of 

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care, typically moderate sedation using intravenous midazolam and a narcotic analgesic, or 
sedation per anesthesia if required.  
Lesions will be identified using conventional colonoscopic views and further characterized 
using 
digital 
chromoendoscopy 
(e.g. 
narrow 
band 
imaging 
or 
i-Scan). 
Digital 
chromoendoscopy utilizes integrated electronically activated filters or electronic post-image 
processing techniques to enhance mucosal architecture and microvasculature. It allows 
detailed examination of polyp morphology and delineation of the lesion. Polyp 
characteristics will be recorded (see outcome measures).  
Complete polyp resection during the first colonoscopy is intended. Endoscopic mucosal 
resection (EMR) using the strip biopsy method, as described by Karita et al24, will be used 
for all resections.  
This study will include the following standard steps (all considered standard of care): 
1. The polyp will be submucosally injected, so that the lesion will lift and demarcate 
from the submucosal layer.  
2. Polyp margins will be identified. 
3. The polyp will be resected with electrocautery snare using one of two electrocautery 
settings (as per randomization). 
 
Submucosal injectate: The submucosal injection creates a “cushion” between the mucosa 
and the muscularis propria. The idea is that mucosal lesions can be more safely removed. 
The applied injectate fluid will contain a lifting agent and a contrast agent. The lifting agent 
will be at the discretion of the endoscopist (e.g. NaCl or hydroxyethyl starch). The 
recommended preferred lifting agent will consist of a small amount of NaCl followed by an 
injection of a mixture of Hydroxyethyl starch (HES). In one recent study from Australia a 
HES equivalent (Gelufusin) had a similar rate of complications than NaCl, but a 
nonsignificant lower risk of adenoma recurrence (8 vs. 12 %)25. Independent on the lifting 
agent used, it will be mixed with a contrast agent as typically used with EMR. The 
recommended preferred contrast agent will be Indigo carmine 0.4% at a ratio of 
approximately 100:1 (i.e. 0.1ml Indigo carmine and 10ml of HES). Indigo carmine is a 
contrast dye that has been routinely used for submucosal injection and for 
chromoendoscopy to enhance contrast between polyp and surrounding normal mucosa to 
delineate the margin of the polyp and to define the submucosal plane26. Recent studies have 
used a modified EMR without using submucosal injection. Submucosal injection may make it 
more difficult to grasp polyp tissue of some polyps (e.g. flat sessile serrated 
adenomas/polyps). Similarly, immersing the polyp area in water (underwater EMR) may 
enhance engagement of the snare with the polyp and facilitate EMR27. Endoscopists may 
not perform submucosal injection if they consider that it might make resection more difficult. 
Snares: Various resection snares are available that differ in size, shape, and stiffness. 
During a polyp resection, different snares may be used dependent on size and morphology 
of polyp tissue. There are no data on the effect of snares on complications or on 
completeness of polyp resection. Preliminary assessment of resection practice showed that 
individual endoscopists at different study centers use different snares. The type of snare 
used is dependent on prior experience and availability at individual centers. We will 
therefore leave snare selection at the discretion of the endoscopist, document what snares 
were used, and examine whether snare selection had an effect on outcome.  
Following resection, the endoscopist will confirm that the polyp appears to be completely 
resected macroscopically by detailed examination of the resection margin. Visible remaining 
polyp tissue should be resected or ablated  (typically using argon plasma coagulation 
[APC]). Once resection is considered complete the mucosal defect will be either closed or 
not closed with clips, as determined per randomization protocol. After resection, the site will 

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be marked with spot injection to identify the polyp site at a future endoscopy (standard of 
care).  
In some circumstances the endoscopist may consider it as clinically appropriate to place a 
clip, even if the patient was randomized to the non-clipping group.  Such situations may 
include, but are not limited to placing a clip to control bleeding during the polyp resection. In 
these situations the endoscopist will be asked to document the reason for clip placement. 
 
Following the procedure patients will be observed in recovery as per standard of care at 
each institution.  
 
3.2.7. Follow-up procedures 
The primary aim of the study is to assess whether clip closure of the mucosal defect after 
large polyp resection will reduce the risk of delayed bleeding complications. Secondary aims 
include to examine whether clip closure reduces the incidence of complications overall.  
Clip closure can therefore be considered effective if the risk of complications is reduced. 
 
Follow-up:  
• 
Patients will be contacted within 1-3 days to assess for any possible complications 
as per standard of care at each institution.  
• 
Patients will be contacted after 30 days to inquire about possible adverse events.  
• 
Per guideline patients with large polyps that are resected piecemeal should have a 
follow up colonoscopy within 3 to 6 months28. The study will aim to schedule the 
recommended follow-up colonoscopies between 3 to 4 months.  
• 
Assuming complete polyp resection a second follow-up colonoscopy will be 
scheduled one year following the first follow-up exam (within standard of care). 
Additional surveillance colonoscopies will be based on findings (third colonoscopy 
typically three years following the second colonoscopy). At follow-up the prior 
polypectomy site will be inspected for macroscopic residual polyp or recurrence and 
biopsies obtained from the site. We will collect information on colonoscopies and 
clinical course (i.e. need for surgery) up to five years after initial polyp resection.  
 
 
3.2.8. Schedule of activities (Study table) 
Schedule of activities is detailed in Figure 2, Appendix 4. 
 
3.2.9. Study outcome evaluation 
The primary aim of the study is to compare the incidence of delayed bleeding complications 
between patients after the resection of large ≥20mm polyps who underwent clip application 
to those who did not.  
The secondary aim is to compare the incidence of overall complications between patients 
after the resection of large ≥20mm polyps with Endocut vs. low power coagulation.  
 
3.2.9.1. Outcome measures 
Primary Outcome Measure: 
• 
Delayed bleeding complications [Time Frame: 30 days]. 

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Assessment: Patient contact, if severe adverse event, review of medical records, to 
obtain details on complication, treatment and outcome. 
 
Secondary Outcome Measures: 
• 
Overall complications [Time Frame: 30 days]  
Assessment: Patient contact, if severe adverse event, review of medical records, to 
obtain details on complication, treatment and outcome. 
 
• 
Factors associated with complications [Time Frame: 30 days]. 
Assessment: Using patient and polyp characteristics, and procedural data, obtained 
at the time of study polyp resection. 
 
• 
Complete polyp resection [Time Frame: 6 months] 
Assessment: a) immediately after polyp resection, based on evaluation of the 
endoscopist. b) at first follow-up endoscopy, based on results of biopsies from the 
resection site. 
 
• 
Polyp recurrence [Time Frame: 3 months to 5 years]. 
Assessment: at follow-up endoscopies after complete resection was achieved. 
 
• 
Factors associated with incomplete resection or recurrence [Time Frame: 5 years]. 
Assessment: Using patient and polyp characteristics, and procedural data, obtained 
at the time of study polyp resection. 
 
Procedures to assess safety of clip use 
• 
Clip complications [Time Frame: 30 days]. 
Assessment: Patient contact, if severe adverse event, review of medical records, to 
obtain details on complication, treatment and outcome.  
 
 
 
3.2.9.2. Study endpoints 
Endpoints of primary analysis (Comparison between clip group versus no-clip group 
within 30 days of follow-up): 
Primary endpoint:  
• Delayed bleeding complications:  
Delayed bleeding is a serious adverse event that is defined as a patient who left the 
endoscopy unit and subsequently had to return to any health care facility for evaluation of 
rectal bleeding AND who required either hospitalization, transfusion, a repeat colonoscopy 
or sigmoidoscopy for examination of the polypectomy site or control of bleeding, or surgery 
within 30 days after completion of the colonoscopy.  
 
Secondary endpoint: 
• Complications overall: Overall complications will be defined as an aggregate of all 
complications that occur at the time of the procedure (immediate complications) or during 30 
days of follow-up. They include bleeding complications as defined above, perforation, 
postpolypectomy syndrome, and clinical events that require an ED visit, admission to the 
hospital, or additional testing or intervention.  
 
Explorative: 

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• Immediate and delayed complications: Immediate complications are considered all 
complications at the time of polyp resection. They include bleeding that cannot be controlled 
by endoscopic intervention, perforation, or clinical events that require abortion of the 
procedure. Delayed complications are complications that occur following the completion of 
the colonoscopy within 30 days of the procedure. 
 
• Complete and partial clip closure: Degree of closure of the resection defect will be 
categorized as completely closed, partially closed, and not closed. Complete closure is 
defined if opposing resection margins are drawn together by clips from one side to the other, 
with gaps of less than 1cm between the clips. A site is considered partially clipped if only a 
portion of the defect could be closed17.  
 
• Factors associated with complications: Factors that may be associated with complications, 
including polyp size, location of the polyp in the colon (right, left, rectum), histology, polyp 
morphology, time required for resection. 
 
Endpoints of secondary analysis (entire study cohort): 
• 
Complete polyp resection: Rate of complete study polyp resection a) at the initial 
colonoscopy and b) at first follow-up endoscopy 
 
• 
Polyp recurrence: Rate of recurrent polyp at the resection site after complete polyp 
resection. 
 
• 
Factors associated with incomplete resection or recurrence: Factors that may be 
associated with incomplete resection include prior attempts of removal, use of adjunctive 
argon plasma coagulation for residual polyp removal, polyp size, location, and histology. 
 
3.2.9.3. Data collection 
We will collect the following data: 
• 
Patient characteristics, including date of birth, gender, body mass index, ASA 
classification. 
• 
General procedure details, including date of procedure, endoscopist, indication, and 
immediate complications. 
• 
Polyp resection method, including prior biopsy, prior attempt of resection, perceived 
difficulty of positioning the endoscope, use of cap, submucosal injection, cautery 
current, type of snare, resection pieces, use of adjunct resection or cautery 
measures, number of clips placed, retrieval method, polypectomy time, clipping time, 
method of assessment of resection margins (e.g. NBI) 
• 
Polyp characteristics, including polyp size, polyp site, histology polyp morphology 
(e.g. Paris classification), lifting sign, and supplemental methods. 
• 
Follow-up data, including results of histopathology of the removed polyp, delayed 
complications. 
• 
Follow-up procedure, including interval events (e.g. need for surgery), findings, 
presence of polyp/neoplasia at 4-6 months follow-up and within 5 years,  
• 
Endoscopist characteristics include annual endoscopy procedure volume, years since 
training, average number of large polyp resections per year.  
• 
Information on possible complications will be obtained at the time of the procedure, 
and identified based on the subjects' self-report at the post-procedure follow-up 

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14
phone call within 24-72 hours, at a phone call at least 30 days following the 
colonoscopy. Medical records will be reviewed for serious complications. 
 
Image and video recording 
Mandatory images will be taken during each polyp resection. These include an image before 
resection to verify the polyp size (adjacent snare with standardized size), and image after 
complete resection, and an image after clip closure if applicable. Further polyps that were 
not considered resectable will also be photographed. 
Video recordings of all available EMR procedures will be collected from each participating 
endoscopist to understand not yet identified or possible non-measurable technical 
differences between endoscopists that might affect outcomes of interest. 
All images and videos will be recorded without any patient identifier and stored at the 
coordinating site based on the patient, endoscopist, and center identification numbers. 
 
 
3.2.10. Statistical analysis 
3.2.10.1. Primary analysis: Comparison between clip group vs. no-clip group, 30 day follow-
up) 
Primary endpoint: Delayed bleeding complication. 
We will assess the null hypothesis that clipping has no effect on delayed bleeding 
complications using a chi-square test to compare the two study arms (as randomized, 
intention-to-treat), or a Fisher’s exact test if appropriate with a 5% significance level. 
Secondary endpoint: Overall complications. 
The secondary endpoint will be compared between the clip and no-clip arms using a chi-
square test (or Fisher’s exact test if appropriate) with a 5% significance level. 
The primary endpoint (delayed bleeding complication) and secondary endpoint (overall 
complications) are planned to be used to support clip-labeling plans. 
The main analyses of the primary and secondary endpoints will be done on a per subject 
basis. Additional analysis will be conducted at the unit per polyp. Clustering of polyps within 
patients (estimated to occur in approximately 5%) will be accounted for by using the method 
generalized estimating equations as well as mixed-effects-analysis with a random intercept 
for patient. 
Subgroup Analyses: While the study is not powered to look at subgroups we will conduct 
exploratory analyses to determine if any difference in the clip and no-clip arms is modified 
by characteristics such as time of occurrence (immediate vs. delayed) and by etiology 
(bleeding, perforation, etc.). This examination will be descriptive because the study will 
unlikely be sufficiently powered for identifying differences as significant.  
Explorative analysis of the effect of electrocautery setting: The comparison between the two 
electrocautery settings (low power coagulation vs. Endocut) will be explorative. Pilot data 
show that one third of participating endoscopists typically use low power coagulation and two 
thirds use Endocut. Acknowledging a possible effect of cautery on the incidence of 
complications there is a need to standardizing the cautery setting for the EMR procedure. 
Rather than using one cautery setting for all procedures, the cautery setting will be 
standardized by randomizing patients to one or the other setting. At the same time this 
randomization will allow an explorative analysis of the effect of cautery on complications. This 

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information, although descriptive, would provide valuable guidance to develop resection 
standards. 
 
3.2.10.2. Secondary analysis: Entire study cohort 
In secondary analysis we will further describe the rate of complete polyp resection and rate of 
neoplasia recurrence in all patients within 5 years, independent of their randomization. These 
endpoints will be calculated as proportion with 95% confidence interval. We will explore what 
factors might be associated with incomplete resection using logistic regression analysis. 
All data collected will be summarized descriptively, overall, and by subgroups. Means will be 
compared using the student test if normally distributed and the Mann-Whitney test if not 
normally distributed.  
 
3.2.10.3. Interim Analysis 
An interim analysis will be conducted when we have enrolled 50% of the targeted 1020 
patients, and completed 30-day follow-up on them. We will conduct an efficacy and futility 
analyses. For efficacy of clipping we will stop the trial if the two-sided p-value is less than 0.01. 
This alpha spending means that at the final analysis, a two-sided p-value less than 0.044 will 
be consider significant. At the interim look we will calculate the conditional power and 
terminate the study for futility if the conditional power is less than 20%. If the study will be 
continued, we will not modify the sample size based on the results of the interim analysis. 
Because higher risk lesions may be more likely to benefit from clip closure the study should 
not continue to enroll patients if such benefit is apparent before study completion. We will 
therefore perform an interim safety sub-analysis for two groups of patients:  
(a) Patients with study polyps >4cm, and  
(b) Patients who are on anticoagulation or resume anticoagulation within 14 days of the polyp 
resection.  
We assume that either group will contribute 10 to 20% to the study. We plan to conduct this 
safety analysis for each of these subgroups after 60 patients have been enrolled into either of 
the two subgroups (i.e. after enrollment of 60 patients with a >4cm study polyp and separately 
after enrollment of 60 patients who resumed anticoagulation after polyp resection). For 
example, the safety analysis would detect the occurrence of 2 vs. 9 delayed bleeding 
complications in the non-clip vs. the clip group as a significant difference (RR 4.5, 95% CI 
1.01, 19.96). The study should cease to enroll these patients if the interim safety analysis 
shows a significantly increased relative risk in delayed bleeding complications in the non-clip 
group compared to the clip-group (see also Section on Monitoring). 
A second safety analysis for these two groups will be part of the interim analysis after 
enrollment of 50% of patients (see above). Similarly, should this analysis show a significant 
difference in delayed bleeding complications, these patients should not be further enrolled. 
 
3.2.10.4. Sample Size Determination 
Our sample size calculation is based on the primary aim. We hypothesize that polyp 
resection with clip closure of the mucosal defect will reduce the incidence of delayed 
bleeding complications. Prior studies have reported an overall bleeding incidence between 2 
and 24% (table 1). We consider an absolute difference of 5% in delayed bleeding incidence 
(e.g. 8% and 3%) as clinically important. Assuming a two-sided alpha of 0.05 and a power of 
80%, the study will need to include a total of 730 subjects (365 subjects into each group) to 
show such difference as significant. We assume that for approximately 20% of patients clip 

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16
closure will not be considered possible. Therefore a approximately 920 patients will need to 
be included. However, approximately 10% of potential study polyps of referred patients will 
not meet inclusion criteria (screen failures). We estimate therefore that we need to enroll 
(=consent) a total of 1,020 patients for 920 patients to undergo the study intervention.  
Because the primary outcome measure (delayed bleeding) will be assessed after 30 days of 
the colonoscopy we do not expect any dropouts. 
 
3.2.11. Timetables  
We expect to complete enrollment within two and a half years. The main outcome measure 
will assessed between 30 and 45 days for each enrolled patient. The duration of the study to 
obtain information on the major outcome of interest is expected to be completed within three 
years. 
a) Length of participant involvement in the study: 5 years   
b) Estimated time to enroll enough participants to complete this study: 2.5 years 
c) Estimated time to achieve primary objective of the study: 3 years 
 
3.2.12. Research setting  
This is a multicenter study. The WRJ VAMC/Dartmouth will be the coordinating center. The 
centers listed below intent to participate in this study. Additional sites may plan to 
participate. These will be added to the research plan when appropriate.  The local IRB will 
review the study protocol at individual sites. We are offering participation to centers outside 
the US. 
Potential study sites: 
Beth Israel Deaconess, MA 
Brigham and Women's Hospital, MA 
Dartmouth-Hitchcock Medical Center, NH 
Georgetown University, Washington D.C. 
Indiana University, IN 
Johns Hopkins Hospital, MD 
Kansas City Veterans Affairs Medical Center, 
Kansas City, MO  
Mayo Clinic, Jacksonville, FL 
Mayo Clinic, Rochester, MN 
Roudebush VA Medical Center in Indianapolis, 
IN  
University of Alabama, AL 
University of Chicago, IL 
University of Iowa, IA 
University of Maryland, MD 
University of Michigan, MI 
University of North Carolina, NC 
University of Texas, TX 
University of Vermont, VT 
University of Washington, WA 
VA Detroit, MI. 
VA Maryland, MD 
VA Oklahoma City, OK 
VA Palo Alto, CA 
VA Seattle, WA 
VA West Haven (Yale) 
VA White River Junction, VT 
Yale University Medical Center, CT 
Montreal University Hospital (CHUM), St. Luc 
Hospital, Montreal, Canada  
University Medical Center, Utrecht, Netherlands 
 
 
 
 
 
 

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Update on currently enrolling sites and those with interest/under IRB review (June 22, 2016) 
 
Beth Israel Deaconess, MA 
Dartmouth-Hitchcock Medical Center, NH 
Indiana University, IN 
Johns Hopkins Hospital, Baltimore, MD 
Sibley Memorial Hospital, DC 
University of Kansas, Kansas City, MO  
University of Chicago, IL 
University of Michigan, MI 
Hershey Medical Center, Hershey, PA 
Medical University of SC, Charleston, SC 
University of North Carolina, NC 
VA Detroit, MI. 
VA West Haven (Yale) 
VA White River Junction, VT 
VA Tampa, FL 
Yale University Medical Center, CT 
Gastroenterology Associates, Asheville, NC 
Florida Hospital, Orlando, FL 
Montreal University Hospital (CHUM), St.  
Hospital Clinic de Barcelona, Spain 
 
3.3. Data and Safety Monitoring Plan 
Appropriate consent documentation and clinical study documentation, progress of the trial, 
including assessments of data quality and timeliness, participant recruitment, and participant 
risk versus benefit will be monitored monthly by the principal investigator.  
The DSMP includes the following: 
• 
Use of standard procedures and precautions for colonoscopy with polyp resection. 
• 
Post-procedure telephone follow-up call within 24 to 72 hours with an appropriate plan of 
action should any clinical signs suggesting complications occur. 
• 
All patients will be asked to contact the endoscopist/or representative, their health care 
provider, or present to the local emergency room, should they experience any problems 
after the colonoscopy (i.e. abdominal pain, bleeding) (see methods section).  
• 
Approximately 3-4 month call-back for follow-up colonoscopy. 
• 
All serious adverse events will be reviewed by the principal and co-investigators to 
assess whether this complication was related to study participation following the event 
and by the DSMB. In addition, procedural complications will be reviewed at individual 
sites per local standard. These reviews will assure additional independent 
assessment and evaluation of possible adverse events. 
o For VA sites: All patients from the WRJ VA are subject to independent review 
for serious adverse events by the local complication board, which meets every 
three months. All serious adverse events that occurred during any endoscopy 
procedure are reviewed by the committee and graded according to the severity 
of the event.   
o For VA sites: The VHA information security officer will be solicited to review 
any potential security violations of the network protected study database. 
 
3.3.1. Monitoring Plan 
The main goals of monitoring the use of the clip as a nonsignificant risk device include  
1) To secure compliance, and 
2) To allow immediate evaluation of an unanticipated adverse device event (FDA, 21CFR 
812.46) 

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The purpose of the monitoring plan is to outline the approach to monitoring this clinical trial.  
The plan is based upon verification of compliance with FDA regulations and guidelines and 
Good Clinical Practice (GCP) guidelines, which require monitor verification that: 
a) The rights and well-being of human subjects are protected 
b) The reported data are accurate, complete, and verifiable from source documents 
c) The conduct of the trial is in compliance with the currently approved protocol, with GCP, 
and with applicable regulatory requirements. 
The monitoring focuses on the primary aim of the study and the safety of the Resolution Clip in 
its off label use as a non-significant risk as a non-significant risk device. Considering the safety 
profile of the clip and the potential that the clip will reduce complications, we plan off site 
monitoring where appropriate. This will include conference calls and upon request sending de-
identified CRFs for review to the monitor according to the following time plan: 
• 
The study will only commence at individual sites if all requirements as outlined in the 
monitoring plan are met. 
• 
After 5 to 10 patients were enrolled at a site, the site will be monitored to assure adherence 
to the study protocol, especially with respect to eligibility, consent process, and 
completeness of data collection.  
• 
Repeat monitoring will be conducted after 20 to 30 patients have been enrolled at a site. 
• 
A final monitoring of each site will be performed after enrollment is complete. 
On-site visits may be conducted based on individual performance criteria, especially with 
respect to adverse event reporting (e.g. sites with the highest or lowest reports of adverse 
events), and enrollment (i.e. sites that are far above or below target).  
 
3.3.2. Data Safety Monitoring Board 
• 
The DSMB consists of three independent gastroenterologists who are considered experts 
with respect to large polyp resection, and one statistician. After half of planned participating 
patients have been enrolled, the members of the DSMB will review all serious adverse 
events and review recruitment based on the proposed timeline.  
• 
The study will be stopped should there be serious adverse events (bleeding, requiring 
additional interventions following the colonoscopy, perforation) related to study 
participation beyond what would be expected with respect to frequency or severity. The 
decision to stop the study will be made by the DSMB. The following stopping rules apply: 
o The study will be stopped should the interim analysis show a substantial 
difference between the clipping and non-clipping group of p<0.01 (see Interim 
Analysis). 
o Patients with >4cm polyps will no longer be enrolled should the interim safety 
subanalysis show a significant absolute difference in delayed bleeding 
complications between the clip and the non-clip group of at least 30% (see 
Interim Analysis).  
o Patients who are on anticoagulation or scheduled to resume anticoagulation 
within 14 days of a study polyp resection will no longer be enrolled should the 
interim safety subanalysis show a significant difference in delayed bleeding 
complications between the clip and the non-clip group (see Interim Analysis).  
 
Research Materials. Data will be collected only if the subjects participate in the study. Data will 
be obtained only for research purposes. 

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Protection. Subjects will be afforded a variety of protections. First, all protocols will be IRB 
approved and subject to oversight by the local IRB. Second, once the data are collected they 
will be dealt with in an anonymous manner with adherence to HIPAA guidelines.  
 
 
4. GENDER/MINORITY MIX 
We expect approximately 45% of the patients to be women. Because several participating 
centers will be VA Medical Centers, the majority of enrolled patients will be men. We will make 
every effort to recruit a diverse group of subjects, but there are no race or ethnic-based 
questions to this protocol. 
 
 
5. RISK ANALYSIS 
5.1. Anticipated Risks 
There are no risks incurred with the study that are beyond those associated with the clinically 
warranted procedure (colonoscopy with EMR, see background section). In theory there is a 
minimal risk associated with an increased time needed to apply clips for closure of the mucosal 
defect. Dependent on the size of the lesion endoscopic clipping may take 5 to 10 additional 
minutes. Considering that an EMR of large polyps often takes more than 60 minutes, the 
additional relative increase in procedure time would be low. Furthermore, there has been no 
study to show that a small proportional increase in procedure time is associated with an 
increased risk. Should there be any concern regarding the safety of the patient related to 
prolonged procedure time when applying clips, the procedure will be aborted. 
 
Risk/Benefit analysis. It is unknown whether the patient will benefit from the proposed study. 
The planned interventions are variations of standard of care and the study compares different 
approaches representing a comparative effectiveness study.  While the risk of added time in the 
clip group may be minimal (if present at all), it is plausible that clip application will decrease 
bleeding risk and may improve polyp resection. If so, fewer follow-up procedures (either 
colonoscopy or surgery) would be needed, which might lower the future overall risk. Whether 
clip application is truly a helpful modification of the EMR resection practice is not known, hence 
the study.  
As for the comparison of cautery settings (Endocut vs. lower power coagulation), it is unclear, 
which mode is associated with fewer complications. It is the purpose of this study to explore 
whether one choice of cautery setting may be associated with a lower risk. This understanding 
may ultimately contribute to an improved polyp resection practice. 
 
5.2. Adverse Event Recording and Reporting 
5.2.1. Adverse event definitions 
Adverse effect: Any untoward medical occurrence in a clinical study of an investigational device; 
regardless of the causal relationship of the problem with the investigational device. 
Associated with the investigational device:  There is a reasonable possibility that the adverse 
effect may have been caused by the investigational device. 

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Disability:  A substantial disruption of a person’s ability to conduct normal life functions. 
Life-threatening adverse effect:  Any adverse effect that places the subject, in the view of the 
investigator-sponsor, at immediate risk of death from the effect as it occurred (i.e., does not 
include an adverse effect that, had it actually occurred in a more severe form, might have 
caused death). 
Serious adverse effect: Any adverse effect that results in any of the following outcomes: death, 
a life-threatening adverse effect, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. 
Hospitalization shall include any initial admission (even if less than 24 hours) to a healthcare 
facility as a result of a precipitating clinical adverse effect; to include transfer within the hospital 
to an intensive care unit.  Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical adverse effect (e.g., for a preexisting condition not associated with a new 
adverse effect or with a worsening of the preexisting condition; admission for a protocol-
specified procedure) is not, in itself, a serious adverse effect.   
Unexpected adverse effect:  Any adverse effect, the frequency, specificity or severity of which is 
not consistent with the risk information described in the clinical study protocol. 
Unanticipated adverse device effect:  Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan, or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 
 
 
5.2.2  Eliciting adverse effect information 
Clinical study subjects will be routinely questioned about adverse effects at study visits. See 
section “Follow-up Procedures”.  
 
 
5.2.3  Recording and assessment of adverse effects 
All observed or volunteered adverse effects (serious or non-serious) and abnormal test findings, 
regardless of treatment group, if applicable, or suspected causal relationship to the 
investigational device will be recorded in the subjects’ case histories.  For all adverse effects, 
sufficient information will be pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the effect (i.e., whether the effect should be classified as a 
serious adverse effect) and; 2) an assessment of the casual relationship between the adverse 
effect and the investigational device.    
 
Adverse effects or abnormal test findings felt to be associated with the investigational device or, 
if applicable, other study treatment or diagnostic product(s) will be followed until the effect (or its 
sequalae) or the abnormal test finding resolves or stabilizes at a level acceptable to the 
investigator-sponsor. 
 
5.2.3.1 Abnormal test findings:   
An abnormal test finding will be classified as an adverse effect if one or more of the following 
criteria are met: 
• 
The test finding is accompanied by clinical symptoms. 

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• 
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug or other therapy.  
• 
The test finding leads to a change in discontinuation of subject participation in the clinical 
study. 
• 
The test finding is considered an adverse effect by the investigator-sponsor. 
 
 
5.2.3.2. Causality and severity assessment:  
The investigator-sponsor 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; and 3) if the adverse effect meets the criteria for a serious adverse effect. 
 
If the investigator-sponsor’s final determination of causality is “unknown and of questionable 
relationship to the investigational device or, if applicable, other study treatment or diagnostic 
product(s)”, the adverse effect will be classified as associated with the use of the investigational 
device for reporting purposes.  If the investigator-sponsor’s final determination of causality is 
unknown but not related to the investigational device, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.  
 
 
5.2.4. Reporting of adverse effects to the responsible IRB 
In accordance with applicable IRB policies, the investigator-sponsor will report, to the IRB, any 
observed or volunteered adverse effect that is determined to meet all of the following criteria: 1) 
associated with the investigational device or, if applicable, other study treatment or diagnostic 
product(s); 2) a serious adverse effect; and 3) an unexpected adverse effect.  Adverse event 
reports will be submitted to the IRB in accordance with the respective IRB procedures.  
 
Applicable adverse effects will be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the investigator-sponsor’s receipt of the respective information.  
Adverse effects which are 1) associated with the investigational device; 2) fatal or life-
threatening; and 3) unexpected will be reported to the IRB within 24 hours of the investigator-
sponsor’s receipt of the respective information.  
 
Follow-up information to reported adverse effects will be submitted to the IRB as soon as the 
relevant information is available. If the results of the sponsor-investigator’s follow-up 
investigation show that an adverse effect that was initially determined to not require reporting to 
the IRB does, in fact, meet the requirements for reporting; the investigator-sponsor will report 
the adverse effect to the IRB as soon as possible, but in no event later than 10 calendar days, 
after the determination was made. 
 
 
5.3. Withdrawal of subjects due to adverse effects 
The study intervention will only applied once after a study polyp resection. The clip will typically 
fall of within 1-2 weeks and excreted with a bowel movement, which is usually not noticed by the 
patient. A continued exposure to the study intervention is therefore not given. 
Should the patient have the wish to withdraw from the study, no he/she will no longer be 
followed as part of the study. 
 

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6. FDA RISK DETERMINATION 
The study will use the Resolution clip, which was approved by the FDA primarily for hemostasis 
(treatment of intestinal bleeding) and closure of perforations (FDA-K122660; December 3, 
2012). Closure of a mucosal defect after polyp resection was not an FDA approved indication at 
the time of study commencement. The FDA reviewed the study protocol, and determined in its 
response from the clip to be a non-significant risk device (March 5, 2014; Q131671,(Appendix 
3). 
The FDA has recently revisited indications for the Resolution clip and determined (based on the 
retrospective study by Liaquat17, table 1) that the clip can be used for “Prophylactic clipping to 
reduce the risk of delayed bleeding post lesion resection” (Appendix 501K, December 1,2014). 
Clip closure (study intervention) is therefore now an FDA approved clip application. 
 
 
7. CONSENT PROCESS 
Standard Consent Process 
Potential study participants include patients between 18 and 89 years of age who are scheduled 
for a colonoscopy and for a resection of a large (≥20mm polyp).  
According to the requirements of local IRBs, patients will be informed about the study within 
appropriate time prior to the study.  
According to the local requirements some site investigators will send out a letter to potential 
participants to inform about the study and include a consent form for review (i.e. VA White River 
junction and Dartmouth-Hitchcock Medical Center). The letter will also contain contact 
information for questions to allow the patient to call the study investigator or coordinator directly 
with questions. The letter will also allow the study investigator/coordinator to contact a potential 
study participant, after they have received the letter, to discuss their interest in participating.  
Upon arrival for the scheduled colonoscopy patient's record will be reviewed to determine 
eligibility. Patients will be informed about the nature of the study and the possibility to enroll in 
the study. The individual, who obtains the consent, will answer possible questions. The consent 
will be obtained at the same time as the consent for the colonoscopy prior to the procedure. 
 
 
Alternative Consent Process 
In addition to the standard of consenting we request the study allows an alteration of the regular 
consent process for patients who are found to have a large (≥20mm) non-pedunculated polyp at 
the time of the colonoscopy.  
Any patient who presents for a colonoscopy between the ages of 18 and 89 and who does not 
meet exclusion criteria, an information sheet about potential study participation will be mailed 
prior to the schedule colonoscopy, and also given to the patient upon arrival for the scheduled 
colonoscopy. This information sheet contains information about possible enrollment into a study, 
if a large ≥20mm polyp is found along with assurance that any approach follows standard of 
care. If the patient does not agree to be considered for the study, he/she can actively opt out by 
initialing the appropriate box at the information sheet. In that case a polyp will be resected per 
endoscopist preference.  
If the patient does not opt out and a large polyp is found the standardized resection protocol (as 
detailed above) will be followed and patients will be randomized accordingly. Following the 
procedure the patient/accompanying person will be informed about the findings, the polyp 
resection, and the possibility to participate in the study. The patient will be given a consent form 
to be read at home and contacted following the procedure (but more than 24 hours) to discuss 

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the consent form. If the patient wishes to participate he/she may then sign the consent form and 
send it to the study coordinator or bring it at his/her next appointment. Only then and if the 
patient signs the consent, he/she will be enrolled into the study. Telephone consent will be 
documented in the patient’s records. 
We believe that such approach is responsible for two reasons – first the studied resection 
methods are all considered standard of care, and it is unclear which one is superior; and 
second, large polyps (≥20mm) are very uncommon (approximately 1-2%), and it would be 
impractical to consent each person who presents for a colonoscopy prior to the procedure just in 
case a large polyp is found.  
 
Privacy and Confidentiality 
All patient information will be kept confidential and only information relevant to the study will be 
recorded. Each site, each patient, and each endoscopist will be given a unique identification 
number and all study data will be recorded on a case report form. Each form will be kept as a 
hard copy and stored in a locked cabinet. Collected data will be transferred from each form to 
an electronic database for further analysis. Data that will be sent to the coordinating center will 
only contain event dates (including procedure dates, surgery dates, and patient contact dates) 
as the only patient identifier. Only dates and no other identifiers will leave each site. Patients will 
be asked in the consent form, whether they agree to share dates with the coordinating center. 
Each site research team will have access to their data, however, only the primary investigator 
and the team at the coordinating center will have access to the entire data set. For de-
identification purposes each site will keep a separate de-identification log (matching name with 
assigned ID). This list will be kept separately at each center in a locked cabinet.  
 
 
8. ADDITIONAL RECORDS AND REPORTS 
8.1. Data handling and record-keeping 
Data will be entered on case report forms (CRF) and transferred into an electronic database after 
establishing a web based data entry. Once established data may be entered directly into the data 
entry site. The site investigator is responsible for complete data ascertainment at the site and 
entry into the database. Data will be collected centrally at the coordinating center. Each site will 
maintain a hard copy of completed CRFs and a de-identification list. 
The electronic system includes safeguards to ensure complete data entry and minimizing 
erroneous entries. The investigator-sponsor is responsible for assuring complete data collection, 
especially with respect to adverse events. If needed, missing or additional information will be 
obtained from local site investigators. 
 
Web based data entry, recording and analysis of clinical and laboratory data related to the 
safety and/or efficacy of the investigational device, will be in compliance with the FDA’s 
electronic records and electronic signatures regulations as detailed in 21 CFR Part 11.   
 
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records (and 
certified copies of original records); including, but not limited to, hospital medical records, 
physician or office charts, physician or nursing notes, x-rays, etc.  When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents.  All 
relevant clinical study data will be recorded on CRF or directly entered into the data collection 
site. These include patient characteristics, procedure data, and clinical events, particularly 
complications. For details see “Data Collection” and “Data Analysis”.  Therefore CRF data or 
those directly entered into the data collection site are considered Source Data. 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
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8.2. Record maintenance and retention 
The investigator-sponsor will maintain records in accordance with Good Clinical Practice 
guidelines; to include: 
• 
FDA correspondence related to the risk determination application and Investigational 
Plan; 
• 
IRB correspondence (including approval notifications) related to the clinical protocol; 
including copies of adverse event reports and annual or interim reports; 
• 
Current and past versions of the IRB-approved clinical protocol and corresponding IRB-
approved consent form(s) and, if applicable, subject recruitment advertisements. 
• 
Signed Investigator’s Agreements and Certifications of Financial Interests of Clinical 
Investigators; 
• 
Curriculum vitae (investigator-sponsor and clinical protocol sub-investigators); 
• 
Certificates of required training (e.g., human subject protections, Good Clinical Practice, 
etc.) for investigator-sponsor and listed sub-investigators; 
• 
Master randomization list (incorporate only if applicable); 
• 
Monitoring reports; 
• 
Copies of investigator-sponsor correspondence to sub-investigators, including 
notifications of adverse effect information; 
• 
Subject screening and enrollment logs; 
• 
Investigational device accountability records, including documentation of device 
disposal; 
• 
Interim data analysis report(s); and the 
• 
Final clinical study report. 
 
 
 
 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
25
 9. FUNDING 
 
The study received funding support from Boston Scientific Corporation (BSC). BSC does not 
take the responsibility as a sponsor. Sponsor responsibilities will stay with the primary 
investigator. The study is therefore not an industry-sponsored study, and continues to be an 
investigator-initiated study. 
 
Veterans Education and Research Association of Northern New England, Inc. 
(VERANNE) will administer the funds (office located at White River Junction VA Medical 
Center). VERANNE and BSC have signed a CRADA (cooperative research and development 
agreement). In addition to monetary funds to create a web-based data entry site and financial 
aid for participating centers, BSC also provides study clips.  
 
 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
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Appendix 1. STUDY DESIGN 
Figure 1. Schematic diagram of the study design, procedures and stages 
 
 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
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Appendix 2. STUDY TABLE 
TABLE 1. Summary of procedures performed at screening, for treatment, and at follow-up. 
 
 
 

LPS sponsor protocol, version 9, September 13, 2019 
 
 
 
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