Randomized Clinical Trial to Compare Underwater Cold Snare Polypectomy (UCSP) to Conventional Cold Snare Polypectomy (CCSP) for Non Pedunculated Colon Polyps of Size 5-10mm [COLDWATER Study]
Phase: NA
Conditions: Colon Polyps, Polypectomy
Sponsor: National and Kapodistrian University of Athens

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
«Randomized clinical trial to compare Underwater Cold Snare Polypectomy 
(UCSP) to Conventional Cold Snare Polypectomy (CCSP) for non 
pedunculated colon polyps of size 5-10mm [COLDWATER study]» 
 
 
 
11.06.2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. ABSTRACT 
 
Backround 
Colon cancer is internationally the third cause of deaths from a malignant disease. 
Screening colonoscopy in adults >45 years of age aims at the early diagnosis and 
treatment colon polyps that are precancerous lesions. Endoscopic polyp removal 
(polypectomy) can be done with various techniques depending on the size, morphology, 
location of the polyp etc. According to updated guidelines, non-pedunculated polyps of 
small size are treated with a cold snare in air dilated intestinal lumen (conventional cold 
snare polypectomy - CCSP).In recent years, several studies have described the benefits of 
water aided colonoscopy, as well as safety and efficacy of underwater polypectomy in 
large colon polyps. However, there is not enough data on small polyps which are the 
most commonly diagnosed. 
Methodology 
This is a prospective  randomized double-blind clinical trial to compare the safety and 
efficacy of CCSP to underwater cold snare polypectomy (UCSP) for  non-pedunculated 
polyps of size of 5-10 mm. A total of 398 polyps will be randomized and randomization 
will be performed via random numbers method of Microsoft Excel 2016. Primary 
outcome of this study is to determine muscularis mucosa resection rate. Secondary 
outcomes are the depth and percentage of R0 excisions, complications and the recurrence 
rate in follow up endoscopy 6-12 months after polypectomy 
 
Discussion 
We expect UCSP to ensure a higher muscularis mucosa resection rate and we attempt 
examine whether it achieves a deeper resection in the submucosal layer. We will also 
examine if there are differences in complications and recurrence rate between the two 
treatment groups. These results will provide useful data for the development of guidelines 
in polypectomy techniques for non-pedunculated polyps 5-10mm. 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL INFORMATION PAGE 
 
Trial Title 
Randomized clinical trial to compare Underwater Cold Snare Polypectomy (UCSP) to 
Conventional Cold Snare Polypectomy (CCSP) for non pedunculated colon polyps of size 
5-10mm» 
 
Acronym 
COLDWATER STUDY 
 
Trial Identification Number 
PN61759 (Medical School, National and Kapodistrian University of Athens) 
 
Sponsor 
Athens Medical School, National and Kapodistrian University of Athens 
 
Funding 
No 
 
Investigators 
Zachou Maria 
Department of Gastroenterology, Sismanogleio General Hospital of Athens, Greece 
 
Kalaitzakis Evangelos  
Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 
Greece 
 
Varytimiadis Konstantinos 
Department of Gastroenterology, Sismanogleio General Hospital of Athens, Greece 
 
Zoumpouli Christina 
Department of Pathology, Sismanogleio General Hospital of Athens, Greece 
 
Katsaras George  
Paediatric Department, General Hospital of Pella - Hospital Unit of Edessa, Greece 
 
Sougioultzis Stavros 
Gastroenterology Division, Department of Pathophysiology, National and Kapodistrian 
University of Athens, Laikon University Hospital , Athens , Greece 
 
Kykalos Stylianos 
2nd Department of Propaedeutic Surgery, National and Kapodistrian University of 
Athens, Laikon University Hospital , Athens , Greece 

 
TABLE OF CONTENTS 
 
1. Introduction 
1.1. Overview of underwater polypectomy 
1.2. Overview of cold vs hot snare polypectomy 
 
2. Study Rationale 
2.1. Study Hypothesis 
 
3. Study Objectives 
3.1. Primary objective 
3.2. Secondary objectives 
 
4. Methods and design 
4.1. Study Design 
4.2. Study Sites 
4.3. Study Patients 
4.3.1. Inclusion Criteria 
4.3.2. Exclusion Criteria 
 
5. Study Interventions 
5.1. Polypectomy 
5.2. Excision Procedure 
5.3. Resection point overview 
5.4. Biopsies from resection site 
5.5. Marking of lesion’s position  
 
6. Study Procedures 
6.1. Randomization 
6.2. Pathological Examination 
6.3. Blinding 
 
7. Safety Assessments 
7.1. Risks and benefits 
7.2. Follow up for adverse events 
7.3. Follow up endoscopy 
 
8. Statistical Considerations 
8.1. Sample size 
8.2. Data analysis 
 
 

9. Data Collection and Quality Assurance 
9.1. Data Collection and Management 
9.2. Quality Assessment 
9.2.1. Monitoring 
 
10.Ethical considerations 
10.1. Ethical compliance 
10.2. Informed consent  
10.3. Publication 
 
11.References 
 
12.Abbreviations 
 
 
1.BACKGROUND 
 
1.1. OVERVIEW OF UNDERWATER POLYPECTOMY 
Polyp removal during colonoscopy is carried out in a dilated colon lumen after air 
insufflation. However, using water infusion to dilate the enteric lumen instead of standard 
air insufflations has been associated with higher patient comfort, less dose of intravenous 
sedation and higher adenoma detection rate [1-5] Underwater Polypectomy (UP) was first 
described as Underwater Endoscopic Mucosal Resection (UEMR) in 2012. The term 
“EMR” (Endoscopic Mucosal Resection has been improperly used to describe this new 
method, due to its unique feature to create a natural separation between 
mucosal/submucosal and muscular layer of the colon wall. In conventional EMR such 
separation is achieved by submucosal injection (lifting). During Endoscopic Ultrasound 
examination of the colon, where water is infused as an acoustic window, Binmoeller 
noticed that the water driven partial dilation of the colon lumen causes a “floating” effect 
on the colon wall. This causes the mucosal and submucosal layers to create protrusions 
towards the lumen (resembling the Gastric rugae) and to move away from the underlying 
muscular layer. The latter appears to remain circular and retain its normal thickness. [6-
7]. Also, water due to its higher refractive index compared to air increases the sensitivity 
of the endoscopy, causing an optical zoom effect of the mucosal architecture [7-8]. This 
increases the sensitivity of the endoscopic overview [7-8], improving identification of the 
lesion margins before polypectomy and of any residual lesion or recurrence after 
polypectomy [7, 9].Another advantage of UP is that the colon is not fully dilated, making 
mucosal lesions more compact with polypoid configuration in comparison with the flatter 
appearance of the same lesions in a fully dilated colon. This allows the endoscopist to 
capture larger mucosal surface with the snare increasing the chance of en-block resection 
even in larger lesions (eg. flat polyps of 20-40mm) [10]. As a result of all the above, UP 
offers shorter resection time, lower cost due to the reduced use of disposable materials 
(injection needles, syringes, lifting agents), higher en-block resection rates (89% vs 73%) 

in large lesions and higher rates of R0 resection (based on histology results) in 
comparison with the conventional EMR. [10-17].  
 
1.2.OVERVIEW OF COLD VS HOT SNARE POLYPECTOMY 
UP has been applied in studies with colonic lesions >10mm and >20mm in particular. 
Nevertheless only 5% of the polyps found in everyday clinical practice are of large size 
with the majority of the polyps being smaller. In regard to small polyps European 
Guidelines recommend the use of Cold Snare (CS) over Hot Snare (HS) due to improved 
safety profile. [18] HSP can cause thermal injury of the vessels and of the colonic wall 
and lead to delayed bleeding (0,04%- 7,8%) [19-23], post polypectomy syndrome, 
abdominal pain or even perforation with the latter being a rare (1.4%- 1.5%), but 
clinically serious complication [24-25]. Complication risk after HSP is proportional to the 
polyp size, histological grade, use of antiplatelet agents and it is higher in Right Colon 
lesions [26-29]. Incomplete Resection Rate (IRR) in HSP is 6.8% based on CARE study 
[30]. Complete Resection Rate (CRR) using CSP (R0 resection proved on histology 
results) ranges from 32.9% to 96.6% in various studies, [31] with the highest rates being 
demonstrated in the most recent ones. [32-34] One disadvantage of CSP is that the depth 
of the vertical resection margin is shorter and that found in HSP. This is based on 
histological examination of the center of the resection specimen, where the muscularis 
mucosa layer is identified. This finding highlights the incomplete mucosal resection 
during CSP rendering the method suitable for resecting intraepithelial lesions. [35-36] A 
metanalysis in 2020 showed that using CSP for polyps up to 9mm IRR was 17.3% vs 
14.2% when using HSP, [35] justifying the need for further research regarding the most 
suitable polypectomy method for this polyp group.  
 
2.STUDY RATIONALE 
 
The aforementioned disadvantage has led many endoscopists to continue to use HS for 
the removal of small polyps despite the increased risks associated with the electrocautery. 
[36-37] In order to overcome the relatively short vertical resection margin found in CSP, 
UCSP has emerged given the theoretical advantage of improved complete polyp 
resection. Both the safety and efficiency of UCSP has been shown in a study published in 
Digestive Endoscopy in 2019. This study included 209 adenomatous colon lesions 
removed by UCSP which were compared with lesions removed previously by 
conventional CSP where air insufflation had been used to dilate the colon lumen. [38] 
The vast majority of colon polyps however were microscopic <5mm (157/209, 75.1%) 
and the rest were 6-8mm in size (52/209, 24.9%). The study showed that both techniques 
were equally safe, but R0 resection rate was 80.2% for UCSP vs 32.7% for CCSP 
respectively (p<0.001). The percentage of mucosal layer per polyp removed was 50% vs 
35.3% (p= 0.015), in UCSP and CCSP respectively, while the presence of submucosa in 
the removed polyps was found to be 20.8% in UCSP and 12.9% in CCSP. The rate of R0 
resections in this study was calculated similar to the rate of R0 resections with HSP as 
described in other studies. [38] 

 
2.1. STUDY HYPOTHESIS 
Underwater cold snare polypectomy ensures a higher muscularis mucosa resection rate  
than conventional cold snare polypectomy 
 
 
3.STUDY OBJECTIVES 
 
The aim of this study is to compare the safety and efficacy between the two endoscopic 
polypectomy techniques (UCSP vs CCSP) regarding resection of non-pedunculated colon 
polyps with size 5mm to 10mm 
 
3.1.PRIMARY OBJECTIVE 
Primary outcome of the study is the investigation of the difference in the rate of area 
containing muscularis mucosa (%) between the two polypectomy techniques. 
 
3.2.SECONDARY OBJECTIVES 
Investigation of the difference at the following points between UCSP and CCSP group 
- Presence or absence of submucosal in the specimen and its depth (if present) 
- R0 Resection Rate (R0RR) 
- Incomplete Resection Rate (IRR) 
- Complication rate 
- Residual lesion rate during repeat colonoscopy in 12months 
 
 
4. METHODS AND DESIGN 
 
4.1. STUDY DESIGN 
   This is a prospective  randomized, double-blind, controlled study to compare 
underwater cold snare polypectomy (UCSP) to conventional cold snare polypectomy 
(CCSP) for non-pedunculated colon polyps of size 5-10mm.    
Prior to this study, the safety and effectiveness of the UCSP method was confirmed in the 
literature and by the experience of two qualified endoscopists of the General Hospital 
Sismanogleio in 35 patients who agreed to undergo UCSP.  
 
 
4.2 STUDY SITES 
The Gastroenterology Department of General Hospital of Athens "Sismanogleio” will 
participate in this trial. 
 
 
 

4.3. STUDY PATIENTS 
Patients scheduled for colonoscopy will be prospectively screened for eligibility. The 
workflow is shown in Fig.4 
 
 
 
Figure 4. Study Workflow 
 
 
4.3.1. INCLUSIONCRITERIA 
The inclusion criteria for this study are: 
 1. Age > 20years 
 2. Non pedunculated polyps (Paris classification Isp, Is, IIa, IIb) 
 3. Polyp size: diameter of 5 to 10mm 
 4. Endoscopic diagnosis of mucosal lesions – must not present malignant submucosal 
infiltration evidence (NICE 1, NICE 2A, BASIC) 
 5. Informed consent 
 
Patients > 20 years of age with non-pedunculated polyps (Paris classification Ιsp, Is, IIa, 
IIb – figure 1) with a diameter of 5 to 10 mm. The endoscopic diagnosis of mucosal 
lesions will be based on their macroscopic appearance depending on the available 
equipment of the Endoscopy Department . Narrow-Band Imaging (NBI) findings or Blue 
Light Imaging (BLI) may be used. Endoscopic polypectomy will only be indicated for 
lesions that: 
 According to the NICE (Narrow-Band Imaging International Colorectal 
Endoscopic Classification) are classified as type 1 or 2A. (Attached classification 
table - figure 2) 
Endoscopy 
Room 
Gastroenterology Department
Outpatient Clinic
1.Patients Enrollment
2.Inform Concent
Patients 
excluded receive 
standard care
Eligible Patients
- Randomization
- Allocation : UCSP or CCSP for 
target lesion

 According to the BASIC (Blue Light Imaging Adenoma Serrated International 
Classification) classification do not show evidence of malignant submucosal 
infiltration. (Attachment classification table - figure 3) 
 Do not present macroscopic malignant submucosal infiltration evidence 
(deepening, ulceration / ulcer, abnormal vessels, irregular surface) 
 The size of the lesion will be determined according to its endoscopic appearance by 
comparing the lesion with the closed (2mm) or open (7mm) biopsy forceps and will be 
confirmed before resection by comparing it with the open snare (10mm). 
Patients who receive antiplatelet / anticoagulant therapy are included in the study only if 
their treatment has been modified according to ESGE guidelines. 
All patients will complete a written consent to participate in the study, after being 
thoroughly informed about the procedure. 
 
Figure 1 Paris classification for polyps 
 
 
 
 
 
4.3.2. EXCLUSION CRITERIA 
The exclusion criteria for this study are: 
1.Age <20 years old  
2.Pedunculated polyps 
3.Lesions with macroscopic elements of high-grade dysplasia or submucosal infiltration 
4.Sites with previous polypectomy 
5.Patients with idiopathic inflammatory bowel disease 
6.Patients with coagulation disorders 
7.Patients with severe organ failure 

7.Patients who during endoscopy will undergo any technique using electrocautery / 
electrocoagulation will not be eligible for participation in the study. 
 
 
 
 
Figure 2. 
Diagnostic performance of Japan NBI Expert Team classification for differentiation among noninvasive, superficially invasive, 
and deeply invasive colorectal neoplasia. Sumimoto K. GastrointestEndosc. 2017 Oct;86(4):700-709. doi: 
10.1016/j.gie.2017.02.018. Epub 2017 Feb 28. PMID: 28257790. 
 

 
 
Figure3.  
Optical diagnosis of colorectal polyps with Blue Light Imaging using a new international classification. Subramaniam S. United 
European Gastroenterol J. 2019 Mar;7(2):316-325. doi:10.1177/2050640618822402.  PMID: 31080616 
 
 
5. STUDY INTERVENTIONS 
 
 
5.1. POLYPECTOMY 
All endoscopic procedures will be performed with High Definition (HD) instruments. In both groups of 
patients, the use of a cap and the performance of the colonoscopy with water / air / CO2 will be chosen 
according to the preferences of the physician.Additionally, in both groups, a 0.3mm dedicated cold snare 
will be used for polypectomy.  
 
5.2. EXCISION PROCEDURE 
The procedure of Underwater Cold Snare Polypectomy (UP) will be as follows: 
1.      Complete suction of air from the intestinal tract 
2.      Partial opening of the intestinal lumen by using sterile room temperature water via a 
water pump 
3.      Complete immersion of the lesion in water 
4.      Snaring of the lesion and a small amount of surrounding healthy tissue (1-2mm) 
5.      Excision 
 
The procedure of Conventional Cold Snare Polypectomy (CCSP) will be as follows: 
1.      If the entry during the endoscopy has been made with water, the water will be 
aspirated, and the intestinal lumen will be re-stretched using air / CO2 

2.      Snaring of the lesion and a small amount of surrounding healthy tissue (1-2mm) 
3.      Excision 
 
In both groups of patients, the objective will be the en bloc resection of the lesion 
including healthy tissue (about 2mm). If the en bloc resection fails, a piecemeal resection 
will be performed on as few specimens as possible. 
The tissue specimen(s) will be placed in a vial with formol (Vial 1). 
 
 
 
5.3. RESECTION POINT OVERVIEW 
After the resection of the lesion, a careful review of the resection point for bleeding or 
perforation will follow. 
- Bleeding that lasts over a period of < 60 seconds will not be treated with 
endoscopic hemostasis (endoscopic clips) and will be recorded as self-limited. 
- Bleeding that will persist > 60 seconds is characterized according to the 
instructions of ESGE 2017 as intraprocedural bleeding and can be treated either by 
water sprinkling or by placing hemostatic clips. The use of electrocautery or 
electrocoagulation methods will not be permitted. 
 This will be followed by a meticulous evaluation of the resection margins with digital 
endoscopy and a photograph of the site after the polypectomy if possible. 
Where residual damage is observed, it will be removed using Cold Snare or biopsy 
forceps, but once again without using electrocautery or electrocoagulation methods. In 
any case, in the end of the procedure the resection should be judged as endoscopically 
complete. 
 
5.4. BIOPSIES FROM RESECTION SITE 
Often the resection margins cannot be clearly defined during the pathological 
examination for reasons such as : the destruction of the tissue particles during aspiration 
into the working canal of the endoscope, specimens’ autolysis and orientation inability. In 
order to determine the R0 resection rate and the incomplete resection rate, additional 
biopsies will be taken from the resection site as follows : 
Horizontal margins : 
In order to determine the horizontal margins, 2-4 biopsies will be taken from the 
resection area (2 biopsies antidiametrically in polyps of 5-7 mm size, 4 biopsies in polyps 
of 8-10 mm size). One cup of forceps will be placed in the defect and the second in the 
macroscopically normal mucosa. 
The received tissue pieces will be placed in a new vial with formol (Vial 1A) 
At the end of the endoscopic removal there will be 2 vials. 
 
 
 
 

5.5. MARKING OF LESION’S POSITION 
In order to easily locate the point of the polypectomy in the repeated colonoscopy, a 
submucosal tattoo should be made 2-3 cm peripherally of the lesion. The tattoo will 
always be performed after the polypectomy and biopsy. For rectal or cecum polyps, 
positioning does not require a submucosal tattoo, and may be aided by photographic 
recording prior to polypectomy. 
 
 
 
6. STUDY PROCEDURES 
 
 
6.1. RANDOMIZATION 
Randomization will be conducted at the patient level. If more than one polyp is diagnosed 
in a patient, then all will be resected by the same method. Specifically, the randomization 
process will be done by using the random numbers method of Microsoft Excel 2016. A 
research assistant, who will not participate in clinical practice, will allocate patients with 
a 1:1 ratio to the UCSP and CCSP group and will inform the endoscopist of the 
polypectomy method when a polyp is found. The Excel distribution table will not be 
accessible by the endoscopists. After written consent, patients will not be aware of the 
polypectomy method that will be applied (blinding) 
 
 
 
6.2. PATHOLOGICALEXAMINATION 
Specimens will be placed in vials with 10% formol (a total of 2 vials as mentioned above) 
and will be sent to the Pathological Laboratory. The slides will be stained in the DAKO 
CoverStainer using the DAKO Hematoxylin&Eosin Staining Kit. The slides will be then 
evaluated by two independent experienced pathologists, under a Nikon Eclipse 50i and a 
Nikon Eclipse E400 optical microscope (4X). Dysplastic changes will be classified using 
the Vienna classification system. In case multiple tissue fragments were biopsied, the 
aforementioned parameters will be calculated cumulatively. 
Pathologists examining the tissues will be blinded and will not know the resection 
method (CCSP or UCSP) of each specimen. 
Vial 1: 
- Determination of polypectomy margin according to Residual Tumor Classification 
- Determination of percentage of muscularis mucosa included in specimen. The 
determination of the area containing muscularis mucosa layer will be done by 
measuring the lenght of muscularis mucosa mm^2 / length of specimen 
mm^2x100%. Using an ocular and stage micrometer, the length of the muscularis 

mucosa underlining a neoplastic lesion was measured, along with the maximum 
depth of the muscularis mucosae and the specimen’s maximum diameter 
- Presence or absence of submucosa 
- Measurement of submucosa depth in μm (when submucosa is present in the 
specimen) 
Vial 1A : 
- Determination of horizontal margins: presence of residual damage or not 
 
A Nikon 10X microscope lens is used for microscopic measurement. 
 
 
6.3. BLINDING 
This is a double blinded study. As it was mentioned above, pathologists and patients will 
be blinded. Blinding cannot be applied in the endoscopist level because of the nature of 
the intervention. 
 
 
 
 
 
7. SAFETY ASSESSMENTS 
 
7.1. RISKS  
Regardless patients’ participation in the study, those who are diagnosed with colon 
polyps will undergo polypectomy according to ESGE & ASGE guidelines in order to 
prevent malignancy in the future. UCSP and CCSP are both safe methods used in 
everyday clinical practice. Although as polypectomy is an interventional procedure, 
adverse events may occur but they are not study-related. 
- Intraprocedural bleeding - IPB (bleeding during polypectomy), is defined 
according to the guidelines of ESGE (2017) bleeding that occurs during 
polypectomy and lasts more than 60 secs or bleeding that requires endoscopic 
intervention. In these cases, the hemostasis will be performed by using hemostatic 
clips. Bleeding episode during polypectomy that lasts less than 60 secs will be 
characterized as self-limited. 
 
- Post-procedural bleeding - PPB (bleeding after polypectomy), is defined according 
to the guidelines of ESGE (2017) bleeding that occurs up to 30 days after 
polypectomy, and leads to the need for unplanned medical evaluation, or as a visit 
to the emergency room, or as the need for hospitalization or invasive treatment 
(repeated endoscopy for hemostasis, transfusion, angiography, surgery).  
>Early post procedural bleeding (after polypectomy) is defined as rectal bleeding 
within 48 hours of polypectomy.  

>Late bleeding (after polypectomy) is defined as rectal bleeding from 48 hours to 
30 days after polypectomy 
 
New endoscopy is indicated in patients with two or more episodes of moderate / severe 
bleeding, drop in hemoglobin of at least 2 g / dl, and / or hemodynamic instability. 
 
- Perforation: presence of air or intestinal contents outside the gastrointestinal tract 
[39] Perforation is a rare adverse events and occurs in polypectomies of large size 
lesions and when electrocautery is used. 
- Abdominal pain not due to perforation [39] 
 
All complications and treatment of them will be recorded.  
 
 
7.2 FOLLOW UP FOR ADVERSE EVENTS 
The aforementioned complications will be evaluated by a study physician of the 
Gastroenterology Department 30 days after the polypectomy with a phone call and 
clinical examination if needed. Patients will be able to communicate with a physician 
who participates in the study 24h/24h. 
 
 
7.3. FOLLOW UP ENDOSCOPY 
After 6-12 months, endoscopy will be repeated to check for recurrence of the lesion. The 
procedure will be done with a careful overview of the area of the previous resection. The 
area of the previous resection will be indicated by the tattoo or by the photofile or by the 
endoscopists descriptions at their reports. If the scar from the prior polypectomy can be 
located, two biopsies will be conducted from the scar area to determine the occurrence or 
absence of a microscopic recurrence.  
 
 
8. STATISTICAL CONSIDERATIONS 
 
8.1. SAMPLE SIZE 
It was estimated that to find a mean difference of 15% at the main endpoint of the study 
(rate of the area containing muscularis mucosa%) and based on the literature data 
provided by a relevant research [Ref: 38], 198 people will be required per group (total 
396) in order to find differences in significance level 0.05. 
 
 
8.2. DATA ANALYSIS 
Absolute and relative frequencies, 95% confidence intervals and frequency graphs will be 
used to illustrate the qualitative variables of the study. The mean values, standard 
deviations, median values, intra-quadratic ranges (25th-75th percentage points). 

Histogramsand boxplotswill be used to describe the quantitative variables. The 
Kolmogorov - Smirnov test will be run to check the normality of the 
distributions.Pearson’s chi-square and Fisher’s exact test will be applied to compare the 
ratios between the study groups. On the other hand, the Student's t-test or the non-
parametric Mann-Whitney test will be used to compare quantitative variables between the 
two groups, depending on whether the data follow the normal distribution. Moreover, 
linear or logarithmic models will be used to check for differences between the studied 
groups, taking into account other factors (e.g. demographic and clinical characteristics). 
In case of asymmetrical distribution, logarithmic transformations of the variables will be 
used. Significance levels will be bilateral and the statistical significance will be set at 
0.05. The analysis will be run with the statistical program SPSS 26.0. 
 
 
 
9. DATA QUALITY 
 
9.1. DATA COLLECTION AND MANAGEMENT 
A data collection form (source document) will be completed for each patient including all 
patient’s details according to the study protocol.  Especially trained investigator staff will 
enter the data required by the protocol into the case report forms (CRFs) and into the 
database. The Primary Investigator must check and certify that CRFs are complete and 
accurate. According to GCP patients’ data will be available for sponsor’s essential 
documents too. 
 
 
9.2. QUALITY ASSESSMENT 
 
9.2.1 MONITORING 
Quality control will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. Monitor will verify that the rights of human 
subjects are protected, the reported trial data are accurate, complete, and verifiable from 
source documents, the conduct of the trial is in compliance with the currently approved 
protocol, with GCP, and with the applicable regulatory requirements. 
Monitoring plan: first visit before initiation of patients enrollment and following regular 
visits site according to an agreed monitoring plan every 4-6 weeks. 
 
 
10. ETHICAL CONSIDERATIONS 
 
10.1. ETHICAL COMPLIANCE 
The study design conforms with ICH–GCP, the Declaration of Helsinki, and local ethical 
and legal requirements. The study protocol is approved by the Insitutional Review Board 

of Sismanogleio General Hospital of Athens and approval by the Committee of Bioethics 
and Ethics of the Medical School - National and Kapodistrian University of Athens  is 
pending. This trial protocol was written in accordance with the Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT).  
 
10.2. INFORMED CONSENT  
IRB-approved, written informed consent (witnessed, where required by law or regulation) 
will be obtained from all participants during the visit at the out-patient clinic before 
enrollment in the study. All participants will take a copy document, and the original 
document will be kept as one of the essential documents for trial’s master file (TMF). 
 
10.3. PUBLICATION POLICY 
This protocol will be posted in clinicaltrials.gov which is a publicly accessible database. 
Study’s results and outcomes will be submitted for publication in international medical 
journal and presented in medical conferences related to interventional gastrointestinal 
endoscopy and polypectomy techniques. 
 
 
 
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12. ABBREVIATIONS 
 
ASGE : American Society for Gastrointestinal Endoscopy 

CCSP : Conventional Cold Snare Polypectomy 
CRF : Case Report Form 
CRR : Complete Resection Rate 
CS : Cold Snare 
CSP : Cold Snare Polypectomy 
EMR : Endoscopic Mucosal Resection 
ESGE : European Society of Gastrointestinal Endoscopy 
GCP : Good Clinical Practice 
HS : Hot Snare 
HSP : Hot Snare Polypectomy 
IPB : Intraprocedural Bleeding 
IRR : Incomplete Resection Rate 
MM :Millimetre 
UCSP : Underwater Cold Snare Polypectomy 
UEMR : Underwater Endoscopic Mucosal Resection 
UP : Underwater Polypectomy 
PPB :Postprocedural bleeding 
R0RR : R0 Resection Rate 
RCT : Randomized Controlled Trial 
SOP :Sponsor's Standard Operating Procedures 
SPIRIT :Standard Protocol Items: Recommendations for Interventional Trials 
TMF : Trial’s Master File