Contribution of Narrow Band Imaging (NBI) for the Characterization of Scalloped Polyps
Phase: NA
Conditions: Polyps of Colon
Sponsor: Centre Hospitalier Departemental Vendee

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  « NBI – COLON POLYPS » 
 
 
 
 
 
 
 
 
 
 
 
- Contribution of Narrow Band Imaging (NBI) to the 
Characterization of Scalloped Colon Polyps - 
 
Minimal Risk, Minimal Constraint Interventional Research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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“NBI - POLYPES COLIQUES" project 
 
Registration number: n°2017-A01245-48 
Ref : CHD010-17 
Ref. CPP: 17.12.73 
 
 
"Contribution of Narrow Band Imaging (NBI) for the 
characterization of Scalloped Colon Polyps". 
 
 
Coordinating Investigator:   
 
Dr Vincent MACE, PH 
Gastroenterology Department 
 CHD de La Roche sur Yon, 
 Tel: 02 50 44 61 68 
 
 
Methodologist :  
 
Lucie PLANCHE, Methodologist - Clinical Research Unit  
CHD La Roche Sur Yon 
Boulevard Stéphane Moreau 
85 925 La ROCHE SUR YON Cedex 09 
Tel: 02 51 44 65 72 
 
 
Sponsor : 
Center Hospitalier Départemental Vendée 
Clinical Research Unit 
Boulevard Stéphane MOREAU 
85 925 LA ROCHE SUR YON Cedex 09 
Tel: 02 51 44 65 72 
Fax: 02 51 08 05 91 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
 
SPONSOR'S SIGNATURE 
 
 
The person in charge of the research undertakes to carry out this study in accordance 
with all the legislative and regulatory provisions that may apply to the research and in 
accordance with the protocol.  
 
Name and position of signing 
representative : 
Mr Francis SAINT-HUBERT 
 General Manager  
 
Date : 
 
Signature : 
 
SIGNATURE OF INVESTIGATOR S 
 
I have read all the pages of the protocol for the clinical trial for which the CHD Vendée is 
responsible. I confirm that it contains all the information required to conduct the trial. I 
undertake to carry out the trial in compliance with the protocol and the terms and conditions 
defined therein.  
I am aware that this research falls within the scope of routine care research as defined by 
paragraph 2° of article L 1121-1 and article R 1121-3 of the French Public Health Code. The 
procedures are performed and the products are used in the usual way, but special monitoring 
procedures are provided for in this protocol. 
I undertake to carry out the test in compliance with : 
• 
the principles of the "Declaration of Helsinki",  
• 
international (ICH) and French rules and recommendations of good clinical practice 
(rules of good clinical practice for biomedical research involving medicinal products 
for human use - decisions of November 24, 2006) 
• 
national legislation and regulations governing clinical trials 
• 
compliance with the current European Directive governing clinical trials  
 
I also undertake to ensure that the investigators and other qualified members of my team 
have access to copies of this protocol and documents relating to the conduct of the trial to 
enable them to work in compliance with the provisions set out in these documents. 
 
 
Coordinating 
investigator 
Name : 
Dr. Vincent MACE 
 CHD Vendée 
 
Date : 
Signature : 
Principal 
investigator 
Name and address : 
 
 
 
Date : 
Signature : 
 
 
  

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LIST OF ABBREVIATIONS 
 
 
ANSM 
Agence Nationale de Sécurité du Médicament et des Produits de 
Santé (French Agency for the Safety of Medicines and Health 
Products) 
AMM 
Marketing Authorization 
ARC 
Clinical Research Associate  
BPC 
Good Clinical Practice 
JRC 
Colorectal cancer 
CE 
European conformity  
CEC 
Clinical Studies Coordinator 
CNIL 
Commission Nationale de l'Informatique et des Libertés (French 
Data Protection Authority) 
PPC 
Comité de Protection des Personnes  
CRF 
Case Report Form (observation booklet) 
DM 
Medical Devices 
eCRF 
Electronic Case Report Form (cahier d'observation électronique) 
EMA 
European Medicines Agency 
EIG  
Serious adverse effect 
EIGI  
Unexpected Serious Adverse Effect 
EM 
Medication error 
EvIG  
Serious Adverse Event 
HAS 
French Health Authority 
ICH 
International Conference on Harmonization 
IRC 
Clinical Research Nurse 
LB 
White Light 
IBD 
Chronic Inflammatory Bowel Disease 
MR 
Reference methodology (CNIL) 
NBI 
Narrow Band Imaging 
NICE 
Narrow band imaging International Colorectal Endoscopic 
RCH 
Hemorrhagic Rectocolitis 
CPR 
Summary of Product Characteristics 
SUSAR (=EIGI) 
Suspected Unexpected Serious Adverse Reaction 
TEC 
Clinical Study Technician 
UFR 
Training and Research Unit 
WASP 
Workgroup serrAted polypS and Polyposis 
WHO 
World Health Organization  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
SIGNATURE PAGE .................................................................................................................................... 3 
LIST OF ABBREVIATIONS .......................................................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................................... 5 
INTRODUCTION ....................................................................................................................................... 7 
1. 
Justification for the study ........................................................................................................ 8 
1.1 
Research positioning ............................................................................................................... 8 
1.2 
Benefits and risks for research subjects ................................................................................ 11 
1.2.1 
Benefits .............................................................................................................................. 11 
1.2.2 
Risks ................................................................................................................................... 12 
1.2.3 
Justification for positioning as research with minimal risks and constraints .................... 12 
2. 
Objectives and judging criteria ............................................................................................. 13 
2.1 
Objective and primary endpoint ........................................................................................... 13 
2.1.1 
Main objective ................................................................................................................... 13 
2.1.2 
Primary endpoint ............................................................................................................... 13 
2.2 
Objectives and secondary endpoints .................................................................................... 13 
2.2.1 
Secondary objectives ......................................................................................................... 13 
2.2.2 
Secondary endpoints ......................................................................................................... 14 
3. 
Study population ...................................................................................................................... 15 
3.1 
Description of the population ............................................................................................... 15 
3.2 
Pre-inclusion criteria ............................................................................................................. 15 
3.3 
Inclusion criteria .................................................................................................................... 15 
3.4 
Non-inclusion criteria ............................................................................................................ 15 
4. 
Course of the study ................................................................................................................. 16 
4.1 
General research methodology ............................................................................................. 16 
4.2 
Study and analysis techniques .............................................................................................. 16 
4.2.1 
Detailed description of evaluation parameters ................................................................ 16 
4.2.2 
Description of techniques and analyses ............................................................................ 16 
4.3 
Study schedule ...................................................................................................................... 17 
4.4 
Identification of source data not included in the medical record ......................................... 18 
4.5 
Rules for terminating a person's participation ...................................................................... 18 
4.5.1 
Criteria for premature termination of a person's participation in research ..................... 18 
4.5.2 
Procedure for premature termination of a person's participation in research ................ 18 

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4.5.3 
Criteria for discontinuing all or part of a research project (excluding biostatistical 
considerations) .................................................................................................................................. 18 
5. 
Data management and statistics .......................................................................................... 19 
5.1 
Study data collection and processing .................................................................................... 19 
5.1.1 
Data collection ................................................................................................................... 19 
5.1.2 
Data coding ........................................................................................................................ 19 
5.1.3 
Data processing ................................................................................................................. 20 
5.2 
Statistics................................................................................................................................. 20 
5.2.1 
Description of planned statistical methods, including schedule of planned interim 
analyses and statistical justification of number of inclusions ........................................................... 20 
5.2.2 
Expected statistical significance ........................................................................................ 21 
5.2.3 
Method for taking into account missing, unused or invalid data ..................................... 21 
5.2.4 
Managing changes to the initial strategy analysis plan ..................................................... 21 
5.2.5 
Choosing the people to include in analyses ...................................................................... 21 
6. 
Vigilance and management of undesirable events ......................................................... 22 
6.1 
Definitions ............................................................................................................................. 22 
6.2 
List of expected adverse events ............................................................................................ 23 
6.3 
Managing adverse events ...................................................................................................... 24 
6.3.1 
Collection of EvI/EI ............................................................................................................ 24 
6.3.2 
Notification of SAEs / EvIG ................................................................................................ 24 
6.3.3 
Notification period to sponsor .......................................................................................... 25 
6.4 
Methods and duration of follow-up care following the occurrence of undesirable events . 25 
7. 
Administrative and regulatory aspects .............................................................................. 26 
7.1 
Right of access to source data and documents ..................................................................... 26 
7.2 
Data confidentiality ............................................................................................................... 26 
7.3 
Computerized data and submission to CNIL ......................................................................... 26 
7.4 
Trial monitoring ..................................................................................................................... 26 
7.5 
Inspection / Audit .................................................................................................................. 27 
7.6 
Ethical considerations ........................................................................................................... 27 
7.6.1 
Informed consent express ................................................................................................. 27 
7.6.2 
Personal Protection Committee ........................................................................................ 27 
7.6.3 
Informing the competent authorities................................................................................ 27 
7.7 
Protocol amendments ........................................................................................................... 28 
7.8 
Financing and insurance ........................................................................................................ 28 
7.9 
Publication rules .................................................................................................................... 28 
7.10 
Archiving source data ............................................................................................................ 28 

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INTRODUCTION 
 
 
This is a prospective bicentric study to assess the diagnostic performance of NBI (Narrow 
Band Imaging) characterization of scalloped colonic polyps less than 20mm in patients 
undergoing screening colonoscopy. 
 
NBI is a "virtual" electronic staining technique available on conventional OLYMPUS and 
FUJIFILM endoscopes, with no additional intervention required. 
 
The colonoscopy procedure for each patient will be no different from a conventional 
colonoscopy examination with excision of all polyps visualized and anatomopathological 
analysis, apart from a brief period of NBI analysis for each polyp detected prior to excision, 
enabling the polyp to be classified according to existing endoscopic classifications (i.e. NICE 
classification for adenomatous polyps and WASP classification for scalloped polyps). 
 
This joint CHD-CHU project is original in that there are currently no data on the 
characterization of colonic polyps in NBI by large groups of "non-expert" endoscopists. 
Indeed, studies carried out to date on this subject, notably in the United States and England, 
have involved small numbers of NBI expert endoscopists. A recent "pilot" study carried out at 
Nantes University Hospital showed that NBI is becoming reliable, with a diagnostic accuracy 
of over 90%, for differentiating adenomatous polyps from typical hyperplastic polyps, but did 
not assess the contribution of NBI to the characterization of scalloped polyps, a still poorly 
understood entity. The technological improvement of endoscopes and the publication in 2016 
of a classification (WASP) enabling the recognition of sessile scalloped polyps using NBI 
now necessitate evaluating the contribution of NBI for the recognition of these lesions. A 
study of this kind in general and university hospitals is essential to determine the feasibility of 
community implementation, with the ultimate aim of better detecting scalloped colonic 
lesions, which are often unrecognized but have a clearly demonstrated degenerative 
potential, and differentiating them from typical adenomatous polyps. The clinical 
gastroenterology departments of the CHD and CHU are very involved in clinical research, 
and collaborate on joint care and research projects. Both are equipped with the latest 
generation of Olympus and Fujifilm (for CHU de Nantes) systems with NBI, and have a 
significant endoscopic activity, notably in the field of colorectal cancer screening.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
Justification of the study  
1.1 
Research positioning 
Colorectal cancer is a major public health problem worldwide, particularly in industrialized 
countries. In France, the incidence of colorectal cancer ranked 3e among all cancers, with 
40,500 new cases and an estimated 17,500 deaths in 2011. (1). Most sporadic colorectal 
cancers arise from pre-cancerous lesions, adenomatous polyps, according to a now well-
known carcinological development sequence (2). Colonoscopy combined with resection of 
adenomatous polyps reduces the risk of colorectal cancer (3,4). In France, colonoscopy is 
the reference method for colorectal cancer screening in populations selected as being at risk, 
according to the recommendations of the French National Authority for Health (HAS), and in 
patients suspected of having a colorectal neoplastic lesion in the presence of suggestive 
symptoms. (5).   
Although colonoscopy is effective overall in reducing the risk of colorectal cancer, it is 
an imperfect tool, with 15-27% of lesions 'missed' and left in place (6,7), which can lead to 
the occurrence of interval cancers. Interval cancers are cancers that occur between two 
colonoscopies, and could account for up to 10.5% of colon cancers. They occur within 6 to 
60 months (7). Among the possible causes of missed lesions, the involvement of 
adenomatous scalloped polyps currently raises major questions, as these lesions are still a 
poorly understood entity, but have a demonstrated degenerative potential (8). Their 
involvement in interval cancers is suggested both by their preferential right-sided location 
(the protective effect of colonoscopy being much less for the right colon than for the left), and 
by their lack of relief, which makes them more difficult to detect. Moreover, until recently, 
there was no clear endoscopic description enabling the endoscopist to recognize them and 
treat them effectively. As a result, the rate of incomplete endoscopic resections of scalloped 
adenomatous polyps is estimated at 30% (9). 
From an anatomopathological point of view, the situation has become relatively 
complex in recent years, with the description of new colonic polyp entities (8). Historically, 
only conventional adenomatous polyps (at risk of degeneration) and typical hyperplastic 
polyps (without risk of degeneration) were distinguished, which explains why endoscopic 
classifications have focused on the ability to distinguish these 2 anatomopathological entities. 
The new WHO anatomopathological classification describes scalloped polyps, which it 
subdivides into 4 different morphological entities constituting evolutionary lesion spectra. The 
histological appearance of these lesions distinguishes between 1) typical hyperplastic polyps 
(reclassified as non-adenomatous scalloped lesions, and accounting for some 80-90% of 
scalloped lesions overall), 2) sessile scalloped adenomas/polyps, 3) sessile scalloped 
adenomas with dysplasia, and 4) traditional scalloped adenomas. While typical hyperplastic 
polyps have virtually no degenerative potential, other scalloped (adenomatous) lesions may 
degenerate. Descriptively, typical hyperplastic polyps are generally small and occur 
throughout the colon. Sessile scalloped polyps/adenomas do not show cytological lesions of 
dysplasia in the basal state. They are essentially characterized by abnormalities in the 
maturation of colonic crypt cells. They share many morphological features with hyperplastic 
polyps of the microvesicular subtype, in particular their predominantly right-sided location. 
They are generally larger than hyperplastic polyps. Foci of dysplasia identical to that of 
"classic" adenomas may appear in sessile scalloped polyps/adenomas. Sessile scalloped 
lesions with dysplasia are thought to progress more rapidly to adenocarcinoma than classical 
adenomas of equivalent dysplasia grade. Traditional scalloped adenomas are different from 
sessile scalloped lesions. They generally appear in the left colon and rectum, and are of 
villeinous or filiform architecture. They are characterized by the presence of a dysplasia rich 
in cells with penicillate eosinophilic cytoplasm and ectopic crypts not anchored to the 

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muscularis mucosa. Many of them are associated with a classic adenomatous component, 
and their evolutionary kinetics are identical to those of classic adenomas. 
As far as endoscopy is concerned, it is accepted that, in routine practice, it is 
relatively easy to distinguish typical hyperplastic polyps from classic adenomas, thanks to 
optical advances. On the other hand, it remains very difficult to recognize adenomatous 
scalloped polyps. This poses a real problem, since adenomatous scalloped polyps are 
probably responsible for around 30% of colorectal cancers, including interval cancers (9). 
The best way to detect adenomatous scalloped polyps is therefore to learn how to recognize 
these lesions, which requires a high-quality optical examination and the use of optical filters 
such as Narrow Band Imaging (NBI). 
 
A major challenge is therefore to distinguish conventional adenomatous polyps from 
scalloped lesions, particularly sessile adenomatous scalloped polyps. These lesions have an 
increased risk of developing colorectal cancer and represent around 12% of colonic polyps in 
a population referred for screening colonoscopy, but are often missed at colonoscopy due to 
their very flat nature.  
 
These strategies require highly reliable optical prediction techniques during the endoscopic 
examination. However, standard diagnostic colonoscopy using white light, as currently 
practised, does not effectively differentiate between different polyp subtypes. Indeed, the 
diagnostic efficiency of white light for histological prediction of colonic polyps is only around 
60-80%. (10). The most promising advances concern so-called "virtual chromoendoscopy" 
techniques such as Narrow Band Imaging (NBI) (Olympus and Fujifilm, Japan). With NBI, the 
image can be colored simply and immediately, at the touch of a button on the endoscope 
handle, to enhance mucosal microarchitecture and vessels. In technical terms, this involves 
the activation of an optical filter limiting the light spectrum to 2 specific wavelengths, 415nm 
(blue) and 540nm (green) respectively. As the two absorption peaks of hemoglobin occur at 
these wavelengths, the NBI allows blood vessels to appear darker, enabling better 
visualization of both mucosal surface details and capillaries. Several studies have 
demonstrated the value of NBI for characterizing colonic polyps, particularly small ones, with 
very good diagnostic accuracy and a high degree of confidence on the part of endoscopists. 
Indeed, these studies show diagnostic efficacy rates in the order of 96 to 98% for colonic 
polyps of 6 to 9mm, and 91 to 92% for those under 5mm (11-14).  
The population of gastroenterologists around the world who could potentially use NBI 
is extremely large, since NBI has been available on all Exera (Olympus) and 760 (Fujifilm) 
series video processors for around 5 years in routine practice. However, published scientific 
data comes mainly from expert centers, and has been acquired by endoscopists with 
considerable expertise in the interpretation of NBI images. Moreover, analysis of published 
data is confounded by the multiplicity of classifications used, whose diagnostic criteria can 
vary significantly (15-17). Thus, all the following classifications have been proposed: 
Vascular Pattern Intensity (VPI), Sano classification, Hiroshima, Showa, etc. In order to 
standardize diagnostic criteria and harmonize practices, Tanaka and Sano proposed a new 
classification in 2011 called the NICE classification (Narrow band imaging International 
Colorectal Endoscopic) (18)which has been validated by other groups from expert centers 
(19) which differentiates between typical hyperplastic polyps and conventional adenomatous 
polyps (Figure 1), but did not include recognition of adenomatous scalloped polyps. Recently, 
the WASP classification has been developed for the diagnosis of scalloped adenomatous 
polyps, and appears extremely promising (20). This classification was published in Gut in 
2016 (Figure 2), but no external validation study is currently available, nor is it currently 
underway to our knowledge. It therefore seems particularly interesting to evaluate this new 
classification, all the more so as studies carried out in the field of learning NBI semiology in 
general are in favour of relatively short learning curves (21-24). 
 
Our aim is to evaluate and compare, using the CONECCT classification, the diagnostic 
performance of NBI for histological prediction of the nature of colonic polyps (conventional 

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adenomatous versus scalloped polyps) during colonoscopy, compared with histological 
analysis (taken as the reference method), in a large population of "non-expert" NBI 
endoscopists, after rapid and simple training in the NBI technique.  
 
The gastroenterology clinical departments of the CHD and CHU collaborate on joint care and 
research projects. They are both equipped with the latest generation of Olympus and Fujifilm 
systems with NBI, enabling the use of appropriate classifications, and have significant 
endoscopic activity, particularly in the field of colorectal cancer screening.  
 
This study in no way alters the patient's clinical management or care pathway. During 
colonoscopy in the presence of polyp(s) <20 mm, an observation sequence and image 
acquisition are performed in NBI, which does not significantly alter the duration of the 
endoscopic examination. The NBI is integrated into the high-definition endoscope (Olympus, 
Fujifilm) and the transition from white light to NBI is instantaneous. 
  
 
 
Figure 1: NICE (Narrow band imaging International Colorectal Endoscopic) classification. 
Diagnostic criteria in favor of a typical hyperplastic polyp (type I) are: a) absence of dark 
appearance of the polyp in relation to the adjacent mucosa, b) absence of brownish vessels, 
c) absence of oval structures within the polyp.  
Conversely, the presence of one or more of the above-mentioned criteria is indicative of a 
conventional adenomatous polyp (type II).  
 
 
 
 
Figure 2: WASP (Workgroup Serrated PolypS and Polyposis) classification. Diagnostic 
criteria in favor of an adenomatous scalloped polyp are: a) the existence of a cloudy 
appearance of the polyp, b) an irregular shape, c) the presence of black spots within the 
colonic glands. 
 

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Figure 3: CONECCT classification (Colorectal Neoplasia Classification to Choose the 
Treatment).  
 
1.2 
Benefits and risks for research subjects 
1.2.1 Benefits 
The results of this research will contribute to the development of knowledge in the field of 
pathology. 

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1.2.2 Risks  
- NBI prediction: poor lesion targeting, erroneous use of NBI methodology and tests 
(despite learning) leading to misdiagnosis.  
 
- The risk associated with histological analysis is not specific to this study, but applies to all 
procedures for processing, reading and interpreting histological specimens. It relates to 
malfunctions and quality defects at various stages (preparation, staining....), and can lead to 
misdiagnosis.      
 
- Associated procedures: the risks of colonoscopy and biopsies are those incurred when 
these examinations and techniques are carried out as part of everyday practice, i.e. pain, 
bleeding, perforation and infectious risks.  
 
- Added to this are the risks associated with drugs administered for colonic preparation 
and those administered for anesthesia/analgesia during and after the examination. These 
risks are described in the SPCs of the drugs concerned, administered within the scope of 
their marketing authorization. 
 
- Pathology under study: colorectal cancer screening/risk monitoring: risk of underdiagnosis 
and latent progression. 
 
1.2.3 Justification for positioning as research with minimal risks 
and constraints 
The person in charge of the research qualifies it in first intention as interventional research 
with minimal risks and constraints, since : 
• 
All procedures are routinely performed (colonoscopy) and defined in the order of April 
12, 2018 set by the Ministry.  
Research does not focus on innovative or obsolete techniques or strategies. 
 
Apart from the transition to NBI, all patient management will be identical to usual practice. In 
particular, the date of discharge will be decided by the doctor in charge of the patient, 
independently of the study, but will be recorded in the patient file and the research CRF. 
 
As a result, the particular conditions under which the research is carried out represent 
negligible constraints for the person undergoing the research. (Article R 1121-3 of the French 
Public Health Code (CSP), decree no. 2006-477 of April 26, 2006) 
 
 
Before any research is carried out, the person in charge of the research will submit the 
study protocol to the Comité de Protection des Personnes Ouest III de Poitiers for a 
favorable opinion and confirmation of the research's qualification, in accordance with article L 
1121-1 of the French Public Health Code (CSP), as amended by laws no. 2004-806 of 
August 9, 2004 and no. 2006-450 of April 18, 2006 relating to public health policy. 
 
 
 
Bibliographical references are appended to the document. 

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2. 
Objectives and endpoints 
2.1 
Objective and primary endpoint 
2.1.1 Primary objective 
 
To evaluate the diagnostic performance of the NBI for the characterization of scalloped 
colonic polyps of all types [typical hyperplastic and adenomatous scalloped; i.e. CONECCT 
IH and CONECCT IS] versus conventional adenomatous [i.e. CONECCT IIA] during 
colonoscopy in a population of "non-expert" endoscopists. 
2.1.2 Primary endpoint 
Sensitivity of NBI compared with histological analysis (=reference method). 
Number of polyps characterized as scalloped (CONECCT IS) on reading by NBI compared 
with the number of polyps characterized as scalloped on standard histology. 
2.2 
Objectives and secondary endpoints 
2.2.1 Secondary objectives 
• 
Measurement of diagnostic performance indices (specificities, PPV, NPV) using NBI 
and white light alone for characterization of polyps CONECCT IH and IS versus 
CONECCT IIA  
Within scalloped polyps (according to pathological analysis results), diagnostic capabilities 
(sensitivities, specificities, PPV, NPV) of NBI and white light alone to characterize CONECCT 
IS polyps. 
 
• 
Comparison of the diagnostic performance of NBI and white light alone for the 
characterization of polyps CONECCT IH and IS versus CONECCT IIA  
 
• 
Diagnostic performance by degree of certainty in NBI. 
 
• 
Evaluation of the role of endoscopist seniority in polyp characterization in NBI. 
 
• 
Assessment of the role of polyp size in polyp characterization. 
 
 

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2.2.2  Secondary endpoints 
1-2 Polyp characterization using white light according to CONECCT classification  
Polyp characterization using NBI according to CONECCT classification  
Polyp characterization using standard histology according to CONECCT classification  
 
3- Evaluation of the degree of certainty of characterization after examination by: strong or 
weak 
 
4- Endoscopist seniority: junior or senior: <2000 vs ≥ 2000 colonoscopies performed. 
 
5- Polyp size defined on NBI examination: 1-5mm vs 6-9mm vs 10-20mm 
 
 
 

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3. 
Study population 
3.1 
Description of the population 
- Any adult patient having a colonoscopy scheduled in one of the participating hospitals. 
 
The expected number of patients is around 690, with the aim of characterizing at least 690 
polyps. The average number of polyps per patient is estimated at between 1 and 2.  
A limit of 4 polyps per patient will be set for data collection. Data collected for the study 
should relate to the first 4 polyps removed.  
3.2 
Pre-inclusion criteria 
- Patients over 18 having a colonoscopy scheduled in one of the participating hospitals (CHD 
Vendée and CHU de Nantes). 
- Patient having agreed to participate in the study and having given express consent  
- Patient affiliated with or benefiting from a social security system 
3.3 
Inclusion criteria 
• 
Patients with 1 or more polyps smaller than 20mm observed during colonoscopy 
3.4 
Non-inclusion criteria 
• 
Patient undergoing emergency colonoscopy for ongoing GI bleeding or occlusion 
symptoms 
• 
Patients with chronic inflammatory bowel disease (IBD): UC, Crohn's disease or 
unclassified colitis 
• 
Patients with familial adenomatous polyposis 
• 
Pregnant or breast-feeding women 
• 
Minor patient 
• 
Patients under guardianship or deprived of their liberty 
• 
Patient unable to understand protocol and/or give express consent  
• 
Patient not affiliated to a social security system or beneficiary of such a system 
• 
Patients hospitalized or treated without their consent 

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4. 
Conduct of the study 
4.1 
General research methodology 
 
The research has the following characteristics:  
• 
Type of research: Interventional research with minimal risks and constraints 
(Study of electronic staining techniques (also known as 'virtual chromoscopy') during 
colonoscopy, without the addition of contrast media or specific intervention). 
• 
Bicentric study: CHD Vendée, CHU de Nantes 
• 
Prospective study  
4.2 
Study and analysis techniques 
4.2.1 Detailed description of evaluation parameters 
 
Parameters assessed :  
• 
Characterization of polyps, using different analysis techniques: conventional 
adenomatous versus typical hyperplastic or scalloped adenomatous. 
4.2.2 Description of techniques and analyses 
 
Study diagram :  
 
• 
All endoscopists participating in the study will receive an initial one-hour 
training course in NBI polyp characterization, delivered by an expert 
endoscopist in image analysis (Dr. Guillaume VELUT, graduate of the DIU 
'Endoscopie Diagnostique Avancée'). 
 
• 
A verification test (rate of correct answers >95%) will be carried out before 
each operator is authorized to take part in the study, based on an independent 
set of images of 30 colonic polyps. 
 
• 
Each patient corresponding to the pre-inclusion criteria and agreeing to take 
part in the study is "pre-included". During colonoscopy, the presence of any 
polyp(s) smaller than 20mm is determined. The right colon, which is the 
preferred site for adenomatous scalloped polyps, will be examined with 
particular attention by a second pass under white light. This 2ème pass is 
routinely performed in standard practice, for example to check fast-moving 
areas during colonoscopy, and will only increase examination time by around 
2-3 minutes. Patients without a polyp smaller than 20 mm are not included in 
the study.  

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• 
Each polyp measuring less than 20mm will be analyzed in white light and NBI, 
as follows:  
1) White-light image analysis  
2) Switch to NBI mode by simply pressing the 'NBI' button on the endoscope handle 
(immediate acquisition of the NBI image with photographic recording in LB and NBI). 
A prediction of the histological type of polyp according to the CONECCT classification 
is made by the endoscopist and noted in the CRF, together with the degree of 
certainty (strong or weak). 
The study is limited to 4 polyps per patient. Only data from the first 4 polyps removed 
will therefore be collected.  
 
• 
All polyps detected and analyzed by NBI are then removed by excision 
(forceps excision, mucosectomy) according to the usual procedure and 
analyzed by conventional histology (gold standard). 
 
• 
If it is impossible to characterize a polyp by NBI (image of poor quality or 
diagnosis impossible), the examination will be considered a technical failure of 
NBI, but the polyp will be removed for histological analysis in accordance with 
current recommendations. 
• 
If the polyp is not recovered for histological analysis, or if interpretation is 
impossible (coagulation artifacts after standard resection, for example), the 
examination will be considered a technical failure of standard histology. 
• 
Anatomopathology departments will be involved and will collaborate between 
the 2 centers to ensure standardized interpretation of polypectomy specimens. 
4.3 
Study schedule 
A one-hour training session on the NBI technique, based on clinical cases and 
commented image analysis for the characterization of colonic polyps, will be given by 
an expert endoscopist (Dr. VELUT) at Nantes University Hospital and La Roche Sur 
Yon Hospital for all endoscopists taking part in the study. Dr. VELUT is a graduate of 
the DIU "Endoscopie Diagnostique Avancée" (Advanced Diagnostic Endoscopy) and 
will be taking over the "colonic polyps" course of this training program. The training 
course will therefore not call on the services of an outside consultant, and will not 
require a specific budget. 
 
 
The inclusion period is 48 months. 
 
For patients :  
• 
Inform patients about the study when they schedule their endoscopy examination in 
consultation or during hospitalization before the examination is performed. 
• 
Each patient corresponding to the pre-inclusion criteria and having the presence of at 
least one polyp of less than 20 mm at colonoscopy will be included.  
• 
Colonoscopy with white-light analysis and NBI for each patient. 
• 
Polyp excised for standard histological analysis. 

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4.4 
Identification of source data not included in the medical record 
- Total number of polyps 
- Total number of polyps <2cm 
- Quality of colonic preparation according to Boston classification 
- Suggested monitoring interval per patient after polyp analysis (by NBI and pathology) 
- Endoscopist seniority 
- Information on polyps (Paris classification, prediction in white light and NBI, CONECCT 
classification, image quality in white light and NBI, degree of certainty of prediction) 
4.5 
Rules for terminating a person's participation 
4.5.1 Criteria 
for 
premature 
termination 
of 
a 
person's 
participation in research 
For details of how and for how long people who left the study prematurely were followed up, 
please refer to the statistics section. 
 
 
-Patient consent can be withdrawn at any time during the study, before results are 
published. 
 
Right to object to data processing at any time during the study, before publication of 
results s. 
4.5.2 Procedure for premature termination of a person's 
participation in research 
Please refer to the statistics section for details of how to use data from people who left the 
study prematurely. 
 
4.5.3 Criteria for discontinuing all or part of a research project 
(excluding biostatistical considerations) 
Part or all of the study may be stopped permanently or temporarily by decision of the ANSM, 
the CPP or the study sponsor.  
  
A written confirmation will be sent to the study coordinating investigator (specifying the 
reasons for premature termination) and to the principal investigator of each center, if 
applicable. 

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5. 
Data management and statistics 
5.1 
Study data collection and processing 
5.1.1 Data collection 
An electronic case report form (eCRF) will be created for each patient. All information 
required by the protocol must be provided in the eCRF. It must include the data needed to 
confirm compliance with the protocol and all the data required for statistical analysis, and to 
detect major deviations from the protocol. 
 
 
Data will initially be collected on paper in an observation notebook, with a form for each polyp 
visualized, filled in by the endoscopist.  
All data are then entered into the eCRF by investigators, clinical study coordinators (CECs) 
or clinical research nurses (CRNs). 
 
The people responsible for filling in the eCRF (investigator, CEC, IRC, etc.) must be 
identified and their responsibilities defined in each center's table of delegated responsibilities 
(kept in the investigator binder). 
 
5.1.2 Data coding 
By signing this protocol, the principal investigator and all co-investigators undertake to keep 
confidential the identities of the patients who have participated in the study.  
 
The transmission of a person's data for research purposes will therefore only be possible if a 
coding system is used; the presentation of research results must exclude any direct or 
indirect identification. 
 
Patients (and polyps) will be identified in order of inclusion by a number automatically 
assigned by the Clinsight software (eCRF), then completed by the patient's initials. 
 
This code will be the only information on the eCRF that can be used to link the eCRF to the 
patient.  
The person in charge of the research is also required to code patient data on any documents 
in his/her possession (reports of imaging or biological examinations, etc.) which may be 
attached to the CRF. 
 
A correspondence table will be set up at each center. This table will be kept in a secure place 
by the center's principal investigator, and will contain the patient code and nominative data, 
so that it can be traced back to the patient file in the event of missing or erroneous data. No 
clinical data will be collected in these correspondence tables. 
 

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5.1.3 Data processing 
The collection of clinical data will be based on the creation of a clinical database and the 
creation of data entry masks in the image of the observation notebook, in compliance with 
the protocol and regulations currently in force. 
The structure of the database and input screens will be approved by the research manager. 
5.2 
Statistics  
Responsible for statistical analysis: Ms Lucie PLANCHE  
5.2.1 Description of planned statistical methods, including 
schedule of planned interim analyses and statistical 
justification of number of inclusions 
 
Analysis of primary endpoint: 
 
Sensitivity of the NBI technique to pathological findings for the characterization of colonic 
polyps (conventional adenomatous [CONECCT IIA] versus scalloped [CONECCT IS]) at 
colonoscopy will be calculated with its 95% confidence interval.  
 
Secondary endpoints : 
- The diagnostic performance (specificity, positive predictive value, negative predictive value, 
RV+, RV-, diagnostic accuracy (corresponding to the rate of correct responses)) of NBI for 
the characterization of colonic polyps (conventional adenomatous [CONECCT IIA] versus 
scalloped [CONECCT IS]) compared with standard histology will be estimated with their 95% 
confidence interval.  
 
- The sensitivity and specificity of white light compared with standard histology results will be 
estimated with a 95% confidence interval and compared with those obtained by NBI using a 
McNemar test. 
 
 
- If numbers permit, sensitivity analyses will be carried out: 
- The sensitivity of NBI for the characterization of CONECCT IH and IS polyps versus 
CONECCT IIA will be estimated according to the certainty of the polyp characterization in 
NBI: strong or weak. These 2 sensitivities will be compared using a Chi2 test. 
- The same analysis will be carried out on the seniority of the endoscopist: junior or 
senior. 
- The same analysis will be performed according to polyp size: 1-5mm vs. 6-9mm vs. 10-
20mm or 1-5mm vs. 6-20mm depending on numbers. 
 
Number of subjects required : 
Over 48 months, we plan to include 690 patients at Nantes University Hospital and the CHD 
de Vendée, with the aim of characterizing at least 690 polyps measuring less than 20 mm. 
About 50% of these will be CONECCT IIA polyps, 40% CONECCT IH and 10% CONECCT 

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IS. In addition, a majority of these polyps will be <5 mm in size (≈60%), ≈30% between 6-9 
mm and ≈10% >10mm. 
Assuming that 5% cannot be analyzed, and that the sensitivity of the NBI is 90%, we can 
estimate our sensitivity with a confidence interval of ±3%.  
5.2.2 Expected statistical significance 
A p-value < 0.05 is considered statistically significant. 
 
5.2.3 Method for taking into account missing, unused or invalid 
data 
All missing data will be described in terms of numbers and percentages. 
No imputation will be performed on the primary endpoint. 
5.2.4 Managing changes to the initial strategy analysis plan 
NA 
5.2.5 Choosing the people to include in analyses 
All polyps < 20mm characterized by NBI and standard histology of included patients will be 
analyzed. 
 

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6. 
Vigilance and management of undesirable events 
6.1 
Definitions 
  Vigilance 
This is the monitoring of drugs, medical devices and other 
healthcare products. It also involves preventing the risk of 
undesirable effects resulting from their use, whether these 
risks are potential or proven, 
Adverse events (AE) 
Any harmful event occurring in a person undergoing research 
involving the human body, whether or not the event is related 
to the research or to the product to which the research 
relates. 
 
Adverse reactions (AR) 
An adverse event occurring in a person undergoing research 
involving the human body, when this event is related to the 
research or to the product to which this research relates. 
Effects/ Serious adverse 
events (SAE) 
Any adverse effect/event that : 
 
* results in death, 
 
* is life-threatening, 
 
* results in temporary or permanent disability, 
 
* requires or prolongs the patient's hospital stay, 
 
* causes a congenital or neonatal anomaly, 
* is medically important (the list of medically important 
effects/events is defined by the EMA). 
 
Unexpected adverse events  Any undesirable effect whose nature, severity or course is 
not consistent with the information on the products, 
procedures and methods used in the research. 
 
New fact 
 Any new data that could lead to a reassessment of the risk-
benefit ratio of the research or the product under 
investigation, to changes in the use of the product, in the 
conduct of the research, or in the documents relating to the 
research, or to the suspension, interruption or modification of 
the research protocol or similar research. For trials involving 
the first administration or use of a health product in people 
with no medical condition: any serious adverse reaction. 
Abuse 
Intentional, persistent or sporadic excessive use of a drug 
accompanied by harmful physical or psychological reactions. 
Overdose 
Administration of a quantity of drug, given at one time or 
cumulatively, which is above the maximum recommended 
dose according to the rules of compliance or use of the 
product. Clinical judgment should always be applied.  
(actual overdose: due to too large a raw quantity / relative 
overdose: due to predisposing factors such as renal 
insufficiency, hypo-albuminemia...) 
Misuse or off-label use 
Situation where the product is intentionally used in a way that 
does not comply with the product's specifications for use 
(e.g. route of administration/posology or indication different 
from that listed in the reference document). 

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Medication error (ME) 
Corresponds to any proven (or potential) omission or 
unintentional performance of an act during the care process, 
in the circuit (from manufacture to administration) involving a 
product, which may be the cause of a risk or undesirable 
event for the patient. The risk of error or potential error 
concerns situations where the error has not occurred, has 
been intercepted but could have occurred. 
6.2 
List of expected adverse events 
Associated processes : 
- Colonoscopy AEs 
- aches and pains  
- uneasiness 
- bleeding, digestive bleeding 
- perforations  
- black stools 
- fever 
- chills   
- spleen hematoma 
- infectious risks  
 
- Biopsy AEs  
 - pain, 
- uneasiness 
- bleeding, hemorrhage 
- perforations   
- fever 
- chills 
- infectious risks ;  
 
The histological analysis process can generate EvI and situations that interfere with the 
result and therefore the quality of the data required for the study:       
• 
failure in the sample transport and storage process, 
• 
faulty sample preparation 
• 
slide reading/interpretation error   
 
AEs from drugs administered for colonic preparation and those administered for 
anesthesia/analgesia during and after the examination. These risks are described in the 
SPCs of the drugs concerned, administered within the scope of their marketing authorization.   
 
 
EvI of pathology under study (suspicion - search for colorectal cancer) :  
- Signs suggestive of, or aggravated by, bleeding, anemia and/or signs of martial deficiency.  
- Abnormalities or changes in intestinal transit 
- Modification of a known polyp  
 
AEs concerning any ancillary treatments: expected AEs are listed in the RCP for medicinal 
products used within the scope of the AMM, or in the instructions for use for DM used in 
accordance with the CE marking indication, and in the therapeutic procedures implemented 
in accordance with professional recommendations and good practice.   

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6.3 
Adverse events management 
6.3.1 Collection of AE 
In the context of this minimal-risk, minimal-constraint research study, the protocol does not 
involve any change in the usual management of patients, so any adverse events or effects 
observed will be unrelated to the study.   
 
AE related to the intervention, the pathology studied, co-pathologies and their respective 
treatments do not need to be entered in the vigilance section of the CRF, nor do they need to 
be notified to the sponsor if a severity criterion is present.  
Under the investigator's responsibility, and following the example of care, the notification of 
complications arising from these examinations comes under regulated systems: AEs linked 
to drugs and DMs transmitted to pharmacovigilance systems, materialovigilance, 
complications of procedures and examinations integrated into the establishments' risk 
management system.        
 
In this study, which aims to evaluate the diagnostic performance of NBI for the 
characterization of colonic polyps, only complications and AEs of techniques that could have 
a potential impact on the protocol objective will be collected and reported if a severity 
criterion exists. 
For this purpose, investigators will be asked to provide the sponsor with an anonymized copy 
of their declaration made in the appropriate regulated declaration system. 
 
The sponsor therefore wishes to receive :  
- All new facts arising in the course of the study 
- Any unexpected SAEs arising from the protocol procedure (for both types of analysis: white 
light/NBI and conventional histology) 
- Pregnancy reports 
6.3.2 Notification of SAE 
SAE are notified to the appropriate vigilance circuits (a copy is kept in the patient's clinical 
file). 
 
For the purposes of this protocol, the complications required to analyze the objective (see 
paragraph 6.3.1) are collected in the CRF and will be analyzed according to the study 
schedule (end of study).  
When a severity criterion exists, in the context of RIRCM, it is not necessary to send a 
notification to the sponsor (entry on the CRF is sufficient). 
 
Only "new facts" that may interfere with the research (new information on the technique, 
etc.), any SUSAR linked to protocol procedures and pregnancy reports must be transmitted 
to the sponsor as soon as possible after the investigator has become aware of them.    
All correspondence between the investigator and the vigilance cell must be copied to the 
sponsor at the same time. 
 

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6.3.3 Notification period to sponsor 
The investigator is responsible for collecting and reporting to the appropriate vigilance 
system the various complications presented by patients. 
It is the investigator's responsibility to note and report all AEs, SAEs, special situations or 
new facts, with the exception of those previously excluded, whether expected or not, 
occurring during the entire study: 
 
-from the start of the examination (colonoscopy) 
-and  up to histological analysis  
6.4 
Methods and duration of follow-up care following the 
occurrence of undesirable events 
All events, particularly serious ones, must be monitored until recovery, consolidation or death 
(closed event).  
NB: If a pregnancy occurs during the course of the study, it should be monitored until the 
child is born or reaches the age of majority. 

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7. 
Administrative and regulatory aspects 
7.1 
Right of access to source data and documents 
Each patient's medical data will only be transmitted to the sponsor or any person duly 
authorized by the latter, and, where applicable, to the authorized health authorities, under 
conditions guaranteeing confidentiality.  
The sponsor and the regulatory authorities may request direct access to medical records for 
verification of clinical trial procedures and/or data, within the limits authorized by laws and 
regulations. 
7.2 
Data confidentiality 
Persons having direct access will take all necessary precautions to ensure the confidentiality 
of information relating to the persons concerned, in particular as regards their identity and the 
results obtained. 
These people, like the investigators themselves, are bound by professional secrecy (under 
the conditions defined by articles 226-13 and 226-14 of the French penal code). 
During or at the end of the research, the data collected on the subjects and transmitted by 
the participants will be rendered anonymous. 
Under no circumstances may the names or addresses of the persons concerned appear in 
clear text.  
Only the first two letters of the subject's last name and the first letter of his or her first name 
will be recorded, along with a coded number specific to the study, indicating the order of 
inclusion of subjects.  
7.3 
Computerized data and submission to CNIL 
This study falls within the scope of the "Reference Methodology" (MR-001) in application of 
the provisions of article 54 paragraph 5 of the amended law n°78-17 of January 6, 1978 
relating to information technology, files and freedoms. This change was approved by 
decision dated August 14, 2016. The CHD Vendée de La Roche sur Yon, sponsor of the 
study, has signed a commitment to comply with this "Reference Methodology".  
7.4 
Trial monitoring  
Monitoring will be carried out by the Promotion Department of the Research Division. A 
Clinical Research Associate (CRA) will visit each investigator site to check the quality of the 
data reported in the case report forms. 
 
The monitoring plan is defined in consultation between the research team and the institution 
in charge, according to the objectives of the study. 
 

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On-site monitoring visits will be organized by appointment with the investigator. The CRAs 
must have access to each site: 
- data collection notebooks for included patients, 
- patient medical and nursing records, 
- investigator's binder. 
7.5 
Inspection / Audit 
In the context of this study, an inspection or audit may take place. The sponsor and/or 
participating centers must be able to provide inspectors or auditors with access to data. 
7.6 
Ethical considerations 
7.6.1 Informed consent express 
The investigator undertakes to obtain the person's free, informed and express consent, given 
orally, after having provided information on the protocol (information note and consent form 
in appendix). He will give the person a copy of the information note. The person can only be 
included in the study after having read the information note and given oral consent, after 
having had time to reflect, if necessary.   
 
The patient's information and agreement to participate in the research must be recorded in 
his or her medical file. 
7.6.2 Personal Protection Committee 
The person in charge of the research undertakes to submit the study project for prior 
authorization by a Comité de Protection des Personnes (CPP). The information provided 
covers the nature of the research and the safeguards provided for patients taking part in the 
trial. 
 
7.6.3 Informing the competent authorities 
The ANSM will be informed of this protocol. 
 
 
 
 
 

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7.7 
Protocol amendments 
Requests for substantial modifications will be sent by the sponsor to the relevant CPP for its 
opinion, in accordance with the law in force and its implementing decrees. 
 
An updated, dated version of the modified protocol is required. 
The information form will be modified if necessary. 
 
7.8 
Financing and insurance 
The sponsor finances the study and takes out an insurance policy covering the financial 
consequences of its civil liability, in accordance with regulations. 
 
7.9 
Publication rules 
The 1er author will be the doctor from the CHD de la Roche/Yon who wrote the article (Dr. 
Macé), with a place as second author for the Nantes doctor who included the most patients 
in Nantes. The last author will be the Nantes University Hospital doctor who supervised the 
study at the Nantes University Hospital (Pr Coron), with a possible penultimate author slot for 
the La Roche/Yon hospital doctor who supervised the study at the hospital (Dr Faroux). The 
other places will be allocated according to the number of patients recruited in the 2 centers, 
alternating between the centers (1 author/2). A co-author position (unspecified) will be 
reserved for the person in charge of biostatistical analysis. 
 
7.10 Archiving source data 
The investigator must keep all information relating to the study for at least 15 years after the 
end of the study. 
At the end of the study, the investigator will also receive a copy of each patient's data from 
his or her center, via a CD-ROM sent by the institution responsible for the research.