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Trial registered on ANZCTR


Registration number
ACTRN12618001712291
Ethics application status
Approved
Date submitted
22/09/2018
Date registered
17/10/2018
Date last updated
17/10/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Comparing standard colonoscopy versus colonoscopy associated to a special technique of virtual chromoendoscopy named Fuji Intelligent Colour Enhancement (FICE) in the endoscopic surveillance of ulcerative colitis for neoplasia
Scientific title
High-definition virtual chromoendoscopy with Fuji Intelligent Colour Enhancement (FICE) versus standard white light endoscopy in the targeted and random evaluation of colorectal mucosa during surveillance of ulcerative colitis
Secondary ID [1] 296030 0
Nil known
Universal Trial Number (UTN)
U1111-1220-0820
Trial acronym
FICE-UC
Linked study record
none

Health condition
Health condition(s) or problem(s) studied:
ulcerative colitis 309561 0
Condition category
Condition code
Oral and Gastrointestinal 308387 308387 0 0
Inflammatory bowel disease
Oral and Gastrointestinal 308633 308633 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This was a prospective, parallel trial, in which consecutive patients with long-lasting ulcerative colitis who were scheduled for surveillance colonoscopy at our centre are submitted to a withdrawal colonoscopy with standard with-light endoscopy or virtual chromoendoscopy with FICE.
The intervention includes full colonoscopy with one of two type of colonoscopes which differred about the technology of image visualisation in vivo: standard resolution white light endoscopy (WLE) versus high-definition virtual chromoendoscopy with Fuji Intelligent Colour Enhancement (FICE).
The endoscopic procedures are performed in a single day by endoscopists with more than 10 years of experience in IBD endoscopy and with experience in chromoendoscopy.
The day before the procedure, the patients receive a bowel preparation.
Bowel preparation is performed with a no fibers diet 5 days before the exam, a liquid diet the day before the procedure and 4 liters of liquids with macrogol the day before the examination.
Before starting the procedure, the patients receive a sedation with intravenous midazolam (1-5 mg) and/or meperidine (25-50 mg) according to our institutional guideline (standard dose: midazolam 5 mg ev plus meperidine 50 mg; lower dosages in cases of cardiopulmonar comorbidities).
In the WLE arm, standard white light colonoscopy is performed using the Olympus CV-180 Evis Exera II system (Olympus Corp., Tokyo, Japan) for both intubation and extubation.
In the FICE arm, virtual chromoendoscopy is activated during extubation from the caecum and performed with a high-definition magnification colonoscope (Fujinon EG-590ZW, Fujinon Corp, Saitama, Japan), equipped with the EPX4400 processor.
The patients enrolled are prospectively allocated to one arm or to the other one, according to the availability of the endoscopic instrument, a colonoscope with WLE or FICE, this latter being only one in our centre and therefore being available only after its washing and disinfection.
In patients with the inclusion criteria, therefore, the experimental instrument (equipped with FICE) is choosen for colonoscopy if immediately available at the scheduled timetable of the procedure, otherwise the patient receives colonoscopy with any other standard colonoscope with white light endoscopy.
Assessment of the colon to search for visible lesions is performed systematically during withdrawal of the instrument with a minimum diagnostic extubation time that was set at 10 minutes. Maximum duration of the intervention will be dependent by the number of lesions found and by the number and type of procedures required for biopsies or removal of each lesion.
In both arms, the large bowel is divided into 6 segments (caecum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum) and evaluated systematically in terms of bowel preparation, endoscopic disease activity (according to the Mayo subscore) and the presence and classification of any mucosal lesion according to its morphology, size, location and judgement on suspected neoplasia.
In the WLE arm, areas suspected for neoplasia are defined as any mucosal irregularity, ulceration, polypoid or non-polypoid lesion that are not entirely consistent with chronic or active UC according to the usual clinical practice, as previously described.
In the FICE arm, neoplasia is suspected according to a modified Kudo classification of pit patterns at the surface of each lesion. In particular, in the FICE arm,, lesions are defined not suspected for neoplasia if they show:
- homogeneous, type I (round regular pit pattern, similar to the surrounding normal mucosa) or type II (round stellar or papillary pit pattern), Kudo pit patterns, without visible microvessels;
- type III-L Kudo pit-pattern (tubular or round pit-pattern larger than the normal mucosa) if associated with a fibrin cap and without visible microvessels;
- lesions unclassified by the conventional Kudo classification if associated with a fibrin cap and without visible microvessels.
On the contrary, lesions are considered suspected for neoplasia if they show:
- the combination of type I and II Kudo pit-patterns as a marker of pits heterogeneity;
- type II Kudo pit-pattern with visible microvessels;
- type III-L, III-S or IV Kudo pit pattern without a fibrin cap, with or without visible microvessels;
- any type V (irregular, non-structural pit pattern) Kudo pit-patterns.
In both arms, three types of histological samples are obtained for the detection of neoplasia:
1) random biopsies of otherwise normal flat mucosa, obtained every 10 cm from the caecum to the rectum;
2) targeted biopsies or full endoscopic resection of visible suspected neoplastic lesions (polypoid or non-polypoid), as appropriate;
3) targeted biopsies of unsuspected neoplastic lesions (polypoid or non-polypoid).
All samples are collected in separate containers and then processed and stained by using standard methods.
All specimens are analysed by two pathologists with expertise in IBD, who are blinded to the endoscopic report. The pathologists classify the inflammatory activity of each specimen into the following categories: no inflammation, mild to moderate inflammation or severe inflammation. Neoplastic changes are classified according to the new Vienna classification as low-grade intramucosal, high-grade intramucosal and invasive neoplasia.
Non neoplastic lesions, including serrated and inflammatory polyps, are described according to current classifications.
Intervention code [1] 312367 0
Diagnosis / Prognosis
Intervention code [2] 312536 0
Treatment: Devices
Comparator / control treatment
The comparator is the standard protocol which uses white light endoscopy in the WLE arm. In the WLE arm, standard white light colonoscopy is performed using the Olympus CV-180 Evis Exera II system (Olympus Corp., Tokyo, Japan) for both intubation and extubation.
As in the FICE group, the large bowel is divided into 6 segments (caecum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum) and evaluated systematically in terms of bowel preparation, endoscopic disease activity (according to the Mayo subscore), the presence and classification of any mucosal lesion according to its morphology, size, location and judgement on suspected neoplasia.
In the WLE arm, areas suspected for neoplasia are defined as any mucosal irregularity, ulceration, polypoid or non-polypoid lesion that are not entirely consistent with chronic or active UC according to the usual clinical practice, as previously described.
The diagnostic performance of WLE is compared to that one of FICE by comparing the endoscopic evaluation (suspected or unsuspected neoplasia) with the histological diagnosis (reference test).
In both arms, three types of histological samples are obtained for the detection of neoplasia:
1) random biopsies of otherwise normal flat mucosa, obtained every 10 cm from the caecum to the rectum;
2) targeted biopsies or full endoscopic resection of visible suspected neoplastic lesions (polypoid or non-polypoid), as appropriate;
3) targeted biopsies of unsuspected neoplastic lesions (polypoid or non-polypoid).
Unsuspected neoplastic lesions are defined as any mucosal irregularity, ulceration, polypoid or non-polypoid lesion consistent with chronic or active UC
All samples are collected in separate containers and then processed and stained by using standard methods.
All specimens are analysed by two pathologists with expertise in IBD, who are blinded to the endoscopic report. The pathologists classify the inflammatory activity of each specimen into the following categories: no inflammation, mild to moderate inflammation or severe inflammation. Neoplastic changes are classified according to the new Vienna classification as low-grade intramucosal, high-grade intramucosal and invasive neoplasia.
Non neoplastic lesions, including serrated and inflammatory polyps, are described according to current classifications.
Control group
Active

Outcomes
Primary outcome [1] 307361 0
To analyze the rate of true positive lesions in the FICE arm compared with the WLE arm, defined as the number of lesions suspected for neoplasia according to the FICE or WLE criteria and confirmed as neoplastic by histology.
Timepoint [1] 307361 0
after histological evaluation (using histology as reference test for both arms) performed within 72 hours of colonoscopy
Primary outcome [2] 307772 0
To analyze the rate of false negative lesions in the FICE arm compared with the WLE arm, defined as the number of lesions not suspected for neoplasia according to the FICE or WLE criteria but which were diagnosed as neoplastic by histology.
Timepoint [2] 307772 0
after histological evaluation (using histology as reference test for both arms) performed within 72 hours of colonoscopy
Secondary outcome [1] 351607 0
nil
Timepoint [1] 351607 0
nil

Eligibility
Key inclusion criteria
- a previous confirmed diagnosis of UC according to clinical, endoscopic and histological data
- disease duration of at least 8 years since onset of symptoms
- no or mild clinical activity according to a maximum Mayo score of 4 points
- at least one visible, polypoid or non-polypoid lesion during the surveillance colonoscopy, according to the Paris classification
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- proctitis
- coagulopathy
- pregnancy
- melanosis coli
- previous colorectal surgery
- a previous colonoscopy in the last 3 months with unresected neoplasia
- massive pseudopolyposis (set as more than 30 polyps).

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
nil
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The diagnostic performance of FICE and WLE are evaluated by comparing the endoscopic evaluation (suspected or unsuspected neoplasia) with the histological diagnosis (reference test).
In the FICE arm, the interpretation of suspected neoplastic lesions is made using the new modified Kudo classification (FICE-NEW). The diagnostic performance of the classical Kudo classification (FICE-KUDO) is also calculated.
The analyses are performed per patient and per lesion. Sensitivity and specificity 95% CI are estimated applying the binomial exact method. Data are described using means and standard deviation, or medians and interquartile range, when appropriate. To test the difference between WLE and FICE-NEW, the z test are applied and the two tails probability reported.
Statistical analyses are conducted using IBM-SPSS for Windows 24th version and Excel 2013.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
17/09/2012
Date of last participant enrolment
Anticipated
Actual
18/01/2016
Date of last data collection
Anticipated
Actual
18/02/2016
Sample size
Target
100
Accrual to date
Final
100
Recruitment outside Australia
Country [1] 20830 0
Italy
State/province [1] 20830 0
Milan

Funding & Sponsors
Funding source category [1] 300621 0
Hospital
Name [1] 300621 0
ASST Fatebenefratelli Sacco, Gastroenterology Unit
Country [1] 300621 0
Italy
Primary sponsor type
Hospital
Name
ASST Fatebenefratelli Sacco
Address
via Giovanni Battista Grassi 74, 20157 Milan
Country
Italy
Secondary sponsor category [1] 300127 0
None
Name [1] 300127 0
nil
Address [1] 300127 0
nil
Country [1] 300127 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301409 0
Comitato Etico Milano Area 1
Ethics committee address [1] 301409 0
via Giovanni Battista Grassi 74, 20157 Milan
Ethics committee country [1] 301409 0
Italy
Date submitted for ethics approval [1] 301409 0
13/06/2018
Approval date [1] 301409 0
12/09/2018
Ethics approval number [1] 301409 0

Summary
Brief summary
Conventional colonoscopic surveillance with WLE in long-standing UC is based on multiple random biopsies and targeted biopsies of suspected neoplastic lesions, but its diagnostic yield has been criticised in favour of targeted dye-based chromoendoscopy. No controlled studies have analysed the diagnostic performance of virtual chromoendoscopy with FICE in this setting. However, the conventional Kudo classification which is used in non-IBD chromoendoscopy for screening of colorectal neoplasia has been criticized due to a high rate of false positives in IBD patients, where non neoplastic, mainly inflammatory, lesions are frequent and difficult to morphologically differentiate from neoplasic lesions. Therefore, a new modified Kudo classification has been developed, but not validated in clinical practice in controlled randomised trials.
This new classification for FICE specific for IBD is used for the first time in this prospective, parallel study, in which FICE is compared to WLE for the surveillance of long-standing UC.
Trial website
not available
Trial related presentations / publications
nil
Public notes
Ethical approval was requested after the collection of the endoscopic reports of all procedures performed during the study, in order to obtain the approval to perform the analysis of these data prospectively collected during the scheduled colonoscopies in our patients with endoscopic surveillance for UC.
The patients received standard colonoscopies independently of the trial primary outcome, as a part of their usual monitoring for long-standing disease. For this purpose, starting from the first patient enrolled in the study, they signed an informed consent form about colonoscopy, at the time of the scheduled procedure, according to our institutional guideline.

Contacts
Principal investigator
Name 86898 0
Dr Andrea Cassinotti
Address 86898 0
ASST Fatebenefratelli Sacco
via Giovanni Battista Grassi 74, 20157 Milan
Country 86898 0
Italy
Phone 86898 0
0030239042925
Fax 86898 0
Email 86898 0
[email protected]
Contact person for public queries
Name 86899 0
Andrea Cassinotti
Address 86899 0
ASST Fatebenefratelli Sacco
via Giovanni Battista Grassi 74, 20157 Milan
Country 86899 0
Italy
Phone 86899 0
00390239042925
Fax 86899 0
Email 86899 0
[email protected]
Contact person for scientific queries
Name 86900 0
Andrea Cassinotti
Address 86900 0
ASST Fatebenefratelli Sacco
via Giovanni Battista Grassi 74, 20157 Milan
Country 86900 0
Italy
Phone 86900 0
0030239042925
Fax 86900 0
Email 86900 0
[email protected]

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No Supporting Document Provided



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