Registry Trial to Determine pCLE Image Interpretation Criteria and Preliminary Accuracy for PSC Biliary Strictures

pCLE (probe based confocal laser endomicroscopy) is an innovative technology, which provides
real- time, microscopic imaging of tissue at the cellular level via a small diameter probe.
The pCLE probe has been designed to fit into standard endoscopes and has been studied
extensively in the gastrointestinal tract for real time diagnosis of conditions such as
Barrett's Esophagus (BE), biliary strictures and endoscopic mucosal resection of colorectal
lesions. Over 300 publications have documented the safety and efficacy of pCLE in the GI
tract.

Ductal pathologies are presently diagnosed, characterized and sometimes treated during
Endoscopic Retrograde CholangioPancreatography (ERCP) in which a catheter is advanced through
the endoscope and inserted into the biliary or pancreatic duct, where a contrast agent is
injected and X-rays are taken. But multiple tissue sampling (biopsies or brushing) requires
considerable time and technical expertise with the risk of losing guide wire access across
the biliary or pancreatic stricture. Tissue sampling techniques have shown to lead to highly
specific results for diagnosing a malignant tumor (100%), but with low sensitivity (45- 75%).
Furthermore, pancreatitis is one common and serious complication of ERCP, occurring in 5-7%
of cases.

The CholangioFlex confocal miniprobe was specifically designed to explore bile and pancreatic
ducts (diameter ranging from 0.9 to 2.5mm). Intended to be used via an ERCP procedure, it can
be passed through the operating channel of a cholangioscope or inserted through a standard
catheter.

Dr. Meining examined a small series of 14 patients with biliary strictures and Mucosal
imaging was performed with a miniaturized confocal miniprobe introduced via the working
channel of a cholangioscope. Thereafter, targeted biopsies were taken from the same regions.
All strictures could be reached, leading to a pCLE accuracy of 86%, sensitivity of 83%, and
specificity of 88%. The respective numbers for standard histopathology were 79%, 50%, and
100%.

Dr. Giovannini evaluated the diagnostic accuracy of pCLE for cholangiocarcinoma detection, on
37 patients with biliary or pancreatic strictures. The CholangioFlex confocal miniprobe was
introduced in the bile or pancreatic ducts using a catheter, and strictures were imaged.
Tissue sampling was then performed at the same location. In this study, the overall pCLE
accuracy was 86% (vs. 53% for histology), the sensitivity and specificity of pCLE were 83%
and 75% respectively compared to 65% and 53% for histology.

An observational prospective, "Cellvizio ERCP registry", was conducted which enrolled 102
patients with indeterminate or suspected biliary and/or pancreatic strictures, mass or
neoplasm indicated for ERCP and/or cholangioscopy. The purpose of this multicentric trial was
to compare the combination of Cellvizio with ERCP imaging to ERCP alone, using the Miami
Classification (a set of image interpretation criteria developed to differentiate benign from
malignant strictures). Physicians could choose whether to deliver the CholangioFlex confocal
miniprobe through a cholangioscope or a catheter. Patients were followed until the physicians
were able to confirm malignancy through histopathology or for a year if repeat tissue
sampling led to benign results.

There were no pCLE-related adverse events in the study and 89 patients were finally
evaluable, of whom 40 were proven to have cancer. The sensitivity, specificity,
positive-predictive value, and negative- predictive value of pCLE for detecting cancerous
strictures were 98%, 67%, 71%, and 97%, respectively,compared with 45%, 100%, 100%, and 69%
for index pathology. This resulted in an overall accuracy of 81% for pCLE compared with 75%
for index pathology. Accuracy for combination of ERCP and pCLE was significantly higher
compared with ERCP with tissue acquisition (90% vs. 73%; P .001).

Due to the relatively low specificity, a group of investigators reviewed the false positive
cases of the registry and new criteria characterizing inflammatory strictures, which are
known to present pCLE features very similar to malignant strictures. 60 pCLE along with final
diagnosis were reviewed by 3 pCLE-experienced gastroenterologists who refined the already
existing Miami classification by devising novel pCLE criteria for the characterization of
inflammatory strictures. The 4 criteria devised for diagnosing dysplasia in BE were: 1)
Multiple thin white bands, 2) Dark granular pattern with scales, increased space between
scales, thickened reticular structures. These criteria were then reviewed and validated in
consensus by 6 pCLE experts using a set of 40 pCLE sequences. The overall accuracy was 82.5%
vs. 81% for the prospective registry (n=98), resulting in a sensitivity of 81.2% (vs. 98% for
the prospective study) and a specificity of 83.3% (vs. 67% for the prospective study). The
corresponding interobserver agreement was fair (k=0,37). This new criteria are currently
tested in a prospective multicentric trial, aiming at evaluating the impact of pCLE on the
management of patient with indeterminate biliary stricture.

The purpose of the present pCLE Registry will be to study a condition with a high unmet
medical need and preliminary differentiating criteria: Primary sclerosing cholangitis.

This condition offers challenges for the diagnostic pathway and could benefit from direct
visualization of the tissue via a minimally invasive ductal approach.

Inclusion Criteria:

- Male or female > 18 years of age

- Clinically Indicated for ERCP and/or cholangioscopy for PSC stricture

- Inclusion of patients either previously stented or not

Exclusion Criteria:

- Subjects for whom ERCP procedures are contraindicated

- Known allergy to fluorescein dye

- Presence of well-defined intrahepatic mass

- Ascending cholangitis, febrile at time of procedure

- Pregnancy