Endoscopic Stenting Across the Papilla Versus the Leak Site to Treat Bile Leak

1.0 BACKGROUND 1.1) Biliary duct injuries are a relatively frequent complications of
hepatobiliary surgery, most commonly laparoscopic cholecystectomy1. Such injuries can
manifest clinically in a number of ways including biliary leakage, biliary stricture
formation, or associated infectious complications. Biliary leakage is the most common of
these postoperative complications and is estimated to be clinically significant in 0.8 to
1.1% of such surgeries.

Prior to the development of more sophisticated endoscopic interventions, repeat surgery was
often necessary for management of biliary leaks. However, advances in technique and
technology in gastrointestinal endoscopy have largely replaced surgery as a first line
intervention for biliary leaks. The generally accepted goal in the endoscopic management of
biliary leaks is to equalize the pressure between the biliary system and the duodenum, so as
to allow bile to flow into the lower pressure small bowel and thereby affording the leak time
to close.

How to best achieve this goal has been a topic of considerable interest. Randomized studies
have shown that endoscopic plastic biliary stent placement alone is highly efficacious and
equivalent to biliary stent placement with endoscopic biliary sphincterotomy. Thin (7
French[Fr]) and wide (10 French) diameter stents seem to have similar efficacy with regards
to leak resolution. Beyond these well-validated techniques, there are other variations in
clinical practice that are not supported by high-levels of evidence.

1.2) One area of variation is in whether the biliary stent should cross the papilla (with a
shorter stent) versus the site of the leak (with a longer stent).

2.0 OBJECTIVES AND PURPOSE

To assess whether placing a biliary stent across the leak versus across the papilla alone
improves the treatment of biliary leaks.

3.0 STUDY DESIGN:

The study will be a prospective randomized controlled trial. All patients undergoing
Endoscopic Retrograde Cholangiopancreatography (ERCP) for the treatment of bile leaks will be
eligible for inclusion (see section and initial collection form). During the ERCP if
cholangiogram demonstrates a leak, the patient will be randomized to either A) papillary
stenting strategy or B) crossing the leak site strategy. Please see the diagram below to
complement the written description of the study design.

A) In the papillary stenting strategy, regardless of where the leak is identified, a stent is
placed into the duodenal papilla and into the most distal (proximal to duodenum) portion of
the bile duct. The goal of this strategy is to use the stent to keep the papilla open,
thereby decreasing the pressure gradient and allowing for bile to flow preferentially into
the duodenum away from the leaking area. All stents in this strategy will be 7 Fr in diameter
and 5 cm long.

B) In the crossing the leak strategy (left), once the area of bile leakage is identified in
the biliary tree, a stent will be placed endoscopically across the leaking area. This
theoretically allows the underlying injured bile duct tissue to heal. The same diameter stent
(7Fr) as the papillary stenting strategy will be used but the length will vary in order to
bridge the leaking region (5-15cm).

The decision whether or not to perform sphincterotomy will be entirely determined by the
attending endoscopist and not part of the study. The 7Fr stents we are using may be easily
placed whether or not a sphincterotomy is performed. It will be recorded whether or not a
sphincterotomy was performed. All procedures evaluated in this study are done as part of
standard clinical care.

Following the initial ERCP intervention, the patients will receive routine post-procedural
care. They will have serial monitoring.

CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS

The primary outcome will be a successful resolution of bile leak with the ERCP strategy. This
will require will require 2 criterion:

A. No further leakage of bile on the follow up ERCP at 5 weeks. Resolution is confirmed by
the demonstration of no leaking of contrast from the prior leakage site on cholangiography.

B. No ERCP or other procedure has to be done between the initial ERCP and the 5 week ERCP to
treat the bile leak.

The proportion of patients in each randomized arm with the resolution of bile leak at 5 weeks
will be compared.

There will be several secondary outcomes:

A. Time from ERCP to removal of surgical drain (days) B. Time from ERCP to complete cessation
of output from drain (days) C. Presence of other significant findings on the 5th week
cholangiogram. These include bile duct stone or biliary stricture.

D. Requirement of surgery to treat the bile leak. E. Endoscopic complications of the 1st and
2nd ERCP including pancreatitis, bleeding perforation, cholangitis, and stent occlusion
within 5 weeks of initial or 2nd ERCP.

STATISTICAL CONSIDERATONS:

Patients will be randomized in a 1:1 fashion to either the papillary stenting strategy group
or crossing the leak stenting strategy group.

Dichotomous outcomes including primary outcome (successful resolution of the bile leakage)
will be compared using a Fischer's exact or chi squared test. Continuous baseline
charactersistics or outcomes will be compared using a Wilcoxan rank sum test or T test
depending on distribution. If imbalances occur, logistic regression models will be developed
to control for these imbalances as covariates in the primary outcome model. Secondary
outcomes involving time to clinical improvement in the arms will be compared using Cox
Regression analysis, allowing for the inclusion of covariates depending on degree of balance
of baseline characteristics. Analyses will be performed using SPSS v.23 and SAS v9; two-sided
p = 0.05 will be used for primary and secondary outcomes.

Based on a retrospective query of the 32 consecutive previous cases of bile leaks managed at
the Los Angeles County hospital using stents which did or did not bridge the leak we used
G*Power to estimate that a total sample size of 88 will be adequate (2 sided alpha of 0.05
and beta of 0.2) to detect an 20% difference (80 vs 99%) in successful resolution of bile
leak in the two groups. Based on data from the past 1 year at Los Angles County hospital it
was estimated that there would be a 5% 5-week attrition thus the sample size was determined
to be 92 patients.

Inclusion Criteria:

- Patients undergoing ERCP for the treatment of suspected acute bile leaks will be
eligible for inclusion (bile leaks felt to be complications of surgical intervention).
A patient is suspected to have an acute bile leak if the patient is referred within
two weeks following the original surgery.. Legally authorized representatives may
serve as surrogates to consent for inclusion in this study.

Bile leaks are suspected based on the following:

A) Persistent, significant drainage of bilious fluid from post-surgical drains following
hepatobiliary surgery or cholecystectomy,.

B) Compatible symptoms plus imaging findings on abdominal ultrasonography, computed
tomography, HIDA scanning, or MRCP of an abnormal intra-abdominal fluid collection in the
setting of recent hepatobiliary surgery.

Exclusion Criteria:

- Patients with bile duct transection (in which the duct has been totally severed into 2
parts) will be excluded as these are known to not be amenable to endoscopic therapy.
Further, suspected bile leaks of non-surgical etiology will be excluded from the study
(malignancy, trauma, spontaneous perforation, and other rarer causes). Bile leaks
suspected two weeks post surgery will also not be included. Additionally patients who
are pregnant, imprisoned, under age 18, unable to give informed consent, or have
undergone prior biliary diversion surgery will be excluded.