Laser Versus Mechanical Lithotripsy of Bile Duct Stones

TITLE: Randomized trial of combination of cholangioscopic guided laser lithotripsy and
conventional mechanical versus conventional mechanical methods for the endoscopic removal of
large bile duct stones

STUDY ARMS: Laser guided lithotripsy and conventional methods vs conventional methods alone
alone

BACKGROUND AND HYPOTHESES: Large bile duct stones are challenging to remove at time of
endoscopic retrograde cholangiopancreatography (ERCP) and classically have required the
utilization of mechanical baskets and balloons. These maneuvers may be associated with bile
duct trauma, bleeding, pancreatitis, and the requirement for additional procedures. Many
patients require multiple sessions using conventional mechanical approaches. A recent
prospective audit of patients undergoing ERCP during the past year at LAC+USC Medical Center
indicates that of approximately 500 procedures more than 250 were for bile duct stones and
100 (40%) required multiple procedures and stent placement. Scheduling challenges and
limited resources make it difficult for many of these patients to return for stent changes
and increases the risk of complications including cholangitis.

Cholangioscopy enables therapeutic intervention including intracorporeal electro-hydraulic
and laser lithotripsy for biliary stone disease with favorable efficacy and safety. Direct
visualization by cholangioscopy minimizes the risk of laser related bile duct injury and is
potentially much less traumatic and more efficacious than traditional mechanical approaches.

A recent 15 center prospective clinical cohort study demonstrated a high success rate, 89%,
and low rate of complications, 7.5%, for the single user cholangioscopy system. In a group
of patients who underwent stone removal using the cholangioscope introduced laser or
electrohydraulic systems the success even higer 92% and complications potentially lower.
Available literature indicates that in cases in which ERCP with mechanical lithotripsy is
required the complication rate is approximately 5-12% and risk of cholangitis is 1.4-4%. If
ERCP is performed with laser lithotripsy in addition to conventional mechanical methods the
complications rate is 6.1% and risk of cholangitis is 2.4%. Cholangioscopy guided laser
treatment to enhance stone removal is currently widely used by gastroenterologists at
academic centers including the hospitals of the University of Southern California as well as
in leading community centers such as the Kaiser Permanente Hospitals of Southern California.
While it is a standard of care procedures for large bile duct stones studies directly
comparing its efficacy to traditional mechanical approaches are needed.

The long term goal of this project is to assess whether the addition of cholangioscopy
guided laser lithotripsy facilitates the removal of large bile duct stones at time of ERCP.
Previous prospective studies have demonstrated that the technology is safe and method
feasible.

The goal of this pilot study will be to determine the effect size of the difference between
laser lithotripsy vs currently available methods on stone removal with the aim of estimating
sample size for a fully powered randomized trial. Additional aims will be to assess for
procedure duration, cost, and the number of additional procedures required for stone
clearance. Complications, hospitalization related to stent dysfunction (frequently placed
between lithotripsy sessions), and eventual need for surgery will also be outcomes. Healing
time and time prior to return to work will also be outcomes.

OBJECTIVES AND PURPOSE: This is a pilot project to measure the effect of cholangioscopy
guided laser lithotripsy in addition to the currently available methods. Large multicenter
prospective studies have already demonstrated that the technique is safe and feasible. The
overall aims are to assess whether laser lithotripsy combined with conventional methods
enhances the rate, efficacy, and cost of stone removal compared to conventional methods
including mechanical lithotripsy.

STUDY DESIGN: The study will be a prospective single blind randomized control trial. All
patients presenting with choledocholithiasis will be considered for the study. If their
ultrasound, computed tomography, and magnetic resonance imaging demonstrates a large stone
(>1cm) or biliary dilatation (>1cm) and they do not fulfill the exclusion criterion they
will be consented for the study. Randomization will be stratified based on whether or not
the procedure is a first or repeat ERCP.

At that point the full time study coordinator will use a computer generated randomization
schedule with concealed allocation to generate a 2:1 assignment (laser versus conventional).

At the time of the cholangiogram, which is done immediately prior to stone removal, an
assessment will be made by the attending endoscopist to confirm that the stone is greater
than 1cm in size.

If confirmed, stone removal will then be attempted using laser lithotripsy using a holmium
probe introduced using a single operator cholangioscopy system versus conventional methods.
Conventional methods including mechanical baskets and balloon may also be used to remove
debris following laser lithotripsy in the laser lithotripsy group. The cholangioscope will
not be introduced in those randomized to mechanical lithotripsy and conventional methods
alone will be employed. Stents will be placed at the discretion of the attending endoscopist
in both groups.

Multiple ERCP procedures may be required to remove the stones. Patients will remain in their
assigned treatment groups during subsequent studies. Whether the stones can be successfully
removed by the end of the course of therapy and the number of ERCP required for stone
clearance are outcomes of interest.

The patients will be blinded to whether or not the cholangioscope was used.

The patient will be followed clinically by the principal investigator assisted by a full
time study coordinator daily on the inpatient basis and by a bimonthly phone call on the
outpatient basis until 2 months after complete clearance of stones from the bile duct has
been confirmed.

DEVICE INFORMATION: The following devices will be used:

Spyglass Direct Visualization System Coherent Holmium Laser VP

Spyglass Direct Visualization System is made by Boston Scientific and the Coherent Holmium
Laser VP are produced by Convergent Laser Technologies but is rented by Mobile Med.

All devices used in the study are approved by the FDA for this indication.

SELECTION AND WITHDRAWAL OF SUBJECTS

See Inclusion/Exclusion Criterion

STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME

Patient will be stratified by whether or not they have undergone a prior ERCP or whether the
procedure in question is their first ERCP.

The descriptive factors that will be recorded for each patient enrolled in the study
include: age, race, gender, and comorbidities at time of presentation.

Following stratification by whether or not they have undergone an ERCP, a computer generated
randomized schedule with concealed allocation will generate a 2:1 assignment for the
patient, placing them into either the intervention arm (laser lithotripsy using a holmium
probe introduced using a single operator cholangioscopy system) or the control arm
(conventional methods). As this is a pilot study, designed to gauge the extent of treatment
effect and power a larger study 60 patients will be enrolled.

ASSESSMENT OF EFFICACY AND SAFETY

Side effects/Toxicities to be monitored.

Patients in either group may develop post procedure pain, pancreatitis, cholangitis, bile
duct injury, or bleeding.

Adverse Event Reporting:

All adverse events will be reported to the principal investigator. The study physicians and
coordinator will meet monthly to review these. Adverse events will be reported to the IRB,
Data Monitoring Committee, and included in publications.

Data Monitoring Committee:

The study physicians and coordinator will meet monthly to review any adverse events. After
no more than 50 patients have been collected all data will be reviewed by a monitoring board
including the PI, coinvestigators, study coordinator, and two senior physicians who are part
of the clinical gastroentrology faculty

CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS

Endpoint Definitions The principle endpoint will be the endoscopic clearance of ductal
stones during the course of therapy. Secondary endpoints will be to assess for procedure
duration, cost, and the number of procedures required for stone clearance. Complications,
hospitalization related to stent dysfunction (frequently placed between lithotripsy
sessions), and need for bile duct surgery will also be endpoints.

STATISTICAL CONSIDERATIONS

Descriptive statistics will be performed for all patient characteristics and pre-treatment
clinical measures, and comparisons between groups made to ensure balanced. Any variables
significantly different between groups will be included in further models as covariates.
Intent to treat will be tested for the primary outcome of clearance of ductal strons will be
tested using Fisher's exact chi-squared to compare the rate of clearance between groups.
Results from this test will allow for estimation of sample size for a fully powered clinical
trial. This same method will be used to test dichotomous secondary outcomes: hospitalization
related to stent dysfunction and further bile duct surgery. Other secondary aims, which
include the count of complications, healing time, and time prior to returning to work will
be tested using Poission regression. Total cost will be compared using independent t-tests.
Alpha = 0.05 for all analyses. Additionally, because this is a pilot study, effect sizes
will be computed to determine potential clinical relevance of outcomes. Statistical analyses
will be performed by biostatisticians at the Biostatistical and Bioinformatics Resource
Group within the SC CTSI.

Inclusion Criteria:

- Bile duct stone >1cm demonstrated on ultrasound, computed tomography, or magnetic
resonance imaging

- Bile duct dilatation >1cm

Exclusion Criteria:

- Biliary, gallbladder or pancreatic malignancy

- Pregnant

- Prior biliary diversion surgery

- Under age 18

- Unable to give informed consent