Urine Trypsinogen 2 Dipstick for the Early Detection of Post-ERCP Pancreatitis

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most
common, serious complication of ERCP. More than 500,000 ERCP procedures are performed from
which 25,000 cases of PEP occur in the U.S.A. annually. PEP accounts for significant
morbidity and health care expenditures. While symptoms of PEP arise immediately after ERCP,
they are non-specific. Consequently, unnecessary admissions of outpatients without PEP and
inadvertent discharge of outpatients with PEP from ERCP recovery are common. An accurate,
confirmatory test for diagnosis of PEP immediately after ERCP is lacking. Actim Pancreatitis
(Medix Biochemica) is a urine trypsinogen-2 dipstick test (UTDT) that uses trypsinogen-2 as a
biomarker for acute pancreatitis. Urine Trypisinogen-2 Dipstick test (UTDT) is a simple,
inexpensive test with promising preliminary data for accuracy for immediate diagnosis of PEP.
Prior studies of ITDT test characteristics lack rigorous scientific design.

Proposed Study and Methods:

Investigators will enroll 1825 ERCP outpatients at our institution in a prospective cohort
study. A pre-ERCP UTDT test and diagnostic UTDT 2 hours after the ERCP will be performed.
Patients with a positive baseline UTDT will be followed clinically as part of this study
without 2 hour testing. Care providers and study primary investigators will be blinded to the
2 hour UTDT results. Baseline, intra-procedure and recovery room clinical data will be
recorded. Diagnosis of PEP will be made blinded to the UTDT result. Admission status for PEP
will be assessed by review of records and phone/e-mail contact 5 days and 30 days after ERCP
procedure. Sensitivity and specificity of 2 hour post ERCP UTDT for the diagnosis of PEP will
be calculated.

Aims: 1) To determine the test characteristics of UTDT for the diagnosis of PEP 2 hours after
completion of ERCP. 2) To identify and describe patients with baseline UTDT positivity, in
whom this test offers limited utility.

Specific Aims:

Primary Aim 1.1 To determine the test characteristics (sensitivity and specificity) of the
UTDT for the diagnosis of PEP:

Hypotheses:

1. UTDT is a sensitive and specific test for the diagnosis of PEP for patients undergoing
ERCP.

2. At a cutpoint for a negative test of <50ug/L, UTDT will be accurate at 2 hours post ERCP
in patients whose baseline test is negative.

Secondary AIM:

1.1 To identify and describe patients with baseline UTDT positivity.

Hypothesis:

1) A subgroup of patients will demonstrate baseline positivity for UTDT. Based on previous
studies, the subgroup is likely to include patients with chronic inflammatory or obstructive
conditions of the pancreatic duct (pancreatic ductal adenocarcinoma, obstructive chronic
pancreatitis)1 This subgroup will represent a minority (<6%) of outpatients presenting for
ERCP. 1

Patients will be recruited in the pre-procedure area prior to ERCP. Only patients who would
be offered ERCP as part of their previously outlined care plan will be included in this
study. Patients will be screened according to inclusion/exclusion criteria described above.

Study Procedures

Informed Consent: Eligible patients will sign an IRB-approved, written informed consent to
verify their willingness to participate in this study. Informed consent will be obtained on
the day of their scheduled ERCP. Consent for the study will be obtained by one of the
participating endoscopists and/or a research assistant. Patients will receive a copy of the
signed and dated informed consent document. Original informed consent documents will be
maintained on-file. A note may be made in the subject's medical record regarding
participation in the research study. Once consented and enrolled into the trial, patients
will be issued a unique identifier for the purposes of data entry.

Pre-Procedure data and sample collection: After obtaining informed consent, patients will be
asked health questions prior to ERCP to assess and quantify current and prior alcohol use,
current and prior tobacco use, quantification of narcotic use and quantification of
non-steroidal anti-inflammatory drug (NSAID) use. Narcotic and NSAID use in the 7 days prior
to ERCP will be recorded.

Pain scores will be collected at baseline and post ERCP. Subjects will be shown the study
pain scale (appendix 1) and asked to pick a number on the scale to rate their pain at
baseline and 2-3 hours (+ or - 15 minutes from time of Scope out) post ERCP.

Data will be collected on the indication of ERCP, history of acute pancreatitis, recurrent
acute pancreatitis, or chronic pancreatitis, history of pancreatic surgery, presence of
peri-pancreatic fluid collection and prior sphincterotomy. Prior imaging may be reviewed for
the presence of pancreatic mass and/or pancreatic duct obstruction.

Baseline tests may be obtained prior to undergoing ERCP including serum pancreatic enzymes
(amylase, lipase), serum liver enzymes, and coagulation profile as is the standard for our
endoscopy unit. Available outpatient laboratory data within 48-72 hours of ERCP will be
reviewed. Lack of baseline labs will not be a criterion for exclusion from the study.

Patients with baseline, pre-procedure positivity for UTDT (> or = 50ug/L) will undergo all
study procedures as outlined below with the exception of 2 hour UTDT level.

Patients who are unable to provide a urine sample for post ERCP testing will still be
included in the final analysis of baseline UTDT level. Subjects who are excluded due to the
inability to access the ampulla at ERCP will also still be Included in the final analysis of
baseline UTDT level.

Intra-procedural Data Collection: Patients will undergo ERCP as intended. All clinical
decisions and endoscopic interventions prior to, during and after ERCP will be performed at
the discretion of the treating physician. Data on duration of procedure, placement of
pancreatic or biliary duct stents, ERCP maneuvers deployed for cannulation (e.g. needle
knife), findings associated with chronic pancreatitis (e.g pancreatic duct stones),
pancreatic duct leak, peri-procedural NSAIDs administration, amount of intraoperative IV
fluids and any immediate complications including perforation, bleeding, or hemodynamic
instability will be recorded.

Immediate Postoperative Care, Data and Sample collection: At our institution, patients
typically remain in the recovery area for 2-3 hours after completion of the ERCP. This time
interval in part is related to two-phase recovery after general anesthesia, which is the
standard sedation approach for ERCP outpatients. Patients will remain for recovery after ERCP
for at least two hours for a post procedure observation period and collection of UTDT result.
During this time, a urine sample for UTDT testing will be collected at 2 -3 hours (+ or - 15
minutes from time of Scope out) after ERCP by the study research technician. Patients, study
investigators, ERCP care team, nursing staff will be blinded to the results. The statistician
will be blinded to the urine trypsinogen-2 test during statistical analysis.

The decision to admit/monitor the patient will be left to the discretion of the endoscopist /
ERCP care team and will occur blinded to the UTDT results. Data regarding symptoms (e.g.
nausea/vomiting, abdominal pain scores), narcotic administered for pain symptoms, duration in
recovery, volume of IV fluids administered in recovery and decision to admit or discharge
will be recorded.

Patients will receive a risk assessment for post-ERCP pancreatitis. This will calculated and
tracked for the purposes of this study.

Follow Up Data Collection: Patients who are hospitalized will have serum amylase and lipase
drawn after the ERCP procedure per standard clinical protocol timelines. Patients who are
discharged to home/other after ERCP will be contacted by telephone and/or email 5 days (+ 4
days or - 2 days) and 30 days ( + or - 10 days) after the ERCP by a study team member to
determine whether PEP occurred and was managed outside of our institution. Patients will be
asked about ERCP procedure complications such as infection, bleeding, perforation and death.
This contact may be made by phone, email or text message. Subjects will be asked for their
preferred method of contact at study enrollment. Records confirming post ERCP pancreatitis
will be requested if the patient is admitted and/or initially managed at an outside
institution for PEP. Patients without hospitalization for symptoms attributable to post ERCP
pancreatitis will be classified as not having developed PEP. Records pertaining to any ERCP
procedure complications will also be requested.

PEP will be defined by the primary ERCP team. The ERCP team will be blinded to the UTDT
result when determining PEP.

Clinical data regarding volume of IV fluids administered at 24, 48 hours of admission and
severity of pancreatitis (based on Cotton criteria, Modified Marshall Score and graded
presence of necrosis) will be assessed recorded for all patients admitted with PEP.

Inclusion Criteria:

1. 18 years of Age

2. Undergoing Outpatient ERCP

Exclusion Criteria:

1. Unwillingness or inability to consent for the study

2. Acute pancreatitis on presentation or within 1 month

3. Recent ERCP (i.e. within 1 month)

4. Amylase or Lipase elevation greater than 2 x upper limit of normal within 7 days prior
to ERCP

5. Stage 3 or 4 renal disease and/or oliguria

6. Inability to access the ampulla at ERCP attempt (e.g. gastric outlet obstruction)

7. Unable to provide baseline urine sample