Urine Trypsinogen 2 Dipstick for the Early Detection of Post-ERCP Pancreatitis
Phase: NA
Conditions: Post-ERCP Acute Pancreatitis
Sponsor: Indiana University

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Urine Trypsinogen 2 Dipstick for the 
 Early Detection of Post-ERCP Pancreatitis 
 
 
 
Principal Investigator: Jeffrey Easler, MD 
 
 
Assistant Professor of Medicine 
IU School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
 
 

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1.0 
Background 
 
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis 
(PEP) is the most common, serious complication of ERCP and accounts for a 
significant proportion of morbidity, mortality, and health care expenditures 
accrued in the post procedure setting.3-5 Large studies have shown that PEP 
occurs approximately 4-10% procedures with a mortality rate up to 0.7%.6-8  
 
ERCP is most often performed in the outpatient setting with the expectation for 
patients to be discharged home the same day of the procedure.  Patients are 
often observed for symptoms of complications after procedures. Data suggests 
prolonged observation (4-6 hours) captures symptoms indicative of a 
complication in 80% of these patients and consequently prevents un-intended 
discharge with subsequent hospitalizations.9 However, a standardized 
observation protocol for this interval of time is not practical at ERCP centers. 
Given 11% of patients require admission after ERCP and fewer patients 
ultimately are verified as having complications; the majority of centers do not 
have a 4-6 hour observation protocol for post-ERCP care. Moreover, such a 
protocol for all ERCP outpatients would create unnecessary costs, strain on 
recovery room resources (staff, nursing and space), and significant 
inconvenience for patients.10 While several factors including peri-procedural pain, 
history of pancreatitis, and performance of sphincterotomy predict need for 
hospital admission after ERCP, no single clinical factor has proven accuracy. 
Complex models for predicting admission are cumbersome and struggle to 
achieve a AUC ROC beyond 0.90 for predicting need for admission, much less 
post ERCP pancreatitis.11 However, while same-day discharge after ERCP is 
widely utilized and relatively safe, it has been associated with readmissions.9 We 
have reported rates of inadvertent discharge and readmission of outpatients with 
post ERCP pancreatitis to occur in up 25%. 12 A recent review of patients 
enrolled in a prospective study, at risk for post ERCP pancreatitis demonstrated 
that rate of inappropriate discharge may occur in over 50% of patients. This delay 
in recognition may be clinically important as this represents a missed opportunity 
for timely interventions. For instance, early intravenous fluid hydration after the 
development of pancreatitis can reduce the morbidity and mortality at least 3-
fold.12,13 
 
By definition, a confirmatory diagnosis of post ERCP pancreatitis requires an 
assessment well after the ERCP procedure. Post ERCP pancreatitis is defined 
by the presence of two of three criteria: characteristic abdominal pain, elevation 
in serum lipase or amylase three times greater than the upper limit of normal 
assessed 24 hours following ERCP, and characteristic findings of acute 
pancreatitis on cross sectional imaging.14.15 Consequently, PEP is confirmed for 
the majority of patients with PEP symptoms in the inpatient setting a day or more 
after the ERCP procedure. This delay in confirmation requires empiric admission 
and treatment for PEP for many patients that develop suspicious symptoms after. 
Early measurement of serum amylase and lipase levels have been studied; 
however offer limited accuracy and are by no means practical as a rapid, bedside 

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assessment is not possible given time need for serum collection, transport and 
processing.16-19 Also, elevated serum pancreatic enzymes are common in 
asymptomatic patients after ERCP ( up to 75% of patients) with confirmed clinical 
pancreatitis being much less common.20 Therefore, an early diagnostic tool is yet 
to be identified.   
 
Trypsinogen is the main proteolytic proenzyme in pancreatic secretions. 
Activation of trypsinogen and other proenzymes is part of the initial pathobiology 
of acute pancreatitis. Trypsinogen-2 is an isoenzyme that peaks at 6 hours with a 
median level of 1790 ug/L in patients with pancreatitis, compared to 3.6ug/L in 
patients without.21,22 The isoenzyme trypsinogen-2 is both preferentially elevated 
in pancreatitis23 and poorly reabsorbed in the renal tubules24, making this a 
potentially useful early diagnostic marker for acute pancreatitis. In contrast, 
serum amylase peaks at 12 hours and lipase 24 hours after pancreatitis. While 
amylase and lipase are currently the established diagnostic tests for the 
diagnosis of PEP; the delay in physiologic peak is likely the reason their utility as 
an early marker for PEP is limited. A urine trypsinogen-2 dipstick (UTDT) is 
commercially available for purchase ($3.18/unit) with promising studies for 
accuracy of its cut point for pancreatitis. Trypsinogen-2 urine testing for PEP 
potentially offers several advantages including an earlier peak concentration, 
ease of deployment (at the bedside), interpretation (positive/negative test strip) 
and a low cost. 
 
Actim Pancreatitis (Medix Biochemica) is a urine trypsinogen-2 dipstick test 
(UTDT) that uses trypsinogen-2 as a biomarker for acute pancreatitis. At a 
cutpoint of 50 ug/L it has been assessed in 3 small prospective studies for the 
diagnosis of PEP.1,25,26 Kemppainen et al.25 demonstrated an adequate 
sensitivity (81%) and specificity (97%) with the UTDT for diagnosing PEP at 6 
hours after ERCP in 106 patients. Limitations include the impracticality of a 6 
hour testing interval after ERCP and unclear inclusion/exclusion criteria. 
Sankaralingam et al.26 demonstrated a very high sensitivity (100%) and 
specificity (96%) with the UTDT for diagnosing PEP at 4 hours after ERCP, but 
was limited by the small sample size of 29 patients. Tseng et al.1 demonstrated a 
sensitivity of 85%, specificity of 97%, and a superior accuracy of 96% compared 
to serum amylase/lipase for the diagnosis of PEP at 3 hours after ERCP in 150 
patients, but limitations include a high number (100) of excluded patients. A 
meta-analysis of these available studies calculated an overall sensitivity of 86%, 
specificity of 94% and area under the operator curve of 0.92. 27 However, as 
mentioned above, the published studies suffer from variation in timing of UTDT, 
inclusion/exclusion criteria, and lack of rigorous study design with adequately 
powered sampled size. Consequently, further study is needed to assess its 
accuracy of UTDT in the post ERCP setting. 
 
The primary study objective is to determine the test characteristics of UTDT for 
the diagnosis of PEP 2 hours post ERCP.   
 

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2.0 
Rationale and Specific Aims 
 
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. 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: 
We 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. 
 
 
 
 

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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 
 
 
3.0 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
18 years of Age 
 
Undergoing Outpatient ERCP 
Exclusion Criteria 
Unwillingness or inability to consent for the study 
 
Acute pancreatitis on presentation or within 1 month 
 
Recent ERCP (i.e. within 2 Weeks) 
 
 
 
 Known stage 3B or higher renal disease (GRF less than 45) 
and/or oliguria per Pre-_ERCP labs or outside hospital labs within 
7 days prior to the 2-hour Post- ERCP urine collection procedure. 
 
History of renal transplant 
 
Consumed supplemental Biotin within 7 days prior to enrollment 
 
Total Pancreatectomy 
 
MRCP with secretin within 48 hours prior to ERCP  
 
Inability to access the ampulla at ERCP attempt (unable to attempt 
cannulation of the ampulla or minor papilla, e.g. gastric outlet 
obstruction)  
 
Unable to collect Baseline or Post -ERCP urine sample. 

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4.0 
Enrollment/Randomization 
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.  
 
 
5.0 
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. 
Abdominal 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 abdomial pain at baseline and post ERCP. Amount and 
type of IV fluids given Pre-ERCP may be collected. Post- ERCP Pain scores will 
be attempted 2 -3 hours Post –ERCP, but if necessary may be collected prior to 
the 2 hours Post –ERCP time point up to the time of patient discharge by the 
study research technician.   
 
 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. Data will 
also be collected to note if subjects underwent an endoscopic ultrasound with 
fine needle aspirate during the same visit as baseline ERCP. 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. If Pre- ERCP baseline lab 

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results are not yet available at the time of the 2 hour Post- ERCP urine test this 
will not be a criterion for exclusion from the study.  If the GFR is less than 45 
after the 2 hour Post ERCP urine collection has been completed, these patients 
will not be contacted for the 5 day and 30 day follow-up call and their data will not 
be included in the final analysis.      
 
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 at baseline or for Post- ERCP 
testing will be considered a study screen failure. Subjects who provided a 
baseline urine sample 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 all ERCP  
procedure findings and interventions including, 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 and 
any immediate complications including perforation, bleeding, or hemodynamic 
instability will be recorded. Amount and type of intraoperative IV fluids may be  
collected. 
 
 
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 may remain for recovery after ERCP for two hours for a post procedure 
observation period and collection of UTDT result. During this time, urine sample 
collection for UTDT testing will be attempted 2 -3 hours Post –ERCP, but if 
necessary may be collected prior to the 2 hours Post –ERCP time point up to the 
time of patient discharge 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 hour test during statistical 
analysis.  
 
 
 
 
 

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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), anti –emetic 
use and narcotics administered for pain symptoms, duration in recovery and 
decision to admit or discharge will be recorded. Volume and type of IV fluids 
administered in recovery may also be collected. 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 and type 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. 

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Figure 2: Study Flow Diagram for Outpatient ERCP Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ERCP as Planned, 
Prospective Follow Up: 
 Intra-procedure Data Collection 
Post procedure Data Collection 
Follow Up Phone/E-mail Contact 
ERCP as Planned 
Absence of Exclusion Criteria 
Intra-procedure Data 
Collected 
Baseline UTDT and Urine Sample 
No, D/C Home 
 
Admission per ERCP care team (blinded to UTDT result)? 
2 Hr UTDT and Urine Sample 
Follow Up Procedures: 
1) Clinical Follow Up and Data collection for Hospital Course if Admitted 
2) Day 5 phone/email contact if outpatient 
3) Day 30 phone/email if outpatient 
Patients Meets Inclusion Criteria 
Informed Consent, 
Pre-procedure Health Questions 
Baseline 
UTDT Positive 
UTDT Negative 
Yes 
 

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6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
  
 An adverse event will be considered a complication that occurred due to the 
collection of urine for testing or administration of health questions. Associated 
adverse events will be reported to the IRB per the IRB reporting criteria.  
 
 
  Study Withdrawal/Discontinuation 
 
Patients may withdraw from the study at any time upon their request. Data collected 
prior to their withdrawal may still be used in the final analysis.  
 
7.0 
Statistical Considerations 
 
Descriptive statistics will be performed for all continuous variables (mean ± 
standard deviation for normally distributed variables and median ± interquartile 
range for non-normal variables) and categorical variables (count and proportion).  
Categorical outcomes will be analyzed using Χ2 test or Fisher’s test for small 
samples.  Comparison of group outcomes will be analyzed using Student’s t test 
for normally distributed data and nonparametric Wilcoxon-Mann-Whitney test for 
data that violate the normality assumption. Univariate logistic regression analysis 
will be used to identify predictors of interest and multiple predictor analysis will 
estimate effects adjusted for covariates.  
Diagnostic test characteristics including sensitivity, specificity, positive predictive 
value, negative predictive value, and accuracy will be assessed for the UTDT in 
diagnosing PEP and for different severity levels of PEP. In addition, the UTDT 
will be assessed in predicting additional outcomes as outlined above.  
 
Specific pre-procedure, intra-procedure, or post-procedure characteristics as 
noted above will be assessed in univariate and multivariable regression models 
to assess whether they contribute to the inaccurate diagnosis of PEP based on 
the UTDT. Similar multivariable regression analysis will be done to assess for 
additional risk factors of PEP. 
 
A cost analysis will also be performed to determine the number of UTDT strips 
needed to prevent one inadvertent discharge of a patient with PEP. 
 
 
8.0 
Privacy/Confidentiality Issues 
 
Each subject will be assigned a unique study number.  Study material will be kept 
on a limited number of password protected computer stations, and paper records 
will be kept in locked cabinets/offices in areas with limited public access.  Study 
material will be retained until seven years after study closure, at which point 
records will be destroyed, and hard drives containing study data will be erased. 

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9.0 
Follow-up and Record Retention 
We anticipate a 30-month enrollment period to achieve our estimated sample 
size.  We expect a 30- 40 day period from the onset of patient enrollment to 
completion of follow-up.  This does not include final statistical analysis and 
interpretation.  Data collected for research purposes will be retained for seven 
years after the study is closed.  At that time, all paper and electronic records 
pertaining to this study will be destroyed. 
 
 
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Tseng CW, Chen CC, Lin SZ, Chang FY, Lin HC, Lee SD. Rapid urinary trypsinogen-2 test 
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Appendix 1 
 
 
 
 
 
 
Pain Scale