Preoperative Endoscopic Biliary Drainage With Self Expanding Metal Stents (SEMS) vs. Direct Surgical Resection for Patients With Severe Obstructive Jaundice
Phase: NA
Conditions: Pancreatic Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

1 
THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
PREOPERATIVE ENDOSCOPIC BILIARY DRAINAGE WITH SELF EXPANDING METAL 
STENTS (SEMS) VS. DIRECT SURGICAL RESECTION FOR PATIENTS WITH SEVERE 
OBSTRUCTIVE JAUNDICE 
Principal Investigator: 
Thomas Kowalski, MD  
Gastroenterology and Hepatology 
132 S. 10th Street 
Suite 585 
Philadelphia, PA 19107  
(215) 955-8900 
Harish Lavu, MD 
Hepatopancreaticobiliary Surgery 
1100 Walnut Street 
5th Floor 
Philadelphia, PA 19107 
(215) 955-9402  
Co-Investigator(s): 
David Loren, MD 
Ali Siddiqui, MD 
Haroon Shahid, MD 
Benjamin Leiby, PhD 
Gastroenterology and Hepatology 
132 S. 10th Street 
Suite 585 
Philadelphia, PA 19107  
Funding Sponsor: 
This is a non-funded study 
Regulatory Sponsor: 
IND Number: 
Study Product: 
Protocol Number: 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON UNIVERSITY.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
version 2/01/2017
16D.759

2 
Table of Contents 
Study Summary ............................................................................................................................................. 5 
1 
Introduction .......................................................................................................................................... 6 
1.1 
Specific Aims and Hypothesis ..................................................................................................... 6 
1.2 
Background .................................................................................................................................. 6 
1.3 
Study Therapy ............................................................................................................................. 6 
1.4 
Preclinical Data ........................................................................................................................... 6 
1.5 
Clinical Data to Date ................................................................................................................... 6 
1.6 
Dose Rationale and Risk/Benefits ............................................................................................... 7 
2 
Study Objectives .................................................................................................................................. 7 
2.1 
Primary Objective ........................................................................................................................ 6 
2.2 
Secondary Objective(s)................................................................................................................ 6 
3 
Study Design ........................................................................................................................................ 7 
3.1 
General Design ............................................................................................................................ 7 
3.2 
Primary Study Endpoints ............................................................................................................. 7 
3.3 
Secondary Study Endpoints ......................................................................................................... 7 
3.4 
Primary Safety Endpoints ............................................................................................................ 8 
4 
Subject Selection and Withdrawal ....................................................................................................... 8 
4.1 
Inclusion Criteria ......................................................................................................................... 8 
4.2 
Exclusion Criteria ........................................................................................................................ 8 
4.3 
Gender/Minority/Pediatric Inclusion for Research ...................................................................... 8 
4.4 
Subject Recruitment and Screening ............................................................................................. 8 
4.5 
Early Withdrawal of Subjects ...................................................................................................... 9 
4.5.1 
When and How to Withdraw Subjects .................................................................................... 9 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 9 
5 
Study Drug/Therapy ............................................................................................................................. 9 
5.1 
Description .................................................................................................................................. 9 
5.2 
Treatment Regimen ..................................................................................................................... 9 
5.3 
Risks ............................................................................................................................................ 9 
5.4 
Method for Assigning Subjects to Treatment Groups ................................................................. 9 
5.6 
Subject Compliance Monitoring ................................................................................................ 10 
5.7 
Prior and Concomitant Therapy ................................................................................................ 10 
5.9 
Blinding of Study Drug ............................................................................................................. 11 
6 
Study Procedures ................................................................................................................................ 12 
6.1 
Study Visit Schedule ................................................................................................................. 12 
7 
Statistical Plan .................................................................................................................................... 12 
7.1 
Sample Size Determination ....................................................................................................... 12 
7.2 
Statistical Methods .................................................................................................................... 12 
7.3 
Subject Population(s) for Analysis ............................................................................................ 12 
8 
Safety and Adverse Events ................................................................................................................. 13 
8.1 
Definitions ................................................................................................................................. 13 
8.2 
Recording of Adverse Events .................................................................................................... 15 
8.3 
Unblinding Procedures .............................................................................................................. 15 
8.4 
Stopping Rules ........................................................................................................................... 15 

 
 
 
 
 
3 
8.5 
Data and Safety Monitoring Plan .............................................................................................. 16 
8.5.1 
Medical Monitoring and AE/SAE Reporting ........................................................................ 17 
8.5.2 
Data and Safety Monitoring Committee ............................................................................... 19 
9 
Data Handling and Record Keeping ................................................................................................... 19 
9.1 
Confidentiality ........................................................................................................................... 19 
9.2 
Source Documents ..................................................................................................................... 20 
9.3 
Case Report Forms .................................................................................................................... 20 
9.4 
Records Retention ..................................................................................................................... 20 
10 
Study Monitoring, Auditing, and Inspecting ...................................................................................... 21 
10.1 
Study Monitoring Plan............................................................................................................... 21 
10.2 
Auditing and Inspecting............................................................................................................. 23 
10.2.1 Independent External and Internal Audits ............................................................................. 24 
11 
Ethical Considerations........................................................................................................................ 25 
12 
Study Finances ................................................................................................................................... 26 
12.1 
Funding Source .......................................................................................................................... 26 
12.2 
Conflict of Interest ..................................................................................................................... 26 
12.3 
Subject Stipends or Payments .................................................................................................... 26 
13 
Publication Plan.................................................................................................................................. 26 
14 
References .......................................................................................................................................... 26 
15 
APPENDices ...................................................................................................................................... 27 
 

 
 
 
 
 
4 
List of Abbreviations 
 
 
 
SEMS; Self Expanding Metal Stents   
 
 
ERCP; Endoscopic Retrograde Cholangiopancreatogram 
 
 
CBC; Complete Blood Count 
 
 
CMP; Comprehensive Metabolic Panel 
 
 
INR; International Normalized Ratio

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6 
1.0 INTRODUCTION 
3 
Pancreatic cancer is the second most common digestive cancer and fourth leading cause of cancer 
4 
death in the United States for both men and women.  Pancreatic tumors arising in the peri-
5 
ampullary region present with biliary obstruction in 64-77% of cases. Preoperative biliary 
6 
decompression has been advocated in an attempt to reduce postoperative complications following 
7 
attempted curative-intent surgery. 
8 
 
9 
This document is a protocol for a human research study. This study is to be conducted according 
10 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
11 
International Conference on Harmonization guidelines), applicable government regulations and 
12 
Institutional research policies and procedures.  
13 
1.1 Specific Aims and Hypothesis 
14 
The primary aim of this study is to compare the 30 and 90-day overall/cumulative grade III or 
15 
higher complication rates between patients with severe obstructive jaundice undergoing 
16 
preoperative endoscopic biliary drainage with SEMS and patients undergoing direct surgical 
17 
resection. In this study, One arm undergoes preoperative biliary drainage followed by surgery and 
18 
the other arm undergoes surgical resection without prior biliary drainage . Secondary aims will be 
19 
to compare surgical outcomes including mortality, intra-operative parameters, hospital length of 
20 
stay, ICU length of stay, readmission rate and time to commencement of adjuvant treatment. 
21 
1.2 Background and Rationale 
22 
Despite the fact that endoscopic and percutaneous placement of biliary stents is technically 
23 
successful in 90-95% of cases, routine preoperative biliary drainage for pancreatic cancer remains 
24 
controversial.[4, 5]  Pooled data from retrospective studies published over the past several years 
25 
have shown similar rates of 30-day mortality after pancreaticoduodenectomy in those who have 
26 
undergone biliary decompression as compared to those who have not. A few studies have 
27 
suggested that routine preoperative drainage in patients undergoing surgery for cancer of the 
28 
pancreatic head may increase overall complications, likely due to complication related to the 
29 
endoscopy itself  (i.e. pancreatitis, bleeding, perforation) and complications related to stent 
30 
failure.[6]  In the largest, multicenter, randomized trial to date, patients were randomly assigned 
31 
to undergo either endoscopic preoperative biliary drainage for 4 to 6 weeks, followed by surgery, 
32 
or surgery alone after diagnosis.  In this study, endoscopic preoperative biliary drainage did not 
33 
have a beneficial effect on the surgical outcome but rather was associated with an increase in 
34 
serious complications.[7] 
35 
 
36 
On the other hand, outcome measures have not been standardized and the lack of complete data 
37 
on surgical complications following preoperative drainage make direct comparisons difficult and 
38 
potentially biased. Many of the prior studies used plastic stents for preoperative decompression, 
39 
which when compared to self-expanding metal stents (SEMS) result in greater rates of re-
40 
intervention and cholangitis.  A recent meta-analysis of 1989 patients showed that SEMS have 
41 
higher stent insertion success, lower risk of stent occlusion, lower re-intervention rate, fewer  
42 
therapeutic failures, and fewer episodes of cholangitis compared to plastic stents making them the 
43 
optimal choice for biliary decompression.[8] Also a recent randomized controlled trial confirmed 
44 
that SEMS are superior to plastic stents with regard to functional stent time and showed that the 
45 
total health care cost is similar for placing SEMS or plastic stents even in patients with survival 
46 
less than 3 months.[9]  Thus, this study will provide unique perspective on the potential 
47 
advantages of biliary decompression using SEMS. Additionally, prior studies have excluded 
48 
severely jaundiced patients (serum bilirubin > 14.6), a population that may have derived the 
49 

 
 
 
 
 
7 
greatest benefit from preoperative drainage, since these patients are more likely to have impaired 
50 
liver function.  In fact, patients with malignant obstruction who present with severe jaundice 
51 
(>10mg/dL) are likely at higher risk for poor outcome following surgery.[10] These patients may 
52 
also benefit from preoperative drainage to alleviate pruritus and correct coagulation 
53 
disturbances.[11] Thus, although preoperative biliary drainage may not be routinely 
54 
recommended for all patients with malignant biliary obstruction, drainage may be potentially 
55 
advantageous for those patients with severe jaundice using a SEMS.  
56 
1.3 Study Therapy 
57 
Both preoperative SEMS placement and direct surgical resection are considered acceptable 
58 
standard of care in this patient population. 
59 
 
60 
SEMS (Wallflex, Boston Scientific) will be used. The WallFlex Biliary Stent System is FDA-
61 
cleared in the US, and is indicated for use in the palliative treatment of biliary strictures produced 
62 
by malignant neoplasms. Also, the WallFlex Biliary RX Stent is 510(k) cleared for the treatment 
63 
of biliary strictures produced by malignant neoplasms and relief of malignant biliary 
64 
obstruction prior to surgery. This represents the first biliary metal stent with labeling to support 
65 
pre-operative drainage in the US. 
66 
1.4 Preclinical Data 
67 
Please see clinical data below 
68 
1.5 Clinical Data to Date 
69 
A recent meta-analysis of 1989 patients  showed that SEMS have higher stent insertion success, 
70 
lower risk of stent occlusion, lower re-intervention rate, fewer  therapeutic failures, and fewer 
71 
episodes of cholangitis  compared to plastic stents making them the optimal choice for biliary 
72 
decompression.[8] Also a recent randomized controlled trial confirmed that SEMS are superior to 
73 
plastic stents with regard to functional stent time and showed that the total health care cost is 
74 
similar for placing SEMS or plastic stents even in patients with survival less than 3 months 
75 
1.6 Dose Rationale and Risk/Benefits 
76 
The study doesn’t involve drug administration.  
77 
2.0 STUDY OBJECTIVES 
78 
 
79 
2.1 Primary Objective: 
80 
The primary aim of this study is to compare the 30 and 90-day overall complication rates between 
81 
patients with severe obstructive jaundice undergoing preoperative endoscopic biliary drainage 
82 
with SEMS and patients undergoing direct surgical resection. 
83 
 
84 
2.2 Secondary Objective: 
85 
Secondary aims will be to compare surgical outcomes including hospital length of stay, ICU 
86 
length of stay, readmission rate, disposition from hospital, emergency room visits, urgent care 
87 
center visits and time to commencement of adjuvant treatment. 
88 
3.0 STUDY DESIGN 
89 
3.1 General Design 
90 
This is a Randomized controlled trial. 
91 

 
 
 
 
 
8 
ERCP will be performed on those who are randomized to the intervention group with 24 hours of 
92 
randomization. The patient will be followed at 30 days and 90 days post-operatively.  
93 
3.2 Primary Study Endpoints 
94 
30 and 90 day- complication rates between patients with severe obstructive jaundice undergoing 
95 
preoperative endoscopic biliary drainage with SEMS and patients undergoing direct surgical 
96 
resection 
97 
3.3 Secondary Study Endpoints 
98 
Secondary aims include the total number of complications, intraoperative estimated blood loss, 
99 
number of required fluid boluses, postoperative hospital LOS, readmission rate, disposition from 
100 
hospital, time to commencement of adjuvant treatment, emergency room visits, urgent care center 
101 
visits, and perioperative mortality.  Complications will include pancreatic fistula, delayed gastric 
102 
emptying, intra-abdominal abscess, cardiac complications, respiratory complications, deep vein 
103 
thrombosis, pulmonary embolism, urinary tract infection, wound infection, acute renal failure, 
104 
hemorrhage, hepaticojejunostomy leak, and duodenojejunostomy leak. Pancreatic fistula was 
105 
defined and graded according to the International Study Group of Pancreatic Fistula criteria. 
106 
Delayed gastric emptying was defined and graded according to the International Study Group of 
107 
Pancreatic Surgery. Wound infections and urinary tract infection were defined according to the 
108 
Centers for Disease Control and Prevention guidelines. Cardiac complications were defined 
109 
according to the American College of Cardiology and renal complications were defined by the 
110 
Acute Dialysis Quality Initiative. 
111 
3.4 Primary Safety Endpoints 
112 
Both SEMS placement and direct surgical resection are considered acceptable standard of care 
113 
practices. 
114 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
115 
4.1 Inclusion Criteria 
116 
-Adult patients age >18 regardless of gender or ethnicity 
117 
-Patients with peri-ampullary pancreatic cancer.  
118 
-Patients with serum bilirubin greater than 10mg/dL 
119 
-Adequate birth control 
120 
4.2 Exclusion Criteria 
121 
-Patients with evidence of distant metastasis on CT or MRI 
122 
-Patients anticipated to require vascular reconstruction 
123 
-Patients with cholangitis 
124 
-Patients who previously underwent biliary decompression for cholangitis by ERCP or PTC 
125 
-Patients with low performance score (Karnofsky performance status scale < 50) 
126 
-Patients with known preexisting liver disease with associated elevated bilirubin 
127 
-Patients who are pregnant or actively breast feeding.  
128 
 
129 
4.3 Gender/Minority/Pediatric Inclusion for Research 
130 
Any patient can be included if older than 18 years of age irrespective of gender, color, or 
131 
ethnicity.  
132 

 
 
 
 
 
9 
4.4 Subject Recruitment and Screening 
133 
One Hundred patients older than 18 years with periampullary cancer presenting with jaundice and 
134 
total bilirubin greater than 10mg/dL will be included in the study. 
135 
Patients will be recruited from clinic (gastroenterology and pancreaticobiliary surgery) or when 
136 
admitted to the hospital for workup and/or management and will be consented at that time. 
137 
 
138 
4.5 Early Withdrawal of Subjects 
139 
4.5.1 When and How to Withdraw Subjects 
140 
Patients can withdraw from the study at any time. Stent placement is the standard of care and thus 
141 
subjects who elect to withdraw from the study will continue to have the biliary stent in place and 
142 
be followed regularly similar to patients that are enrolled in the study.   
143 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
144 
Subjects who elect to withdraw from the study will continue to be followed on a regular basis. 
145 
Data that is important to the integrity of the final study analysis and the safety profile of the 
146 
SEMS will be collected after obtaining approval of the subjects.  
147 
  
148 
5.0 STUDY DRUG/THERAPY  
149 
5.1 Description 
150 
 The stents to be used in this study are FDA approved WallFlex Biliary RX Stents (Boston 
151 
Scientific Corporation, Natick, MA, USA) which are available in diameters of 8 or 10 mm and 
152 
lengths of 40, 60, and 80 mm. 
153 
5.2 Treatment Regimen 
154 
Stent to be placed pre-operatively in the intervention group to be removed during surgery. 
155 
5.3 Risks 
156 
• Pain  
• Infection  
• Tumor overgrowth around 
ends of stent  
• Bleeding  
• Inflammation  
• Mucosal hyperplasia  
• Fever  
• Recurrent obstructive 
jaundice 26% (likely) 
• Cholangitis  
• Nausea  
• Stent occlusion  
• Cholecystitis 10% (likely) 
• Vomiting  
• Tumor ingrowth through the 
stent  
• Pancreatitis 6% (possible) 
• Bile duct ulceration  
• Perforation of duodenum or 
bile duct  
• Stent migration 8% 
(possible) 
• Perforation of the gall 
bladder due to the stent 
covering the cystic duct  
• Stent misplacement  
 
 
157 
  
158 
Once again, placement of SEMS is the standard of care for patient with profound jaundice despite 
159 
the lack of evidence to support this practice.  
160 

 
 
 
 
 
10 
5.4 Method for Assigning Subjects to Treatment Groups 
161 
A randomization schedule will be created by the study statistician using the method of random 
162 
permuted blocks.  Randomization assignments will be loaded into a REDCap database before 
163 
study enrollment begins.  Randomization assignments will be accessed through the REDCap 
164 
randomization facility.   
165 
5.5 Preparation and Administration of Study Drug/Therapy 
166 
The intervention group will receive a WallFlex Biliary RX Stents (Boston Scientific Corporation, 
167 
Natick, MA, USA) 
168 
5.6 Subject Compliance Monitoring 
169 
The stent will placed by ERCP and won’t be removed before surgery unless indicated. Follow up 
170 
phone calls to ascertain secondary endpoints will be made at 30 and 90 days. 
171 
5.7 Prior and Concomitant Therapy 
172 
Subject in the study are to continue any medications that they are on. Those who are randomized 
173 
to the intervention group may be asked to hold antiplatelet/anticoagulation agents prior to the 
174 
ERCP in coordination with their prescribing doctor.  
175 
5.8 Blinding of Study Drug 
176 
Unblinded study 
177 
6.0 STUDY PROCEDURES 
178 
 
179 
6.1 Study Visit Schedule 
180 
Screening: 
181 
Patients will be screened in clinic or if admitted as inpatients. Patient must satisfy the inclusion 
182 
criteria listed above. Patient must carry a diagnosis of per-ampullary cancer. Basic labs will be 
183 
withdrawn including CBC, CMP and INR.  
184 
 
185 
Randomization 
186 
Peri-operative: The patient will be admitted and labs will obtained including CBC, CMP and 
187 
INR prior to surgery. 
188 
 
189 
Post-operative: 
190 
Visit 1: This will be scheduled 3-4 weeks after hospital discharge. Labs and imaging may be 
191 
ordered by the surgeon if needed. 
192 
Follow-up 
193 
Patients will be followed up to 90 days after the surgery. A phone call will be placed to the 
194 
patient by research staff to ascertain secondary endpoints. Jefferson EMR will be accessed 
195 
to ascertain primary endpoint data. 
196 
  
197 
7.0 STATISTICAL PLAN 
198 
7.1 Sample Size Determination 
199 
 
Based on previous data, we assumed an overall grade III or higher complication rate of 
200 
50% in the control group.  Although we are unsure of the expected rate in the pre-operative 
201 
biliary stenting group, a 30% or greater reduction in the grade III or higher complication 
202 

 
 
 
 
 
11 
would be meaningful.  The sample size will be 100 subjects (50 per arm).  We calculated 
203 
power under various alternatives for the biliary stenting group complication rate using a 
204 
two-group large-sample normal approximation test of proportions, with a one-sided 
205 
significance level of 0.05, to test the null hypothesis that the grade III or higher 
206 
complication rate in surgery with biliary stenting is greater than or equal to the control rate 
207 
(50%).  We have 84% power to detect a reduction if the true rate with biliary stenting is 
208 
25%, 66% power if the true rate is 30%, and 44% power if the true rate is 35%.   
209 
7.2 Statistical Methods 
210 
 
Baseline characteristics will be summarized by randomization arm using means, standard 
211 
deviations, and ranges for continuous variables and counts and frequencies for categorical 
212 
variables.   
 
213 
 
214 
 
Rates of grade III or higher complication rates will be estimated separately at 30 and 90 
215 
days.  The risk difference will be calculated (stent minus control) with a one-sided 95% 
216 
confidence interval.  If the upper bound of the confidence interval is less than 0 at both 
217 
times, surgery with biliary stenting will be considered effective at reducing the rate of 
218 
grade III or higher complications.   
219 
 
 
220 
 
Group comparisons with respect to continuous outcomes will be performed using two-
221 
sample t-tests or Wilcoxon rank sum tests.  Comparisons for categorical outcomes will be 
222 
performed using chi-square tests or Fisher’s exact test.  Comparisons for count outcomes 
223 
will use Poisson regression.  Kaplan-Meier analysis will be used to estimate the 
224 
distribution of time-to-event outcomes. Groups will be compared using the log rank test.   
225 
7.3 Subject Population(s) for Analysis 
226 
All randomized patients will be included in the analysis as randomized.  A per-protocol analysis 
227 
will be performed if there are any patients who do not receive the assigned surgical technique.   
228 
8.0 SAFETY AND ADVERSE EVENTS 
229 
8.1 Definitions 
230 
Adverse Event 
231 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
232 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
233 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
234 
be adverse events if the abnormality: 
235 
• 
results in study withdrawal 
236 
• 
is associated with a serious adverse event 
237 
• 
is associated with clinical signs or symptoms 
238 
• 
leads to additional treatment or to further diagnostic tests 
239 
• 
is considered by the investigator to be of clinical significance 
240 
 
241 
Serious Adverse Event 
242 
Adverse events are classified as serious or non-serious.   
243 
 
244 
A serious adverse event is any AE that is:  
245 
• 
fatal 
246 

 
 
 
 
 
12 
• 
life-threatening 
247 
• 
requires or prolongs hospital stay 
248 
• 
results in persistent or significant disability or incapacity 
249 
• 
a congenital anomaly or birth defect 
250 
• 
an important medical event 
251 
 
252 
Important medical events are those that may not be immediately life threatening, but are 
253 
clearly of major clinical significance. They may jeopardize the subject, and may require 
254 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
255 
overdose or abuse, a seizure that did not result in in-patient hospitalization or intensive 
256 
treatment of bronchospasm in an emergency department would typically be considered 
257 
serious.  
258 
 
259 
All adverse events that do not meet any of the criteria for serious should be regarded as 
260 
non-serious adverse events.  
261 
Adverse Event Reporting Period 
262 
The study period during which adverse events must be reported is normally defined as the 
263 
period from the initiation of any study procedures to the end of the study treatment follow-
264 
up.  For this study, the study treatment follow-up starts at randomization and ends at 90 
265 
days after the surgery.  
266 
Preexisting Condition 
267 
A preexisting condition is one that is present at the start of the study.  A preexisting 
268 
condition should be recorded as an adverse event if the frequency, intensity, or the 
269 
character of the condition worsens during the study period. 
270 
General Physical Examination Findings 
271 
At screening, any clinically significant abnormality should be recorded as a preexisting 
272 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
273 
that meet the definition of an adverse event must also be recorded and documented as an 
274 
adverse event.  
275 
Post-study Adverse Event 
276 
All unresolved adverse events should be followed by the investigator until the events are 
277 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
278 
the last scheduled visit, the investigator should instruct each subject to report any 
279 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
280 
reasonably be related to participation in this study.  The investigator should notify the study 
281 
sponsor of any death or adverse event occurring at any time after a subject has discontinued 
282 
or terminated study participation that may reasonably be related to this study.  The sponsor 
283 
should also be notified if the investigator should become aware of the development of 
284 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that 
285 
has participated in this study. 
286 
Abnormal Laboratory Values 
287 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
288 
the following conditions is met:  
289 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
290 
abnormality 
291 
• 
The abnormality suggests a disease and/or organ toxicity 
292 

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14 
 
324 
 
325 
The clinical course of each event should be followed until resolution, stabilization, or until it has 
326 
been determined that the study treatment or participation is not the cause.  Serious adverse events 
327 
that are still ongoing at the end of the study period must be followed up to determine the final 
328 
outcome.  Any serious adverse event that occurs after the study period and is considered to be 
329 
possibly related to the study treatment or study participation should be recorded and reported 
330 
immediately. 
331 
8.4 Stopping Rules  
332 
 
We will do an interim analysis after reaching 50 patients, and if there is a significant 
333 
difference (> 20%) in post operative mortality or morbidity in one group versus the other, 
334 
then the study will be discontinued. 
335 
8.5 Data and Safety Monitoring Plan 
336 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
337 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
338 
events as noted above, as well as the compliance and implementation of the KCC data and safety-
339 
monitoring plan.  Medical monitoring will include a regular assessment of the number and type of 
340 
serious adverse events by both the assigned Medical Monitor and the KCC DSMC. 
341 
 
342 
 
343 
8.5.1 Medical Monitoring and AE/SAE Reporting 
344 
A Medical Monitor is assigned to this study at the Thomas Jefferson University.  This is a 
345 
physician/pharmacist who is not directly involved in the trial, and is not currently collaborating with 
346 
the sponsor/investigator on any other trial.  The role of the Medical Monitor is to review all 
347 
reportable AEs/SAEs (in real-time) including grading, toxicity assignments, non-reportable AEs 
348 
(quarterly), protocol violations/deviations, as well as all other safety data and activity data observed 
349 
in the ongoing clinical trial occurring at the participating sites and at Thomas Jefferson University. 
350 
The Medical Monitor may recommend reporting of adverse events and relevant safety data, and may 
351 
also recommend suspension or termination of the study to the DSMC and TJU IRB.   
352 
 
353 
Every KCC investigator initiated protocol includes requirements for reporting of adverse events 
354 
based on CTC 4.0. All events are reported to the IRB and Medical Monitor using a password 
355 
protected web-site. In addition all unexpected and serious adverse events (SAEs) are reported to 
356 
the TJU IRB and to the Food and Drug Administration (FDA) if applicable. The investigator is 
357 
required to submit all unexpected and serious adverse events to the TJU IRB and the Medical 
358 
Monitor within the timeframes outlined in the below table. All AE/SAEs will be reported to the 
359 
DSMC at the quarterly DSMC review meetings; however, if the Medical Monitor determines 
360 
corrective action is necessary, an “ad hoc” DSMC meeting will be called. Fatal adverse events 
361 
related to treatment which are unexpected must be reported within 24 hours to the TJU IRB 
362 
and the DSMC. Fatalities not related to the study drug/device must be reported within 5 days 
363 
 
364 
8.5.2 Data and Safety Monitoring Committee 
365 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring Board 
366 
(DSMB) for the KCC. The DSMC is a multidisciplinary committee charged with overseeing the 
367 
monitoring of safety of participants in clinical trials, and the conduct, progress, validity, and 
368 
integrity of the data for all clinical trials at the Thomas Jefferson University KCC. The committee 
369 
meets quarterly to review the progress and safety of all active research protocols that are not 
370 
monitored by another safety and data monitoring committee or board. 
371 

 
 
 
 
 
15 
• 
The DSMC meets quarterly. Additional DSMC meetings are scheduled based on the 
372 
nature and number of trials being monitored over a specified time period. The DSMC 
373 
meets (by conference call) within 24 hours following the notification of an 
374 
unexpected adverse event felt to be related to the study drug.  
375 
• 
Prior to each DSMC meeting, each board member, is provided a printout of all 
376 
reported AEs and SAEs occurring during the reporting period for this clinical trial. 
377 
The principal investigator provides a detailed and comprehensive narrative 
378 
assessment of current adverse events to date, indicating their possible significance and 
379 
whether these toxicities have affected the conduct of the trial. DSMC members are 
380 
provided with the principal investigator’s assessment, a written report summarizing 
381 
adverse events, safety data, and activity data observed during the specified time 
382 
period described in each protocol, as well as  
383 
 
384 
recommendations from the Medical Monitor. A review of outcome results (response, 
385 
toxicity and adverse events) and factors external to the study (such as scientific or 
386 
therapeutic developments) is discussed, and the Committee votes on the status of each 
387 
study.  
388 
• 
A summary of the board’s action is sent to each investigator, the CCRRC and TJU 
389 
IRBs. The DSMC actions may include recommendations/requirements that will lead 
390 
to improved patient safety and/or efficacy, significant benefits or risks that have 
391 
developed, or other changes determined to be necessary. The DSMC may also take 
392 
note of slow accrual or lack of scientific progress, and refer such issues to the 
393 
CCRRC. The DSMC provides the investigator with the rationale for any decision 
394 
made.  
395 
 
396 
The Thomas Jefferson University Data and Safety Monitoring Committee reviews all 
397 
AE/SAE’s on open protocols.  Therefore, once AE/SAE reports from participating 
398 
site are received by the Thomas Jefferson University Coordinating Site, a copy will be 
399 
submitted to the TJU IRB/Medical Monitor/DSMB. Medical Monitor and DSMB 
400 
review and monitoring of participating site AEs/SAEs will follow the TJU DSMP.  
401 
 
402 
9.0 DATA HANDLING AND RECORD KEEPING 
403 
9.1 Confidentiality 
404 
Information about study subjects will be kept confidential and managed according to the 
405 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
406 
Those regulations require a signed subject authorization informing the subject of the following:  
407 
• 
What protected health information (PHI) will be collected from subjects in this study 
408 
• 
Who will have access to that information and why 
409 
• 
Who will use or disclose that information 
410 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
411 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
412 
regulation, retains the ability to use all information collected prior to the revocation of subject 
413 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
414 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
415 
of their scheduled study period. 
416 

 
 
 
 
 
16 
 
417 
9.2 Source Documents 
418 
Source data is all information, original records of clinical findings, observations, or other 
419 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
420 
data are contained in source documents   Examples of these original documents, and data records 
421 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
422 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
423 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
424 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
425 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
426 
the clinical trial. 
427 
9.3 Case Report Forms 
428 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
429 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
430 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
431 
If the item is not applicable to the individual case, write “N/A”.  All entries should be printed 
432 
legibly in black ink.  If any entry error has been made, to correct such an error, draw a single 
433 
straight line through the incorrect entry and enter the correct data above it.  All such changes must 
434 
be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of 
435 
illegible or uncertain entries, print the clarification above the item, then initial and date it. 
436 
 
437 
Please refer to CRF in the Appendix 
438 
9.4 Records Retention 
439 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
440 
the last approval of a marketing application in their country and until there are no pending or 
441 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
442 
formal discontinuation of clinical development of the investigational product.  These documents 
443 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
444 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
445 
these documents no longer need to be retained.  
446 
 
447 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
448 
10.1 Study Monitoring Plan 
449 
The investigator will allocate adequate time for monitoring activities.  The Investigator will also 
450 
ensure that the medical monitor or other compliance or quality assurance reviewer is given access 
451 
to all the above noted study-related  
452 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
453 
adequate space to conduct the monitoring visit. 
454 
10.2 Auditing and Inspecting 
455 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
456 
funding sponsor, government regulatory bodies, and University compliance and quality assurance 
457 
groups of all study related documents (e.g. source documents, regulatory documents, data 
458 

 
 
 
 
 
17 
collection instruments, study data etc.).  The investigator will ensure the capability for inspections 
459 
of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
460 
 
461 
Participation as an investigator in this study implies acceptance of potential inspection by 
462 
government regulatory authorities and applicable University compliance and quality assurance 
463 
offices. 
464 
 
465 
10.2.1 Independent External and Internal Audits  
466 
In addition to review by the DSMC, all studies initiated by KCC investigators are audited by an 
467 
independent auditor once they have achieved 10% of target accrual. However, a study can be 
468 
audited at any time based on recommendations by the IRB, DSMC, CCRRC and/or the Director 
469 
of Clinical Investigations, KCC. Studies are re-audited once they have achieved 50% of target 
470 
accrual. Special audits may be recommended by the IRB, DSMC or CCRRC based on prior 
471 
findings, allegations of scientific misconduct and where significant irregularities are found 
472 
through quality control procedures. Any irregularities identified as part of this process would 
473 
result in a full audit of that study.  
474 
 
475 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 percent of all 
476 
patients entered into therapeutic KCC trials and other trials as necessary, on at least a bi-annual 
477 
basis, to verify that there is a signed and dated patient consent form, the patient has met the 
478 
eligibility criteria, and that SAEs are documented and reported to the TJU IRB.  
479 
 
480 
All audit reports are submitted to the DSMC for review and action (when appropriate). A copy of 
481 
this report and recommended DSMC action is sent to the CCRRC and TJU IRB. The committee 
482 
regards the scientific review process as dynamic and constructive rather than punitive. The review 
483 
process is designed to assist Principal Investigators in ensuring the safety of study subjects and 
484 
the adequacy and accuracy of any data generated. The TJU IRB may, based on the DSMC and 
485 
auditor’s recommendation, suspend or terminate the trial.  
486 
 
487 
Coordinating Site Study Team 
488 
Representatives from the Thomas Jefferson University Study Team will monitor on site at the 
489 
participating site (or virtually if geographically impossible) within 4 weeks of the first subject 
490 
enrolling.   
491 
 
492 
Additional study monitoring by an independent auditing agency will be conducted at 10% and 
493 
50% site accrual per the TJU Data and Safety Monitoring Plan. This will either occur on-site, if 
494 
feasible, or will require participating sites to send TJU all source documents, patient charts, etc. to 
495 
TJU for the audit. 
496 
 
497 
Study Team Conference Calls 
498 
Teleconferences with the PIs, research nurses/coordinators, and regulatory staff will occur 
499 
quarterly. This will be a forum to discuss study related issues including accrual, SAE/AEs 
500 
experienced, study response, deviations/violations and study management issues.  Minutes of 
501 
these discussions will be taken to document the date of these meetings, the participants and the 
502 
issues that were discussed.  Copies of these minutes will be maintained in the Regulatory Binders 
503 
at both sites. 
504 
 
505 

 
 
 
 
 
18 
11.0 ETHICAL CONSIDERATIONS 
506 
This study is to be conducted according to US and international standards of Good Clinical 
507 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
508 
applicable government regulations and Institutional research policies and procedures. 
509 
 
510 
This protocol and any amendments will be submitted to a properly constituted independent 
511 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
512 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
513 
in writing to the investigator before commencement of this study.   
514 
 
515 
All subjects for this study will be provided a consent form that is compliant with local and federal 
516 
regulations, describing this study and providing sufficient information for subjects to make an 
517 
informed decision about their participation in this study.  See Attachment for a copy of the 
518 
Subject Informed Consent Form.  This consent form will be submitted with the protocol for 
519 
review and approval by the IRB for the study.  The formal consent of a subject, using the IRB-
520 
approved consent form, must be obtained before that subject is submitted to any study procedure.  
521 
This consent form must be signed by the subject or legally acceptable surrogate, and the 
522 
investigator-designated research professional obtaining the consent.  
523 
 
524 
12.0 STUDY FINANCES 
525 
12.1 Funding Source 
526 
This is an unfunded study.  The protocol prospectively tracks standard clinical care.  It will be 
527 
supported by the investigators, fellows, residents, and research coordinators in the Department of 
528 
Surgery and the Division of Gastroenterology.  There are no additional costs to the study 
529 
 
530 
12.2 Conflict of Interest 
531 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
532 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
533 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
534 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
535 
participation in this study.  All Jefferson University Investigators will follow the TJU Conflicts of 
536 
Interest Policy for Employees (107.03). 
537 
13.0 PUBLICATION PLAN 
538 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
539 
any of the information provided by the sponsor for the purposes of performing the study, will be 
540 
published or passed on to any third party without the consent of the study sponsor.  Any 
541 
investigator involved with this study is obligated to provide the sponsor with complete test results 
542 
and all data derived from the study. 
543 
 
544 
14.0 REFERENCES 
545 
 
546 
1. 
Jemal, A., et al., Cancer statistics, 2010. CA Cancer J Clin, 2010. 60(5): p. 277-300. 
547 
2. 
Hatzaras, I., et al., Predictors of survival in periampullary cancers following 
548 
pancreaticoduodenectomy. Ann Surg Oncol, 2010. 17(4): p. 991-7. 
549 

 
 
 
 
 
19 
3. 
Uchida, H., et al., Ampullary cancer and preoperative jaundice: possible indication of 
550 
the minimal surgery. Hepatogastroenterology, 2009. 56(93): p. 1194-8. 
551 
4. 
NIH 
state-of-the-science 
statement 
on 
endoscopic 
retrograde 
552 
cholangiopancreatography (ERCP) for diagnosis and therapy. NIH Consens State Sci 
553 
Statements, 2002. 19(1): p. 1-26. 
554 
5. 
Chen, V.K., M.R. Arguedas, and T.H. Baron, Expandable metal biliary stents before 
555 
pancreaticoduodenectomy for pancreatic cancer: a Monte-Carlo decision analysis. 
556 
Clin Gastroenterol Hepatol, 2005. 3(12): p. 1229-37. 
557 
6. 
Bonin, E.A. and T.H. Baron, Preoperative biliary stents in pancreatic cancer. J 
558 
Hepatobiliary Pancreat Sci, 2011. 18(5): p. 621-9. 
559 
7. 
van der Gaag, N.A., et al., Preoperative biliary drainage for cancer of the head of the 
560 
pancreas. N Engl J Med, 2010. 362(2): p. 129-37. 
561 
8. 
Sawas, T., et al., Self-expandable metal stents versus plastic stents for malignant 
562 
biliary obstruction: a meta-analysis. Gastrointest Endosc, 2015. 82(2): p. 256-267 e7. 
563 
9. 
Walter, D., et al., Cost Efficacy of Metal Stents for Palliation of Extrahepatic Bile 
564 
Duct Obstruction in a Randomized Controlled Trial. Gastroenterology, 2015. 149(1): 
565 
p. 130-8. 
566 
10. 
Su, 
Z., 
et 
al., 
Factors 
influencing 
infectious 
complications 
after 
567 
pancreatoduodenectomy. J Hepatobiliary Pancreat Sci, 2010. 17(2): p. 174-9. 
568 
11. 
Kloek, J.J., et al., Effect of preoperative biliary drainage on coagulation and 
569 
fibrinolysis in severe obstructive cholestasis. J Clin Gastroenterol, 2010. 44(9): p. 646-
570 
52. 
571 
12. 
Dindo, D., N. Demartines, and P.A. Clavien, Classification of surgical complications: 
572 
a new proposal with evaluation in a cohort of 6336 patients and results of a survey. 
573 
Ann Surg, 2004. 240(2): p. 205-13. 
574 
 
575 
 
576 

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