Clinical trial NCT03174353
Conditions: Pancreatic Leak Pancreatic Fistula Pancreaticoduodenal; Fistula Pancreatectomy; Hyperglycemia
Sponsor: University of Washington
Start date: 2018-02-20; Completion date: 2021-04-01
Enrollment: 114 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm investigator-initiated study designed to test the feasibility and potential efficacy of preoperative lanreotide to reduce the risk of postoperative abscess or pancreatic leak and fistula. All consenting patients undergoing planned elective pancreaticoduodenectomy or distal pancreatectomy for malignancy or suspected malignancy will be treated with a single deep subcutaneous dose of lanreotide prior to planned resection on the day of surgery. Following this intervention, care will be based on standard treatment protocols. Sixty-day mortality and morbidity will be collected for all patients.

Detailed description:
All patients enrolled in this study will receive SOMATULINE DEPOT 120 mg immediately prior to planned pancreatic resection. The pharmacist will dispense loaded syringes of the study drug. The single preoperative dose will be given in the pre-surgical center at the University of Washington by a trained health care professional. The study drug will be injected via the deep subcutaneous route in the superior external quadrant of the buttock.

Safety and efficacy will be assessed throughout the study period. Assessment for pancreatic and non-pancreatic complications will be made at the time of discharge and in follow-up by the attending surgeon. Patients will be evaluated in clinic postoperatively within 21 days of discharge for evaluation of the primary endpoint. The research team will perform long term follow-up by phone or in person with patients at 30 and 60 days (+/- 10 days at each time point).

SCREENING AND ENROLLMENT

Subjects undergoing planned elective pancreaticoduodenectomy or distal pancreatectomy for malignancy or suspected malignancy will be identified and screened for eligibility. Eligible patients who agree to participate will sign a written consent form at this time. At the initial visit, eligibility will be confirmed and documented in the study record. Informed consent will be obtained prior to enrollment utilizing the consent form.

STUDY PROCEDURES

1. Screening Visit (Day -60 to -1) Eligible patients will be identified at the Seattle Cancer Care Alliance (SCCA) and the University of Washington Medical Center (UWMC) surgical oncology clinics. At the screening visit, the Research Coordinator (RC) or one of the investigators will obtain signed informed consent. This will take place prior to any procedures being performed. Subjects will not receive any compensation for participation in the study. In addition, subjects will not incur any additional costs as a result of participation in the study.

   • Obtain and document consent from potential subject on study consent form

   • Review medical history to determine eligibility based on inclusion/exclusion criteria

   • Review medications history to determine eligibility based on inclusion/exclusion criteria

   • Perform physical examination: vital signs, weight, height

   • Collect, or obtain from routine care records, the following laboratory studies within 30 days prior to treatment:

   o Complete blood count with white blood cell differential and platelet counts;

   o Comprehensive profile; prothrombin time and activated partial thromboplastin time (PT\&PTT)

   o Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to study drug administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
2. Preoperative Baseline (Day 0) The baseline visit will take place on the day of surgery, prior to the patient's operation and administration of the study drug. Some subjects initially consented into the study may be deemed ineligible on the day of surgery prior to drug administration. The study team will assess inclusion/exclusion criteria prior to drug administration.

   • Verify inclusion/exclusion criteria

   • Obtain demographic information, medical history/current condition, medication list

   • Collect serum pregnancy test for women of childbearing potential prior to drug administration, unless testing negative within prior 72 hours (for example, if testing was performed at Screening Visit within the previous 3 days), or testing has been performed for routine clinical care

   • Draw blood for correlative research (2 light green top tubes (10 ml)) prior to study drug administration (optional)
3. Preoperative Drug Administration (Day 0) The study drug will be administered and other study procedures performed after baseline procedures are conducted; prior to the surgery.

   • Administer the study drug
   * Administer Symptoms Questionnaire
   * Assess vital signs
   * Record results of pain on visual analog scale from chart
4. Intraoperative

   • Draw blood for correlative research (2 light green top tubes (10 ml)) intraoperatively immediately following resection (optional)
5. Postoperative Follow-up

5.a Hospital Stay (Postoperative Days 0-7) Subjects who receive the study drug but do not have a clinical resection performed during their surgery, will have no additional study procedures performed. The study team will review adverse events related to the study drug during the immediate postoperative hospital stay only.

Subjects who receive the study drug and have a clinical resection will be followed postoperatively for 60 days. The initial postoperative assessment will occur during the subject's hospital stay. Hospital stays will vary widely by patient, but are expected to range from 3-7 days. The study team will periodically review the patient chart for safety and outcomes as available for individual subjects during this timeframe.

* Record adverse events as reported by subject or observed by clinical team and/or investigator. See section 10.2 for list of information to be reviewed for adverse event monitoring
* Obtain medical history/current condition, medication list on the day of discharge
* Record results of physical examination on the day of discharge
* Collect the following laboratory studies, as available from routine care records:

  * Complete blood count with white blood cell differential and platelet counts;
  * Comprehensive profile; prothrombin time and activated partial thromboplastin time (PT\&PTT)
* Assess vital signs
* Record results of pain on visual analog scale from chart
* Administer Symptoms Questionnaire on the day of discharge
* Record drain amylase levels from chart, as available
* Record drain output in ml from chart, as available
* Evaluate for day of drain removal from chart, as available

  5.b Clinic Follow-up Visit (Post discharge Days 1-21) Subjects will typically have a clinical follow-up appointment with their University of Washington (UW) Medicine surgical provider or an external provider within 1 - 21 days following discharge. There may be more than one clinical appointment during this timeframe. The study team will review patient charts and collect information on individual subjects as available from their clinical care. Subjects who are seen at UW Medicine will receive an in-person symptoms questionnaire to complete. Subjects who have their follow-up care performed external to UW Medicine will receive a phone call from the research coordinator (RC) between 1 and 21 after discharge to complete the symptoms questionnaire by phone. Records from external institutions will be obtained and reviewed for the time frame.
* Record adverse events as reported by subject or observed by clinical team and/or investigator
* Obtain medical history/current condition, medication list
* Record results of physical examination
* Collect from routine care records the following laboratory studies, as available:

  o Complete blood count with white blood cell differential and platelet counts;

  o Comprehensive profile; prothrombin time and activated partial thromboplastin time (PT\&PTT)
* Assess vital signs
* Record results of pain on visual analog scale from chart
* Administer Symptoms Questionnaire

  6\. Long Term Follow-up

  6.a Follow-up Phone Call (Postoperative Days 30 \& 60) The RC will follow-up with all subjects by phone at approximately 30 and 60 days postoperative to identify missed complications. If the RC identifies a missed complication by phone, the investigator or co-investigator will then contact the subject with a second phone call to discuss the reported complications in more detail.

Patient charts will be reviewed throughout 60 days postoperative. Some subjects may receive their follow-up care outside of UW Medicine. In this case, records from external institutions will be obtained and reviewed for the timeframe.

* Record adverse events as reported by subject or observed by investigator.
* Obtain medical history/current condition, medication list
* Administer Symptoms Questionnaire
* Review clinical charts for complications, as available

SUBJECT WITHDRAWAL

Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the investigator at any time. Patients may be withdrawn from the study if any of the following occur:

* Pregnancy discovered after enrollment, but prior to study drug treatment
* Protocol violation
* Subject withdrawal of consent
* Lost to follow-up
* Do not have clinical resection performed post drug administration
* Death

  1. Replacement of Subjects Subjects withdrawn from the study prior to administration of the study drug will be replaced. Subjects withdrawn from the study after administration of the study drug and who do not have a clinical resection performed will not be replaced. Other subjects withdrawn prior to complete 60-day follow up will not be replaced. If subjects do not respond to phone follow-up at 30 or 60 days, three repeated attempts will be made over the 10 days following each of these time points. Subjects who have incomplete follow up will be included with limited follow up.

BIOSTATISTICS

1. Sample Size and Power

   We estimate the final target sample size will be 98 patients. We aim to screen 154 patients and enroll n=123 patients into this single-arm study to test whether treatment with lanreotide reduces the risk of postoperative pancreatic fistula. Based upon a 20% probability of not proceeding with surgical resection after drug treatment due to findings of metastatic or unresectable disease at surgery, we anticipate that 123 treated patients will yield 98 evaluable patients.
2. Analysis Plan

As a primary method analysis, we will use a one-sample t-test to compare the rate of postoperative pancreatic fistula among the n=98 patients who were treated with lanreotide and underwent surgical resection against a published rate of 21% for patients treated with a placebo in another study, while 9% of patients treated with pasireotide experienced postoperative pancreatic fistula. The present study has 80% power (one-sided alpha = 0.05) to detect pancreatic fistula rates smaller than 11.5%, the approximate upper estimate of an 80% confidence interval of the pancreatic fistula rate of 9% in the study of pasireotide.

As a secondary exploratory analysis, we will use McNemar's test to compare the pancreatic fistula rate in the present study to that of historical controls at the same institution matched on pancreatic firmness and duct size.

Arms: arm 1: Single arm study. A single deep subcutaneous dose of lanreotide (Somatuline Depot 120 Mg/0.5Ml) will be administered prior to planned resection on the day of surgery.
Interventions: intervention 1: Lanreotide Prefilled Syringe
Intervention descriptions: intervention 1: All patients enrolled in this study will receive SOMATULINE DEPOT 120 mg immediately prior to planned pancreatic resection. The pharmacist will dispense loaded syringes of the study drug. The single preoperative dose will be given in the pre-surgical center at the University of Washington by a trained health care professional. The study drug will be injected via the deep subcutaneous route in the superior external quadrant of the buttock.

Protocol documents:
Prot_SAP_001.pdf: 
A Phase II Trial of Lanreotide for the Prevention of Postoperative Pancreatic Fistula 
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i 
 
A Phase II Trial of Lanreotide for the Prevention 
of Postoperative Pancreatic Fistula 
 
Sponsor-Principal Investigator: Venu G. Pillarisetty, M.D. 
Co-Investigator: James O. Park, M.D. 
 
 
 
 
Draft or Version Number:  1 
 
 October 12, 2017 
 


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STATEMENT OF COMPLIANCE 
 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training. 
 


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SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date:  
Name: Venu G. Pillarisetty, M.D. 
Title: Associate Professor of Surgery, University of Washington 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE ......................................................................................... 2 
SIGNATURE PAGE ................................................................................................................ 3 
LIST OF ABBREVIATIONS .................................................................................................. 7 
PROTOCOL SUMMARY ....................................................................................................... 9 
1 
KEY ROLES AND CONTACT INFORMATION ....................................................... 11 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 12 
2.1 
Background Information ............................................................................................... 12 
2.2 
Overview of Lanreotide autogel (SOMATULINE DEPOT) ........................................... 13 
2.3 
Human Experience ....................................................................................................... 13 
2.4 
Study Rationale ............................................................................................................ 14 
2.5 
Selection of Dose ......................................................................................................... 15 
2.6 
Potential Risks and Benefits ........................................................................................ 15 
2.6.1 
Potential Risks ...................................................................................................... 15 
2.6.2 
Potential Benefits .................................................................................................. 16 
3 
OBJECTIVES ................................................................................................................ 16 
3.1 
Primary objectives ........................................................................................................ 16 
3.2 
Secondary Objectives .................................................................................................. 16 
4 
STUDY DESIGN .......................................................................................................... 17 
4.1 
Study Design ................................................................................................................ 17 
5 
SUBJECT SELECTION ............................................................................................... 19 
5.1 
Subject Inclusion Criteria ............................................................................................. 19 
5.2 
Subject Exclusion Criteria ............................................................................................ 19 
6 
RECRUITMENT PLAN ............................................................................................... 20 
7 
STUDY INTERVENTION ........................................................................................... 20 
8 
INVESTIGATIONAL PLAN ....................................................................................... 21 
8.1 
Duration of Study ......................................................................................................... 21 
8.2 
Screening and Enrollment ............................................................................................ 21 
8.3 
Informed Consent ......................................................................................................... 21 
8.4 
Study Drug ................................................................................................................... 21 
8.4.1 
Acquisition ............................................................................................................. 21 
8.4.2 
Formulation, Packaging, and Labeling .................................................................. 21 
8.4.3 
Drug Storage and Stability .................................................................................... 21 


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8.4.4 
Study Drug Accountability ..................................................................................... 22 
8.5 
Concomitant Medications/Treatments .......................................................................... 22 
8.6 
Study Drug Administration ........................................................................................... 22 
9 
VISIT SCHEDULE AND ASSESSMENTS ................................................................. 22 
9.1 
Screening Visit (Day -60 to -1) ..................................................................................... 23 
9.2 
Day of Surgery to Discharge ........................................................................................ 24 
9.2.1 
Preoperative: Baseline (Day 0) ............................................................................. 24 
9.2.2 
Preoperative:  Drug Administration (Day 0) .......................................................... 25 
9.2.3 
Intraoperative (Day 0) ........................................................................................... 25 
9.2.4 
Hospital Stay (Postoperative Days 0-7) ................................................................ 25 
9.3 
Follow-up Post Discharge ............................................................................................ 26 
9.3.1 
Clinic Follow-up Visit (Post discharge Days 1-21) ................................................ 26 
9.3.2 
Follow-up Phone Call (Postoperative Days 30 & 60) ............................................ 26 
10 
ASSESSMENT OF SAFETY ....................................................................................... 27 
10.1 
Adverse Event Overview .............................................................................................. 27 
10.2 
Data Collection for AE Review ..................................................................................... 28 
10.3 
Serious Adverse Event (SAE) ...................................................................................... 29 
10.4 
Unexpected Adverse Event .......................................................................................... 30 
10.5 
Relationship of Adverse Event to Investigational Drug ................................................ 30 
10.6 
Severity of the Adverse Event ...................................................................................... 31 
10.7 
Adverse Event Documentation ..................................................................................... 31 
10.8 
Reporting of Serious Adverse Events .......................................................................... 31 
10.9 
Stopping Rules ............................................................................................................. 31 
11 
OUTCOME ASSESSMENT ......................................................................................... 32 
11.1 
Primary Endpoints ........................................................................................................ 32 
11.2 
Secondary Endpoints ................................................................................................... 32 
12 
SUBJECT WITHDRAWL ............................................................................................ 32 
12.1 
Replacement of Subjects ............................................................................................. 33 
13 
BIOSTATISTICS .......................................................................................................... 33 
13.1 
Sample Size and Power ............................................................................................... 33 
13.2 
Analysis Plan ................................................................................................................ 33 
14 
DATA MANAGEMENT, MONITORING, AND RETENTION ................................ 34 
14.1 
Data Management ........................................................................................................ 34 


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14.2 
Data and Safety Monitoring .......................................................................................... 34 
14.3 
Availability and Retention of Investigational Records .................................................. 35 
14.4 
Archival of Data ............................................................................................................ 35 
14.5 
Participant Confidentiality ............................................................................................. 35 
15 
ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS ....... 36 
15.1 
Institutional Review Board ............................................................................................ 36 
15.2 
Protocol Modifications .................................................................................................. 36 
15.3 
Informed Consent ......................................................................................................... 36 
15.4 
Research Authorization ................................................................................................ 37 
15.5 
Quality Control and Quality Assurance ........................................................................ 37 
15.6 
Regulatory Authority Approvals/Authorizations ............................................................ 37 
15.7 
Investigator Responsibilities ......................................................................................... 37 
16 
LITERATURE REFERENCES .................................................................................... 39 
APPENDIX A: CONSENT FORM ........................................................................................ 40 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MedDRAÒ 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
OCTOM 
Office of Clinical Trials Operations and Management, NIDCR, NIH 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 


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QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
WHO 
World Health Organization 
 


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PROTOCOL SUMMARY 
Title: 
A phase II trial of lanreotide (SOMATULINE DEPOT) for the 
prevention of postoperative pancreatic fistula 
 
Précis: 
This is a single arm investigator-initiated study designed to test the 
feasibility and potential efficacy of preoperative lanreotide to reduce 
the risk of postoperative abscess or pancreatic leak and fistula. All 
consenting 
patients 
undergoing 
planned 
elective 
pancreaticoduodenectomy or distal pancreatectomy for malignancy or 
suspected 
malignancy 
will 
be 
treated 
with 
a 
single 
deep 
subcutaneous dose of lanreotide prior to planned resection on the day 
of surgery. Following this intervention, care will be based on standard 
treatment protocols. Sixty-day mortality and morbidity will be collected 
for all patients. 
 
 
Objectives: 
 
Primary:  To determine if preoperative lanreotide reduces the 
incidence of intraabdominal abscess or clinically significant (grade B 
or C) postoperative pancreatic fistula, as compared with published 
literature and historical controls. 
 
 
Secondary:   
1. To determine if preoperative lanreotide reduces the incidence 
of grade A postoperative pancreatic fistula, as compared with 
published literature and historical controls. 
2. To determine if preoperative lanreotide reduces the incidence 
of postoperative surgical site infection, as compared with 
published literature and historical controls. 
3. To determine if preoperative lanreotide reduces the incidence 
of overall postoperative morbidity, as compared with published 
literature and historical controls. 
4. To determine if preoperative lanreotide reduces drain amylase 
levels on days 1 & 3 postoperatively, as compared with 
published literature and historical controls 
5. To determine if preoperative lanreotide reduces duration of 
drainage required for patients with pancreatic fistulae, as 
compared with published literature and historical controls. 
 
 
 


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Population: 
Patients undergoing planned elective pancreaticoduodenectomy or 
distal pancreatectomy for malignancy or suspected malignancy will be 
enrolled into this study 
 
Phase: 
II 
Number of Sites: 
1 – University of Washington Medical Center   
Description of 
Intervention: 
A single deep subcutaneous dose of 120 mg of an extended-release 
aqueous-gel formulation of lanreotide (SOMATULINE DEPOT) will be 
administered preoperatively on the day of planned surgical resection. 
All subsequent care and interventions will follow established standard 
care pathways. Outcome data will be gathered during hospital-based, 
and clinical follow up appointments, as well as through scheduled 
phone calls and chart reviews. 
 
 
Study Duration: 
36 months 
Subject 
Participation 
Duration:  
60 days 
Estimated Time to 
Complete 
Enrollment: 
36 months 


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1 KEY ROLES AND CONTACT INFORMATION 
Sponsor:   
Venu G. Pillarisetty, M.D. 
Associate Professor of Surgery 
University of Washington 
1959 NE Pacific St., Box 356410 
phone: 206 616-4924 
fax: 206 543-8136 
vgp@uw.edu  
Medical Monitor: 
TBD   
 
 
Clinical Site 
Investigators: 
Venu G. Pillarisetty, M.D. 
Associate Professor of Surgery 
University of Washington 
1959 NE Pacific St., Box 356410 
phone: 206 616-4924 
fax: 206 543-8136 
vgp@uw.edu 
 
James O. Park, M.D. 
Associate Professor of Surgery 
University of Washington 
1959 NE Pacific St., Box 356410 
phone: 206 685-4672 
fax: 206 598-1984 
jopark@uw.edu 
 
Institution: 
University of Washington  
1959 NE Pacific St. 
Seattle, WA. 98195 
 


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2 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
 
Pancreatic surgery is highly complex and is associated with 90-day mortality rates of up to 8%, 
depending upon the level of experience of the surgeon and the hospital.(1) Even in the best of 
hands, perioperative morbidity of pancreatic surgery is quite common, affecting nearly half of 
patients undergoing pancreatic resections.(2) Among the causes of major morbidity and 
mortality following pancreatic resections, the most important one is postoperative pancreatic 
fistula (POPF).(3)  
 
POPFs result from leakage of pancreatic juice from the cut edge of the gland. Following distal 
pancreatectomy, which accounts for approximately 20% of pancreatic resections, the cut edge 
is typically closed with surgical staples or sutures, and leakage can occur from inadequate 
sealing of the main pancreatic duct or from small ducts. In contrast, the cut edge of the 
pancreas in a pancreaticoduodenectomy – the most commonly performed pancreatic resection 
– is anastomosed to a segment of small intestine or, less often, the stomach. POPF from this 
anastomosis is associated with even 
greater risks than leaks following distal 
pancreatectomy, 
as 
the 
pancreatic 
enzymes in this situation may be in a 
more activated state due to contact with 
intestinal contents. In order to facilitate 
cross-institutional study of this major 
problem, the International Study Group 
of 
Pancreatic 
Surgery 
(ISGPS) 
developed a uniform method for grading 
POPF (Table 1).(4) POPF which alter 
the patient’s clinical course or require 
intervention are classified as grade B or 
C, while grade A fistula have no major 
clinical significance. Methods to reduce 
the incidence of clinically significant 
POPF are highly sought after and have 
the potential to dramatically improve 
patient outcomes and reduce the cost of 
care.  
 
Although multiple methods for closure or anastomosis of the pancreatic cut edge have been 
studied, none have convincingly demonstrated superiority; therefore, POPF remains a common 
source of perioperative morbidity.(5,6) Natural somatostatin and its analogues, especially 
octreotide, have been extensively studied as a potential method to reduce pancreatic exocrine 
secretion and can be used to treat enterocutaneous fistulae. Somatostatin analogues have also 
 
The International Study Group of Pancreatic Surgery 
(ISGPS) developed this classification scheme for grading 
POPF that has been widely used to standardize reporting. 
Bassi et al., 20052  
Table 2.1: ISGPS Grading of POPF 
Grade
A
B
C
Clinical conditions Well
Often well Ill appearing/
bad
Speciﬁc teatment* No
Yes/no
Yes
US/CT
(if obtained)
Negative Negative/
positive
Positive
Persistent drainage
(after 3 weeks)y
No
Usually yes Yes
Reoperation
No
No
Yes
Death related to
POPF
No
No
Possibly yes
Signs of infections No
Yes
Yes
Sepsis
No
No
Yes
Readmission
No
Yes/no
Yes/no
US, Ultrasonography; CT, computed tomographic scan; POPF, postoper-
ative pancreatic ﬁstula.
*Partial (peripheral) or total parenteral nutrition, antibiotics, enteral
nutrition, somatostatin analogue and/or minimal invasive drainage.
yWith or without a drain in situ.


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been used to reduce the incidence of POPF, and subcutaneously (SC) injected octreotide is 
indicated for this purpose in some countries, but not the United States.(7)   
2.2 
Overview of Lanreotide autogel (SOMATULINE DEPOT) 
Lanreotide is an injectable synthetic somatostatin analogue. Its chemical name is 3-(2 
naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide 
(2->7)-disulfide. Lanreotide binds with high specificity to type 2 and 5 somatostatin receptors 
(SSTR), and has lower affinity to SSTR 1, 3, and 4. Through its agonist activity, lanreotide 
reduces endocrine secretion of such hormones as insulin, glucagon, and growth hormone, while 
also reducing exocrine secretion of enzymes involved in digestion. The extended release, SC 
delivered formulation, lanreotide autogel (Somatuline Depot; herein referred to as lanreotide) 
will be used in this study.  
 
Lanreotide is indicated for the long-term treatment of acromegalic patients with inadequate 
response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an 
option. The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin-like 
growth factor 1 (IGF-1) levels to normal. Importantly, Lanreotide 120 mg is also indicated for the 
treatment of patients with unresectable, well-or moderately-differentiated, locally advanced or 
metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-
free survival.  
2.3 
Human Experience  
 
As noted above, lanreotide is approved by the FDA for the long-term treatment both of 
acromegaly and advanced GEP-NETs. Overall, it is a well-tolerated drug at SC doses of 60, 90, 
or 120 mg every 4 to 8 weeks. Having been approved for the treatment of acromegaly in 2007, 
there is a great deal of evidence that lanreotide is a safe, well tolerated drug. In the recent 
PRIMARY treatment of macroadenomas in acromegaly with Somatuline (PRIMARYS) study, 
treatment-naïve patients with acromegaly were treated with 120 mg of lanreotide Autogel every 
4 weeks for 1 year.(8) A majority of the achieved clinically significant tumor shrinkage and the 
drug was well tolerated, and no patients discontinued treatment due to gastrointestinal 
symptoms. 
In the Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors 
(CLARINET) Trial, 204 patients were treated with 120 mg lanreotide (n=101) or placebo (n=103) 
every 4 weeks for 96 weeks, and total number of adverse events, most of which were mild or 
moderate, were similar between the two groups (88% vs. 90%, respectively).(9) Study 
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were seen in 28% of patients 
receiving 
placebo. 
The 
most 
common 
treatment-related 
adverse events in this long-term 
treatment study were mild (Table 
2). Furthermore, serious adverse 
events were similar between 
groups (25% lanreotide vs. 31% 
placebo), 
as 
were 
serious 
adverse events related to study 
treatment (3% lanreotide vs. 1% 
placebo). 
2.4 
Study Rationale  
 
The most important source of morbidity and mortality following pancreatic surgery is leakage of 
enzyme-rich digestive fluid from the major or minor ducts along the pancreatic parenchymal 
margin of resection. In the case of distal pancreatectomy, which involves removal of pancreatic 
tissue to the left of the portosplenic venous confluence, this leakage is typically along the 
parenchymal margin that has been stapled or sutured closed. In contrast, following 
pancreaticoduodenectomy, which is used to remove tumors involving the head or uncinate 
process of the pancreas, the leakage is usually from a connection made between the pancreatic 
duct and the small intestine.  
  
While inherent characteristics of the patient, the texture of the pancreas (soft vs. firm), and the 
size of the pancreatic duct (small vs. dilated) impact the risk of pancreatic leak, surgical 
technique is an incredibly important factor. Perhaps due to improved training and concentration 
of surgical volume at specialized centers, patients undergoing pancreatic surgery today enjoy 
significantly better outcomes than did patients being treated as little as a decade ago. However, 
pancreatic resections continue to be plagued by high morbidity and mortality rates. The 
University of Washington Medical Center (UWMC) is an academic tertiary hospital with a high-
volume pancreatic surgery program, and is a member of the American College of Surgeons 
(ACS) National Surgical Quality Improvement Program (NSQIP) Hepatopancreatobiliary (HPB) 
Collaborative. As evidenced by the NSQIP HPB Collaborative hospital report for UWMC, we 
performed 
a 
total 
of 
91 
pancreatectomies 
(25 
distal 
pancreatectomies 
and 
66 
pancreaticoduodenectomies) in 2015 without any mortalities and with a serious morbidity rate 
under 20%, which is half the NSQIP average for these procedures. 
 
As our field continues to improve techniques and perioperative management, we have also 
looked for methods to inhibit pancreatic enzyme secretion as way to reduce the incidence of 
pancreatic leak and subsequent POPF or abscess. Due to somatostatin’s pleiotropic effects on 
endocrine and exocrine function, activating this axis has been heavily studied as a potential 
means to achieve the goal of reducing pancreatic leaks. The routine administration of 
somatostatin and its analogues to reduce POPF is supported by some data; however, 
Table 2.2: Common treatment-related adverse events in 
the CLARINET trial 
Adverse event 
Lanreotide 
Placebo 
Diarrhea 
26% 
9% 
Abdominal pain 
14% 
2% 
Cholelithiasis 
10% 
3% 
Flatulence 
8% 
5% 
Injection site pain 
7% 
3% 
Nausea 
7% 
2% 
Vomiting 
7% 
0 
Headache 
5% 
2% 
Lethargy 
5% 
2% 
Hyperglycemia 
5% 
0 
Decreased level of pancreatic enzymes 
5% 
0 


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challenges remain with respect to medication dosing and administration, particularly for short 
half-life drugs. A recent, high-quality single-institution randomized controlled trial comparing one 
week of twice-daily administration of pasireotide vs. placebo demonstrated significantly reduced 
postoperative pancreatic fistula rate with pasireotide.(10) Although the results with pasireotide 
are compelling, its gastrointestinal side effect profile and the need for twice daily dosing make it 
a less than ideal perioperative pharmacologic intervention.  
 
Lanreotide possesses many characteristics that provide a strong rationale for testing its efficacy 
in reducing POPF. First, its depot formulation that we will be testing rapidly achieves therapeutic 
blood levels that are stable for nearly the entire perioperative period, thus allowing for an 
extremely simple treatment strategy of one preoperative dose. Second, it has a well-established 
safety record and is FDA-approved for two separate indications. Third, the most common 
adverse events associated with lanreotide administration – diarrhea, abdominal pain, and 
flatulence – are likely at least partly due to its inhibition of pancreatic enzyme secretion. We 
therefore believe that a single preoperative dose of lanreotide will provide a similar reduction in 
postoperative pancreatic fistula rates to that seen with pasireotide. 
 
2.5 
Selection of Dose  
The dose of 120 mg was selected based upon the pharmacokinetic data demonstrating rapid 
(peak reached by first day) and long-lasting (nearly 2 months) therapeutic blood concentrations 
of lanreotide. Furthermore, the standard dose for treatment of patients with unresectable, well- 
or moderately-differentiated, locally advanced or metastatic GEP-NETs is 120 mg every 4 
weeks. That patient population has significant overlap with the population planned to be treated 
in the present study, as a large proportion of our patients will be undergoing resection for 
pancreatic NETs. 
2.6 
Potential Risks and Benefits 
2.6.1 
Potential Risks 
 
A single dose of SOMATULINE DEPOT 120 mg has been well tolerated with mostly mild, 
transient side effects reported. In the treatment of Acromegaly, the most common adverse 
events seen have been diarrhea, cholelithiasis, abdominal pain, nausea, and injection site 
reactions. In the treatment of GEP-NET, the most common adverse events seen have been 
abdominal 
pain, 
musculoskeletal 
pain, 
vomiting, 
headache, 
injection 
site 
reaction, 
hyperglycemia, hypertension, and cholelithiasis. For more information on SOMATULINE 
DEPOT please refer to Section 2.3 Human Experience or the SOMATULINE DEPOT Package 
Insert.   
 
Natural somatostatin and somatostatin analogues (octreotide and pasireotide) have been 
extensively studied in the perioperative setting to reduce the risk of POPF. Although there have 
been mixed results with regards to efficacy, these drug treatments have proven to be quite safe. 


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Long-term somatostatin analogue therapy has been associated with cholelithiasis and 
cholecystitis; however, treatment in this study is by-definition short-term. Additionally, the risk in 
our study is further reduced because approximately two-thirds of the patients (all of those 
undergoing pancreaticoduodenectomy) will have a cholecystectomy performed as part of their 
operation.  
 
Overall, our study design, which is based on drug treatment on the day of surgery further limits 
risk by having the patient in a highly monitored setting immediately following drug 
administration. Therefore, study drug-associated pain, nausea, vomiting, hypertension, and 
hyperglycemia, which are all commonly expected adverse events in the perioperative period for 
pancreatic surgery will be readily managed. 
 
2.6.2 
Potential Benefits 
Although the operative mortality following pancreatectomy has decreased to approximately 2% 
at high-volume institutions the morbidity of this procedure remains significant. The most 
important complications of pancreatic resection arise from leakage of enzyme-rich pancreatic 
fluid from the cut edge of pancreas. The physical and emotional burden these complications 
place upon patients, as well as the financial cost to the health care system, cannot be 
overestimated. Currently no preoperative or intraoperative technique has demonstrated the 
ability to decrease the risk of these complications. Preoperative lanreotide may prove to reduce 
the rates of pancreatic fistulas, intraabdominal abscesses, surgical site infections, and overall 
morbidity. 
3 OBJECTIVES  
3.1 
Primary objectives 
To determine if preoperative lanreotide reduces the incidence of intraabdominal abscess or 
clinically significant (grade B or C) postoperative pancreatic fistula, as compared with published 
literature and historical controls. 
 
3.2 
Secondary Objectives  
 
1. To determine if preoperative lanreotide reduces the incidence of grade A postoperative 
pancreatic fistula, as compared with published literature and historical controls. 
2. To determine if preoperative lanreotide reduces the incidence of postoperative surgical 
site infection, as compared with published literature and historical controls. 
3. To determine if preoperative lanreotide reduces the incidence of overall postoperative 
morbidity, as compared with published literature and historical controls. 


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4. To determine if preoperative lanreotide reduces drain amylase levels on days 1 & 3 
postoperatively, as compared with published literature and historical controls 
5. To determine if preoperative lanreotide reduces duration of drainage required for 
patients with pancreatic fistulae, as compared with published literature and historical 
controls. 
4 STUDY DESIGN  
4.1 
Study Design  
 
This is a single arm phase II trial of preoperative lanreotide in patients undergoing planned 
elective pancreaticoduodenectomy or distal pancreatectomy for malignancy or suspected 
malignancy at the University of Washington Medical Center. All patients will receive a single 
deep subcutaneous dose of 120 mg of an extended-release aqueous-gel formulation of 
lanreotide (SOMATULINE DEPOT) administered immediately prior to the planned surgical 
resection. Our goal accrual is 98 evaluable patients who receive the study drug and undergo the 
planned surgical resection. These subjects will be followed at 30, and 60 days postoperatively 
for data collection purposes. We anticipate 3 years for the completion of the study.  
 
The study design of a single arm phase II trial was chosen because, although there are many 
data on the use of somatostatin analogues for the prevention of postoperative pancreatic 
fistulae, there is currently no consensus on their use and there have been no prior trials using 
lanreotide for this purpose. A clinical or biological signal in this study would potentially provide 
justification for a large-scale multicenter randomized controlled trial of lanreotide to prevent 
pancreatic fistulae. Below is a schema of the study design:  
 


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Prior to  
Enrollment 
 
 
 
Visit 1 
1 to 60 days prior to 
planned operation 
 
 
 
 
Day of operation 
 
 
 
 
 
 
  
 
 
 
 
During initial  
hospitalization 
and at clinic 
follow-up visit 
 
 
 
 
~30 and 60  
days postop 
 
 
 
 
 
 
 
 
 
Obtain informed consent. Screen potential subjects by inclusion and exclusion 
criteria; obtain history, document. 
Perform baseline assessments. 
Follow-up assessments of outcome measures and safety 
Standard perioperative care and evaluations 
Telephone interviews by research staff 
 
No resection. 
Exclude from analysis. 
Perform 30 and 60 day 
assessments. 
Collect blood for correlative research (optional). 
Administer lanreotide.  
Operating room for attempt at surgical resection.  
Collect blood for correlative research (optional). 
N = 98 subjects undergo surgical resection 
(pancreaticoduodenectomy or distal pancreatectomy +/- 
splenectomy) 
Review medications 
Physical examination 
Laboratory values recorded 


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5 SUBJECT SELECTION  
5.1 
Subject Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Male or female patients age ≥ 18 years 
 
• 
Candidate for planned elective pancreaticoduodenectomy or distal pancreatectomy for 
malignancy or suspected malignancy 
 
• 
Able to provide informed consent 
 
• 
Able to adhere to dose and schedule of visits  
 
• 
Female subject of childbearing potential should have a negative clinical urine or serum 
pregnancy test within 72 hours prior to study drug administration. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
• 
Female subjects who are at risk of becoming pregnant must agree to use an effective 
method of contraception such as double barrier contraception, an injectable, combined 
oral contraceptive or an intra-uterine device (IUD). The subject must agree to use the 
contraception during the whole period of the study and for three months after the study 
drug administration. Non childbearing potential is defined as being postmenopausal for 
at least 1 year, or permanently sterilized at least 3 months before study entry. 
 
 
5.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
• 
Use of disallowed concomitant medications 
• 
Has been treated with an SSA at any time prior to planned study drug administration, 
except if that treatment was for less than 15 days of short acting SSA or one dose of 
long acting SSA and the treatment was received more than 6 weeks prior to 
randomization 
• 
Planned tumor enucleation or total pancreatectomy 
• 
Pregnancy or breastfeeding 
• 
Malabsorption syndrome, short bowel, or chologenic diarrhea uncontrolled by specific 
therapeutic interventions 
• 
NYHA Class III or IV congestive heart failure, unstable angina, sustained ventricular 
arrhythmia, advanced heart block, clinically significant bradycardia, or acute myocardial 
infarction within six months before enrollment; patients with asymptomatic sinus 


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bradycardia will not be excluded, but will be intensively monitored on telemetry for at 
least 6 hours following drug administration, even in the event that complete surgical 
resection is not performed. 
• 
Severe renal insufficiency as defined by a calculated creatinine clearance <30 mL/min 
• 
Moderate to severe hepatic impairment as defined by liver enzyme elevation more than 
5 times the upper limit of normal (either AST >190 U/L or ALT >320 U/L); patients with 
normalization of their liver enzymes to below these levels prior to study enrollment will 
not be excluded 
• 
Known allergic reactions to components of the study drug 
• 
Has been treated with Peptide Receptor Radionuclide Therapy (PRRT) at any time prior 
to randomization 
• 
Treatment with systemic immunosuppressive medications, such as cyclosporine, 
tacrolimus, or prednisone (≥10 mg daily) within 3 months prior to dosing of study drug 
• 
Treatment with another investigational drug within 10 days prior to dosing of study drug 
• 
Anything that would place the individual at increased risk or preclude the individual’s full 
compliance with or completion of the study. 
6 RECRUITMENT PLAN  
Patients will be recruited from the University of Washington Medical Center and the Seattle 
Cancer Care Alliance. Patient records will be assessed to determine eligibility. Prior to 
enrollment, patients will be told about all potential risks and benefits associated with the study. 
Informed consent will be obtained from all subjects prior to participation in the study. Subjects 
will not receive any compensation for participation in the study. In addition, subjects will not 
incur any additional costs as a result of participation in the study.  
 
7 STUDY INTERVENTION  
All patients enrolled in this study will receive SOMATULINE DEPOT 120 mg immediately prior 
to going to the operating room for planned pancreatic resection. The pharmacist will dispense 
loaded syringes of the study drug. The single preoperative dose will be given in the pre-surgical 
center at the University of Washington by a trained health care professional. The study drug will 
be injected via the deep subcutaneous route in the superior external quadrant of the buttock. 
 
Safety and efficacy will be assessed throughout the study period. Assessment for pancreatic 
and non-pancreatic complications will be made at the time of discharge and in follow-up by the 
attending surgeon. Patients will be evaluated in clinic postoperatively within 21 days of 
discharge for evaluation of the primary endpoint. The research team will perform long term 
follow-up by phone or in person with patients at 30 and 60 days (+/- 10 days at each time point). 


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8 INVESTIGATIONAL PLAN  
8.1 
Duration of Study  
Once enrolled, subjects will receive a SOMATULINE DEPOT 120 mg immediately prior to 
planned pancreatic resection. Subjects will be followed for 60 days. The proposed enrollment 
period and study duration will be 36 months.  
8.2 
Screening and Enrollment 
Subjects undergoing planned elective pancreaticoduodenectomy or distal pancreatectomy for 
malignancy or suspected malignancy will be identified and screened for eligibility. Eligible 
patients who agree to participate will sign a written consent form at this time. At the initial visit, 
eligibility will be confirmed and documented in the study records. 
8.3 
Informed Consent  
Informed consent will be obtained prior to enrollment utilizing the consent form found in 
Appendix A.  
 
8.4 
Study Drug  
 
Lanreotide (SOMATULINE DEPOT) is formulated as a solution for injection in prefilled syringes 
at the dosage for this study of 120 mg/0.5mL. 
 
8.4.1 
Acquisition  
Lanreotide (120 mg/0.5 mL) will be labeled and provided in a single, sterile, prefilled, ready-to-
use polypropylene syringe (fitted with an automatic needle guard) by Ipsen Biopharmaceuticals, 
Inc.  
8.4.2 
Formulation, Packaging, and Labeling  
 
Lanreotide will be formulated as a solution for injection at 120 mg/0.5mL in single-use prefilled 
syringes fitted with an automatic needle guard (SOMATULINE DEPOT). The prefilled syringes 
contain a white to pale yellow, semi-solid formulation. Each prefilled syringe is sealed in a 
laminated pouch and packed in a carton.  
 
8.4.3 
Drug Storage and Stability 
Lanreotide must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light 
in its original package. Keep pouch sealed until injection. Each syringe is intended for single 
use, and will not be used beyond the expiration date on the packaging.   


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8.4.4 
Study Drug Accountability  
SOMATULINE DEPOT 120 mg will be shipped from Ipsen Pharma Biotech to the University of 
Washington Medical Center, Investigational Drug Service (IDS) Pharmacy. The IDS Pharmacist 
will maintain accurate records (including dates) of all supplies received. Current dispensing 
records will be maintained, including the date and amount of medication dispensed per subject. 
If a subject is enrolled but does not receive the study drug because he/she becomes ineligible, 
the unused study drug will be returned to the Investigational Drug Pharmacy. All unused and 
returned study medication not required by applicable federal and state regulations to be held by 
the clinical facility must be destroyed in accordance with applicable federal and state regulations 
or be returned as directed immediately after the study is completed. 
8.5 
Concomitant Medications/Treatments 
A complete list of all medications being taken by subjects will be evaluated during screening, 
prior to enrollment, and on the day of study drug administration. A history of current or previous 
natural somatostatin or somatostatin analog therapy will be specifically elicited, as this would 
lead to exclusion from the study.  
Insulin and oral hypoglycemic medications will be specifically noted, as effects of lanreotide on 
insulin and glucagon secretion may require adjustment of antidiabetic treatments. For patients 
who undergo planned resection, routine aggressive blood glucose monitoring (every 1-2 hours 
for the first day) and administration of intravenous glucose and insulin solutions as needed will 
be performed. 
As noted above (5.2 Subject Exclusion Criteria), patients having taken cyclosporine, tacrolimus, 
or prednisone (≥10 mg daily), or similar immunosuppressive medications, within 3 months of 
study drug dosing are excluded from this study.  
8.6 
Study Drug Administration  
 
All patients enrolled in this study will receive SOMATULINE DEPOT 120 mg on the day of 
surgery, prior to planned surgical resection. The single preoperative dose will be administered 
by a healthcare professional in the pre-surgical center at the University of Washington Medical 
Center. The study drug will be injected via the deep subcutaneous route in the superior external 
quadrant of the buttock. Approximately thirty (30) minutes prior to injection, the sealed pouch of 
SOMATULINE DEPOT will be removed from refrigerator and allowed to come to room 
temperature. The pouch will be kept sealed until injection. 
9 VISIT SCHEDULE AND ASSESSMENTS 
Table 9 lists all of the assessments and the visits at which they are to be performed with an “X”. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. 
 


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Table 9.1: Visit Schedule and Assessments  
 
Visits 
Screen
ing 
visit 
 
Day of surgery to  
Discharge 
Follow-up  
post-discharge 
  
Day -
60 to -1 
Pre-op 
Intra-op 
*Post-op 
Clinic 
follow-up 
days 1-21  
Day 30 
post-op  
Day 60 
post-op 
Informed consent 
X 
 
 
 
 
 
 
Medical history/current medical 
conditions from subject and/or chart 
X 
X 
 
X 
X 
X 
X 
Medication review  
X 
X 
 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Physical exam  (Use clinical results if 
available)  
X 
 
 
X 
X 
 
 
Pregnancy test for women of 
childbearing potential (Use clinical 
test if available) 
X 
X 
 
 
 
 
 
Basic metabolic panel from chart 
X 
 
 
X 
 
 
 
CBC from chart 
X 
 
 
X 
 
 
 
PT, PTT from chart as available 
X 
 
 
X 
 
 
 
AST & ALT from chart 
X 
 
 
X 
 
 
 
Blood glucose from chart 
X 
X 
X 
X 
X 
 
 
Review intensive blood glucose 
monitoring and management per 
clinical protocol 
 
 
X 
X 
 
 
 
Draw blood for correlative research 
(optional) 
 
X 
X 
 
 
 
 
Administer study drug  
 
X 
 
 
 
 
 
Record pain assessments from chart  
 
X 
 
X 
X 
 
 
Administer Symptoms Questionnaire 
 
X  
 
X 
X 
X 
X 
Review vital signs(clinical results) 
X 
 
 
X 
X 
 
 
If surgical drain present: 
 
 
 
 
 
 
 
 
Record drain amylase 
 
levels from chart 
 
 
 
X 
X 
X 
X 
 
Record drain output  
 
in ml from chart 
 
 
 
X 
X 
X 
X 
 
Determine day of drain 
 
removal from chart  
 
 
 
X 
X 
X 
X 
Review for adverse events  
 
 
X 
X 
X 
X 
X 
*Hospital length of stay varies 
 
 
9.1 
Screening Visit (Day -60 to -1)  
Eligible patients will be identified at the SCCA and UWMC SSC surgical oncology clinics. At the 
screening visit, the Research Coordinator (RC) or one of the investigators will obtain signed 


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informed consent. This will take place prior to any procedures being performed. Subjects will not 
receive any compensation for participation in the study. In addition, subjects will not incur any 
additional costs as a result of participation in the study.  
• 
Obtain and document consent from potential subject on study consent form 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria 
• 
Perform physical examination: vital signs, weight, height (use clinical results if available) 
• 
Collect, or obtain from routine care records, the following laboratory studies within 30 
days prior to treatment:   
o Complete blood count with white blood cell differential and platelet counts;  
o Prothrombin time and activated partial thromboplastin time (PT&PTT) 
o Basic metabolic panel, including blood glucose level 
o AST and ALT 
o Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to study drug administration performed for 
routine care. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required for entry into the study. 
9.2 
Day of Surgery to Discharge 
9.2.1 
Preoperative: Baseline (Day 0) 
The baseline visit will take place on the day of surgery, prior to the patient’s operation and 
administration of the study drug. Some subjects initially consented into the study may be 
deemed ineligible on the day of surgery prior to drug administration. The study team will assess 
inclusion/exclusion criteria prior to drug administration.  
• 
Verify inclusion/exclusion criteria 
• 
Obtain demographic information, medical history/current condition, medication list from 
subject and/or chart 
• 
Review results of clinical serum pregnancy test for women of childbearing potential prior 
to drug administration, unless testing negative within prior 72 hours (for example, if 
testing was performed at Screening Visit within the previous 3 days) 
• 
Review preoperative blood glucose level as part of standard perioperative care 
• 
Draw blood for correlative research (Up to 30 ml ml)) prior to study drug administration 
(optional research) 
 


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9.2.2 
Preoperative:  Drug Administration (Day 0) 
The study drug will be administered and other study procedures performed after baseline 
procedures are conducted; prior to the surgery.  
• 
Administer the study drug 
• 
Administer Symptoms Questionnaire 
• 
Review vital signs from chart 
• 
Record results of pain scale from chart  
 
9.2.3 
Intraoperative (Day 0)  
• 
Draw blood for correlative research  (Up to 30 ml) intraoperatively immediately following 
resection (optional research) 
• 
Review results of clinical  intensive blood glucose management consisting of 
approximately hourly blood glucose level checks and insulin infusion per standard 
perioperative care protocol 
 
9.2.4 
Hospital Stay (Postoperative Days 0-7) 
Subjects who receive the study drug and have a clinical resection will be followed 
postoperatively for 60 days. The initial postoperative assessment will occur during the subject’s 
hospital stay. Hospital stays will vary widely by patient, but are expected to range from 3-7 days. 
The study team will periodically review the patient chart for safety and outcomes as available for 
individual subjects during this timeframe.  
• 
Record adverse events as reported by subject or observed by clinical team and/or 
investigator. See section 10.2 for list of information to be reviewed for adverse event 
monitoring 
• 
Obtain medical history/current condition, medication list from subject’s chart 
• 
Record results of physical examination  from subject’s chart 
• 
Review results of clinical intensive blood glucose management per standard 
perioperative care protocol.  
• 
Collect the following laboratory studies, as available from routine care records:  
o Complete blood count with white blood cell differential and platelet counts;  
o Prothrombin time and activated partial thromboplastin time (PT&PTT) 
o Basic metabolic panel 
o AST and ALT 
• 
Review  vital signs from chart 
• 
Record results of pain scale from chart  


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• 
Administer Symptoms Questionnaire 
• 
Record drain amylase levels from chart, as available  
• 
Record drain output in ml from chart, as available 
• 
Evaluate for day of drain removal from chart, as available 
For subjects who receive the study drug but do not have a clinical resection performed during 
their surgery, the study team will review adverse events related to the study drug during the 
immediate postoperative hospital stay, and contact them by phone at 30 and 60 days to ask 
about their symptoms. No other procedures will be performed.  
 
9.3 
Follow-up Post Discharge  
9.3.1 
Clinic Follow-up Visit (Post discharge Days 1-21)  
Subjects will typically have a clinical follow-up appointment with their UW Medicine surgical 
provider or an external provider within 1 – 21 days following discharge. There may be more 
than one clinical appointment during this timeframe. The study team will review patient 
charts and collect information on individual subjects as available from their clinical care. 
Subjects who are seen at UW Medicine will receive an in-person symptoms questionnaire to 
complete. Subjects who have their follow-up care performed external to UW Medicine will 
receive a phone call from the research coordinator (RC) between 1 and 21 after discharge 
to complete the symptoms questionnaire by phone. Records from external institutions will be 
obtained and reviewed for the timeframe.  
• 
Record adverse events as reported by subject or observed by clinical team and/or 
investigator 
• 
Obtain medical history/current condition, medication list from subject and/or chart 
• 
Record results of clinical physical examination 
• 
Collect from routine care records the following laboratory studies, as available:  
o Complete blood count with white blood cell differential and platelet counts;  
o Comprehensive profile; prothrombin time and activated partial thromboplastin 
time (PT&PTT) 
• 
Review vital signs from chart 
• 
Record results of pain scale from chart  
• 
Administer Symptoms Questionnaire 
9.3.2 
Follow-up Phone Call (Postoperative Days 30 & 60) 
The RC will follow-up with all subjects by phone at approximately 30 and 60 days 
postoperatively to identify missed complications. If the RC identifies a missed complication by 
phone, the Principal Investigator or Co-Investigator will then contact the subject with a second 
phone call to discuss the reported complications in more detail.  


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Patient charts will be reviewed throughout 60 days postoperatively. Some subjects may receive 
their follow-up care outside of UW Medicine. In this case, records from external institutions will 
be obtained and reviewed for the timeframe.  
• 
Record adverse events as reported by subject or observed by investigator. 
• 
Obtain medical history/current condition, medication list 
• 
Administer Symptoms Questionnaire 
• 
Review clinical charts for complications, as available  
10 ASSESSMENT OF SAFETY  
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse 
Events—Version 4.03. A copy of the CTCAE 
v4.03 can be downloaded from the NIH at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_
4.03_2010-06-
14_QuickReference_8.5x11.pdf 
10.1 
Adverse Event Overview  
 
An adverse event in this protocol is the 
appearance of, or worsening of preexisting, 
undesirable sign, symptom, or medical 
condition, after signing the informed consent, 
that 
is 
not 
considered 
to 
be 
a 
postoperative complication, whether or 
not the event is considered to be related to 
the study drug. Common postoperative 
complications that will not considered be an 
adverse event of the study drug are 
presented in Table 10.1.  
 
An adverse event is any untoward medical 
occurrence in a clinical investigation in 
which a subject has been administered a 
pharmaceutical product.  The adverse event 
does not necessarily have to have a causal 
relationship with this treatment. An adverse 
event can therefore be any unfavorable or 
unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of an 
investigational product, whether or not 
Table 10.1:  The most frequent complications 
following 351 pancreatic resections performed 
at the University of Washington Medical 
Center from 2011 through 2016, based upon 
data from the National Surgical Quality 
Improvement Program. 
Complication 
n (%) 
Hemorrhage requiring blood 
transfusion  
37 (11%) 
Intra-abdominal infection/abscess 
25 (7%) 
Sepsis or septic shock 
22 (6%) 
Wound Infection 
18 (5%) 
Delayed gastric emptying†  
4 (5%) 
Pneumonia or unplanned 
intubation or mechanically 
ventilated >48 hours 
13 (4%) 
Anastomotic leak, biliary or 
pancreas* 
5 (3%) 
Fistula, pancreatic or biliary  
8 (2%) 
Urinary tract infection, acute renal 
failure or progressive renal 
insufficiency 
6 (2%) 
Pulmonary embolus or DVT 
requiring therapy 
6 (1%) 
†Data only available for last 87 cases 
*Data only available for last 164 cases 


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considered related to the medicinal product.  Adverse events associated with the use of a drug 
in humans, whether or not considered drug related, include the following: 
• 
An adverse event occurring in the course of the use of a drug product in professional 
practice. 
• 
An adverse event occurring from drug withdrawal. 
• 
An adverse event where there is a reasonable possibility that the event occurred purely 
as a result of the subject’s participation in the study  
 
The clinical manifestation of any failure of expected pharmacological action is not recorded as 
an adverse event if it is already reflected as a data point captured in the case report form and 
source documents.  If, however, the event fulfills any of the criteria for a “serious” adverse 
event, it must be recorded and reported as such. 
 
Separate instructions will be provided on how to complete the adverse events and SAE forms. 
 
If grading does not exist for a particular adverse event, the severity of mild, moderate, severe, 
life threatening, and leading to death, or grades 1 - 5, will be used. Adverse event monitoring 
will be continued for approximately 60 days following the administration of the study drug. 
Adverse events (but not serious adverse events) occurring before starting study treatment but 
after signing the informed consent form will be recorded. Abnormal laboratory values or test 
results constitute adverse events and will be recorded only if they induce clinical signs or 
symptoms and are considered clinically significant or require therapy.  
 
Subjects will be carefully monitored for adverse events.  An adverse event will be evaluated to 
determine:    
1. Its severity grade 
2. Its relationship to study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. If action was taken (no action taken; medication administered; non-drug therapy given; 
subject hospitalized or hospitalization prolonged) 
5. Whether it is serious 
10.2 
Data Collection for AE Review 
The study team will review patient charts to assess safety for this study throughout 60 days 
postoperative. If a clinical complication is identified, the following variables will be reviewed for 
adverse event monitoring:   
 
• 
Readmission 
• 
Admission to ICU 
• 
Pain scale 
• 
Drain placement 
• 
Reoperation 
• 
Institution of antimicrobial therapy 
• 
Vital signs 


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• 
WBC 
• 
Presence or absence of abscess on CT scan 
• 
Drain amylase level 
• 
Drain output in ml per day 
10.3 
Serious Adverse Event (SAE) 
 
A serious adverse event is an undesirable sign, symptom or medical condition that is not felt to 
be a postoperative complication and has one or more of the following characteristics: 
 
• 
Results in death. 
• 
Is life threatening. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event  
 
Life threatening:  The term “life-threatening” in the definition of “serious” refers to an adverse 
event in which the subject was at risk of death at the time of the event.  It does not refer to an 
adverse event, which hypothetically might have caused death if it were more severe. 
 
Re-admission to the hospital is common following pancreatic resection (~20%) and will not be 
reported as an SAE nor will it be reported in an expedited manor, unless probably or definitely 
related to study drug administration. The planned admission to the hospital will not be reported. 
However, it should be noted that invasive treatment during any hospitalization may fulfill the 
criteria of ‘medically important’ and as such may be reportable as a serious adverse event 
dependent on clinical judgment.  In addition where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedent. 
 
Disability:  a substantial disruption of a person’s ability to conduct normal life functions. 
 
Important medical event:  Any adverse event may be considered serious because it may 
jeopardize the health of the subject and may require intervention to prevent another serious 
condition.  As guidance for determination of important medical events refer to the “WHO 
Adverse Reaction Terminology-Critical Terms List.”  These terms either refer to or might be 
indicative of a serious disease state. Such reported events warrant special attention because of 
their possible association with a serious disease state and may lead to more decisive action 
than reports on other terms.   
SAEs will be reported to the study medical monitor within 24 hours of learning of the event and 
followed up until resolution, in accordance with the guidelines set forth by federal agencies. 
Listings of adverse events will be generated quarterly to assess for trends or unexpected 
events, and examined for possible patterns between the groups and over time. If potential 
trends or unexpected events are noted, a summary will be provided to the medical monitor for 
review and evaluation.  


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10.4 
Unexpected Adverse Event 
 
An unexpected adverse event is any adverse drug event, which is not consistent with the 
current package insert.  Also, if a report adds information, which is more specific or severe than 
the documented adverse event, this constitutes an unexpected adverse event.  For example, 
an event more specific or more severe than described in the Investigator Brochure would be 
considered “unexpected.”  
10.5 
Relationship of Adverse Event to Investigational Drug  
 
The assessment of the relationship of an adverse event to the administration of study drug is a 
clinical decision based on all available information at the time of the completion of the case 
report form. 
 
An assessment of ‘No’ would include: 
 
• 
The existence of a clear alternative explanation  
 
 
 
OR 
 
• 
Non-plausibility (e.g., The subject is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing 
a few days after the drug administration). 
 
An assessment of ‘Yes’ indicates that there is a reasonable suspicion that the adverse event is 
associated with the use of the investigational drug. 
 
Factors to be considered in assessing the relationship of the adverse event to the study drug 
include: 
 
• 
The temporal sequence from drug administration: the event should occur after the drug 
is given. The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
• 
Underlying, concomitant, intercurrent diseases: each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have. 
• 
Concomitant medication or treatment:  the other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might be suspected to cause the event in question. 
• 
The 
pharmacology 
and 
pharmacokinetic 
properties 
(absorption, 
distribution, 
metabolism, and excretion) of the test drug, coupled with the individual subject’s 
pharmacodynamics should be considered. 


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10.6 
Severity of the Adverse Event 
 
The severity of adverse events should be graded as follows: 
 
1 – Mild - usually transient in nature and generally not interfering with normal activities 
2 – Moderate – sufficiently discomforting to interfere with normal activities 
3 – Severe – prevent normal activities 
4 – Life-threatening – leads to severe disability 
5 – Death 
 
10.7 
Adverse Event Documentation 
 
All adverse events occurring after the subject has signed the informed consent up through the 
60-day follow up period, must be fully recorded in the subject’s case report form. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, 
should be reported as an adverse event.  Each event should be described in detail along with 
start and stop dates, severity, relationship to investigational product, action taken and outcome.   
10.8 
Reporting of Serious Adverse Events 
 
SAE’s including laboratory test abnormalities fulfilling the definition of serious, after signing the 
informed consent must immediately (within 24 hours of the investigator’s awareness) be 
reported to the person detailed in the study file.  A SAE form must also be completed within 24 
hours of the investigator awareness and forwarded to the designated person as detailed in the 
study file.  Each serious adverse event must be followed up until resolution or stabilization by 
submission of updated reports to the designated person. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Institutional Review Board at each trial site where the SAE occurs. SAEs will 
also be reported to the coordinating center at the University of Washington.  
10.9 
Stopping Rules 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause.  
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the FDA.  If the study is prematurely 
terminated or suspended, the principal investigator will promptly inform the IRB and will provide 
the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 


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• 
Determination of unexpected, significant, or unacceptable risk to subjects. 
• 
Insufficient adherence to protocol requirements. 
• 
Data that are not sufficiently complete and/or evaluable.  
11 OUTCOME ASSESSMENT 
11.1 
Primary Endpoints  
The primary outcome variable is reduction in the incidence of intraabdominal abscess or 
development of clinically significant (grade B or C) pancreatic fistula before 60 days 
postoperatively.  These complications are being considered together, as they represent a 
common etiology (pancreatic leak), clinical presentation (systemic signs of infection or sepsis), 
and treatment (antimicrobial therapy with or without percutaneous or operative drainage).  
 
Assessment for the diagnosis of intraabdominal abscess or the development of grade B or C 
pancreatic fistula will be made at the time of discharge and in follow-up by the attending 
surgeon in clinic postoperatively within 21 days of operation. The clinical findings used in 
Grading POPF noted in Table 1 (clinical condition, specific treatment, imaging results, 
persistence of drainage after 21 days, reoperation, death related to POPF, signs of infection, 
sepsis, and readmission) will be gathered during inpatient admission(s), at postoperative visit(s), 
and at planned 30- and 60-day follow up phone calls. 
11.2 
Secondary Endpoints 
 
The secondary endpoints include the following: 
1. Grade A pancreatic fistula will be defined based on principles noted in evaluation of 
Primary endpoint. 
2. Surgical site infection is defined as purulent drainage from a surgical wound, requiring 
intervention including, but not limited to, institution of antimicrobial therapy or opening of 
the wound. 
3. Overall morbidity will be an aggregate of all perioperative complications. 
4. Drain amylase levels on day 1 & 3 postoperatively will be collected on a routine basis, as 
part of our standardized care pathway. Mean and median drain amylase levels at each 
time point will be calculated. 
5. Duration of drainage for patients with pancreatic fistulae will be defined based upon the 
date of drain removal subtracted from the date of drain placement. 
12 SUBJECT WITHDRAWL  
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following occur: 
 


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• 
Pregnancy discovered after enrollment, but prior to study drug treatment 
• 
Protocol violation 
• 
Subject withdrawal of consent  
• 
Lost to follow-up 
• 
Do not have clinical resection performed post drug administration  
• 
Death 
12.1 
Replacement of Subjects 
Subjects withdrawn from the study prior to administration of the study drug will be replaced. 
Subjects withdrawn from the study after administration of the study drug and who do not have a 
clinical resection performed will not be replaced. Other subjects withdrawn prior to complete 60-
day follow up will not be replaced. If subjects do not respond to phone follow-up at 30 or 60 
days, three repeated attempts will be made over the 10 days following each of these time 
points. Subjects who have incomplete follow up will be included with limited follow up. 
13 BIOSTATISTICS  
13.1 
Sample Size and Power 
 
We estimate the final target sample size will be 98 patients. We aim to screen 154 patients and 
enroll n=123 patients into this single-arm study to test whether treatment with lanreotide 
reduces the risk of postoperative pancreatic fistula. Based upon a 20% probability of not 
proceeding with surgical resection after drug treatment due to findings of metastatic or 
unresectable disease at surgery, we anticipate that 123 treated patients will yield 98 evaluable 
patients. 
13.2 
Analysis Plan  
 
As a primary method analysis, we will use a one-sample t-test to compare the rate of 
postoperative pancreatic fistula among the n=98 patients who were treated with lanreotide and 
underwent surgical resection against a published rate of 21% for patients treated with a placebo 
in another study, while 9% of patients treated with pasireotide experienced postoperative 
pancreatic fistula. The present study has 80% power (one-sided alpha = 0.05) to detect 
pancreatic fistula rates smaller than 11.5%, the approximate upper estimate of an 80% 
confidence interval of the pancreatic fistula rate of 9% in the study of pasireotide. 
 
As a secondary exploratory analysis, we will use McNemar’s test to compare the pancreatic 
fistula rate in the present study to that of historical controls at the same institution matched on 
pancreatic firmness and duct size.  
 


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14 DATA MANAGEMENT, MONITORING, AND RETENTION 
A RC will be assigned to the study. The responsibilities of the RC include project compliance, 
data collection, abstraction and entry, data reporting, regulatory monitoring, problem resolution 
and prioritization, and coordinate the activities of the protocol study team. The data collected for 
this study will be entered into a secure database. Source documentation will be available to 
support the computerized patient record. 
14.1 
Data Management  
All data procedures will be conducted using good computing practices for the handling and 
analysis of data for clinical trials. Study personnel will enter data from source documents 
corresponding to a participant’s day on study onto the CRF when the information corresponding 
to that day is available. The data collected for this study will be entered into a secure database. 
Source documentation will be available to support the computerized patient record. Study 
participants will not be identified by name on any study documents to be collected by the 
Sponsor or authorized designee, but will be identified by an identification number and participant 
initials. 
All clinical information requested in this protocol will be entered on the CRFs. CRF corrections 
will be made without obliterating the original entry.    
The Principal Investigator is responsible for all information collected on participants enrolled in 
this study. All data collected will be reviewed by the PI throughout the course of the study for 
completeness and accuracy.  
14.2 
 Data and Safety Monitoring 
This study will be monitored for subject safety, protocol compliance, and data integrity. In 
addition to the PI’s responsibility for oversight, a medical monitor will provide objective review of 
the protocol and protect the safety of the subjects. The medical monitor will be independent of 
the study team; with expertise in surgery. The medical monitor will assess for safety and 
efficacy data (if applicable), study progress, and data integrity for the study. The medical 
monitor will review the study data after the first 15 subjects have completed the 60 day study 
period. Thereafter, the medical monitor will review the study data after 50 subjects and 123 
subjects have completed study procedures. The medical monitor can recommend early 
termination of the trial at any time for safety concerns. The medical monitor will be informed of 
all serious adverse events at the reviews, and at other times if substantial numbers or unusual 
kinds of serious adverse events occur.  
 
Serious adverse events (as defined in 21 CFR 312.32) will be reported to the study medical 
monitor and Ipsen within 24 hours of learning of the event and followed up until resolution, in 
accordance with the guidelines set forth by federal agencies. Listings of adverse events will be 
generated at the end of enrollment to assess for trends or unexpected events, and examined for 


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possible patterns between the groups and over time. If potential trends or unexpected events 
are noted, a summary will be provided to the medical monitor for further review and evaluation. 
 
In addition, all SAEs will be emailed to Ipsen at drugsafety@propharmagroup.com 
  
14.3 
Availability and Retention of Investigational Records 
The Sponsor or authorized designee must make study data accessible to regulatory authorities 
upon request. A file for each participant must be maintained that includes the signed Informed 
Consent and copies of all source documentation related to that participant. The Investigators 
must ensure the reliability and availability of source documents from which the information on 
the CRF was derived. 
14.4 
Archiving of Data 
At all times, appropriate backup copies of the database and related software files will be 
maintained and the information will be appropriately protected from illegitimate access. 
Databases will be backed up by the database administrator in conjunction with any updates or 
changes to the database. Tape or cartridge backup copies will be maintained at an off-site safe 
storage location.  When the structure of the database is changed, a permanent archive of the 
database will be made to protect against loss of data in the changeover. When each backup is 
made, the media will be checked for usability and the integrity of the database will be verified. 
At completion of data verification, a permanent archive of the database will be made. Archived 
versions of the database will be saved for at least three years after the end of the study.  
14.5 
Participant Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations will not be made publicly available. 
To maintain participant confidentiality, only an identification number, and participant initials will 
identify all study participants in reports and on specimens. Only the subject number will be 
recorded in the case report form, and if the subject name (or initials) appears on any other 
source document, (e.g. lab work), it must be obliterated before a copy of the document is 
included in the case report form. 
All records identifying the subject, including contact information, will be kept confidential and in a 
location, separate from the case report form. Study findings stored on a computer will be stored 
in accordance with local data protection laws.  The subjects will be informed in writing that the 
IRB or Regulatory Authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.   
If the results of the study are published, the subject’s identity will remain confidential. The 
investigator will maintain a list to enable subjects’ records to be identified. 


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15 ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
15.1 
Institutional Review Board 
 
Documented approval from the IRB will be obtained prior to the start of the study from the 
University of Washington Human Subjects Division. The written approval of the IRB together 
with the approved ICF will be stored in the study files. When necessary, an extension, 
amendment or renewal of the IRB approval will be obtained.  
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice guidelines and under the guiding principles detailed in the Declaration of 
Helsinki. The study will also be carried out in keeping with applicable local law(s) and 
regulation(s). This may include an inspection by Regulatory Authority representatives at any 
time.  The investigator must agree to the inspection or study-related records by the Regulatory 
Authority representative, and must allow direct access to source documents to the Regulatory 
Authority representatives. 
15.2 
Protocol Modifications  
 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment. Some modifications also require approval by the IRB.  These requirements for 
approval should in no way prevent any immediate action from being taken by the investigator in 
the interests of preserving the safety of all patients included in the trial. If an immediate change 
to the protocol is felt to be necessary by the investigator and is implemented for safety reasons, 
the IRB must be notified immediately. Any deviations from the protocol must be fully explained 
and documented by the investigator. 
15.3 
Informed Consent 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed 
consent, which must conform to UW IRB guidelines. An Informed Consent Form (ICF) will be 
provided to eligible subjects. The ICF will document the study-specific information the 
Investigator provides to the participant and the participant’s agreement to participate. Among 
other things, the Investigator will fully explain in layman's terms the nature of the study, along 
with the aims, methods, anticipated benefits, potential risks, and discomforts.  The ICF must be 
signed and dated by both patient and investigator before any study-related procedures are 
performed.  The original and any amended signed and dated ICFs must be retained in the 
participant’s file; one copy will be returned to the patient, and one will be placed in the patient’s 
medical record.  
 
 


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15.4 
Research Authorization 
 
In addition to signing the ICF, all patients must sign the Research HIPAA Authorization Form. 
This contains information about the Health Insurance Portability & Accountability Act (HIPAA) 
that protects the participant’s individually identifiable health information (protected health 
information) and authorization (or agreement) for researchers to be able to use or disclose the 
participant’s protected health information for research purposes. The Research HIPAA 
Authorization requires a separate set of signatures from the patient. The original signed 
documents will become part of the patient’s medical record, and each patient will receive a copy 
of the signed documents. 
15.5 
Quality Control and Quality Assurance  
The PI or authorized designee will conduct audits.  Study site audits will include review of 
regulatory documents, including study drug and device accountability records and medical 
source documents.  Data and information will be disclosed to the regulatory authorities in full 
compliance with applicable regulations.   
15.6 
Regulatory Authority Approvals/Authorizations 
 
Regulatory Authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start. 
15.7 
Investigator Responsibilities 
The Investigators agree to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the PI (or authorized designee), except when to protect the safety, rights, or welfare of 
subjects/participants. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the PI/Medical Monitor any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments and are listed on the 
appropriate study documents. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the PI or authorized designee. 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. To promptly report to the IRB and the PI or authorized designee all changes in the research 
activity and all unanticipated problems involving risks to subjects/participants or others. 


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9. Not make any changes in the research study without IRB approval, except when necessary 
to eliminate hazards to the subjects/participants. 
10. To comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements listed in § 21 CFR part 312. 
 


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16 LITERATURE REFERENCES 
1. 
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Dec;21(13):4059–67.  
2. 
van der Gaag NA, Rauws EAJ, van Eijck CHJ, Bruno MJ, van der Harst E, Kubben 
FJGM, et al. Preoperative Biliary Drainage for Cancer of the Head of the Pancreas. N 
Engl J Med. 2010 Jan 14;362(2):129–37.  
3. 
Reid-Lombardo KM, Farnell MB, Crippa S, Barnett M, Maupin G, Bassi C, et al. 
Pancreatic Anastomotic Leakage After Pancreaticoduodenectomy in 1,507 Patients: A 
Report from the Pancreatic Anastomotic Leak Study Group. J Gastrointest Surg. 
Springer-Verlag; 2007;11(11):1451–9.  
4. 
Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative 
pancreatic fistula: an international study group (ISGPF) definition. 2005. pp. 8–13.  
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Hashimoto Y, Traverso LW. Pancreatic anastomotic failure rate after 
pancreaticoduodenectomy decreases with microsurgery. J Am Coll Surg. 2010 Oct 
1;211(4):510–21.  
6. 
Shukla PJ, Barreto SG, Fingerhut A, Bassi C, Büchler MW, Dervenis C, et al. Toward 
improving uniformity and standardization in the reporting of pancreatic anastomoses: a 
new classification system by the International Study Group of Pancreatic Surgery 
(ISGPS). Surgery. 2010 Jan 1;147(1):144–53.  
7. 
Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic 
surgery. Gurusamy KS, editor. Cochrane Database Syst Rev. Chichester, UK: John Wiley 
& Sons, Ltd; 2013;4:CD008370.  
8. 
Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prévost G, et al. Tumor 
shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a 
prospective multicenter clinical trial. J Clin Endocrinol Metab. 2014 Apr;99(4):1282–90.  
9. 
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in 
metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 
17;371(3):224–33.  
10. 
Allen PJ, Gönen M, Brennan MF, Bucknor AA, Robinson LM, Pappas MM, et al. 
Pasireotide for postoperative pancreatic fistula. N Engl J Med. 2014 May 
22;370(21):2014–22.  
 
 
 


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APPENDIX A: CONSENT FORM