A Phase II Trial of Pre-Operative Endoscopic Botulinum Toxin Injection in the Prevention of Postoperative Pancreatic Fistula Following Distal Pancreatectomy
Phase: PHASE2
Conditions: Pancreatic Carcinoma
Sponsor: OHSU Knight Cancer Institute

 
 
 
 
Full Study Title: 
A Phase II Trial of Pre-operative Endoscopic Botulinum Toxin 
Injection in the Prevention of Postoperative Pancreatic Fistula 
following Distal Pancreatectomy  
Protocol Number:  IRB # 22619 
ClinicalTrials.gov ID:  NCT04965311 
Investigational Product: Botulinum Toxin (OnabotulinumtoxinA; Botox) 
Version Number:  2.0 
Version Date: 10/2/2023 
Replaces: 1.5 
Principal Investigator: Brett Sheppard, MD 
 
Department of Surgery 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, L223  
Portland, OR 97239  
Phone:  503-494-1502 
Fax: (503)494-8884 
Email: sheppard@ohsu.edu 
Statistician: 
Byung Park, PhD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road  
Phone: 503-418-0127 
Email: parkb@ohsu.edu 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
SUMMARY OF CHANGES 
 
# 
Section 
Summary of Changes 
Justification 
1 
3.1, 
11.4.5 
Changed the protocol driven DSMC 
review to be done following the 
completion of the first three 
participant’s safety evaluations periods 
(30 days following BTX injection or 
30 days following surgery, whichever 
is longer).  The study DSMC review 
was originally planned following the 
completion of 6 patients, however due 
to the slow study accrual we have 
revised it to be following the 
completion of three patients. 
Clarification was requested by 
Knight DSMC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
SYNOPSIS 
 
Full Study Title 
A Phase II Study of Pre-operative Endoscopic Botulinum Toxin 
Injection in the Prevention of Postoperative Pancreatic Fistula following 
Distal Pancreatectomy 
Protocol # 22619 
Coordinating Center OHSU, Knight Cancer Institute    
Clinical Phase Phase II - Single Agent  
 
Study Description 
 
Pancreatic resections are inherently morbid operations with complication 
rates of approximately 40%, the most feared of which is leakage of 
pancreatic digestive enzymes into the abdominal cavity, termed 
postoperative pancreatic fistula (POPF). POPF occurs in approximately 
30% of distal pancreatectomies, and can dramatically alter the recovery 
pathway. Pre-operative endoscopic botulinum toxin (BTX) injection into 
the Sphincter of Oddi has been hypothesized to reduce the rate of POPF 
following distal pancreatectomy.  The present study is a single-arm Phase 
II interventional study investigating the use of endoscopic botulinum 
toxin injection into the Sphincter of Oddi prior to distal pancreatectomy 
to prevent POPF. Intervention will occur 7-14 days prior to planned distal 
pancreatectomy, and further data collection/treatment will occur per 
standard of care. Safety of the intervention will be assessed, and patients 
will be compared to matched historical patients for analysis of POPF rates.  
 
Primary Objective To determine the effect of pre-operative endoscopic BTX injection on 
clinically relevant POPF rates following distal pancreatectomy 
Secondary Objectives 
1) To determine the safety of pre-operative endoscopic BTX injection 
2) To determine the effect of pre-operative endoscopic BTX injection on 
the rate of all POPF (biochemical and clinically relevant) following 
distal pancreatectomy 
Exploratory Objectives 
To evaluate differences in:  
1) crPOPF,  
2) POPF,  
3) postoperative length of hospital stay,  
4) rate of Clavien-Dindo grade III or greater complications,  
5) rate of percutaneous drainage,  
6) rate of unplanned re-operation,  
using a historical population matched for potential confounding 
clinicopathologic variables.  
Primary Endpoint Rate of clinically relevant POPF (crPOPF) in intervention group  
Secondary Endpoints 
1) Rate of serious adverse events following endoscopic BTX 
injection (e.g., clinical pancreatitis, bleeding, perforation, or other 
events delaying time to surgery or receipt of surgery) 
2) Rate of any POPF in intervention group  
Exploratory Endpoints 1) Clinically relevant POPF (binary) 
2) Any POPF (binary) 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
3) Postoperative Length of Hospital Stay (continuous) 
4) Clavien-Dindo III or greater postoperative complications 
(binary) 
5) Rate of percutaneous drainage procedure (binary) 
6) Rate of unplanned re-operation (binary) 
 
Key Inclusion Criteria 
1. Patient scheduled for elective distal pancreatectomy or radical 
antegrade modular pancreatosplenectomy (RAMPS), via open or 
laparoscopic technique 
2. Participant aged ≥ 18 years 
3. Ability to understand nature and individual consequences of clinical 
trial 
4. Written informed consent 
5. For participants of childbearing potential, a negative pregnancy test 
and adequate contraception until 14 days after trial intervention 
 
Key Exclusion Criteria 
 
1. Known hypersensitivity to any BTX preparation or to any 
of the components in the formulation 
2. Infection at the proposed injection site, including 
cholangitis 
3. Anatomy incompatible with planned intervention (e.g., 
Roux-en-Y gastric bypass, distal gastrectomy with Roux-
en-Y or Billroth II reconstruction) 
4. Acute pancreatitis within 2 weeks of planned study 
intervention 
5. Pancreas divisum 
6. ASA score > III 
7. Serious cardiovascular disease (e.g., Myocardial infarction 
in the past year, NYHA III/IV congestive heart failure, 
unstable angina). 
8. Creatinine clearance <30mL/min 
9. Liver cirrhosis (of any Child-Pugh grade) 
10. Neuromuscular or any neurological disease with associated 
increased risk for a participant undergoing BTX injection 
11. Prior BTX administration 
12. Inability to obtain informed consent from participant or 
legally authorized representative.  
13. Inability to comply with study and/or follow-up procedures 
14. Pregnancy or lactation 
15. Any condition that could result in undue risk for the 
participant and/or influence outcome measures (in the 
opinion of the investigator) 
 
Number of Participants 
Up to 64 participants will be consented. Up to 55 patients will undergo 
the study intervention such that 50 patients will undergo the study 
intervention and complete 30-day postoperative follow-up. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of Therapy A one-time endoscopic injection of BTX with no further study 
interventions 
Duration of Follow Up Up to 30 days following distal pancreatectomy. 
 
Description of Study
Intervention
Preoperative endoscopy with Sphincter of Oddi BTX injection will be the 
only trial-related intervention for patients participating in this trial. All the 
other procedures, including assessment of laboratory parameters, belong 
to the standard perioperative and postoperative procedures performed in 
patients undergoing distal pancreatectomy. In patients with childbearing 
potential, a pregnancy test will be performed during the routine 
preoperative laboratory examinations. 
 
Statistical Analyses 
This is a single arm, open-label, Phase II study to estimate the rate of 
clinically relevant POPF in participants that receive pre-operative 
endoscopic BTX injection.  Using a Simon’s 2-stage, a total of 50 
evaluable participants will achieve an 88% power to detect a difference 
in crPOPF rate of 9.2% (H0: π = 0.112 versus Ha: π =0.02; with a one-
sided alpha level of 0.05). The trial will be continued following stage 1 
if there is one or fewer crPOPF among the first 25 participants. If the 
study proceeds to stage 2, a total of 50 participants will be evaluated 
towards the primary endpoint, and the intervention considered promising 
if there are two or fewer cases of crPOPF.   
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
 
 
 
SCHEMATIC OF STUDY DESIGN  
 
BTX Injection 
Surgery and Postoperative Period 
Procedure 
Day 
1 
Day 7-14 (Pre-
operative 
Medicine 
Appointment)* 
Day 1 (Day 
of 
Surgery) 
Day 4 
(Postoperative 
Day 3) 
Day of 
Discharge 
Discharge + 7-
14 Days (Post-
Operative 
Follow-up) 
Day 
30  
Physical exam 
X 
 
  
X* 
X* 
 X* 
 X* 
  
  
Vital signs1 
X 
X* 
X* 
X* 
X* 
X* 
 
  
ECG (if 
indicated) 
X* 
X* 
 
  
  
  
  
Routine blood 
draw2 
(1 tablespoon) 
X* 
X* 
X* 
 
 
 
Drain Fluid 
Analysis 
 
 
 
X* 
 
 
 
Pregnancy test 
(if indicated) 
X 
X* 
X* 
 
 
 
 
  
Review any 
adverse events 
X 
X 
 
 
 
X 
Review all other 
medications 
X 
  
X 
X 
 
 
 
 
BTX Injection 
X 
 
 
 
 
 
 
Distal Pancreas 
Resection 
 
 
X* 
X* 
 
 
 
IN THE EVENT OF OPERATIVE DELAYS, PATIENTS STILL EVALUABLE FOR EFFICACY IF RECEIVING SURGERY UP TO 
28 DAYS FROM BTX INJECTION. A PRE-OPERATIVE MEDICINE APPOINTMENT PRIOR TO BTX INJECTION IS 
GENERALLY NOT NEEDED, BUT MAY BE REQUESTED FOR SOME PATIENTS DEPENDING ON HEALTH STATUS AND 
CLINICIAN DISCRETION 
 
 
 
 
 
 
 
 
* Interventions/monitoring per standard of care 
1 Can include heart rate, blood pressure, height, weight, oxygen saturation, temperature 
2 Can include CBC with differential, chemistry, magnesium, uric acid 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .........................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
SCHEMATIC OF STUDY DESIGN ...........................................................................................6 
TABLE OF CONTENTS ............................................ ERROR! BOOKMARK NOT DEFINED. 
LIST OF TABLES .......................................................................................................................12 
LIST OF FIGURES .....................................................................................................................12 
LIST OF ABBREVIATIONS .....................................................................................................13 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...........................14 
1.1 
Background ...................................................................................................................14 
1.1.1 Overview of study TERMS ......................................................................................15 
1.1.2 Overview study intervention(s) ................................................................................15 
1.2 
Study Rationale .............................................................................................................16 
1.3 
Risk/Benefit Assessment ...............................................................................................16 
1.3.1 Known Potential Risks .............................................................................................16 
1.3.2 Known Potential Benefits .........................................................................................17 
2. OBJECTIVES AND ENDPOINTS .......................................................................................17 
2.1 
Primary Objective and Endpoint ...................................................................................17 
2.2 
Secondary Objectives and Endpoints ............................................................................18 
2.3 
Exploratory Objectives and Endpoints .........................................................................18 
3. STUDY DESIGN .....................................................................................................................19 
3.1 
Description of the Study Design ...................................................................................19 
3.2 
End of Study Definition ................................................................................................20 
3.3 
Study Discontinuation and Closure ...............................................................................20 
4. STUDY POPULATION .........................................................................................................21 
4.1 
Participant Inclusion Criteria ........................................................................................21 
4.2 
Participant Exclusion Criteria .......................................................................................21 
4.3 
Lifestyle Considerations................................................................................................21 
4.4 
Strategies for Recruitment and Retention .....................................................................21 
4.4.1 Accrual Estimates .....................................................................................................22 
4.4.2 Inclusion of Children ................................................................................................24 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
5. PARTICIPANT SCREENING, ENROLLMENT, AND WITHDRAWAL ......................24 
5.1 
Consent and Screening ..................................................................................................24 
5.1.1 Screening Period ......................................................................................................24 
5.1.2 Re-testing During Screening ....................................................................................24 
5.2 
Enrollment Procedures ..................................................................................................24 
5.2.1 Enrollment Procedures for the OHSU Site ..............................................................25 
5.2.2 Enrollment Procedures for Sub-Sites .......................................................................25 
5.3 
Screen Failures ..............................................................................................................25 
5.3.1 Re-Screening Allowance / Procedures .....................................................................26 
5.4 
Participant Discontinuation or Withdrawal ...................................................................26 
5.4.1 Handling Participant Discontinuation from Study ...................................................27 
5.5 
Lost to Follow-up ..........................................................................................................27 
6. STUDY INTERVENTION .....................................................................................................28 
6.1 
onabotulinumtoxinA .....................................................................................................28 
6.1.1 Study Intervention Description ................................................................................28 
6.1.2 Acquisition ...............................................................................................................28 
6.1.3 Formulation, Appearance, Packaging and Labeling ................................................28 
6.1.4 Product Storage and Stability ...................................................................................28 
6.1.5 Compatibility ............................................................................................................28 
6.1.6 Preparation ...............................................................................................................29 
6.1.7 Administration ..........................................................................................................29 
6.1.8 Special Considerations for Administration ..............................................................29 
6.1.9 Accountability ..........................................................................................................29 
6.1.10 
Destruction and Return ........................................................................................30 
7. TREATMENT PLAN .............................................................................................................30 
7.1 
Dosage and Administration ...........................................................................................30 
7.2 
Discontinuation from Study Intervention .....................................................................31 
7.3 
Treatment Period and Maintenance ..............................................................................31 
7.4 
Concomitant Medication and Supportive Care Guidelines ...........................................31 
7.5 
Precautionary Medications, Treatments, and Procedures .............................................32 
7.6 
Prohibited Medications, Treatments, and Procedures ...................................................32 
8. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE..........................................32 
8.1 
Study-Specific Procedures ............................................................................................32 
8.1.1 Medical history .........................................................................................................32 
8.1.2 Disease Assessment ..................................................................................................32 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
8.1.3 Medication review ....................................................................................................33 
8.1.4 Physical examination ................................................................................................33 
8.1.5 Adverse event evaluation .........................................................................................33 
8.2 
Laboratory Procedures and Evaluations........................................................................34 
8.2.1 Hematology ..............................................................................................................34 
8.2.2 Comprehensive metabolic Panel ..............................................................................34 
8.2.3 Coagulation panel .....................................................................................................34 
8.2.4 Pregnancy test ..........................................................................................................34 
8.2.5 Amylase Assay .........................................................................................................34 
8.3 
Screening Assessments .................................................................................................34 
8.4 
Early Termination or End of STUDY Visit ..................................................................34 
8.5 
Follow-up ......................................................................................................................35 
8.6 
Unscheduled Visits .......................................................................................................35 
8.7 
Schedule of Events ........................................................................................................36 
9. EFFICACY MEASURES .......................................................................................................37 
9.1 
Definition of Efficacy Measures ...................................................................................37 
9.1.1 Any POPF ................................................................................................................37 
9.1.2 Clinically Relevant POPF (Grade B and C POPF) ..................................................37 
10. SAFETY ................................................................................................................................38 
10.1 Specification Of Safety Parameters ..............................................................................38 
10.2 Definitions .....................................................................................................................38 
10.2.1 
Adverse Event (AE) ............................................................................................38 
10.2.2 
Serious Adverse Event (SAE) .............................................................................39 
10.2.3 
Unanticipated Problems (UP) ..............................................................................39 
10.2.4 
Severity of Event .................................................................................................39 
10.2.5 
Assessment of Causality Relationship To Study intervention ............................40 
10.3 Expectedness .................................................................................................................40 
10.4 Adverse Event List(s) ....................................................................................................40 
10.4.1 
Adverse Event List for BTX ................................................................................40 
10.4.2 
Adverse Event List for Endoscopy ......................................................................41 
10.5 Time Period And Frequency For Event Assessment And Follow-Up ..........................42 
10.6 Reporting Procedures ....................................................................................................43 
10.6.1 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events .............43 
10.6.2 
Central Reporting of Adverse Events for Multi-Site Studies ..............................43 
10.6.3 
FDA Reporting ....................................................................................................43 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
10.6.4 
Suspected Unexpected Adverse Reactions (SUSARs) ........................................44 
10.6.5 
Reporting Of Pregnancy ......................................................................................44 
10.7 Study Stopping Rules ....................................................................................................44 
11. STATISTICAL CONSIDERATIONS ................................................................................45 
11.1 Statistical Hypothesis ....................................................................................................45 
11.2 Sample Size Determiniation ..........................................................................................45 
11.3 Populations for Analyses ..............................................................................................45 
11.4 Description of Statistical Methods ................................................................................46 
11.4.1 
Analysis of Primary Endpoint(s) .........................................................................46 
11.4.2 
Analysis Of The Secondary Endpoint(S) ............................................................46 
11.4.3 
Analysis Of The Exploratory Endpoint(s) ...........................................................46 
11.4.4 
Safety Analyses ...................................................................................................47 
11.4.5 
Planned Interim Analyses and Stopping rule ......................................................47 
11.5 Handling of Missing Data .............................................................................................47 
12. CLINICAL MONITORING ...............................................................................................47 
12.1 OHSU Knight Cancer Institute Data & Safety Monitoring Plan ..................................48 
12.2 Clinical Data & Safety Monitoring ...............................................................................48 
12.3 Quality Assurance & Quality Control ...........................................................................49 
13. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..49 
13.1 Source Data/Documents ................................................................................................49 
13.1.1 
Participant & Data Confidentiality ......................................................................49 
13.1.2 
Data Collection & Storage: Privacy, Confidentiality & Security ........................50 
13.1.3 
Maintenance of Records ......................................................................................51 
13.2 Multi-Site Guidelines ....................................................................................................51 
13.3 Publication and Data Sharing Policy ............................................................................52 
13.4 Conflict of Interest Policy .............................................................................................52 
14. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...............................................53 
14.1 Ethical Standard ............................................................................................................53 
14.2 Institutional Review Board ...........................................................................................53 
14.3 Informed Consent ..........................................................................................................53 
14.3.1 
Consent Procedures and Documentation .............................................................53 
14.4 Protocol Review ............................................................................................................54 
14.5 Changes to Protocol ......................................................................................................54 
15. REFERENCES .....................................................................................................................55 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
LIST OF TABLES 
 
Table 1. Population Demographics - Oregon (%).................................................................... 22 
Table 2. Projected Accrual for the Present Study ................................................................... 23 
Table 3. Adverse Events Associated with N=73029 Endoscopic Procedures32 ...................... 41 
 
LIST OF FIGURES 
 
Figure 1: Botulinum Toxin Mechanism and Endoscopic Injection Method ......................... 16 
 
 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ASA 
American Society of Anesthesiologists 
BTX 
Botulinum Toxin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CONSORT 
Consolidated Standards of Reporting Trials 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
crPOPF 
Clinically-relevant postoperative pancreatic fistula 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG, EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IND 
Investigational new drug application 
IRB 
Institutional Review Board 
ISGPF 
International Study Group of Pancreatic Fistula 
IV 
Intravenous 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
N/A 
Not applicable 
NYHA 
New York Heart Association 
NSQIP 
National Surgical Quality Improvement Project 
OHSU 
Oregon Health & Science University 
PDAC 
Pancreatic Ductal Adenocarcinoma 
PI 
Principal Investigator 
PO 
Per os (by mouth, orally) 
POPF 
Postoperative pancreatic fistula 
RAMPS 
Radical antegrade modular pancreatosplenectomy 
SAE 
Serious adverse event 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SNAP 
Soluble N-ethylmaleimide sensitive fusion protein 
SNARE 
Soluble N-ethylmaleimide sensitive fusion protein receptors 
TSMP 
Trial Specific Monitoring Plan 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
WBC 
White blood cell (count) 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
1.1 
BACKGROUND 
 
Over 50,000 new cases of pancreatic cancer are diagnosed in the United States each year,1 with 
96% being pancreatic ductal adenocarcinoma (PDAC).2 PDAC carries a dismal prognosis with an 
overall 5-year survival of 7.2%,2 however patients with resected disease can achieve 5-year 
survival rates of up to 30%.3 Pancreatic resections are inherently morbid operations with 
complication rates of approximately 40%; one of the most feared complications by clinicians and 
patients is leak of pancreatic digestive enzymes from the cut pancreas into the abdominal cavity, 
termed a postoperative pancreatic fistula (POPF).  
 
POPF occurs in approximately 13% of pancreaticoduodenectomies and up to 30% of distal 
pancreatectomies,4 and can dramatically alter the recovery pathway. In pancreatic cancer, major 
postoperative complications (including POPF) are associated with non-receipt and delays to 
adjuvant chemotherapy, significantly reducing long-term survival following a curative-intent 
resection.5 Interventions to reduce the rate of POPF therefore have the potentially to dramatically 
improve both short and long-term outcomes in patients undergoing distal pancreatectomy.  
 
One proposed mechanism for POPF following distal pancreatectomy is that the Sphincter of Oddi, 
which normally regulates the flow of pancreatic secretions into the intestine, continues to serve as 
a barrier and acts like a dam, promoting pancreatic fluid exit from the cut edge of the pancreas, 
causing a POPF. Pre-operative endoscopic injection of botulinum toxin (BTX) into the Sphincter 
of Oddi has been suggested to lower the rate of POPF after distal pancreatectomy,6 as paralyzing 
the muscle theoretically removes this resistance and would promote normal flow of pancreatic 
fluids into the duodenum until healing is complete. These results have not been uniformly 
reproduced, with one study performing BTX injection at a median of 1 day pre-operative not 
demonstrating a difference in POPF rates, possibly due to the delayed onset of BTX efficacy7, 8 
Additionally, this intervention has never been studied in an American population, though a 
randomized trial is accruing patients in Europe.9 Of note, endoscopic BTX injection into the 
Sphincter of Oddi has previously been shown to be efficacious for abdominal pain resulting from 
Sphincter of Oddi dysfunction10, 11 and post-cholecystectomy biliary pain12, suggesting that the 
paralysis afforded by BTX can be therapeutic.  
 
Endoscopic BTX administration is an innovative method to reduce POPF, as previously 
investigated strategies for POPF prevention have primarily been either intraoperative (such as 
absorbable mesh placement13) or postoperative medication-based interventions (such as 
pasireotide or hydrocortisone).14, 15 Additionally, while external pancreatic duct stenting has shown 
efficacy in preventing POPF in patients undergoing pancreaticoduodenectomy16, prophylactic 
endoscopic stenting and sphincterotomy has not been well-studied in the prevention of POPF 
following distal pancreatectomy17, though prospective trials are accruing (NCT03314337). 
Importantly, sphincterotomy and instrumentation of the pancreatic duct during stent placement 
imparts a higher risk of acute pancreatitis than BTX administration, which does not instrument the 
duct itself.  
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
In short, the present study represents a novel application of an established technique, and may have 
a significant positive impact on clinical practice by improving the perioperative care and outcomes 
of patients undergoing distal pancreatectomy. In the case of pancreatic cancer, a reduction of POPF 
rates may translate to higher receipt and fewer delays to adjuvant chemotherapy and improved 
survival. 
 
1.1.1 OVERVIEW OF STUDY TERMS 
 
Distal Pancreatectomy. Distal pancreatectomy (removal of the distal pancreas +/- spleen) is 
indicated in nonmetastatic PDAC, and other neoplasms when disease is localized in the 
pancreatic tail, as well as in certain patients with chronic pancreatitis.18 A variant technique of 
distal pancreatectomy, termed radical antegrade modular pancreatosplenectomy (RAMPS) is 
often used specifically for malignancies of the pancreas.19 Pancreatic surgery is technically 
difficult and highly morbid, with POPF being the most feared complication by clinicians and 
patients.  
 
Postoperative Pancreatic Fistula (POPF). POPF results when digestive enzymes normally 
secreted by the pancreas leak into the abdominal cavity following an operation, leading to a wide 
range of inflammatory and auto-digestive complications. POPF is defined by the International 
Study Group of Pancreatic Fistula (ISGPF) as an amylase level obtained from drainage fluid or 
abscess of greater than three times the upper limit of normal, starting from the third postoperative 
day (POD3).20, 21 POPF is further classified by the ISGPF into biochemical leaks (asymptomatic 
elevations in amylase from surgical drain fluid that do not require additional treatment), Grade B 
POPF (requiring percutaneous or endoscopic drainage), or Grade C POPF (resulting in organ 
failure); together, Grades B/C constitute clinically-relevant POPF (crPOPF). Rates of POPF 
following distal pancreatectomy range from 20-50% with an average of 30%,22, 23 with a 10-year 
average of at OHSU of 30.9% for all POPF and 11.3% for crPOPF. 
 
Sphincter of Oddi. The Sphincter of Oddi is a smooth muscle valve located at the Ampulla of 
Vater that regulates the flow of bile and pancreatic secretions into the duodenum.24 Following 
distal pancreatectomy, the resting muscle tone of the Sphincter of Oddi may act as a dam, 
causing the “path of least resistance” for pancreatic secretions to be the cut edge of the pancreas, 
resulting in POPF as secretions exit into the abdominal cavity and cause and intense 
autodigestive and inflammatory reaction. 
 
1.1.2 OVERVIEW STUDY INTERVENTION(S) 
 
Botulinum Toxin (BTX). BTX is a neurotoxin produced by the bacterium Clostridium 
botulinum, which secretes eight exotoxins, (A, B, C(1), C(2), D, E, F, G), all of which block the 
release of acetylcholine (the primary neurotransmitter at the neuromuscular junction) by cleaving 
soluble N-ethylmaleimide sensitive fusion protein (SNAP) Receptors (SNARE), leading to 
muscle paralysis.25 A commercial formulation of BTX (onabotulinumtoxinA; Botox) has been 
used for decades with great efficacy in multiple conditions, including strabismus, dystonias, 
spastic movement disorders, headaches, hyperhidrosis, as well as innumerable cosmetic 
applications such as reducing the prominence of wrinkles.25, 26 BTX has an excellent safety 
profile, with one systematic review of 36 randomized controlled trials noting no serious adverse 
events.27  

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
Botulinum Toxin Injection to Sphincter of Oddi: Endoscopic injection of BTX into the lower 
esophagus is a well-described and FDA-approved treatment for achalasia, and BTX injection 
into the Sphincter of Oddi is a well-described treatment for Sphincter of Oddi Dysfunction.10, 11, 
28 Injection of BTX into the sphincter of Oddi (Figure 1) performed a median of 6 days prior to 
distal pancreatectomy reduced POPF rates,6 but not when performed at a median of one day pre-
operatively.7 This is suspected to be due to the fact that BTX reaches maximal paralytic efficacy 
at one week.8 
 
Figure 1: Botulinum Toxin Mechanism and Endoscopic Injection Method 
 
 
1.2 
STUDY RATIONALE 
 
The overall objective of this application is to establish the preliminary efficacy and safety of 
Sphincter of Oddi BTX injection in the prevention of POPF in the setting of a phase II clinical 
trial. The central hypothesis is that BTX injection is both safe and efficacious in the prevention 
of POPF. The rationale for this study is that prevention of POPF would enhance postoperative 
recovery and quality of life in patients undergoing distal pancreatic resections. These results are 
expected to have a significant positive impact on clinical practice by improving the perioperative 
care of patients undergoing distal pancreatectomy for pancreatic cancer and other nonmalignant 
conditions. 
 
 
 
1.3 
RISK/BENEFIT ASSESSMENT 
 
1.3.1 KNOWN POTENTIAL RISKS  
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Botulinum toxin (onabotulinumtoxinA; Botox) has been used for decades with great efficacy in 
multiple conditions.25, 26 BTX has an excellent safety profile, with one systemic review of 36 
randomized controlled trials noting no serious adverse events, with focal weakness at/around the 
injection site being the only mild-moderate adverse event that occurred more often than controls, 
which is not a relevant risk for endoscopic injection.27 Post-marketing reports indicate that the 
effects of all botulinum toxin products may spread from the area of injection to produce 
symptoms consistent with botulinum toxin effects. These may include asthenia, generalized 
muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and 
breathing difficulties, depending on the site of injection. These symptoms have been reported 
hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and 
there have been reports of death. The risk of symptoms is probably greatest in children treated 
for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, 
particularly in those patients who have underlying conditions that would predispose them to 
these symptoms. In unapproved uses, including spasticity in children, and in approved 
indications, cases of spread of effect have been reported at doses comparable to those used to 
treat cervical dystonia and at lower doses. 
 
In cases of endoscopic BTX injection, side-effects apart from asymptomatic serum lipase 
elevations or mild pancreatitis have not been previously reported when administered for 
Sphincter of Oddi dysfunction10, 11, post-cholecystectomy biliary pain12, or for prevention of 
POPF.6, 7   
 
Risks specific to endoscopy represent  additional study-related risks, and include 
postinterventional pancreatitis defined by the Atlanta criteria which includes two of the 
following: 1) abdominal pain consistent with acute pancreatitis; 2) serum lipase > 3 ULN; 3) 
characteristic imaging findings).29 Rare risks with the upper endoscopy procedure include 
cardiopulmonary compromise with procedural sedation, intraprocedural hemorrhage, and bowel 
perforation.30 
 
1.3.2 KNOWN POTENTIAL BENEFITS 
 
Immediate potential benefits include a reduced risk of POPF per other studies, which may result 
in shorter hospital stay and quicker postoperative recovery on average. Long-term potential 
benefits include the possibility of a higher chance of receiving life-prolonging adjuvant 
chemotherapy with the avoidance of POPF (due to the study intervention), which would 
otherwise have delayed or disqualified a patient from adjuvant chemotherapy.  
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
 
Primary Objective 
Endpoint 
Start  
End  
Evaluate the efficacy of pre-
operative BTX injection 
compared to no therapy for the 
prevention of clinically relevant 
Rate of clinically relevant 
(Grade B and Grade C) 
POPF following distal 
pancreatectomy/RAMPS, 
Day of 
Surgery 
 
 
Postoperative 
Day 30 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
POPF 
defined by standard 
biochemical definitions of 
POPF per the ISGPF 
criteria 
 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
 
Secondary Objective 
Endpoint 
Start  
End  
Evaluate the safety of 
pre-operative BTX 
injection into the 
Sphincter of Oddi  
Rate of serious adverse 
events following BTX 
injection defined as: 
pancreatitis requiring 
hospitalization, 
gastrointestinal 
hemorrhage or 
perforation, other events 
delaying time to surgery 
or receipt of surgery, or 
grade 3 or higher AEs 
attributable to BTX 
Day of 
study 
intervention 
30 days following 
surgery or study 
intervention or until date 
of surgery 
 
Evaluate the efficacy of 
pre-operative BTX 
injection compared to no 
therapy for the 
prevention of all POPF 
Rate of any POPF 
following distal 
pancreatectomy/RAMPS, 
defined by standard 
biochemical definitions 
of POPF per ISGPF 
criteria 
Day of 
Surgery 
Postoperative day 30 
 
 
2.3 
EXPLORATORY OBJECTIVES AND ENDPOINTS 
 
Exploratory Objective 
Endpoint 
Start  
End  
Using a historical population 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in POPF, 
Rate of POPF  
Day of Surgery Postoperative 
Day 30 
 
Using a historical population 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in crPOPF. 
Rate of crPOPF 
Day of Surgery Postoperative 
Day 30 
Using a historical population 
Postoperative length of 
Day of Surgery Postoperative 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in postoperative length of 
hospital stay. 
hospital stay 
Day 30 
Using a historical population 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in rate of Clavien-Dindo grade 
III or greater complications 
Clavien-Dindo grade 
III or greater 
complications 
Day of Surgery Postoperative 
Day 30 
Using a historical population 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in rate of percutaneous 
drainage, 
Postoperative 
percutaneous drainage 
Day of Surgery Postoperative 
Day 30 
Using a historical population 
matched for potential 
confounding clinicopathologic 
variables, evaluate differences 
in rate of unplanned re-
operation. 
Unplanned re-operation Day of Surgery Postoperative 
Day 30 
 
3. STUDY DESIGN 
 
3.1 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 11, Statistical Analysis for additional information regarding statistical methods 
used in this study. 
 
This is a Phase II, open-label study to estimate the rate of crPOPF in patients that receive pre-
operative endoscopic BTX injection into the sphincter of Oddi as a single agent prior to 
undergoing distal pancreas resections. The study design consists of a single arm intervention 
group (n=50) with comparison to historical rates for crPOPF. BTX injection will occur 7-14 days 
before the planned date of surgery as an outpatient endoscopic procedure. Thereafter, 
participants will receive all surgery and postoperative treatment in accordance with institutional 
standards.  
 
The trial will commence with the enrollment of the first six patients for a safety-run in of the 
endoscopic BTX injection technique. During the safety run-in, the PI will evaluate patient safety 
outcomes including grade 3 or higher adverse events. Additionally, the study will be evaluated 
by the DSMC following the completion of the first three participant’s safety evaluation periods 
(30 days following BTX injection or 30 days following surgery, whichever is longer). 
Progressive study enrollment will continue throughout the safety run-in, and enrollment will be 
halted if recommended by the DSMC after completion of the run-in. If 2 or more of the first 6 
participants enrolled experience delay in planned surgery ≥ 14 days (due to significant GI 
hemorrhage, perforation, or adverse reaction to BTX) or pancreatitis requiring hospitalization, 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
then the study will be halted for safety. A total of 25 patients will be enrolled prior to a planned 
interim analysis for the primary endpoint of interest (crPOPF). If sufficient number of 
participants have experienced crPOPF (2 or greater), the trial will be prematurely terminated. If 
the interim analysis does not result in study termination, enrollment of the remaining participants 
will resume to enroll a total of 50 patients completing study intervention and follow-up.  
 
The study schedule will be divided into 2 periods: (1) the post-treatment period which starts at 
the time of BTX injection and ends on the day of surgery (2) the postoperative period which 
begins at the time of surgery and ends 30 days postoperatively. 
 
In addition to comparing study patients with the historical rate of POPF, exploratory analysis 
will be performed by matching study patients with historical patients on relevant 
clinicopathologic characteristics that are associated with risk of POPF. Historical controls are 
appropriate, as the study could not be completed in a timely and cost-efficient manner with 
prospective enrollment of both study groups. Additionally, many surgeons involved in the 
present study would not support enrollment of a placebo group as many currently utilize 
preventive medications such as pasireotide or hydrocortisone. 
 
At the completion of the proposed study, the expected outcomes are to have evaluated the safety 
and efficacy of pre-operative BTX administration in the prevention of POPF.  
 
3.2 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of Events 
(Section 7.11). 
 
3.3 
STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification that documents the reason for study suspension or 
termination will be provided by the suspending or terminating party to OHSU Coordinating 
Center, local IRB, and other regulatory authority (if required). If the study is prematurely 
terminated or suspended, the Investigator must promptly inform the IRB and provide the 
reason(s) for the termination or suspension. The OHSU Coordinating Center will notify sub-
site(s) of any study suspension or discontinuation. 
 
Reasons for terminating the study may include the following: 
• 
Unfavorable assessment of risk/benefit ratio 
• 
Incidence or severity of adverse events, in this or other studies, that indicates a  
potential health hazard to participants 
• 
Demonstration of lack of efficacy that warrants stopping 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Investigator not adhering to the study protocol or applicable regulatory guidelines in 
conducting the study 
• 
Participant enrollment is unsatisfactory  
• 
Submission of knowingly false information from the study site to OHSU 
Coordinating Center or regulatory authority 
• 
Upon instruction by local or other regulatory or oversight authority.  
 
The study may resume once concerns about safety, protocol compliance, and/or data quality are 
addressed as applicable and requirements of the OHSU Coordinating Center, funder, IRB and/or 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
other applicable regulatory authority are satisfied. 
 
4. STUDY POPULATION 
 
4.1 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all following criteria: 
 
1. Participant scheduled for elective distal pancreatectomy or radical antegrade modular 
pancreatosplenectomy (RAMPS), via open or laparoscopic technique 
2. Participant ≥ 18 years of age 
3. Ability to understand nature and individual consequences of clinical trial 
4. Written informed consent from participant or legally authorized representative.  
5. For participants of childbearing potential, a negative pregnancy test and adequate 
contraception until 14 days after trial intervention 
 
4.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1.  Known hypersensitivity to any BTX preparation or to any of the components in the 
formulation  
2. Infection at the proposed injection site, including cholangitis  
3. Anatomy incompatible with planned intervention (e.g., Roux-en-Y gastric bypass, distal 
gastrectomy with Roux-en-Y or Billroth II reconstruction)  
4. Acute pancreatitis within 2 weeks of planned study intervention  
5. Pancreas divisum  
6. ASA score > III  
7. Serious cardiovascular disease (e.g., Myocardial infarction in the past year, NYHA III/IV 
congestive heart failure, unstable angina).  
8. Creatinine clearance <30mL/min  
9. Liver cirrhosis (of any Child-Pugh grade)  
10. Neuromuscular or any neurological disease with associated increased risk for a 
participant undergoing BTX injection  
11. Prior BTX administration 
12. Inability to obtain informed consent due to comprehension or language barrier.  
13. Inability to comply with study and/or follow-up procedures  
14. Pregnancy or lactation  
15. Any condition that could result in undue risk for the participant and/or influence outcome 
measures (in the opinion of the investigator) 
 
4.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are not asked to modify lifestyle or diet apart from standard of 
care peri-procedural measures prior to upper endoscopy or distal pancreatic resection. 
 
4.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
This study will be conducted in the United States. Participants for this study will primarily be 
recruited from surgical clinics within OHSU, but additional collaborative study sites may also be 
invited to participate in this trial.  Participants may be identified and referred to this study by 
their primary treating physician from within OHSU/CHO, collaborating study sites, or from the 
outside community.  Participants may be identified by a member of the participant’s treatment 
team, the PI, research team, or medical and surgical oncology clinics part of OHSU/CHO or 
collaborating study sites.  As a member of the treatment team, the investigator(s) will screen 
their participant’s medical records for suitable research study participants and discuss the study 
and their potential for enrolling in the research study.  Referral of potential participants to 
investigator(s) of this study is made as part of standard of care, with the referring physician 
seeking advice on the diagnosis, evaluation, and/or treatment of the participant’s malignancy.   
 
The investigator(s) may also screen the medical records of potential participants with whom the 
investigator does not have a treatment relationship.  This will be done for the limited purpose of 
identifying patients who would be eligible to enroll in the study and to record appropriate contact 
information in order to approach these potential individuals regarding the possibility of 
participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
In the event of an insufficient rate of accrual at OHSU, additional patients undergoing distal 
pancreas resections at Legacy Good Samaritan will be enrolled. If accrual remains insufficient, 
patients undergoing distal pancreas resection at Providence Portland will be enrolled. Should 
either of these events occur, a modification to the study protocol will be submitted and approved 
prior to enrollment of patients at sites outside of OHSU.  
 
 
4.4.1 ACCRUAL ESTIMATES 
 
Total accrual of all participants is anticipated to take a total of 36 months. 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset.  No participant will be excluded from the study on the basis of gender, racial or ethnic 
origin.  Male, female and minority volunteers will be recruited for this study from the general 
population and approximately 50% men and 50% women will be studied.  Gender-
nonconforming and gender-fluid individuals as members of the general population will also be 
recruited. 
The projected gender, racial, and ethnic composition of the study will represent that of the state 
of Oregon.  
 
Table 1. Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
6.6 
 
6.5 
13.1 
Not Hispanic or Latino 
 
43.8 
 
43.1 
86.9 
Ethnic Category: Total of all participants* 
 
 
 
 
100* 
 
Racial Category 
 
American Indian or Alaskan Native 
 
0.9 
 
0.9 
1.8 
Asian 
 
2.4 
 
2.3 
4.7 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
Table 2. Projected Accrual for the Present Study  
 
Prospective Cohort: 
Ethnic Category 
Sex/Gender 
Females 
Males 
Other/Unknown 
Total 
Hispanic or Latino 
4 
4 
0-1 
6 
Not Hispanic or Latino 
26 
26 
0-1 
44 
Unknown 
0-1 
0-1 
0-1 
0 
Ethnic Category: Total of all 
participants* 
30-31 
30-31 
0-3 
63 
Racial Category 
 
American Indian or Alaskan Native 
0-1 
0-1 
0-1 
0-3 
Asian 
1 
1 
0-1 
2-3 
Black or African American 
1 
1 
0-1 
2-3 
Native Hawaiian or other Pacific Islander 
0-1 
0-1 
0-1 
0-3 
White 
27 
27 
0-1 
54-55 
More than one race 
1 
1 
0-1 
2-3 
Unknown 
0-1 
0-1 
0-1 
0-3 
Racial Category: Total of all 
participants* 
30-31 
30-31 
0-7 
63 
Source: Adapted from U.S. Census Bureau, 2017. 
 
*Totals may not equal 100 due to rounding. 
 
While malignant histology or chronic pancreatitis are associated with lower odds of crPOPF in 
proximal pancreas resections, this has not been shown to be the case for distal pancreas 
resections.23 Nevertheless, we will attempt to enroll an approximately equal proportion of 
patients with PDAC or chronic pancreatitis as the operative indication as historical patients at 
OHSU (130 of 353 distal pancreas resections since 2011, 37%). Due to the lack of evidence that 
this impacts crPOPF in distal pancreatectomy, however, no enrollment thresholds will be set. 
 
Table 1. Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Black or African American 
 
1.1 
 
1.1 
2.2 
Native Hawaiian or other Pacific Islander 
 
0.2 
 
0.2 
0.4 
White 
 
43.9 
 
43.2 
87.1 
Two or more races 
 
1.9 
 
1.9 
3.8 
 
Racial Category: Total of all participants* 
 
 
100* 
TOTALS 
 
50.4 
 
49.6 
100* 
Source: Adapted from U.S. Census Bureau, 2017. 
*Totals may not equal 100 due to rounding. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
4.4.2 INCLUSION OF CHILDREN 
 
This protocol does not include children for the following reason:  
 
1. The number of children with this type of cancer/condition is limited 
 
5. PARTICIPANT SCREENING, ENROLLMENT, AND WITHDRAWAL 
 
This is a single-arm phase II clinical trial (without randomization).   
 
Each individual that consents to participate in this study must be entered into OHSU’s electronic 
clinical research information system, eCRIS, regardless of Screening outcome. 
 
5.1 
CONSENT AND SCREENING 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant or the participant's legally acceptable representative.  The current IRB approved 
informed consent form must be signed and dated by each participant prior to undergoing any 
study procedures or before any prohibited medications are withheld from the participant in order 
to participate in this study.  The informed consent discussion must be documented, and a copy of 
their signed IRB approved informed consent form must be scanned in the participant’s medical 
record. 
 
Each site must maintain a screening log of all participants who are approached for the study, as 
well as source documentation related to the consent and screening outcome for each, including 
an explanation for exclusion due to screen failure where applicable. Each site is required to 
retain, in a confidential manner, sufficient information on each participant so that the participant 
may be contacted should the need arise. 
 
5.1.1 SCREENING PERIOD 
 
The screening period begins once the participant has provided written informed consent to 
participate in the study and ends once BTX injection is initiated. All screening and baseline 
evaluations will be performed during the screening period. Day 1 of the clinical trial will be 
when participants are started on the study intervention. 
 
5.1.2 RE-TESTING DURING SCREENING 
 
Re-testing of laboratory parameters and/or other assessments within the Screening or Lead-in 
period will be permitted (in addition to any parameters that require a confirmatory value). 
 
The most current result prior to Enrollment is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 
 
Laboratory parameters and/or assessments may be repeated in an effort to find all possible well-
qualified participants. Consultation with the Principal Investigator may be needed to identify 
whether repeat testing of any particular parameter is clinically relevant.  
 
5.2 
ENROLLMENT PROCEDURES 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
This is a Phase II trial, and there is no randomization for treatment. 
 
5.2.1 ENROLLMENT PROCEDURES FOR THE OHSU SITE 
 
Eligibility must be confirmed and documented by the Principal Investigator prior to enrollment.  
 
Materials required to complete the eligibility review include, at minimum: 
• 
Current IRB-approved consent form and HIPAA Authorization for the study signed 
& dated by the participant 
• 
Documented (signed and dated) attestation by the PI confirming participant’s 
eligibility based on available source documentation and authorizing enrollment 
• 
Endoscopic evaluation at the time of planned study intervention to verify anatomic 
eligibility for BTX injection 
 
Once eligibility is confirmed, the participant is considered ‘enrolled’ once study intervention is 
performed. 
 
5.2.2 ENROLLMENT PROCEDURES FOR SUB-SITES 
 
The OHSU Coordinating Center oversees the participant enrollment process for all sub-sites. 
 
When a potential participant is identified, a sub-site must notify the Coordinating Center of their 
intent to consent and screen the individual for study participation. The Coordinating Center will 
inform the site in writing whether or not they may proceed. 
 
The sub-site investigator, or study team designee, must send source documents that support 
eligibility to OHSU for review and verification before the sub-site may enroll the participant. 
• 
Current IRB-approved consent form and HIPAA Authorization for the study signed 
& dated by the participant; 
• 
Completed eligibility checklist signed and dated by the site investigator or designee; 
and 
• 
Source documents that support eligibility. 
 
The OHSU Coordinating Center team is responsible for verifying completeness of documents, 
entering participant information into OHSU’s clinical research information system (eCRIS), and 
assigning a study number/identifier for each individual participant. The Coordinating Center will 
notify the sub-site in writing to indicate whether or not a participant is eligible and will assign a 
participant number/identifier.  
 
Once the OHSU Coordinating Center confirms a subject’s eligibility, the participant is 
considered ‘enrolled’ and study intervention may begin. If the OHSU Coordinating Center 
deems the participant ineligible, this participant is considered a screen failure. 
 
For any participant deemed locally by the sub-site as a screen failure, the sub-site must still 
provide sufficient documentation to the Coordinating Center for entry into eCRIS. 
 
5.3 
SCREEN FAILURES 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
failing to meet eligibility criteria may be rescreened. Rescreened participants should be assigned 
the same participant number as for the initial screening. 
 
Any participant that has signed the consent form (for either screening or study participation) but 
does not meet all of the study eligibility criteria, or meets study eligibility criteria but terminates 
their participation prior to receiving study treatment, will be considered a screen failure and not 
counted towards total number of planned enrollments.  The reason for screen failure should be 
captured in the research record for each participant who fails to meet all of the eligibility criteria. 
 
5.3.1 RE-SCREENING ALLOWANCE / PROCEDURES 
 
This study permits the re-screening of a participant that has discontinued the study as a screen 
failure (i.e., participant has not been treated). If re-screened, the participant must be re-
consented. 
 
5.4 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment.  If a participant no longer wants to receive 
investigational product, but is willing to come for follow-up appointments, the participant’s 
request should be honored, if possible. 
 
If a participant withdraws consent, they should be asked to specify if they are withdrawing 
consent to all further participation in the study, including any further follow up (e.g., survival 
contact telephone calls) or if they are choosing to withdraw only from further study intervention, 
meaning that further follow-up and data collection about their disease and health status is 
allowable. The participant should also be asked about their consent to the future use of their 
study-generated data and any biological samples, as applicable.  
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study.  Information about the reason(s) for discontinuation and collection of 
any new or ongoing AEs should be collected at the time the participant withdraws consent.   
 
A participant may also be withdrawn from the study by the Sponsor/Sponsor-Investigator, 
Investigator, local IRB, or regulatory authorities.   
 
Reasons for a participant to discontinue the study may include the following: 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
• 
Participant dies or is lost to follow-up 
• 
Participant withdraws consent for any further participation 
• 
The end of study is reached 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition 
or situation occurs such that continued participation in the study would not be in the best interest 
of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
 
In the event of a pregnancy, the study treatment will not be administered.  Refer to Section 
10.6.5 regarding reporting of pregnancy.  Participants who withdraw or discontinue after 
receiving study intervention count towards the enrollment total. 
 
5.4.1 HANDLING PARTICIPANT DISCONTINUATION FROM STUDY 
 
When a participant discontinues participation in the study, the reason the participant is no longer 
participating, the study name, IRB study number, and the date of discontinuation must be 
documented in the participant’s medical record.  The change in study status must be documented 
in the appropriate clinical trial management system (e.g., eCRIS) per OHSU policy.   
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 8, STUDY 
PROCEDURES/EVALUATIONS AND SCHEDULE. 
 
Participants enrolled in this study who withdraw prior to initiating their treatment will be 
replaced.   
 
Participants who sign the informed consent form, receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study prior to undergoing 
planned pancreatic surgery will count towards enrollment totals  
. 
 
5.5 
LOST TO FOLLOW-UP 
 
A participant will be considered “lost to follow-up” if the participant: 
1. Undergoes BTX injection and does not present for planned surgical intervention and is 
unable to be contacted by study staff for 30 days following BTX injection 
2. Undergoes BTX injection and planned surgical intervention, but does not present for 
planned post-operative follow-up appointment and is unable to be contacted by study 
staff for 30 days following postoperative hospital discharge.   
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within two 
weeks, and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record 
or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
6. STUDY INTERVENTION 
 
A list of the adverse events and potential risks associated with the study intervention 
administered in this study can be found in Section 10.4, Adverse Events. 
 
6.1 
ONABOTULINUMTOXINA 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
 
Botulinum Toxin (BTX). BTX is a neurotoxin produced by the bacterium Clostridium 
botulinum, which secretes eight exotoxins, (A, B, C(1), C(2), D, E, F, G), all of which block the 
release of acetylcholine (the primary neurotransmitter at the neuromuscular junction) by cleaving 
soluble N-ethylmaleimide sensitive fusion protein (SNAP) Receptors (SNARE), leading to 
muscle paralysis.25 BTX (onabotulinumtoxinA; BTX) has been used for decades with great 
efficacy in multiple conditions, including strabismus, dystonias, spastic movement disorders, 
headaches, hyperhidrosis, as well as innumerable cosmetic applications such as reducing the 
prominence of wrinkles.25, 26 BTX has an excellent safety profile, with one systematic review of 
36 randomized controlled trials noting no serious adverse events.27  
 
 
6.1.2 ACQUISITION 
 
OnabotulinumtoxinA (BTX) will be obtained from OHSU research pharmacy services. Where 
possible, a single manufacturer of generic BTX (Allergan, Dublin, Ireland) will be used 
throughout the conduct of this trial. However, BTX may be sourced from alternative 
manufacturers.  
 
6.1.3 FORMULATION, APPEARANCE, PACKAGING AND LABELING  
 
BTX (onabotulinumtoxinA) is an FDA approved drug and available for human use. Each vial of 
Botox® Cosmetic contains either 100 Units of Clostridium botulinum type A 
neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride or 50 Units of 
Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of 
sodium chloride in a sterile, vacuum-dried form without a preservative 
 
6.1.4 PRODUCT STORAGE AND STABILITY 
 
BTX (onabotulinumtoxinA) 
 
6.1.5 COMPATIBILITY 
 
BTX (onabotulinumtoxina) may only be reconstituted with 0.9% sodium chloride.  
 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
6.1.6 PREPARATION 
 
The commercial preparation of BTX (onabotulinumtoxinA) is supplied in vials containing 100 U 
of the lyophilized powder. The entire required dose of BTX (onabotulinumtoxinA) will be 
withdrawn from the vial and reconstituted in 1 mL of 0.9% sodium chloride. During this time 
period, unused reconstituted BTX (onabotulinumtoxinA) should be stored in a refrigerator (2° to 
8°C) for up to 24 hours until time of use. BTX (onabotulinumtoxinA) vials are for single-dose 
only. Used vials of BTX will be discarded. For this trial, the entire required dose of BTXTX will 
be withdrawn from each vacuum-dried vial and reconstituted in 1 mL of 0.9% sodium chloride. 
Endoscopic administration of the drug will be performed by trained endoscopists within 24 hours 
of reconstitution.  
 
 
6.1.7 ADMINISTRATION 
 
Endoscopic injection of BTX into the lower esophagus is a well-described treatment for 
Sphincter of Oddi Dysfunction.10, 11, 28 Subjects will undergo an outpatient upper endoscopy with 
injection of BTX into the sphincter of Oddi (Figure 1). The endoscope is introduced through the 
mouth and advanced to the duodenum. At the level of the ampulla of the Vater, the injection 
needle will be inserted into the upper margin of the papillary orifice. Then 1 mL of the properly 
reconstituted BTX (onabotulinumtoxinA) solution will be injected as a single deposit. Then the 
endoscope will be removed to complete the procedure. Acceptable window of time for 
administration of agent is the total procedural time during endoscopy. No special IV tubing or 
filtration is needed.  
 
6.1.8 SPECIAL CONSIDERATIONS FOR ADMINISTRATION  
 
All subjects will have their heart rate, respiratory rate, oxygen saturations, blood pressure and 
ventilation will be monitored throughout and after the procedure. If subjects develop 
hypersensitivity symptoms like rash, wheezing, or pruritus, hypersensitivity medications should 
be administered.  
 
There are no other special considerations, including hydration, steroids, special IV tubing, 
filtration, or special equipment required.  
 
6.1.9 ACCOUNTABILITY 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of the study agent. (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage).   
 
Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities or other oversight bodies. 
 
The Investigator or designee will collect and retain all used, unused, and partially used containers 
of study medication until full accounting has been completed. The Investigator or designee must 
maintain records that document: 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
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PI: Brett Sheppard, MD 
• Investigational product delivery to the study site. 
• The inventory at the site. 
• Use by each participant including pill/unit counts from each supply dispensed. 
• Return of investigational product to the Investigator or designee. 
• Destruction or return of investigational product for final disposal. 
 
These records should include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study participants. 
 
The investigational product must be used only in accordance with the protocol. The Investigator 
will also maintain records adequately documenting that the participants were provided the 
correct study medication specified. 
 
Completed accountability records will be archived by the site. There are no study drugs that 
require shipment back to the manufacturer at the end of the study. 
 
6.1.10 DESTRUCTION AND RETURN 
 
At the completion of the study, the Investigator or designee will oversee the destruction of study 
agent per local institutional guidelines.  
 
7. TREATMENT PLAN 
 
7.1 
DOSAGE AND ADMINISTRATION 
 
Subjects will undergo an outpatient upper endoscopy for administration of a single BTX 
injection. The endoscope will be introduced through the mouth and advanced to the duodenum.  
At the level of the Ampulla of the Vater, the injection needle will be inserted into the upper 
margin of the papillary orifice. Then 1 mL (100 units) of the properly reconstituted BTX solution 
will be injected as a single deposit. The volume in syringe will be checked to ensure the entire 
amount is delivered. Then the endoscope will be removed to complete the procedure. Acceptable 
window of time for administration of agent is the total procedural time during endoscopy. No 
special IV tubing or filtration is needed. The participant’s heart rate, respiratory rate, oxygen 
saturations, blood pressure and ventilation will be monitored throughout and after the procedure. 
No additional BTX injection will be administered for each participant. Reported adverse events 
and potential risks are described in Section 10, SAFETY. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
Regimen Description 
Agent 
Premedication; 
Precautions 
Dose 
Route* 
Schedule 
Cycle 
Length 
onabotulinumtoxinA none 
100 units 
in 1 mL 
of 0.9% 
NaCl 
solution 
Endoscopic 
injection into 
intraduodenal 
sphincter of 
Oddi segment 
Days 7-14 
before 
surgery 
Single 
injection 
administe
red once   
*Specify route of administration (e.g., IVB, IVP, IVCI, PO, intra-arterial, peritoneal, intrathecal, intracavity, etc.) and duration 
(e.g., IVP over 10 seconds), including any allowable time windows (+/- minutes). 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
the participant's malignancy. 
 
7.2 
DISCONTINUATION FROM STUDY INTERVENTION 
 
Study intervention is a one-time dose during endoscopic procedure, thereafter all other 
procedures and treatment will be in accordance with institutional standard of care.   
 
7.3 
TREATMENT PERIOD AND MAINTENANCE 
 
Participants will receive BTX (onabotulinumtoxinA) on between 7 to 14 days prior to planned 
distal pancreas resection. No other study-specific interventions or maintenance dosing will occur.  
 
7.4 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Supportive measures for optimal medical care are to be given throughout the study as indicated 
by the treating physician’s assessment of the participant’s medical need and institutional and 
general medical guidelines for the care of participants undergoing distal pancreas resections.  
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive 
care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed in general. 
The participant must be told to notify the investigational site about any new medications begun 
after the start of the study treatment.  
 
Other medications for the prophylaxis of POPF are disallowed, including hydrocortisone and 
pasireotide. These medications may be administered at the treating physician’s discretion 
following diagnosis of any POPF.  
 
All medications (other than investigational products) and significant non-drug therapies 
(including vitamins, herbal medications, physical therapy and blood transfusions) administered 
during the study must be listed on the case report form (CRF).  
 
Treatment recommendations described in the following sections may be modified according to 
institutional standards and guidelines as appropriate. 
 
7.4.1 NAUSEA / VOMITING 
No routine prophylactic anti-emetic treatment is required at the start of treatment, however, 
participant should receive appropriate anti-emetic treatment at the first onset of nausea or 
vomiting and as required thereafter per institutional guidelines.  
 
7.4.2 HYDRATION  
Not applicable to the present study 
 
7.4.3 OBSERVATION PERIOD – Patients will be observed and monitored according to the 
standard of care following upper endoscopy, generally 1-2 hours. 
 
7.4.4 MANAGEMENT OF SERIOUS COMPLICATIONS FROM STUDY INTERVENTION 
 
 
Pancreatitis: Any patient with abdominal pain, nausea, and intolerance to oral intake will be 
evaluated for pancreatitis and managed per the standard of care depending on severity of 
pancreatitis (see American Gastroenterological Association guidelines).31 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
Gastrointestinal Bleeding: Patients reporting hematemesis, hematochezia, or melena following 
study will be evaluated by phone, in clinic, or the emergency department as their clinical status 
dictates. Most gastrointestinal bleeding following endoscopy is self-limited and otherwise 
asymptomatic and not considered a serious complication. If clinically significant bleeding 
occurs, defined as that accompanied by new anemia, hypotension, or other signs/symptoms of 
significant blood loss, patients will be further evaluated in the emergency department and treated 
per the standard of care with serial evaluation of hemoglobin/hematocrit, PT/INR, vitals/physical 
exam, and receive endoscopic, intra-arterial, or surgical management as indicated. 
 
Gastrointestinal Perforation: Patients experiencing new severe abdominal pain following 
discharge from the endoscopic procedural unit will be evaluated in clinic or in the emergency 
department as dictated by clinical status. Patients with gastrointestinal perforation will be treated 
as clinically indicated, typically with surgical intervention.  
 
BTX-Specific Complications: Patients experiencing BTX-related complications will be managed 
according to the clinical scenario. Serious allergy-spectrum reactions (e.g., anaphylaxis) will be 
noted during the observation period and managed accordingly by the clinical staff. Other 
reactions such as local weakness are predominantly reported in cases of skeletal muscle-adjacent 
injections. No specific management is required in most cases, however new-onset symptoms 
following BTX injections will be evaluated by phone or in clinic as indicated, and managed 
appropriately.  
 
Patients will be counseled on warning signs for the above serious complications prior to and after 
BTX injection. 
 
7.5 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Patients will be asked to be nil per os starting at midnight prior to planned upper endoscopy.  
 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
7.6.1 PROHIBITED THERAPIES 
No concomitant therapy or investigational therapy aimed at preventing POPF is allowed during 
the study, including pasireotide. 
 
8. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
8.1 
STUDY-SPECIFIC PROCEDURES 
 
8.1.1 MEDICAL HISTORY  
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, 
and any condition diagnosed within the prior 10 years that are considered to be clinically 
significant by the Investigator. Details regarding the participant’s malignancy, when applicable, 
will be recorded separately and not listed as medical history (e.g., date of diagnosis, staging).  
 
8.1.2 DISEASE ASSESSMENT 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s pancreatic cancer. 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
8.1.3 MEDICATION REVIEW  
A complete medication history will be acquired concurrent with medical history. 
 
8.1.4 PHYSICAL EXAMINATION  
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant, or Advanced Registered Nurse Practitioner as local law permits 
and per institutional standards.  The physical examination to be conducted will include an 
evaluation of: general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular 
system; respiratory system; gastrointestinal system; lymphatic system, musculoskeletal system, 
and nervous system. All other physical exams after baseline will include an evaluation of any 
AEs, or any previously reported symptoms, or prior physical examination findings.  All physical 
examinations will also include: 
 
8.1.4.1 
Vital signs  
Vitals to be collected include blood pressure (BP), heart rate (HR), temperature, and oxygen 
saturation by pulse oximetry. As part of screening/baseline visit, vitals should be obtained within 
10 days prior to first dose of study agent. Vitals will also be obtained during treatment.  
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History eCRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event eCRF page.  
 
8.1.4.2 
Height and weight  
Height will be collected at screening only. Weight will be collected at each in person visit.  
 
8.1.4.3 
Performance status  
Performance status (Eastern Cooperative Oncology Group) will be determined for all 
participants at screening.  
 
8.1.5 ADVERSE EVENT EVALUATION  
Toxicities and adverse experiences will be assessed using the NCI CTCAE 5.0. Safety will be 
monitored by assessing physical examination, vital signs, body height (screening only) and 
weight as clinically indicated. Additionally, hematology, chemistry, coagulation, urinalysis, 
thyroid function, and pregnancy will be assessed as clinically indicated. 
 
Adverse events will be monitored from the time the participant receives treatment on study.  
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs throughout the study, including and up to 30 days. Due to the known 
excellent safety profile of botulinum toxin and FDA-approval for endoscopic injection for 
achalasia, AEs grade 1-2 will not be collected during the study. AEs Grade 3 or higher must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  
 
Abnormal laboratory values will only be recorded as an AE if determined to be clinically 
significant by the investigator. 
 
For details on AE collection and reporting, refer to Section 10. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
8.2 
LABORATORY PROCEDURES AND EVALUATIONS 
 
8.2.1 HEMATOLOGY 
Only as clinically indicated per institutional standard of care.  
 
8.2.2 COMPREHENSIVE METABOLIC PANEL  
Only as clinically indicated per institutional standard of care.  
 
8.2.3 COAGULATION PANEL 
Only as clinically indicated per institutional standard of care.  
 
8.2.4 PREGNANCY TEST  
A serum or urine pregnancy test is required during screening for all persons of childbearing 
potential. The pregnancy test is required within 7 days prior to study intervention and results 
must be available prior to administration of study agent. If the urine pregnancy test is positive, a 
serum pregnancy test must be performed per institutional standards. 
 
8.2.5 AMYLASE ASSAY 
Amylase levels will be drawn from all surgical drains, when present, on postoperative day 3 or 4, 
per standard of care prior following pancreas resections. In patients undergoing percutaneous 
drainage of a postoperative intra-abdominal fluid collection, amylase levels on the drained fluid 
will be drawn to evaluate for crPOPF. An amylase level >3 times the upper limit of normal from 
a surgical drain is sufficient for diagnosis of POPF, while an amylase level >3 times the upper 
limit of normal from a percutaneous drain is sufficient for a diagnosis of crPOPF. 
 
8.3 
SCREENING ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care. If a participant is eligible 
for the study after review of key inclusion/exclusion criteria, additional screening visits will be 
scheduled while staff members are requesting insurance authorization to participate in a clinical 
trial. 
 
The following will be reviewed at screening visit:  
• 
Clinical history and physical exam (per standard of care) 
• 
Informed consent obtained and documented 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis.  Consent 
must be obtained before initiation of any clinical screening procedure that are performed solely 
for the purpose of determining eligibility for this research study.  Evaluations performed as part 
of routine care before informed consent can be utilized as screening evaluations if done within 
the defined time period. 
 
8.4 
EARLY TERMINATION OR END OF STUDY VISIT 
 
Any participant who undergoes early termination will undergo end of study visits depending on 
their progress in the protocol. Participants who have not received BTX injection are not 
considered enrolled, will not require a follow up visit and will be treated per standard of care. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Participants who have received injection but not yet had surgery will have a follow-up visit 
within 30 days of intervention to evaluate for adverse events. Participants undergoing 
termination following pancreatectomy will have an end of study visit at the time of their regular 
post-op visit and will be cared for per the standard of care.  
 
8.5 
FOLLOW-UP 
 
Participants will be followed for 30 days following distal pancreas resection for efficacy. For 
safety, patients will be followed for 30 days following BTX injection if no surgery occurs or 30 
days after surgery, whichever is longer. A follow-up visit will occur 14 days (± 7 days)-
following hospital discharge, consistent with standard of care practices. Additionally, all subjects 
will be contacted by phone by the NSQIP Surgical Clinical Reviewer (Fouad Attia) or other 
study team member approximately 30 days following operation to collect standard NSQIP other 
study datapoints. If a participant is diagnosed with any BTX-related adverse event (of any 
grade), additional follow-up phone calls will be performed monthly for three months following 
BTX injection to ensure resolution at the end of BTX duration of action.  
 
Subjects not undergoing pancreatectomy and those undergoing pancreatectomy greater than 6 
weeks from the date of BTX injection will not be evaluable for assessing efficacy of the study 
intervention but will be evaluable for assessing safety. The 6 weeks timepoint is chosen because 
the maximal efficacy of BTX may begin to wane following this timepoint. In patients 
undergoing BTX injection but not undergoing planned pancreatectomy (or experiencing a delay 
in pancreatectomy due to an AE from BTX), data on the reason(s) for delay or cancelled 
operation will be recorded. 
 
8.6 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (e.g., laboratory or clinical assessments) at those visits that, in the opinion of the 
investigator, are deemed related to this study should be recorded in the CRF. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
8.7 
SCHEDULE OF EVENTS  
 
 
 
Visit Days (± 7 Days) 
Screening 
Days* 
Day 
 of 
 Surgery 
Follow-up 
Days 
-1 to -28 
1 
Days 2-14 (one pre-
operative medicine visit 
within this time frame) 
0-30 Days Post-
Surgery or Two 
Weeks Post-
Discharge (if LOS 
>30 Days)** 
BTX Administration 
 
X 
 
 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Medical history  
X 
 
 
 
Prior/concomitant medications 
X 
X 
 
 
Standard of Care Pre-Intervention Labs 
X 
 
X 
 
Height and weight 
X 
X 
 
 
Comprehensive physical examination 
X 
 
 
 
Physical Examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Efficacy Assessments 
 
 
 
X 
AE assessment 
 
 
X 
X 
Follow-up data collection 
 
 
 
X 
Amylase Measurement(s) 
 
 
 
X 
Phone call for efficacy evaluation 
 
 
 
X 
*Length dependent on scheduling of surgery, but will not be shorter than 7 days 
** Follow-up event can occur two-weeks post discharge (if LOS > 30) but collects information related to first 30 
days post-surgery 
 
Please note that patients will undergo an in-person pre-operative medicine exam prior to distal pancreatectomy/RAMPS per standard 
of care. Additionally, at the clinician’s discretion patients may undergo pre-procedure medicine evaluation appointment prior to upper 
endoscopy and BTX injection. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
9. EFFICACY MEASURES 
 
Therapeutic efficacy will be evaluated in this study by the presence of any POPF, clinically 
relevant POPF, postoperative length of stay, and major postoperative complications.  
 
9.1 
DEFINITION OF EFFICACY MEASURES 
 
9.1.1 ANY POPF 
 
Amylase level >3x the upper limit of normal from a fluid specimen obtained on postoperative 
day 3 or later, from a surgical drain or intra-abdominal fluid collection.  
 
9.1.2 CLINICALLY RELEVANT POPF (GRADE B AND C POPF) 
 
1. Amylase level >3x the upper limit of normal from a fluid specimen obtained on postoperative 
day 3 or later from postoperatively placed percutaneous or endoscopic drain of an intra-
abdominal fluid collection (Grade B POPF). 
 
OR 
 
2. Amylase level >3x the upper limit of normal from a fluid specimen obtained on postoperative 
day 3 or later from a surgical drain, postoperatively placed percutaneous or endoscopic drain 
of an intra-abdominal fluid collection, combined with organ failure clearly attributable to the 
POPF (Grade C POPF). 
 
Major postoperative complications: Any postoperative complication filling criteria for Clavien-
Dindo grade III or higher. 
 
Length of stay: Number of midnights in-hospital following distal pancreas resection 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Clavien-Dindo Complication Grades32: 
 
10. SAFETY 
 
10.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. Safety assessments will be based on medical review of adverse events and the results of 
safety evaluations at specified time points as described in Section 8.7, Schedule of Events. Any 
clinically significant adverse events persisting at the postoperative follow-up appointment will be 
followed by the Investigator until resolution/stabilization or death, whichever comes first. 
 
10.2 
DEFINITIONS 
 
10.2.1 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether considered intervention-related (21 CFR 
312.32 (a)). In general, this includes signs or symptoms experienced by the participant from the 
time of signing the informed consent to completion of the study.  
 
AEs may include, but are not limited to: 
• Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• Clinically significant laboratory abnormalities.  
• A significant worsening of the participant’s condition from study entry.  
• Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
the study treatment that resolve but then recur after treatment.  
• Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 
treatment.  
 
10.2.2 SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator or Sponsor-Investigator, it results in any of the following outcomes: 
  
• Death,  
• A life-threatening adverse event,  
• In-patient hospitalization or prolongation of existing hospitalization,  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect.  
• Pancreatitis requiring hospitalization 
• GI bleeding requiring hospitalization 
• GI perforation requiring hospitalization  
• Any procedure-related complication resulting in delay of surgery 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and/or participant may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include: 
 
• Allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
• Blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
• The development of drug dependency or drug abuse.  
 
10.2.3 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the participant population 
being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
10.2.4 SEVERITY OF EVENT 
 
Due to the known safety profile of botulinum toxin and FDA-approval for endoscopic injection 
for achalasia, AEs grade 1-2 will not be collected during the study. For serious AEs (Grade 3 or  
higher), the Investigator will grade its severity using, when applicable, the current version of the 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL  
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.  
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE.  
Note: a semi-colon indicates ‘or’ within the description of the grade. 
 
 
10.2.5 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY INTERVENTION 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out.  
Possibly Related: There is some evidence to suggest a causal relationship.  
Unrelated: The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely 
related to another etiology.  
 
10.3 
EXPECTEDNESS 
 
The Investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
 
10.4 
ADVERSE EVENT LIST(S)  
 
10.4.1 ADVERSE EVENT LIST FOR BTX 
 
Please refer to package insert for onabotulinumtoxinA for additional details. 
 
Clinical Studies Experience: BTX (onabotulinumtoxinA) and BTX Cosmetic contain the same 
active ingredient in the same formulation, but with different labeled Indications and Usage. 
Therefore, adverse events observed with the use of BTX Cosmetic also have the potential to be 
observed with the use of BTX and vice-versa. In general, adverse events occur within the first 
week following injection of BTX and while generally transient, may have a duration of several 
months or longer and include: 
 
Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising 
may be associated with the injection. Needle-related pain and/or anxiety may result in vasovagal 
responses (including e.g., syncope, hypotension), which may require appropriate medical 

 
 
 
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PI: Brett Sheppard, MD 
therapy. Local weakness of the injected muscle(s) represents the expected pharmacological 
action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread 
of toxin.  
 
Post-Marketing Experience: There have been spontaneous reports of death, sometimes associated 
with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with 
botulinum toxin. There have also been reports of adverse events involving the cardiovascular 
system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of 
these patients had risk factors including cardiovascular disease. The exact relationship of these 
events to the botulinum toxin injection has not been established. New onset or recurrent seizures 
have also been reported, typically in patients who are predisposed to experiencing these events. 
The exact relationship of these events to the botulinum toxin injection has not been established. 
The following events, not already addressed elsewhere in the package insert, have been reported 
since the drug has been marketed: abdominal pain; anorexia; brachial plexopathy; diarrhea; facial 
palsy; facial paresis; hyperhidrosis; hypoacusis; hypoaesthesia; localized numbness; malaise; 
myalgia; paresthesia; pyrexia; radiculopathy; skin rash (including erythema multiforme, and 
psoriasiform eruption); tinnitus; vertigo; visual disturbances; and vomiting. Because these events 
are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to botulinum toxin. 
 
 
10.4.2 ADVERSE EVENT LIST FOR ENDOSCOPY 
 
Overall, the rate of serious adverse events following endoscopy is less than 0.01%. Known risks 
associated with endoscopy are summarized in Table 3 have been extensively reported in large 
observational studies.33 
 
Table 3. Adverse Events Associated with N=73029 Endoscopic Procedures33 
Adverse event 
Total 
Percentage 
Bleed 
51 
0.07 
Cardiorespiratory arrest 
21 
0.03 
Postprocedural pain 
20 
0.03 
Pancreatitis 
17 
0.02 
Arrhythmias 
8 
0.01 
Febrile reaction 
6 
0.01 
Non-cardiac chest pain 
6 
0.01 
Perforation 
5 
0.01 
Hypoxia 
4 
0.01 
Iatrogenic 
4 
0.01 
Hemodynamic 
3 
<0.01 
Myocardial infarction 
2 
<0.01 
Miscellaneous 
2 
<0.01 
Obstruction 
2 
<0.01 
Tooth break 
2 
<0.01 
Anaphylaxis 
1 
<0.01 
Aspiration pneumonia 
1 
<0.01 
Cognitive dysfunction 
1 
<0.01 
Dyspnea 
1 
<0.01 

 
 
 
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PI: Brett Sheppard, MD 
GI obstruction 
1 
<0.01 
Seizures 
1 
<0.01 
Sore throat 
1 
<0.01 
Stricture 
1 
<0.01 
Stridor 
1 
<0.01 
Syncope 
1 
<0.01 
Total 
163 
0.22 
  
 
 
10.5 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, upon review by a study 
monitor, or during an audit. All AEs grade 3 or higher but not meeting the criteria for SAEs will 
be captured on the appropriate CRF. AEs of grade 1 and 2 will not be captured due to the well-
characterized side effect profile of BTX for other indications, including endoscopic BTX 
injection which is FDA approved. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, seriousness, expectedness, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and date of 
resolution/stabilization of the event. All AEs grade 3 or higher occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE after treatment with study 
intervention begins.   
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
 
The Investigator will record all reportable events with start dates occurring after treatment with 
study intervention begins for 30 days (for AEs grade 3 or higher) after the intervention is 
performed or 30 days after date of surgery, whichever is longer. AEs will be evaluated using the 
current version of the CTCAE v5.0.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization.  Any SAE that occurs after treatment with alternative therapy 

 
 
 
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PI: Brett Sheppard, MD 
will be reported only if the Investigator or current treating physician has assessed the SAE as 
related to the study treatment.  
  
10.6 
REPORTING PROCEDURES 
 
10.6.1 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE 
EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801).  Events that meet the 
criteria for OHSU RNI must be reported to the IRB within 5 days of learning of the event.  At a 
minimum, events requiring reporting to the IRB include: 
• Any new or increased risk related to the research, including AEs or IND safety reports 
that require a change to the protocol or consent,  
• New FDA black box warning,  
• Publications identifying new risks,  
• Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• Unanticipated adverse device effect 
• Unauthorized disclosure of confidential participant information 
 
10.6.2 CENTRAL REPORTING OF ADVERSE EVENTS FOR MULTI-SITE STUDIES  
 
A sub-site must notify the OHSU Coordinating Center of any SAE by phone, fax, or email no 
later than 24 hours after learning of the event.  The sub-site must also report each event to the 
institution’s local IRB or other oversight entity per institutional policies/requirements. The sub-
site will send the Coordinating Center supporting materials regarding the SAE, as well as 
[describe what sub-site must submit to coordinating center, for example: Knight SAE form, 
MedWatch form 3500, and/or any other trial specific reporting form (AESI, AECI)].  
 
The Coordinating Center will review and submit SAE information to the FDA, OHSU IRB, sub-
sites, and any other entities as required by federal and local policies/regulations, and any other 
applicable requirements.  
 
The Coordinating Center is responsible for distributing IND and/or IDE Action Letters and/or 
Safety Reports, as applicable, to sub-sites for review and submission to their institution’s local 
IRB as required per site policy. 
 
10.6.3 FDA REPORTING  
 
Some events must be reported to the FDA through the MedWatch Voluntary reporting program, 
even if the trial involves a commercially available agent.  Events to be reported include any UPs 
(i.e., not listed in the package insert) and any SAEs with a suspected association to the study 
intervention. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
For studies conducted under an IND/IDE, the OHSU Coordinating Center Investigator is 
required to report certain events to the FDA per applicable regulations.  
 
For multi-site investigator-initiated trials, the OHSU PI is the study sponsor and the following 
reporting responsibilities and requirements apply.   
 
The sub-site investigator is required to report AEs to the Coordinating Center using a MedWatch 
report form and/or any trial-specific report form and supporting materials. Adverse events to be 
reported include any UPs (i.e., not listed in the package insert and/or IB) and any SAEs with a 
suspected association to the investigational product. The Coordinating Center will centrally 
assess all reported events and report any events to the FDA as warranted using the MedWatch 
3500A Mandatory report form.  
 
10.6.4 SUSPECTED UNEXPECTED ADVERSE REACTIONS (SUSARS) 
 
Per regulatory requirements, if an event is assessed by the Sponsor Institution as a Serious 
Unexpected Adverse Reaction (SUSAR), it is the responsibility of the Sponsor Institution to 
submit the SUSAR to Regulatory Authorities according to applicable regulations.  In addition, 
the SUSAR will be distributed to the Investigators/sites utilizing a Council for International 
Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 3500A form).  The 
Investigator/site will submit a copy of the report to their respective IRB or IEC per the governing 
institutional requirements and in compliance with local laws and guidelines. 
 
10.6.5 REPORTING OF PREGNANCY 
 
To ensure participant safety, each pregnancy or suspected pregnancy in a participant during 
study participation must be reported within 24 hours of learning of its occurrence. The sub-site 
investigator is required to notify the OHSU Coordinating Center by phone, fax, or email no later 
than 24 hours of learning of a pregnancy. The sub-site must also report each event to the 
institution’s local IRB or other oversight entity per institutional policies/requirements. The 
Coordinating Center will centrally assess the event and report to the manufacturer and any other 
entity as warranted.  The sub-site will send the Coordinating Center information regarding the 
pregnancy using secure institutional email. Describe what sub-site must submit to Coordinating 
Center, for example: Knight SAE form template, MedWatch form 3500, and/or any other trial 
specific reporting form.  
 
The investigator must follow the pregnancy to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or any pregnancy- or childbirth-related and/or newborn complications. 
The sub-site must report the outcome of the pregnancy to the Coordinating Center as defined 
above. 
 
If during study participation a participant’s sexual partner becomes pregnant, the pregnancy and 
pregnancy outcomes must also be reported as described above. Consent to report information 
regarding the pregnancy should be obtained from the pregnant individual. 
 
10.7 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 

 
 
 
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Protocol Number (eIRB#) 22619 
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Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is 
unmanageable, or unexpected. 
• 
Death suspected to be related to BTX injection. 
• 
As indicated by statistical stopping rules in this protocol per Section 11.4.5: 1) During 
safety run-in if two or more out of the first six participants experience a surgical delay ≥ 14 days 
past the previously scheduled date. 2) Interim analysis if two or more of the first 25 participants 
experience crPOPF. If either of these events are met the trial will be stopped. In the case of the 
safety run-in, the trial may be resumed if a correctable cause for the serious adverse events can 
be found or a prophylactic treatment administered. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
STATISTICAL HYPOTHESIS 
 
This study is a Phase II, open-label study to determine the effect of pre-operative endoscopic 
BTX injection on crPOPF rates following distal pancreatectomy. It is hypothesized that the rate 
of crPOPF in study participants will be significantly lower than the known historical rate of 
crPOPF. 
 
11.2 
SAMPLE SIZE DETERMINIATION 
 
This will use a Simon’s two-stage design. The two-stage design to test a difference of 9.2% (2% 
vs. 11.2%) has an expected sample size of 30.33 and a probability of early termination of 0.787. 
If the pre-operative BTX injection is effective, there is a 0.124 probability of concluding that it is 
not, equivalently 0.876 power. After the pre-operative BTX injection on 25 patients in the first 
stage, the trial will be terminated if 2 or more crPOPF. If the trial goes on to the second stage, a 
total of 50 participants will be studied. If the total number crPOPF is less than 3, the drug will be 
considered efficacious. Anticipating 10% drop-out (lost follow-up), up to 55 participants need to 
be enrolled to achieve 50 evaluable participants.  The sample size and power analysis were 
conducted is conducted using PASS 15 software (http://www.ncss.com/software/pass/). 
 
11.3 
POPULATIONS FOR ANALYSES  
 
11.3.1 Safety Population 
The safety population includes all enrolled participants who received the single BTX injection.  
All safety analyses related to the intervention will be conducted using the population receiving 
BTX injection. Analysis for demographics, baseline characteristics, disease history, on-study 
treatment summaries, concomitant medications, and participant disposition will also be 
conducted using the safety population.  
 
11.3.2 Efficacy Evaluable Population 
 
The efficacy evaluable population includes all participants enrolled in the study who received the 
single BTX injection, underwent distal pancreatomy/RAMPS, and had up to 30 days or greater 
of postoperative follow-up for POPF assessment.  Participants who experience surgical delay 
greater than 6 weeks are not evaluable. All efficacy analyses will be conducted using the efficacy 
evaluable population. Safety analyses related to surgery will use the efficacy population.   
 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
11.4 
DESCRIPTION OF STATISTICAL METHODS 
 
 
11.4.1 ANALYSIS OF PRIMARY ENDPOINT(S) 
 
Using the efficacy analysis set, the estimate of clinically relevant POPF rate on pre-operative 
endoscopic BTX injection will be measured and reported with 95% exact confidence interval. 
 
11.4.2 ANALYSIS OF THE SECONDARY ENDPOINT(S)  
 
11.4.2.1 
Rate of serious adverse event 
 
Using the safety analysis set, the incidence of serious adverse events following endoscopic BTX 
injection into the sphincter of Oddi as a single agent will be determined for participants 
undergoing distal pancreas resections.  The 95% confidence interval will be reported with the 
point estimate of SAE rate. 
 
11.4.2.2 
Rate of any POPF 
 
Using the efficacy analysis set, the estimate of biochemically or clinically relevant POPF rate on 
pre-operative endoscopic BTX injection will be measured and reported with 95% exact 
confidence interval. 
 
11.4.3 ANALYSIS OF THE EXPLORATORY ENDPOINT(S)  
 
Exploratory analysis will be performed with historical patients accounting for the covariates that 
predict experiencing a crPOPF. That is, to estimate the effect of pre-operative endoscopic BTX 
injection on crPOPF for this non-randomized trial, we will use disease risk score matching34 to 
pair treatment and control units with similar values on the disease riskscore with known risk 
factors for crPOPF with the following endpoints of interest at 30 days postoperatively. The 
disease risk score model will be derived from the historical control cohort, which consists of 
distal pancreas resections from 2013-2020 with pancreas-specific National Surgical Quality 
Improvement Program (NSQIP) information. The historical control group has experienced 
approximately 30 crPOPFs, which is sufficient for estimation of crPOPF risk using the predictive 
variables captured by NSQIP and supplemental chart review. Individual patients from the 
historical and intervention groups will be assigned disease risk scores, and matched according to 
scores.  
 
As data allow, the benefit of pre-operative BTX injection for 30 days outcomes will be analyzed 
using disease risk score matching using known risk factors for crPOPF against historical patient 
controls for the following endpoints : 
1) Clinically relevant POPF 
2) Any POPF 
3) Postoperative Length of Stay 
4) Clavien-Dindo III or greater postoperative complications 
5) Rate of percutaneous drainage procedure 
6) Rate of unplanned re-operation 
 
 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
11.4.4 SAFETY ANALYSES 
 
Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA 
Version 21.1) preferred term and system organ class.  The severity of the AE will be assessed by 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0.  Using the safety analysis set, descriptive statistics will be used to summarize all on-
study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, SAEs, 
treatment-related SAEs, and AEs leading to study therapy discontinuation.  Grade 3-4 laboratory 
abnormalities will be summarized using worst grade NCI CTCAE v5.0 criteria. 
 
 
11.4.5 PLANNED INTERIM ANALYSES AND STOPPING RULE 
 
A safety-run in to test the endoscopic BTX injection technique will be performed. During the 
safety run-in, the PI will evaluate patient safety outcomes including grade 3 or higher adverse 
events. Additionally, the study will be evaluated by the DSMC following the completion of the 
first three participant’s safety evaluation periods (30 days following BTX injection or 30 days 
following surgery, whichever is longer). Progressive study enrollment will continue throughout 
the safety run-in, and enrollment will be halted if recommended by the DSMC after completion 
of the run-in. If 2 or more of the first 6 participants enrolled experience delay in planned surgery 
≥ 14 days (due to significant GI hemorrhage, perforation, or adverse reaction to BTX) or 
pancreatitis requiring hospitalization, then the study will be halted for safety. If 2 or more of the 
first 6 participants experience delay in planned surgery ≥ 14 days (due to significant GI 
hemorrhage, perforation, or adverse reaction to BTX) or pancreatitis requiring hospitalization, 
the study will be halted for safety. An analysis of adverse events will be performed, and if an 
alteration in the intervention technique or other prophylactic treatment cannot be identified the 
study will be terminated. If an alteration or prophylactic treatment can be found, the study will 
resume with an additional 6 patient safety run-in with identical stopping rules.  
 
A futility analysis will be conducted based on the stopping rule of Simon’s two-stage design 
after 25 Stage I participants have met the eligibility criteria for the efficacy evaluable population 
(defined in 11.3.2). All participants enrolled on stage 1 (n=25) will need to complete the study 
intervention, distal pancreas resection, and 30 days of follow up for postoperative pancreatic 
fistula before the interim analysis can be completed. Recruitment will be paused until interim 
analysis is completed. The trial will be terminated if there are 2 or more crPOPF among these 25 
participants.   If there are less than 2 crCOPF among these Stage I participants, the trial will 
continue and enroll 25 additional participants in Stage II. The treatment will be considered 
promising and deserving of further investigation if there are less than 3 crCOPF among the total 
of evaluable 50 participants. 
 
 
11.5 
HANDLING OF MISSING DATA 
Every attempt will be made to obtain data at the defined time points as described in the primary 
and secondary endpoints.  If the data are not sufficient to analyze specific endpoints, the 
participant’s data may be excluded entirely or partially.  No missing value imputation will be 
performed. 
 
12. CLINICAL MONITORING 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
12.1 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN 
 
All clinical trials at the Knight are required to have Data and Safety Monitoring Plan (DSMP). 
This study is under the oversight of the Knight Cancer Institute’s DSMC as described in the 
Knight institutional DSMP.  The Knight DSMP outlines the elements required to ensure the 
safety of clinical trial participants, the accuracy and integrity of the data, and the appropriate 
modification of cancer-related clinical trials for which significant benefits or risks have been 
discovered or when the clinical trial cannot be successfully concluded. The Knight DSMP also 
describes the methods and procedures for ensuring adequate, risk-based oversight of cancer-
related research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The Knight DSMC reviews and monitors study progress, toxicity, safety, and other data for this 
study. The DSMC will address any issue that raises questions about data integrity or trial 
participant safety with the Investigator and study team. Should any major concern arise, the 
Knight DSMC may recommend corrective action, and determine whether to suspend or 
terminate the study. 
 
12.2 
CLINICAL DATA & SAFETY MONITORING 
 
As part of the Quality Assurance plan and in full agreement with NIH policy (NIH Guide, NIH 
Policy for Data and Safety Monitoring, June 10, 1998) that states all clinical trials require 
monitoring to ensure the safety of study participants and the validity and integrity of the data, 
monitoring will be a continuous, ongoing and multifaceted process. This includes external 
review by the DSMC and IRB(s), as well as internal data quality control, review and evaluation. 
Site monitoring visits are central to this process, and will include reporting to appropriate 
individuals with oversight responsibilities.  
The OHSU Investigator is ultimately, singularly responsible for overseeing every aspect of the 
investigation, including design, governing conduct at all sub-sites, and final analysis of study 
data.  
 
In the absence of a formal monitoring plan, the Investigator may work with his/her study team to 
conduct and document internal monitoring of the study to verify protection of human 
participants, quality of data, and/or ongoing compliance with the protocol and applicable 
regulatory requirements. 
 
If at any time Investigator noncompliance is discovered at OHSU or any sub-site, the 
Investigator shall promptly either secure compliance or end the Investigator’s participation in the 
study. 
 
Independent audits will be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
and that evidence of ongoing investigator oversight is present. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
12.3 
QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
All clinical trials at the Knight Cancer Institute are required to have a Data and Safety 
Monitoring Plan (DSMP).  All clinical work conducted under this protocol is subject to ICH 
GCP guidelines.  This includes inspection of study-related records by the lead site, Sponsor, its 
designee, or health authority representatives at any time. 
 
QA audit activities will occur as detailed in the Knight’s institutional DSMP.  All discrepancies, 
queries, deviations, observations, and findings of non-compliance will be compiled into a final 
audit report. The PI must review and assess each finding, and generate a response to the audit 
report that incorporates Corrective and Preventative Action (CAPA).  A CAPA must approach 
analyzes root cause(s) of noncompliance in order to identify and determine changes to correct 
and resolve issues, and prevent recurrence. 
 
Quality Control (QC) activities will occur to monitor and ensure the safety of study participants 
and the validity and integrity of data.  Monitoring will be a continuous, ongoing and multifaceted 
process.  This includes review by the Knight DSMC and applicable IRB(s), as well as internal 
data quality control, review and evaluation.  Site monitoring visits are central to this process, and 
will include reporting to appropriate individuals with oversight responsibilities. 
 
The Sponsor-Investigator, or study monitor, will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, GCP, 
and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 
13. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
13.1 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data. The Investigator will maintain adequate case histories of 
study participants, including accurate CRFs, electronic (e)CRFs and relevant electronic data 
capture (EDC) system (if applicable), and all relevant source documentation. 
 
13.1.1 PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Participant confidentiality is strictly held in trust by the site Investigator(s) and study team. This 
confidentiality is extended to cover testing of biological samples and genetic tests in addition to 
the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor.  
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives. Individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives. At the end of the study, or after the 
appropriate period of record retention stated in Section 13.1.3, all study databases will be de-
identified and archived within the Knight Cancer Institute. 
 
13.1.2 DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation.  Efforts will be made to keep study 
participant identities confidential except as required by law.  Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique coded 
identifier consisting of numbers.  This identifier will be associated with the participant 
throughout the duration of their participation in the trial.  The coded identifier will also be used 
to identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical research information system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon.  Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 

 
 
 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC) system that is approved by OHSU’s office of Information Privacy and 
Security.  To preserve confidentiality, PHI in the EDC system will be limited to just birth date 
and visit dates.  The web-accessible EDC system is password protected and encrypted with role-
based security, and administered by designated informatics staff within OHSU or Knight Cancer 
Institute.  All users of the database are assigned a unique ID, username, and password and must 
complete training appropriate to their role before they are authorized to enter, access, and store 
data in the database. 
 
Where applicable, data from correlative studies may be entered into the EDC system by study 
personnel.  All other electronic data extracts will be stored only on local study site computers 
and restricted drives, which are limited to only study investigators and staff with authorization to 
access the data.  Quality assurance will be conducted as outlined in Section 12.3, Quality 
Assurance & Quality Control 
 
13.1.2.1 
National Surgical Quality Improvement Project (NSQIP) & Efficacy Data Collection 
 
NSQIP is an international initiative sponsored by the American College of Surgeons that records 
patient demographics, treatment regarding surgical interventions, and captures 30-day 
postoperative complications data.35 “Procedure-targeting” allows institutions to capture 100% of 
certain surgical procedures along with an expanded set of procedure-specific datapoints (e.g., 
data on POPF and crPOPF for pancreatectomies). OHSU has been procedure-targeting 
pancreatectomies since 2013. 
 
Data collection for 30-day postoperative complications, including POPF and crPOPF, will be 
performed by a trained NSQIP surgical clinical reviewer. Due to the workflow of NSQIP 
reviewers, a lag period between surgery is anticipated equaling up to 3-months. For the purposes 
of the interim efficacy analysis, subject charts may be reviewed for information relevant to the 
primary endpoint by individuals other than the NSQIP reviewer. Data obtained from the NSQIP 
reviewer relating to primary or secondary endpoints will be separately reviewed by a member of 
the study team and any conflicts or discrepancies resolved. Finalized data will be entered into the 
EDC system and used for final analysis.  
 
13.1.3 MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years. If the Investigator relocates or for any reason withdraws 
from the study, the study records must be transferred to an agreed upon designee, such as another 
institution or another investigator at OHSU. Records must be maintained according to 
institutional or FDA requirements.  
 
13.2 
MULTI-SITE GUIDELINES  
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Each sub-site is expected to maintain appropriate medical and research records in compliance 
with ICH GCP and regulatory and institutional requirements for the protection and 
confidentiality of participants.  
 
OHSU Coordinating Center will provide a manual of procedures and/or data management plan to 
sub-sites to describe required data and document submission requirements and timelines.   
 
OHSU Coordinating Center will communicate with sub-site(s) on a routine basis and will retain 
essential documents in accordance with ICH GCP and regulatory and institutional requirements.   
 
13.3 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may be 
requested from other researchers 2 years after the completion of the primary endpoint by 
contacting the PI.  
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to 
participant enrollment.  
 
 
13.4 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  Conflicts of interest, for all study group members, should be 
disclosed and managed according to OHSU’s established policies and procedures. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
Refer to link: https://o2.ohsu.edu/integrity-department/conflict-of-interest/index.cfm 
 
 
14. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
14.1 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 312, and/or the ICH E6. 
 
14.2 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
14.3 
INFORMED CONSENT 
 
All sites must have IRB approval of informed consent form by the IRB of record before 
consenting any participants. 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50. If a participant’s signature cannot be obtained, the Investigator must 
ensure that the informed consent is signed by the participant’s legally authorized representative.  
Documentation of the consent process and a copy of the signed consent shall be maintained in 
the participant’s medical record.  
 
14.3.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate. Consent forms will be IRB-approved and the participant will be asked to read and 
review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
 
14.4 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study. All sites must have IRB 
approval of protocol by the IRB of record before consenting any participants. 
 
14.5 
CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
sponsor/FDA if under an IND/IDE) within 5 business days after the implementation.  
 
A protocol change intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately provided FDA is subsequently notified by protocol amendment and 
the reviewing IRB is notified in accordance with §56.104(c) (21 CFR 312.30(b)(2)(ii)). 
 
Sub-sites must submit proposed protocol changes to the OHSU Coordinating Center for review 
and endorsement before sub-site may implement changes. 
 
 

 
 
 
Botox in Distal Pancreatectomy - Phase II 
Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
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Protocol Number (eIRB#) 22619 
Version Number 2.0 
Version Date. 10/2/2023 
 
PI: Brett Sheppard, MD 
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