A Phase II Study to Establish the Efficacy of Synthetic Human SecretiN in Human Acute Pancreatitis (SNAP) Study
Phase: PHASE2
Conditions: Pancreatitis, Acute
Sponsor: ChiRhoClin, Inc.

CONFIDENTIAL
v. 2/27/2017
A Phase II Study to Establish the
Efficacy of Synthetic Human SecretiN in
Human Acute Pancreatitis (SNAP) Study
Regulatory Sponsor:
Timothy B. Gardner MD MS
Department of Medicine
One Medical Center Drive
Lebanon, NH 03756
603-650-5225
Funding Sponsor:
Research Coordination and Salary Support:
NIDDK - NIH
R21 Grant Application Pending – February 2017
(Final Funding Decision December 2017)
Study Drug and IND Holder:
ChiRhoClin, Inc
4000 Blackburn Lane, Suite 270
Burtonsville, MD 20866-6129
301-476-8388
301-476-9529 FAX
Study Product:
ChiRhoStim® (Synthetic Human Secretin for Injection)
NDA # 21-256
NDC # 67066-005-01
Cohort 1 Bolus Dose: 40 mcgIV q12hours
Cohort 2 Bolus Dose: 40 mcgIV q6hours
Cohort 3 Bolus Dose: 40 mcgIV q4hours
Protocol Number:
Version 1
IND Number:
56-821
Initial version:
2/27/2017
Amended:
11/27/2017
Amended:
11/30/2017
Amended:
3/13/2018
Amended:
06/06/2018

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Table of Contents
STUDY SUMMARY.................................................................................................................................1
1
INTRODUCTION.............................................................................................................................2
1.1
BACKGROUND ..........................................................................................................................2
1.2
INVESTIGATIONAL AGENT...........................................................................................................4
1.3
PRECLINICAL DATA ...................................................................................................................4
1.4
CLINICAL DATA TO DATE............................................................................................................4
1.5
DOSE RATIONALE AND RISK/BENEFITS ........................................................................................5
2
STUDY OBJECTIVES ....................................................................................................................6
3
STUDY DESIGN .............................................................................................................................7
3.1
GENERAL DESIGN .....................................................................................................................7
3.2
PRIMARY STUDY ENDPOINTS......................................................................................................7
3.3
SECONDARY STUDY ENDPOINTS.................................................................................................7
3.4
PRIMARY SAFETY ENDPOINTS ....................................................................................................8
4
SUBJECT SELECTION AND WITHDRAWAL ................................................................................9
4.1
INCLUSION CRITERIA .................................................................................................................9
4.2
EXCLUSION CRITERIA ................................................................................................................9
4.3
SUBJECT RECRUITMENT AND SCREENING....................................................................................9
4.4
EARLY WITHDRAWAL OF SUBJECTS.............................................................................................9
4.4.1
When and How to Withdraw Subjects .................................................................................9
4.4.2
Data Collection and Follow-up for Withdrawn Subjects........................................................9
4.5
SUBJECT RANDOMIZATION/ASSIGNMENT…..…………………………………………….....…9
5
STUDY DRUG ..............................................................................................................................10
5.1
DESCRIPTION .........................................................................................................................10
5.2
TREATMENT REGIMEN .............................................................................................................10
5.3
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .....................................................10
5.4
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................10
5.5
SUBJECT COMPLIANCE MONITORING.........................................................................................10
5.6
PRIOR AND CONCOMITANT THERAPY.........................................................................................11
5.7
PACKAGING............................................................................................................................11
5.8
BLINDING OF STUDY DRUG.......................................................................................................11
5.9
RECEIVING, STORAGE, DISPENSING AND RETURN ......................................................................11
5.9.1
Receipt of Drug Supplies ..................................................................................................11
5.9.2
Storage.............................................................................................................................11
5.9.3
Dispensing of Study Drug .................................................................................................11
5.9.4
Return or Destruction of Study Drug .................................................................................11
6
STUDY PROCEDURES................................................................................................................12
6.1
PRETREATMENT EVALUATION………………………………………………………………………………..12
6.2
TREATMENT PLAN……………………………………………………………………………………………….12
6.3
INTRA AND POST TREATMENT EVALUATION……………………………………………………………...12
6.4
STUDY ENDPOINTS…………………………………………………………………………………………...…13
6.5
STANDARD OF CARE……………………………………………………………………………………………13
7
STATISTICAL PLAN ....................................................................................................................14
7.1
SAMPLE SIZE DETERMINATION .................................................................................................14
7.2
STATISTICAL METHODS............................................................................................................14
7.3
SUBJECT POPULATION(S) FOR ANALYSIS...................................................................................14
8
SAFETY AND ADVERSE EVENTS ..............................................................................................15
8.1
DEFINITIONS...........................................................................................................................15

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8.2
RECORDING OF ADVERSE EVENTS............................................................................................17
8.3
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS................................17
8.3.1
Investigator reporting: notifying the study sponsor.............................................................17
8.3.2
Investigator reporting: notifying the Dartmouth IRB ...........................................................18
8.3.3
Investigator reporting: Notifying a non-Dartmouth IRB.......................................................19
8.3.4
Sponsor reporting: Notifying the FDA................................................................................19
8.3.5
Sponsor reporting: Notifying participating investigators .....................................................20
8.4
UNBLINDING PROCEDURES ......................................................................................................20
8.5
STOPPING RULES ...................................................................................................................20
8.6
MEDICAL MONITORING.............................................................................................................21
8.6.1
Internal Data and Safety Monitoring Board........................................................................21
9
DATA HANDLING AND RECORD KEEPING ...............................................................................22
9.1
CONFIDENTIALITY....................................................................................................................22
9.2
SOURCE DOCUMENTS .............................................................................................................22
9.3
CASE REPORT FORMS.............................................................................................................22
9.4
RECORDS RETENTION .............................................................................................................22
10
STUDY MONITORING, AUDITING, AND INSPECTING................................................................23
10.1
STUDY MONITORING PLAN .......................................................................................................23
10.2
AUDITING AND INSPECTING.......................................................................................................23
11
ETHICAL CONSIDERATIONS......................................................................................................24
12
STUDY FINANCES.......................................................................................................................25
12.1
FUNDING SOURCE...................................................................................................................25
12.2
CONFLICT OF INTEREST ...........................................................................................................25
13
PUBLICATION PLAN ...................................................................................................................26
14
REFERENCES .............................................................................................................................27
15
ATTACHMENTS...........................................................................................................................30

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List of Abbreviations
AE
Adverse Event(s)
BP
Blood Pressure
CBC
Complete Blood Count
CCK
Cholecystokinin
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator Gene
CMP
Comprehensive Metabolic Panel
CRF
Case Report Form
CRP
C-Reactive Protein
CT
Computed Tomography
e.g.
Exempli Gratia (for example)
ERCP
Endoscopic Retrograde Cholangiopancreatography
etc.
Et cetera (and so forth)
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICU
Intensive Care Unit
IL
Interleukin
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
mcg
Microgram
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeters of Mercury
n
Number
O2 Sat
Oxygen Saturation
PE
Physical Examination
pH
Ion of Hydrogen
SAS®
Statistical Applications Software
USP
United States Pharmacopoeia
VAS
Visual Analog Scale (Score)
vs.
Versus
WSR
Westegren Sedimentation Rate

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Study Summary
Title
A Phase II Study to Establish the Efficacy of Synthetic Human
SecretiN in Human Acute Pancreatitis (SNAP) Study
Short Title
Secretin for acute pancreatitis
Protocol Number
1
Phase
Phase II
Methodology
Randomized, dose escalation trial
Study Duration
Estimated duration for the main protocol (e.g. from start of screening to
last subject processed and finishing the study)
Study Center(s)
Multicenter – Dartmouth-Hitchcock Medical Center and Ohio State
University
Objectives
1) To perform a Phase II Pilot Study to explore the efficacy of
intravenous synthetic human secretin as a pharmacologic
adjunct to modulate the severity of
human acute (non-
obstructive) pancreatitis.
2) To explore the efficacy when escalating the frequency of daily
intravenous synthetic human secretin dosing in the setting of
human acute pancreatitis.
3) To evaluate the safety of intravenous synthetic human secretin
in the acute pancreatitis population.
4) Use data from this phase II pilot study to appropriately design a
definitive,
prospective
trial
of
human
secretin
in
acute
pancreatitis.
Number of Subjects
40 patients at two centers (20 patients at each center)
Diagnosis
and
Main
Inclusion Criteria
1.
Patient
is
male
or
female
≥18 
years 
of 
ag
2.
Patient voluntarily signed written, informed consent agreement.
3.
If patient is female and not more than 1 year post-menopausal,
or surgically sterile, must use medically accepted form of
contraception or abstain from sexual activities during study.
4.
Patient has non-obstructive acute pancreatitis via the 2012 Atlan
Classification.
Study Product, Dose,
Route, Regimen
ChiRhoStim® 40 mcgIV Bolus q12hr (Cohort 1), q6hr (Cohort 2) and
q4hr (Cohort 3)
Mode of Administration: IV Bolus over 1 minute.
Duration
of
administration
40 mcgIV Bolus q 12hr for Cohort 1; 40 mcg IV Bolus q 6hr for Cohort
2 or 40 mcgIV Bolus q 4 hr for Cohort 3 x 3 days
Reference therapy
Standard of care in Cohort X (OBSERVATIONAL cohort)
Statistical
Methodology
No power calculation is necessary for this study since it is a pilot study.
The pilot study will be utilized to calculate the power of a large
multicenter study.

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1.
Introduction
This document is a protocol for a human research study. This study is to be conducted according
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and
International Conference on Harmonization guidelines), applicable government regulations and
Institutional research policies and procedures.
1.1
Background
The development of innovative diagnostic, preventive, and therapeutic approaches to pancreatitis
has the potential to reduce the burden of this disease in both children and adults. The 2009
National Commission on Digestive Diseases (NCDD) recommended a series of research
goals that focused on the most prevalent pancreatic disorders—acute and chronic pancreatitis
and their sequelae.1 This exploratory R21 grant proposal specifically addresses Research
Goal 10.4: Develop and validate therapeutic interventions for the treatment and/or
progression of pancreatitis and its complications. We anticipate that this exploratory study
will demonstrate a promising signal that human intravenous secretin should be investigated
further as a pharmacologic therapy to improve patient outcomes in acute pancreatitis.
Acute pancreatitis is a frequently devastating pancreatic inflammatory process that results in
extensive morbidity, mortality, and hospitalization costs.2 The incidence of acute pancreatitis
has been increasing over the last decade with an overall mortality rate of 5%, although it may be
as high as 30% in the most severe cases.3 It was the most common inpatient gastrointestinal
diagnosis in 2009, totaling over 270,000 hospitalizations with estimated “inpatient costs” of over
2.5 billion dollars in the United States.4 However, despite the significant impact to both
patients and the healthcare system, there is no proven pharmacologic therapy that
improves important clinical outcomes in acute pancreatitis.
Peery et al. Gastroenterology 2012;143:1179-87.4
The pathophysiology of acute pancreatitis involves an inciting event – excessive alcohol use,
transient obstruction of the ampulla of Vater via a biliary stone, excessive free fatty acid
formation in toxic serum concentrations, for example – although the precursor mechanism of
action that leads to acute pancreatitis remains unknown.5,6 Following this acute inciting
event, the exocrine pancreas inappropriately initiates the intra-acinar activation of
trypsinogen to activated trypsin which is normally only activated after reaching the
duodenum.7 This inappropriate synthesis of activated intra-acinar trypsin results in the
generation of large amounts of active trypsin within the pancreas, which then catalyzes the
activation of more trypsin and other proteolytic enzymes such as chymotrypsin and elastase,
with subsequent initiation of other enzyme cascades such as complement, kalikrein-kinin,
coagulation and fibrinolysis.8,9

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As intra-acinar accumulation of activated enzymes exponentially increases, pancreatic
autodigestion occurs, leading to the release of even more active enzymes from damaged
cells.10 The release of pancreatic enzymes then stimulates leukocyte chemo-attraction,
microcirculatory injury and subsequent granulocyte and macrophage activation causing the
release of proinflammatory cytokines (tumor necrosis factor, interleukins 1, 6, and 8),
arachidonic acid metabolites (prostaglandins, platelet-activating factor, and leukotrienes),
proteolytic and lipolytic enzymes, and reactive oxygen metabolites, which overwhelm the
scavenging capacity of endogenous antioxidant systems.3,11-13 These inflammatory mediators
also interact with the pancreatic microcirculation to increase vascular permeability and induce
thrombosis and hemorrhage.14 Finally, as a result of this inflammatory cascade, some patients
will develop a sepsis-like syndrome featuring hypotension, capillary-leak syndrome, acute
respiratory distress syndrome, and in some cases death.3,15
Critical to the pathogenesis of acute pancreatitis is the inability of the pancreas to
secrete these inappropriately activated intra-acinar pancreatic enzymes. The pancreas
normally secretes inactivated trypsinogen into the duodenum via a cAMP mediated process
within the pancreatic ductal cell that is under the control of the secretory hormone secretin16
Discovered over 100 years ago, secretin is a gastrointestinal hormone produced by the S-cells
of the proximal small intestine in response to a meal and acts on the pancreatic ductal epithelial
cells to stimulate the production of bicarbonate-rich fluid (pH 8.5).17 The release of
bicarbonate rich fluid into the pancreatic duct from the ductal cells is an important
mechanism to protect against pancreatitis by two distinct mechanisms:
1. “Flushing” activated enzymes out of the pancreas and into the duodenum thereby
preventing accumulation of activated enzymes within the pancreatic acinus
2. Directly alkalinizing the acinar cells, which limits intra-acinar cell damage by
improving trafficking of inappropriately activated intra-acinar enzymes along the
apical membrane.18-20
Patients with a defect in their ability to generate bicarbonate-rich fluid – i.e. in some gene
mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene – develop
acinar cell injury both from accumulation of activated intra-acinar enzymes and deficient
trafficking of activated enzymes out of the acinar cell.21,22 Data from a study evaluating CFTR
knock-out mice demonstrated that when luminal pH is corrected back to an alkaline
environment, the membrane trafficking defect within the acinar cell reverses.23 Acids within the
lumen of the pancreatic acinus have also been implicated in the disruption of intracellular
junctional links which has been postulated to involve the initiation of pancreatitis.24,25 Thus, a
primary role of the ductal cells is to neutralize the large amount of acid content secreted by the
acinar cells as a means of limiting the ongoing activation of the prematurely activated intra-
acinar enzymes.
Previous efforts to develop clinically effective pharmacologic therapies for acute pancreatitis
have targeted the inflammatory response using anti-proteases such as gabexate mesilate,
antagonists of platelet activating factor such as lexipafant, corticosteroids, anti-IL-10, and anti-
TNF-α; however, none of these therapies have shown clinical efficacy.26 Furthermore,
significant effort has been invested in both animal and human in vitro and in vivo studies to try
and develop an effective therapy for reducing pancreatic secretion in acute pancreatitis.
Randomized clinical trials, based on pre-clinical in vivo studies, however, have not
demonstrated any benefit with somatostatin, octreotide, atropine, glucagon, and/or cimetidine.27-
29 The lack of clinical benefit to suppressing pancreatic secretions in human trials of acute
pancreatitis has driven interest in exploring the opposite hypothesis – i.e. stimulating the
pancreas to enhance secretion of watery, bicarbonate-rich (pH 8.5) pancreatic fluid in

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order to flush the pancreatic ducts of pancreatic enzymes thereby stopping the ongoing
activation of intra-acinar trypsin via pH inhibition.
1.2
Investigational Agent
Fortunately, there is a means available to stimulate secretion from the pancreatic ductal cells
using a pure synthetic human secretin that has the identical 27 amino acid peptide sequence as
the biologic form. Synthetic secretin has several advantages over the biologic form, not the
least of which is a potential for an unlimited supply of drug, biochemical purity, a more
predictable pharmacologic response and nearly no potential for immunogenicity.16 The
hypothesis on which this pilot study is based is that human secretin, given to patients with acute
pancreatitis, will stimulate pancreatic ductal secretion of bicarbonate-rich pancreatic fluid, which
would wash out the pancreatic ducts of pancreatic enzymes, halt the ongoing activation of
trypsin via pH inhibition within the pancreatic acinus and improve pancreatic acinar cell function.
Such an intervention, we believe, has the possibility of improving meaningful outcomes in
human acute pancreatitis.
1.3
Preclinical Data
We have extensive experience with designing, executing, completing and reporting prospective,
clinical research studies studying human pancreatitis.
In addition, we are among the few
investigators who have executed randomized trials in acute pancreatitis and have published
multiple clinical studies using secretin specifically for the diagnosis and treatment of human acute
and chronic pancreatitis.30,31 The proposed pilot study is based on our extensive experience with
administration of secretin and several years of data suggesting efficacy of secretin to treat human
pancreatitis.32,33
Animal studies.
Animal studies have demonstrated that exogenous secretin administration
produces a positive effect on the release of pro-inflammatory cytokines in the well-known cerulein-
induced acute pancreatitis model in the rat without causing harm. Utilizing light microscopy and
electron microscopy, Renner et al showed marked cellular disorganization in the acini of animals
treated with cerulein alone.34
In contrast, there was a striking apical redirection of zymogen
granules, lessening of acinar vacuolization, interstitial edema and preservation of parenchymal
architecture in the acini of animals treated with secretin. They also reported that secretin partially
restored pancreatic function in rats with cerulein-induced acute pancreatitis.35
Niederau et al
reported
that
exogenous
secretin
lowered
serum
amylase
levels,
and
exhibited
less
histopathological changes in cerulein-induced acute pancreatitis.36
From a safety perspective, Evander et al showed no harmful effects of repeated subcutaneous
injections of secretin in a murine acute pancreatitis model using sodium taurocholate.37 From
these animal studies it appears that exogenous secretin administration does not cause damage
or worsen the outcome of cerulean- or sodium taurocholate-induced acute pancreatitis. In fact,
in the cerulein model, secretin administration appears to 1) not be harmful, 2) reduce pancreatic
histopathology, and 3) re-establish pancreatic juice flow and evokes a partial restoration of protein
output when compared to non-secretin treated rats.
1.4
Clinical Data to Date
Human studies.
The only human model of acute pancreatitis that can be studied readily is
pancreatitis induced by instrumentation of the main pancreatic duct at the time of retrograde
pancreatogram injection, otherwise known as ERCP-induced acute pancreatitis.
Jowell and

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colleagues in a prospective, randomized double-blind, placebo controlled trial (n = 844) showed
a beneficial effect of secretin at statistically reducing acute pancreatitis when administered at the
time of the procedure.38
We are currently performing a phase III study (NCT02160808) of 176 patients undergoing
pancreatic resection in which 50% of patients are randomized to intra-operative secretin
administration and the other 50% to placebo with the intervention designed to allow for intra-
operative identification and repair of pancreatic duct leaks. At the mid-point analysis, there was
no evidence of increased leak rates or the development of acute pancreatitis in the secretin arm
strongly arguing for the drug’s safety in this patient population (internal data).
Furthermore, recent studies demonstrating the benefit of early oral and enteral nutrition
administration in acute pancreatitis – a challenge to the long-held belief that pancreatic rest is of
paramount importance – support the hypothesis that enhancing pancreatic secretion is potentially
beneficial, and certainly not harmful.39,40
We performed a pilot study in 12 patients to explore whether intravenous synthetic human secretin
improves refractory type B pain in patients with chronic pancreatitis in a phase II dose escalation
trial.31
We found that in patients, especially women, with refractory type B pain from chronic
pancreatitis, intravenous secretin administration demonstrated a trend toward improvement in
self-reported pain and opiate use at 30 days after infusion. Importantly there was no development
of significant adverse effects in any of the patients with pancreatitis who received intravenous
secretin. See figure below.
1.5
Dose Rationale and Risk/Benefits
In addition to standard care, patients will be divided into 4 cohorts. Cohorts 1,2 and 3 will be
treated with different doses of intravenous synthetic human secretin. Cohort X will not receive
human secretin, but all datapoints and specimens will be collected.
Cohort X (n=10): no ChiRhoStim® administered. All observations
Cohort 1 (n=10): 40 mcgChiRhoStim® two times a day (40 mcg; q 12 hrs)
Cohort 2 (n=10): 40 mcgChiRhoStim® four times a day (40 mcg; q 6 hrs)
Cohort 3 (n=10): 40 mcgChiRhoStim® six times a day (40 mcg; q 4 hrs)
Note: t½ for synthetic human secretin is 45 minutes (no accumulation possible).
The patient cohorts will be entered into the study as follows: Cohort X; Cohort 1; Cohort 2; Cohort
3. 5 patients in each cohort will be evaluated at each center (for a total of n=10 at both centers
for each cohort).
Dosing will start within 24 hours of hospitalization with no further synthetic
human secretin administration beyond Day 3. Patients will continue to be followed for 7 days or
until discharge, whichever comes first. Any data recorded to that point would be included in an
intent-to-treat analysis.

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2. Study Objectives
Aim 1: Perform a phase II pilot study utilizing intravenous human secretin to explore the efficacy
of this pharmacologic adjunct to treat non-obstructive, acute pancreatitis. This pilot study will
allow for the collection of important clinical and serologic endpoints to detect a possible signal
that human secretin improves outcomes in acute pancreatitis. The study is not designed to be a
definitive evaluation of treatment effect, and thus statistical significance for improvements in
clinical and serologic outcomes is not expected. An important aspect of the pilot study will be to
confirm the safety of secretin administration previously observed in preclinical and human studies
of acute pancreatitis.
Aim 2: Explore the optimal dose frequency of intravenous human secretin to treat human acute
pancreatitis.
We chose three dose frequencies and a non-treatment arm for the study
intervention. This dose is based on our dose escalation study of secretin to treat painful chronic
pancreatitis. The dose frequency is based on the T1/2 of human secretin which is only 4 minutes.
A critically important component of this pilot is to determine if increased dosing frequency leads
to improvement in clinical and serologic outcome measures.
Aim 3: Use data from this phase II pilot study to design a prospective trial of human secretin in
acute pancreatitis sponsored under an NIH U-34/U-01 grant mechanism. Data from this pilot
study will be used to develop a multicenter study powered to definitively assess the clinical
efficacy of this intervention. Cytokine expression data will allow further refinement of secondary
outcomes, and provide initial insights into the potential mechanisms of action of secretin in this
clinical setting.
Dose frequency data will allow for design of properly randomized and dosed
cohorts. Finally, completion of the pilot will demonstrate study feasibility using this drug in this
patient population.

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3. Study Design
3.1
General Design
Conceptual Model of the Proposed Study
Study Design: This is a prospective, phase II exploratory pilot study using different dose frequencies of
intravenous human secretin in patients with non-obstructive, interstitial acute pancreatitis
Study Site
Principle Site: Dartmouth-Hitchcock Medical Center (Lebanon, NH) - Dr. Timothy Gardner, MD MS
Secondary Site: The Ohio State University (Columbus, OH) - Dr. Darwin Conwell, MD, MS
Study Population: 40 patients presenting to the emergency room within 24 hours of symptoms with non-
obstructive, interstitial acute pancreatitis at Dartmouth-Hitchcock Medical Center (20 patients – 5 in each
cohort) and Ohio State University (20 patients – 5 in each cohort).
Standard of Care Therapy: All enrolled patients will receive standard of care therapy in regard to fluid
resuscitation, pain control, CT scan or ultrasound imaging and nutritional support
Intervention: In addition to standard of care, patients will be divided into 4 cohorts of 10 patients. Cohorts
1,2 and 3 will receive different doses of intravenous synthetic human secretin. Cohort X will not receive
drug.
Cohort X (n=10): NO human secretin administered (observational)
Cohort 1 (n=10): 40 mcghuman secretin two times a day (40 mcg; q 12 hrs)
Cohort 2 (n=10): 40 mcghuman secretin four times a day (40 mcg; q 6 hrs)
Cohort 3 (n=10): 40 mcghuman secretin six times a day (40 mcg; q 4 hrs)
Dosing will start within 24 hours of hospitalization with no further secretin administration beyond Day 3.
Patients will continue to be followed until discharge.
3.2
Primary Study Endpoints
1.
Decrease in serum C-reactive protein (CRP) level by 50% within 96 hours and/or at discharge
compared with CRP level at admission to determine optimal frequency of dosing.
3.3
Secondary Study Endpoints
1.
Serum measurements of pro- and anti-inflammatory cytokines including sCD40L, EGF,
Eotaxin/CCL11, FGF-2, Flt-3 ligand, Fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IFN-γ, IL-1α, IL-1β, 
IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A,
IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1α, MIP-1β, PDGF-AA, PDGF-AB/BB, RANTES, TGF-α, 
Project Goal: Explore the Efficacy and Safety of Intravenous SecretiN to Improve
Outcomes in Human Acute Pancreatitis by Performing a Phase II Pilot Study (SNAP)
Specific Aim I:
Evaluate for decrease
in CRP at 96 hours
and/or at discharge as
well as adverse events
Specific Aim II:
Identify the optimal
dosing frequency to
ensure maximum clinical
response to clinical
outcomes
Specific Aim III
Use data from the pilot study to
design a large, prospective,
multicenter trial under a U-34/U-
01 grant funding mechanism

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TNF-α, TNF-β, VEGF, HSP 27, HSP 60, HSP 70, HSP 90 at time of study enrollment, days of secretin 
administration, 96 hours and at discharge
2. Clinically relevant outcome measures including hemoconcentration (fall in blood urea nitrogen and
hematocrit from admission), decrease in patient admission pain scores (visual analogue scale),
decrease in systemic inflammatory response, and tolerance of oral nutrition
3. Calculation of the Dynamic Acute Pancreatitis Score - organ failure, systemic inflammatory response
syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake.
4. Length of hospitalization, need for intensive care unit transfer, mortality, need for surgical, endoscopic
or percutaneous intervention
5. Development of pancreatic necrosis and/or persistent organ failure
6. Adverse events and 30 day readmission rate
3.4
Primary Safety Endpoints
See above in Section 3.3 in regards to adverse events

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4.
Subject Selection and Withdrawal
4.1
Inclusion Criteria
1. Patient is male or female ≥18 years of age 
2. Patient voluntarily signed written, informed consent agreement.
3. If patient is female and not more than 1 year post-menopausal, or surgically sterile, must use
medically accepted form of contraception or abstain from sexual activities during study
4. Patient has acute pancreatitis as defined by the Atlanta Classification of 2012
5. No evidence of obstructive pancreatitis on available cross-sectional imaging
4.2 Exclusion Criteria
1.
Pancreatitis with duct obstruction or severe acute pancreatitis defined by Atlanta
Classification
2.
Pregnant woman, nursing mothers, or women of childbearing potential not on birth control
3.
Known adverse reaction to human secretin
4.3 Subject Recruitment and Screening
Subjects will be those admitted to Dartmouth-Hitchcock Medical Center and/or the Ohio State
University Hospital with acute pancreatitis within 24 hours of admission. Subjects will be identified
by daily admission records. All subjects will be those admitted not in transfer.
4.4 Early Withdrawal of Subjects
4.4.1 When and How to Withdraw Subjects
Patients will be withdrawn from the study and not replaced for the following reasons:
1)
Voluntary withdraws-any patient may remove himself from the study at any time without
prejudice to his medical care. They will be analyzed in the “Intent to Treat” analysis.
2)
Excessive toxicity felt secondary to synthetic human secretin necessitating halting of
administration prior to full dose, such as:
a)
Life threatening anaphylactic reaction, or
b)
Any other life threatening reaction felt secondary to the treatment that
results in grade 4 toxicity by CTCAE
3)
Patient develops the need for ICU care.
4.4.2
Data Collection and Follow-up for Withdrawn Subjects
If a subject withdraws consent to participate in the study, attempts will be made to obtain
permission to record at least survival data up to the protocol-described end of subject follow-up
period This should not be difficult for this study as patients will all be inpatients at both Dartmouth-
Hitchcock Medical Center and/or the Ohio State University Medical Center.
4.5
Subject Randomization/Allocation
Patients will be assigned to each of the four groups (three drug doses and observation) in block
groups of five – i.e. five patients will be assigned to the Cohort X, five patients will be assigned
to the Cohort 1, then five to Cohort two, then five to Cohort 3 at each center. Once 20 patients
have been assigned and data collected, the formal interim analysis will be performed. The
process will continue in the same manner for the remaining 20 patients until study completion at
Ohio State. Only 20 patients will be enrolled at each center. See 5.2 below

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Study Drug
5.1
Description
Synthetic human secretin will be administered through an intravenous line. ChiRhoStim® will be
reconstituted according to the package insert.
The contents of each vial (16 mcg) will be
reconstituted with 8 mL of sterile physiologic saline (0.9%) USPand then administeredover 1
minute.
5.2
Treatment Regimen
The study is not blinded and does not require any randomization codes. Ten patients each will
receive one of three treatments for Days 1, 2, and 3:
1.
No secretin – standard of care and observation (Cohort X)
2.
40 mcgIV Bolus every 12 hours (Cohort 1)
3.
40 mcgIV Bolus every 6 hours (Cohort 2)
4.
40 mcgIV Bolus every 4 hours (Cohort 3)
½ of Cohort X (5 patients) will be completed first, then ½ of Cohort 1 (5 patients) will be
completed, followed by ½ of Cohort 2, followed by Cohort ½ of Cohort 3. A Cohort X in 10
patients will not receive any synthetic human secretin but will have all observation and data as
was obtained for the three synthetic human secretin treatment groups. Cohort X represents the
standard of care of the institution without synthetic human secretin treatment. At the conclusion
of 20 patients enrolled – five patients from each group – an interim analysis will be performed. If
the interim analysis is acceptable, five more patients from each cohort will be enrolled.
Guidelines for Off Protocol Use of Synthetic Human Secretin
Synthetic human secretin will not be used for any off protocol use if the patients are enrolled in
the current study.
Bolus Termination
IV bolus of the drug will be halted for any of the following reasons:
1)
Any life-threatening toxicity.
2)
Any anaphylactic reaction to any medication during the procedure.
3)
Significant hypotension (systolic BP less than 90 mmHg) that does not correct with
intravenous fluids.
5.3
Method for Assigning Subjects to Treatment Groups
See sections 4.6 and 5.2 above.
5.4
Preparation and Administration of Study Drug
The drug will be supplied by the investigational pharmacy or delegate. The drug will be received
in its unconstituted form. Authorized and delegated staff will then reconstitute the medication and
administer intravenously at the bedside per standard.
5.5
Subject Compliance Monitoring
All study drug will be given by the investigating physician or authorized and delegated study staff
while the patient is in a hospitalized monitored setting. Thus, issues of compliance should be
easily identified and addressed.

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5.6
Prior and Concomitant Therapy
The patient will receive all standard of care therapies as per usual treatment for acute pancreatitis
including intravenous fluids, analgesics and nutritional support.
5.7
Packaging
The drug will be given per bolus injection in an unlabeled syringe large enough to accommodate
the fully prepared dose. Study drug will be stored under locked conditions, allowing only
Authorized staff access to the study drug.
5.8
Blinding of Study Drug
There is no blinding component to this study.
5.9
Receiving, Storage, Dispensing and Return
5.9.1
Receipt of Drug Supplies
The study drug will be sent directly from ChiRhoClin, Inc. to the Dartmouth Investigational
Pharmacy. Upon receipt of the of the study treatment supplies, an inventory must be performed
and a drug receipt log filled out and signed by the person accepting the shipment. It is important
that the designated study staff counts and verifies that the shipment contains all the items noted
in the shipment inventory. Any damaged or unusable study drug in a given shipment (active drug
or comparator) will be documented in the study files. The investigator must notify study sponsor
of any damaged or unusable study treatments that were supplied to the investigator’s site.
5.9.2
Storage
The drug will be kept in the Dartmouth Investigational Pharmacy and stored in the standard
fashion at -20 degrees Celsius. The drug is stable at controlled room temperature for 6 months.
This will allow for sufficient supply to be stored under controlled (locked) room temperature
conditions for dispensing outside of Investigational Pharmacy hours. Investigational Pharmacy
will continue drug accountability recording and temperature monitoring in the controlled room
temperature conditions.
5.9.3
Dispensing of Study Drug
Regular study drug reconciliation will be performed to document drug assigned, drug consumed,
and drug remaining. This reconciliation will be logged on the drug reconciliation form, and signed
and dated by the study team. The drug will be kept by the Dartmouth Investigational Pharmacy.
5.9.4
Return or Destruction of Study Drug
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed,
and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and
dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or
destruction of unused study drug. Drug destroyed on site will be documented in the study files.

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6
Study Procedures
6.1
PRE-TREATMENT EVALUATION – See Attachment A
Evaluations
1)
Inclusion/Exclusion Criteria
2)
History
3)
Medication Review
4)
Standard of Care CT/Ultrasound Review
5)
Physical Examination
6)
Standard of Care Laboratory Values
7)
Research Specimen Collection
6.2
TREATMENT PLAN
Administration of Study Drug
Forty (40) patients are planned for this pilot study – 20 at each center.
Synthetic human secretin will be administered through an intravenous line.
ChiRhoStim® will be reconstituted according to the package insert. The
contents of each vial (16 mcg) will be reconstituted with 8 mL of sterile
physiologic saline (0.9%) USP. The total dose is given over 1 minute.
Guidelines for Off Protocol Use of Synthetic Human Secretin
Synthetic secretin will not be allowed for any off-protocol use in any
patient enrolled in the current study.
Bolus Termination
IV bolus of the drug will be halted for any of the following reasons:
1)
Any life-threatening toxicity.
2)
Any anaphylactic reaction to any medication during the procedure.
3)
Significant hypotension (systolic BP less than 90 mmHg) that does
not correct with intravenous fluids.
Treatment Assignments
The study is not blinded and does not require any randomization codes. Ten
patients each will receive one of three treatments for Days 1, 2, and 3:
No secretin – standard of care and observation (Cohort X)
40 mcgIV Bolus every 12 hours (Cohort 1)
40 mcgIV Bolus every 6 hours (Cohort 2)
40 mcgIV Bolus every 4 hours (Cohort 3)
A Cohort X of 10 patients will not receive any synthetic human secretin
(observation) but will have all observation and data as was obtained for the three
synthetic human secretin treatment groups.
6.3
INTRA AND POST-TREATMENT EVALUATION – See Attachment A
Evaluation during Study Drug Administration
1)
Administration of study drug will be recorded.
2)
Vital signs will be recorded pre and post dose.
6.4
STUDY ENDPOINTS
Study Endpoints
The change in biochemical parameters that represent local and systemic effects
of acute pancreatitis will be monitored from Day 1 through Day 7,including:

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changes from baseline values of hemoconcentration (fall in hematocrit and BUN),
visual analogue scale pain scores, SIRS score and tolerance of oral nutrition.
Monitoring of vital signs per standard of care and adverse events will be done
throughout the study - See Attachment A
Abdominal pain is a cardinal symptom of pancreatitis and will be monitored daily
in morning and evening (visual analog scale 0-10) and treated based on standard
practice guidelines.
Vital signs will be recorded at baseline prior to administration of study medication
(synthetic human secretin) and throughout the study period per standard of care.
The following adverse events will be monitored throughout the study: any event
resulting in study drug termination, significant change in pre and post dose vital
signs (Heart Rate change 30bpm or greater) or Blood Pressure (20 point change
or greater)) Infection, Organ Failure, and any event resulting in transfer to the ICU
or Death.
Calculation of the Dynamic Acute Pancreatitis Score - organ failure, systemic
inflammatory response syndrome, abdominal pain, requirement for opiates and
ability to tolerate oral intake. Total opiate use will be expressed in morphine
equivalents.
6.5
STANDARD OF CARE
Standard of care therapy for acute pancreatitis including fluid resuscitation, analgesia and
nutritional therapy will be followed for all study participants. The only deviation from standard of
care in this study will be the delivery of the Secretin bolus (depending on the randomization
assignment). In addition, patients will have a tube of blood collected at standard endpoints at time
of study enrollment, days of secretin administration, 96 hours and at discharge

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7
Statistical Plan
7.1
Sample Size Determination
This pilot study does not require a power calculation. This pilot study is intended to collect, evaluate and
assess the efficacy of administering human secretin to patients with acute pancreatitis.
7.2
Statistical Methods
The data obtained from the pilot study will be used to calculate the power and cohort dosing for a large
multicenter study under the guidance of the Biometrics Group at Rutgers University.Planned subsequent analysis
will evaluate C-reactive protein using an area under the curve technique for the first 96 hours and ANCOVA-
type linear model approach for each outcome variable with attempt at log-transformation for skewed or
outlying variables.
7.3
Subject Population(s) for Analysis
The statistical analysis for this study will use an all-treated population – i.e. any subject
randomized into the study that received at least one dose of study drug.

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8 Safety and Adverse Events
8.1
Definitions
Unanticipated Problems Involving Risk to Subjects or Others
Any incident, experience, or outcome that meets all of the following criteria:

Unexpected in nature, severity, or frequency (i.e. not described in study-related documents
such as the IRB-approved protocol or consent form, the investigators brochure, etc)

Related or possibly related to participation in the research (i.e. 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)

Suggests that the research places subjects or others at greater risk of harm (including
physical, psychological, economic, or social harm).
Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events
if the abnormality:

results in study withdrawal

is associated with a serious adverse event

is associated with clinical signs or symptoms

leads to additional treatment or to further diagnostic tests

is considered by the investigator to be of clinical significance
Serious Adverse Event
Adverse events are classified as serious or non-serious. A serious adverse event is any AE
that is:

fatal

life-threatening

requires or prolongs hospital stay

results in persistent or significant disability or incapacity

a congenital anomaly or birth defect

an important medical event
Important medical events are those that may not be immediately life threatening, but are clearly
of major clinical significance.
They may jeopardize the subject, and may require intervention to
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse,
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm
in an emergency department would typically be considered serious.
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.
Adverse Event Reporting Period
The study period during which adverse events must be reported is normally defined as the period
from the initiation of any study procedures to the end of the study treatment follow-up. For this
study, the study treatment follow-up is defined as 30 days following the last administration of study
treatment.

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Preexisting Condition
A preexisting condition is one that is present at the start of the study. A preexisting condition
should be recorded as an adverse event if the frequency, intensity, or the character of the
condition worsens during the study period.
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a preexisting condition.
At the end of the study, any new clinically significant findings/abnormalities that meet the definition
of an adverse event must also be recorded and documented as an adverse event.
Post-study Adverse Event
All unresolved adverse events should be followed by the investigator until the events are resolved,
the subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled
visit, the investigator should instruct each subject to report any subsequent event(s) that the
subject, or the subject’s personal physician, believes might reasonably be related to participation
in this study. The investigator should notify the study sponsor of any death or adverse event
occurring at any time after a subject has discontinued or terminated study participation that may
reasonably be related to this study. The sponsor should also be notified if the investigator should
become aware of the development of cancer or of a congenital anomaly in a subsequently
conceived offspring of a subject that has participated in this study.
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse event if any one of the
following conditions is met:

The laboratory abnormality is not otherwise refuted by a repeat test to confirm the
abnormality

The abnormality suggests a disease and/or organ toxicity

The abnormality is of a degree that requires active management; e.g. change of dose,
discontinuation of the drug, more frequent follow-up assessments, further diagnostic
investigation, etc.
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization should be
documented and reported as a serious adverse event unless specifically instructed otherwise in
this protocol. Any condition responsible for surgery should be documented as an adverse event
if the condition meets the criteria for and adverse event.
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an
adverse event in the following circumstances:

Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures
for a preexisting condition. Surgery should not be reported as an outcome of an adverse
event if the purpose of the surgery was elective or diagnostic and the outcome was
uneventful.

Hospitalization or prolonged hospitalization required to allow efficacy measurement for the
study.

Hospitalization or prolonged hospitalization for therapy of the target disease of the study,
unless it is a worsening or increase in frequency of hospital admissions as judged by the
clinical investigator.

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8.2
Recording of Adverse Events
At each contact with the subject, the investigator must seek information on adverse events by
specific questioning and, as appropriate, by examination.
Information on all adverse events
should be recorded immediately in the source document, and also in the appropriate adverse
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal
diagnostic procedures results should recorded in the source document, though should be grouped
under one diagnosis.
For the purposes of this study the following are the only events that will be collected and recorded:
-
Any event resulting in the termination of study treatment
-
Significant change in pre and post dose vital signs
o
Change in blood pressure greater than 20 points
o
Change in heart rate greater than 30 bpm
-
Infection
-
Organ failure
-
Any event resulting in transfer to the ICU or Death
All specified adverse events occurring during the study period must be recorded. The clinical
course of each event should be followed until resolution, stabilization, or until it has been
determined that the study treatment or participation is not the cause. Serious adverse events that
are still ongoing at the end of the study period must be followed up to determine the final outcome.
Any serious adverse event that occurs after the study period and is considered to be possibly
related to the study treatment or study participation should be recorded and reported immediately.
8.3
Reporting of Serious Adverse Events and Unanticipated Problems
Investigators and the protocol sponsor must conform to the adverse event reporting timelines,
formats and requirements of the various entities to which they are responsible, but at a minimum
those events that must be reported are those that are:

related to study participation,

unexpected, and

serious or involve risks to subjects or others
(see definitions, section 8.1).
If the report is supplied as a narrative, the minimum necessary information to be provided at the
time of the initial report includes:

Study identifier

Study Center

Subject number

A description of the event

Date of onset

Current status

Whether study treatment was discontinued

The reason why the event is classified as
serious

Investigator assessment of the association
between the event and study treatment
8.3.1
Investigator reporting: notifying the study sponsor
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type
of serious adverse event, must be reported to the study sponsor and IND holder by telephone
within 24 hours of the event. To report such events, a Serious Adverse Event (SAE) form must
be completed by the investigator and faxed to the study sponsor within 24 hours. The investigator
will keep a copy of this SAE form on file at the study site. Report serious adverse events by phone
and facsimile to:

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Edward Purich, PhD
4000 Blackburn Lane, Suite 270
Burtonsville, MD 20866-6129
301-476-8388
301-476-9529 FAX
Within the following 48 hours, the investigator must provide further information on the serious
adverse event or the unanticipated problem in the form of a written narrative. This should include
a copy of the completed Serious Adverse Event form, and any other diagnostic information that
will assist the understanding of the event. Significant new information on ongoing serious adverse
events should be provided promptly to the study sponsor
8.3.2
Investigator reporting: notifying the Dartmouth IRB
This section describes the requirements for safety reporting by investigators who are Dartmouth
faculty, affiliated with a Dartmouth research site, or otherwise responsible for safety reporting to
the Dartmouth IRB. The Dartmouth College IRB (CPHS) requires expedited reporting of those
events related to study participation that are unforeseen and indicate that participants or others
are at increased risk of harm. The Dartmouth IRB will not acknowledge safety reports or bulk
adverse event submissions that do not meet the criteria outlined below.
The Dartmouth IRB
requires researchers to submit reports of the following problems within 10 working days from the
time the investigator becomes aware of the event:

Any adverse event (regardless of whether the event is serious or non-serious, on-site or
off-site) that occurs any time during or after the research study, which in the opinion of the
principal investigator is:
Unexpected (An event is “unexpected” when its specificity and severity are not accurately
reflected in the protocol-related documents, such as the IRB-approved research protocol,
any applicable investigator brochure, and the current IRB-approved informed consent
document and other relevant sources of information, such as product labeling and package
inserts.)
AND
Related to the research procedures (An event is “related to the research procedures” if in
the opinion of the principal investigator or sponsor, the event was more likely than not to
be caused by the research procedures.)
Any AE related to the research procedures at Ohio State must be reported to the Dartmouth IRB
(CPHS).
Reporting Process
Unanticipated problems posing risks to subjects or others as noted above will be reported to the
Dartmouth IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others
Including Reportable Adverse Events” or as a written report of the event (including a description
of the event with information regarding its fulfillment of the above criteria, follow-up/resolution and
need for revision to consent form and/or other study documentation).
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical
Investigator’s study file.
Reporting Deaths: more rapid reporting requirements
Concerning deaths that occur during the course of a research study, the following describes the
more rapid reporting requirement of the Dartmouth IRB for specific situations:

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
Report the event within 24 hours when the death is unforeseen (unexpected) and indicates
participants or others are at increased risk of harm.

Report the event within 72 hours, for all other deaths, regardless of whether the death is
related to study participation.
For reportable deaths, the initial submission to the Dartmouth IRB may be made by contacting
the IRB Director or Associate Director. The AE/Unanticipated Problem Form is required as a follow
up to the initial submission.
Other Reportable events:
For clinical drug trials, the following events are also reportable to the Dartmouth IRB:

Any adverse experience that, even without detailed analysis, represents a serious
unexpected adverse event that is rare in the absence of drug exposure (such as
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome).

Any adverse event that would cause the sponsor to modify the investigators brochure,
protocol or informed consent form, or would prompt other action by the IRB to assure
protection of human subjects.

Information that indicates a change to the risks or potential benefits of the research, in
terms of severity or frequency. For example:
–
An interim analysis indicates that participants have a lower rate of response to
treatment than initially expected.
–
Safety monitoring indicates that a particular side effect is more severe, or more frequent
than initially expected.
–
A paper is published from another study that shows that an arm of your research study
is of no therapeutic value.

Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic
used in a research protocol.

Breach of confidentiality

Change to the protocol taken without prior IRB review to eliminate apparent immediate
hazard to a research participant.

Incarceration of a participant when the research was not previously approved under
Subpart C and the investigator believes it is in the best interest of the subject to remain on
the study.

Complaint of a participant when the complaint indicates unexpected risks or the complaint
cannot be resolved by the research team.

Protocol violation (meaning an accidental or unintentional deviation from the IRB approved
protocol) that in the opinion of the investigator placed one or more participants at increased
risk, or affects the rights or welfare of subjects.
8.3.3
Investigator reporting: Notifying another IRB
Investigators who are not Dartmouth faculty or affiliated with a Dartmouth research site are
responsible for safety reporting to their local IRB. Investigators are responsible for complying with
their local IRB’s reporting requirements, though must submit the required reports to their IRB no
later than 10 working days. Copies of each report and documentation of IRB notification and
receipt will be kept in the investigator’s study file.

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8.3.4
Sponsor reporting: Notifying the FDA
The study sponsor is required to report certain study events in an expedited fashion to the FDA.
These written notifications of adverse events are referred to as IND safety reports. The following
describes the safety reporting requirements by timeline for reporting and associated type of event:

Within 7 calendar days
Any study event that is:
– associated with the use of the study drug
– unexpected,
– fatal or life-threatening, and

Within 15 calendar days
Any study event that is:
– associated with the use of the study drug,
– unexpected, and
– serious, but not fatal or life-threatening
-or-
– a previous adverse event that was not initially deemed reportable but is later found to
fit the criteria for reporting (reporting within 15 calendar days from when event was
deemed reportable).
Any finding from tests in laboratory animals that:
– suggest a significant risk for human subjects including reports of mutagenicity,
teratogenicity, or carcinogenicity.
Additional reporting requirements
Sponsors are also required to identify in IND safety reports all previous reports concerning similar
adverse events and to analyze the significance of the current event in light of the previous reports.
8.3.5
Sponsor reporting: Notifying participating investigators
It is the responsibility of the study sponsor to notify all participating investigators, in a written IND
safety report, of any adverse event associated with the use of the drug that is both serious and
unexpected, as well as any finding from tests in laboratory animals that suggest a significant risk
for human subjects. Additionally, sponsors are also required to identify in IND safety reports all
previous reports concerning similar adverse events and to analyze the significance of the current
event in light of the previous reports.
8.4
Unblinding Procedures
Neither medical personnel nor investigators will be blinded in this study.
8.5
Stopping Rules
The study will be stopped if after review of each completed cohort at each center (n=5) of patients
who have receiving study drug (Cohorts 1,2, or 3) there is an increase in the number of adverse
events or worsening of important clinical outcomes (length of stay, organ failure, necrosis, CRP
level, dynamic acute pancreatitis score) compared with Cohort X (observational cohort). Increase
in adverse events and/or worsening of important clinical outcomes will be defined as follows:
Compared to baseline (Cohort X) in 2/5 (40% of patients) at either center, patients in Cohorts
1, 2, or 3 develop:

A change in CRP level from admission at 3 days and/or discharge that exceeds 50%

Persistent organ failure at 3 days as defined by the dynamic acute pancreatitis score

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
Need for intensive care unit transfer

An increase in the dynamic acute pancreatitis score from admission at 3 days and/or
discharge that exceeds 50%

Any other life threatening reaction felt secondary to the treatment that results in grade 4
toxicity by CTCAE
At the conclusion of each cohort enrolled receiving study drug (n=5) interim analysis will be
performed comparing that completed cohort with cohort X. Also at the time of interim analysis of
all three cohorts combined – after five patients in each of the three treatment cohorts and after 20
patients enrolled (five from each cohort including cohort X) – if there is a signal toward harm in
the above outcome measures, the study will be stopped.
8.6
Medical Monitoring
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site
– Dr. Timothy Gardner at Dartmouth and Dr. Darwin Conwell (Chairman of the Section of
Gastroenterology) at Ohio State.
This safety monitoring will include careful assessment and
appropriate reporting of adverse events as noted above, as well as the construction and
implementation of a site data and safety-monitoring plan (see section 9 Auditing, Monitoring and
Inspecting).
Medical monitoring will include a regular assessment of the number and type of
serious adverse events.
8.6.1
Internal Data and Safety Monitoring Board
This trial will employ a data safety monitoring plan to provide oversight and monitoring to ensure
the safety of participants and the validity and integrity of the data.
a. Data Safety Monitoring Board (DSMB)
A data safety monitoring board will be established to provide oversite to both centers at
Dartmouth-Hitchcock Medical and The Ohio State University Wexner Medical Center. The
DSMB will be chaired by Dr. Kerrington Smith, MD (Section Chief, Surgical Oncology,
Dartmouth Hitchcock Medical Center) and will have the following two members - Dr. Phil
Hart, MD (Assistant Professor; Director, Section of Pancreatic Disorders; Division of
Gastroenterology, Hepatology, and Nutrition, Ohio State University) and Dr. Stuart
Gordon, MD (Professor, Section of Gastroenterology and Hepatology, Dartmouth-
Hitchcock Medical Center).
b. The DSMB will meet via telephone prior to the initiation of the study to introduce
themselves and make sure all of the current study protocols are in place.
c.
The DSMB will perform an interim analysis after enrollment of 5 subjects into each
cohort, including Cohort X, combined from both centers. The DSMB will meet by
telephone to discuss study outcomes, identify any adverse events, and propose
modifications to the protocol if needed – this will serve as the interim analysis. The
DSMB will stop the study based on the stopping rules (see 8.5 above). As this is a small
pilot study, it is very unlikely that a significant benefit to the treatment will be seen after
twenty patients. The DSMB will provide a written report of the interim analysis to the
primary investigator, sponsor and funding agency following their meeting after 5 patients
have been enrolled in each cohort at each center.
d. The primary investigator and/or delegate will be responsible for providing a summary
report of adverse events to the NIH funding IC, individual IRBs and to the DSMB.

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e. Following the complete enrollment of each of the four cohorts at each center, the chair of
the DSMB will provide a written report of the research activities to date, with specific
attention to safety and adverse events.

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9 Data Handling and Record Keeping
9.1
Confidentiality
Information about study subjects will be kept confidential and managed according to the
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those
regulations require a signed subject authorization informing the subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by
regulation, retains the ability to use all information collected prior to the revocation of subject
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the
end of their scheduled study period.
9.2
Source Documents
Source data is all information, original records of clinical findings, observations, or other activities
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are
contained in source documents. Examples of these original documents, and data records include:
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments,
copies or transcriptions certified after verification as being accurate and complete, microfiches,
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical
trial.
9.3
Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the study. All data
requested on the CRF must be recorded. All missing data must be explained. If a space on the
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.
If the item is not applicable to the individual case, write “N/A”. All entries should be printed legibly
in black ink. If any entry error has been made, to correct such an error, draw a single straight line
through the incorrect entry and enter the correct data above it. All such changes must be initialed
and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain
entries, print the clarification above the item, then initial and date it.
9.4
Records Retention
It is the investigator’s responsibility to retain study essential documents for at least 2 years after
the last approval of a marketing application in their country and until there are no pending or
contemplated marketing applications in their country or at least 2 years have elapsed since the
formal discontinuation of clinical development of the investigational product. These documents
should be retained for a longer period if required by an agreement with the sponsor. In such an
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when
these documents no longer need to be retained.

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10.
Study Monitoring, Auditing, and Inspecting
10.1
Study Monitoring Plan
This study will be monitored according to the monitoring plan in Attachment B. The investigator
will allocate adequate time for such monitoring activities. The Investigator will also ensure that
the monitor or other compliance or quality assurance reviewer is given access to all the above
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory,
etc.), and has adequate space to conduct the monitoring visit.
10.2
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the
sponsor, government regulatory bodies, and Dartmouth compliance and quality assurance groups
of all study related documents (e.g. source documents, regulatory documents, data collection
instruments, study data etc.).
The investigator will ensure the capability for inspections of
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).
Participation as an investigator in this study implies acceptance of potential inspection by
government regulatory authorities and applicable Dartmouth compliance and quality assurance
offices.

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11.
Ethical Considerations
This study is to be conducted according to US and international standards of Good Clinical
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines),
applicable government regulations and Institutional research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted independent Ethics
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions,
for formal approval of the study conduct. The decision of the EC/IRB concerning the conduct of
the study will be made in writing to the investigator and a copy of this decision will be provided to
the sponsor before commencement of this study. The investigator should provide a list of EC/IRB
members and their affiliate to the sponsor.
All subjects for this study will be provided a consent form describing this study and providing
sufficient information for subjects to make an informed decision about their participation in this
study. See Attachments C1 and C2 for a copy of the Subject Informed Consent Form. This
consent form will be submitted with the protocol for review and approval by the EC/IRB for the
study.
The formal consent of a subject, using the EC/IRB-approved consent form, must be
obtained before that subject undergoes any study procedure. The consent form must be signed
by the subject or legally acceptable surrogate, and the investigator-designated research
professional obtaining the consent.

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12.
Study Finances
12.1
Funding Source
This study will be funded through a United States National Institutes of Health R21 (NIDDK) grant.
This grant was submitted on February 26, 2017. The study drug and clinical monitoring will be
provided for by ChiRhoClin, Inc. the drug IND holder.
If the R21 grant is unsuccessful, the study will be funded by ChiRhoClin, Inc. as indicated in the
sponsor contract.
12.2
Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned
conflict management plan that has been reviewed and approved by the study sponsor prior to
participation in this study. All Dartmouth investigators will follow the Dartmouth conflict of interest
policy.

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13.
Publication Plan
Neither the complete nor any part of the results of the study carried out under this protocol, nor
any of the information provided by the sponsor for the purposes of performing the study, will be
published or passed on to any third party without the consent of the primary investigator and the
research team – including the publication of a negative study, except as required by Federal,
State, or local laws and/or regulations.
However, any investigator involved with this study is
obligated to provide the sponsor with complete test results and all data derived from the study.

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15.
Attachments
Attachment A:
Study Procedures
Attachment B:
Study Monitoring Plan
Attachment C1: Patient Informed Consent – drug cohort
Attachment C2: Patient Informed Consent – observational cohort