Clinical trial NCT02743364
Conditions: Acute Pancreatitis
Sponsor: National Cancer Institute (NCI)
Start date: 2016-09-19; Completion date: 2022-05-11
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well simvastatin works in reducing pancreatitis (the inflammation of the pancreas) in patients with pancreatitis that occurs more than once (recurrent), has worsened quickly (acute), or has persisted or progressed over a long period of time (chronic). Simvastatin may decrease the inflammation of the pancreas by modulating the immune response responsible for inflammation. It is not yet known if simvastatin may be an effective treatment for pancreatitis.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the effect of a simvastatin intervention versus placebo on the change in secretin-stimulated peak bicarbonate concentration in the pancreatic fluid at 6 months post-treatment in patients with a history of at least two episodes of acute pancreatitis in the past 12 months.

SECONDARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline (study visit

1\) on: Ia. Change in the endoscopic ultrasound score (EUS). Ib. Change in serum and pancreatic fluid levels of cytokines, chemokines, and adhesion molecules.

Ic. Change in pancreatitis-related readmissions. Id. Change in quality of life score as measured by the Quality of Life (QLQ)-Core (C)30 and QLQ-Pancreatic modification (PAN)28(Chronic Pancreatitis \[CP\]).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive simvastatin orally (PO) once daily (QD) for 6 months.

ARM II: Patients receive placebo PO QD for 6 months.

After completion of study treatment, patients are followed up at 30, 60, and 90 days.

Arms: arm 1: Patients receive simvastatin PO QD for 6 months. arm 2: Patients receive placebo PO QD for 6 months.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Placebo Administration intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration intervention 5: Simvastatin
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Ancillary studies intervention 5: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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COVER PAGE 
 
DCP Protocol #: 
NWU2014-04-01  
 
Local Protocol #: NCI 2014-04-01 
 
STATIN THERAPY TO REDUCE THE RISK OF RECURRENT PANCREATITIS 
 
Consortium Name*: 
Northwestern Cancer Prevention Consortium 
Name of Consortium Principal 
Seema A. Khan, M.D. 
Investigator: 
Bluhm Family Professor of Cancer Research 
Professor in Surgery-Breast Surgery 
Feinberg School of Medicine 
303 E. Superior, Suite 4-111 
Chicago, IL 60611 
Telephone: (312) 503-4236 
Fax: (312) 503-2555 
E-mail address: skhan@nm.org  
 
Organization Name: 
Cedars-Sinai Medical Center  
Protocol Principal Investigator: 
Marc T. Goodman, Ph.D., M.P.H. 
Director, Cancer Prevention and Control 
Samuel Oschin Comprehensive Cancer Institute 
Director, Community and Population Health Research Institute 
Department of Biomedical Sciences 
Professor of Medicine 
Cedars-Sinai Medical Center 
8700 Beverly Boulevard, Room 1S37 
Los Angeles, CA 90048 
Telephone: (310) 423-6188 
Fax: (310) 423-7182 
E-mail address: marc.goodman@cshs.org  
 
*No participant accrual occurs at this site 
 
 


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Organization Name:  
Cedars-Sinai Medical Center  
Clinical Co-Principal Investigator: Stephen J. Pandol, M.D. 
Director, Basic and Translational Pancreas Research 
Department of Gastroenterology 
Cedars-Sinai Medical Center 
8730 Alden Drive, Suite E222 
Los Angeles, CA 90048 
Telephone: (310) 423-4139 
Fax: (310) 423-1826 
E-mail address: Stephen.Pandol@cshs.org  
 
Organization Name: 
Cedars-Sinai Medical Center  
Investigator: 
Christie Y. Jeon, Sc.D. 
Assistant Professor, Cancer Prevention and Control 
Samuel Oschin Comprehensive Cancer Institute 
Cedars-Sinai Medical Center 
8700 Beverly Boulevard, Room 1S33 
Los Angeles, CA 90048 
Telephone: (310) 423-6345 
Fax: (310) 423-7182 
E-mail address: Christie.Jeon@cshs.org  
 
Organization Name: 
Cedars-Sinai Medical Center  
Investigator: 
Simon K. Lo, M.D. 
Director, Pancreatic and Biliary Diseases Program 
Director, GI Endoscopy 
Department of Gastroenterology 
Cedars-Sinai Medical Center 
8701 Gracie Allen Drive, South Tower 7511 
Los Angeles, CA 90048 
Telephone: (310) 423-6082 
Fax: (310) 423-1826 
E-mail address: Simon.Lo@cshs.org 
 
Organization Name: 
Cedars-Sinai Medical Center  
Investigator: 
Laith H. Jamil, M.D. 
Associate Director, Interventional Endoscopy Service 
Pancreatic and Biliary Diseases Program 
Department of Gastroenterology 
Cedars-Sinai Medical Center 
8701 Gracie Allen Drive, South Tower 7511 
Los Angeles, CA 90048 
Telephone: (310) 423-6082 
Fax: (310) 423-0729 
E-mail address: Laith.Jamil@cshs.org  
 
 


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Organization Name: 
Cedars-Sinai Medical Center  
Investigator: 
Elham Afghani, M.D., M.P.H. 
Staff Physician, Gastroenterology Consultation 
Cedars-Sinai Medical Center 
9033 Wilshire Blvd., Suite 200 
Los Angeles, CA 90048 
Telephone: (310) 651-6108 
Fax: (310) 858-2225 
E-mail address: Elham.Afghani@cshs.org  
 
Organization Name: 
Southern California Permanente Medical Group  
Investigator: 
Bechien U. Wu, M.D., M.P.H. 
Director, Center for Pancreatic Care 
Department of Gastroenterology 
Kaiser Permanente Los Angeles Medical Center 
1526 North Edgemont Street 
Los Angeles, CA 90027 
Telephone: (323) 783-4011 
E-mail address: Bechien.u.wu@kp.org  
 
Organization Name: 
Southern California Permanente Medical Group  
Investigator: 
Karl Kwok, M.D. 
Gastroenterologist, Biliary Endoscopy/Endoscopic Ultrasound 
Department of Gastroenterology 
Kaiser Permanente Los Angeles Medical Center 
1526 North Edgemont Street, 7th Floor 
Los Angeles, CA 90027 
Telephone: (323) 783-6830 
E-mail address: karl.k.kwok@kp.org 
 
Organization Name:  
University of Pittsburgh  
Investigator:  
Dhiraj Yadav, M.D., M.P.H. 
Professor of Medicine 
Division of Gastroenterology, Hepatology & Nutrition  
University of Pittsburgh School of Medicine 
200 Lothrop Street, M-2, C-Wing  
Pittsburgh, PA 15213 
Telephone: (412) 864-7078 
Fax: (412) 648-9378 
E-mail address: yadavd@upmc.edu 
 
Organization Name:  
University of Pittsburgh 
Investigator:  
Georgios I. Papachristou, M.D., Ph.D. 
Associate Professor of Medicine 
Division of Gastroenterology, Hepatology & Nutrition  
University of Pittsburgh School of Medicine 
200 Lothrop Street, M-2, C-Wing  
Pittsburgh, PA 15213 
Telephone: (412) 647-8132 
Fax: (412) 647-1880 
E-mail address: papachristougi@upmc.edu 


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Organization Name:  
Stanford University 
Investigator:  
Walter G. Park, M.D., M.S.  
Assistant Professor of Medicine 
Department of Medicine/Gastroenterology 
Stanford University School of Medicine 
Grant Building, S089 
300 Pasteur Drive, MC: 5187 
Stanford, CA, 94305 
Telephone: (650) 723-4102 
Fax: (650) 723-5488 
E-mail address: wgpark@stanford.edu 
 
Consortium Name*: 
Northwestern University 
Statistician: 
Masha Kocherginsky, Ph.D. 
Associate Professor in Preventive Medicine-Biostatistics 
680 North Lake Shore Drive, Suite 1400 
Chicago, IL 60611 
Telephone: (312) 503-4224 
Fax: (312) 908-9588 
E-mail address: mkocherg@northwestern.edu  
 
*No participant accrual occurs at this site 
 
IND Sponsor: 
NCI/Division of Cancer Prevention 
IND# 
 (Exempt) 
Agent(s)/Supplier: 
Simvastatin / NCI, DCP 
NCI Contract # 
HHSN261201200035I 
Protocol Version Date: 
 January 9, 2020 
Protocol Revision or   
Amendment # 
Version 3.8 
 
Contacting the NCI CIRB. Be sure to specify that you are part of the NCI DCP Consortia. 
For CPC CIRB review and trial-wide questions, send an e-mail to CPCCIRB@emmes.com.  
For other questions, including Local Context Reviews, contact the CIRB Helpdesk. 
E-mail address: ncicirbcontact@emmes.com  
Toll-free telephone: (888) 657-3711 
CIRB website: https://ncicirb.org 
 




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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 5 
TABLE OF CONTENTS .............................................................................................................................. 6 
1. 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objectives .......................................................................................................................................... 8 
1.2 
Secondary Objectives ...................................................................................................................................... 8 
2. 
BACKGROUND ............................................................................................................................. 8 
2.1 
Study Disease .................................................................................................................................................. 8 
2.2 
Study Agent ..................................................................................................................................................... 8 
2.3 
Rationale ......................................................................................................................................................... 9 
3. 
SUMMARY OF STUDY PLAN ................................................................................................... 11 
4. 
PARTICIPANT SELECTION ....................................................................................................... 15 
4.1 
Inclusion Criteria ........................................................................................................................................... 16 
4.2 
Exclusion Criteria .......................................................................................................................................... 16 
4.3 
Inclusion of Women and Minorities .............................................................................................................. 17 
4.4 
Recruitment and Retention Plan .................................................................................................................... 17 
5. 
AGENT ADMINISTRATION ...................................................................................................... 18 
5.1 
Dose Regimen and Dose Groups ................................................................................................................... 19 
5.2 
Study Agent Administration .......................................................................................................................... 19 
5.3 
Run-in Procedures ......................................................................................................................................... 19 
5.4 
Contraindications .......................................................................................................................................... 19 
5.5 
Concomitant Medications .............................................................................................................................. 19 
5.6 
Dose Modification ......................................................................................................................................... 20 
5.7 
Adherence/Compliance ................................................................................................................................. 20 
6. 
PHARMACEUTICAL INFORMATION ...................................................................................... 21 
6.1 
Study Agent (IND #
(Exempt), IND Sponsor: NCI/Division of Cancer Prevention) ........................ 21 
6.2 
Reported Adverse Events and Potential Risks .............................................................................................. 21 
6.3  
Availability .................................................................................................................................................... 22 
6.4 
Agent Distribution ......................................................................................................................................... 22 
6.5  
Agent Accountability .................................................................................................................................... 22 
6.6 
Packaging and Labeling ................................................................................................................................ 22 
6.7 
Storage........................................................................................................................................................... 23 
6.8 
Registration/Randomization .......................................................................................................................... 23 
6.9 
Blinding and Unblinding Methods ................................................................................................................ 23 
6.10 Agent Destruction/Disposal .......................................................................................................................... 24 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ................................................................... 24 
7.1 
Schedule of Events ........................................................................................................................................ 24 
7.2 
Pre-Study Evaluation and Baseline Testing .................................................................................................. 25 
7.3 
Evaluation During Study Intervention ........................................................................................................... 28 
7.4 
Evaluation at Completion of Study Intervention ........................................................................................... 30 
7.5 
Post-intervention Follow-up Period .............................................................................................................. 30 
7.6 
Methods for Clinical Procedures ................................................................................................................... 30 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ........................................... 32 
8.1 
Primary Endpoint .......................................................................................................................................... 32 
8.2 
Secondary Endpoints ..................................................................................................................................... 33 
8.3 
Off-Agent Criteria ......................................................................................................................................... 33 
8.4 
Off-Study Criteria ......................................................................................................................................... 34 
8.5 
Study Termination ......................................................................................................................................... 34 
9. 
CORRELATIVE/SPECIAL STUDIES ......................................................................................... 34 
9.1 
Rationale for Methodology Selection ............................................................................................................ 34 
9.2 
Comparable Methods .................................................................................................................................... 35 
10. 
SPECIMEN MANAGEMENT ...................................................................................................... 35 


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10.1 Laboratories ................................................................................................................................................... 35 
10.2 Collection and Handling Procedures ............................................................................................................. 35 
10.3 Shipping Instructions ..................................................................................................................................... 37 
10.4 Tissue Banking .............................................................................................................................................. 38 
11. 
REPORTING ADVERSE EVENTS ............................................................................................. 39 
11.1 Adverse Events .............................................................................................................................................. 39 
11.2 Serious Adverse Events ................................................................................................................................. 40 
12. 
STUDY MONITORING ............................................................................................................... 42 
12.1 Data Management ......................................................................................................................................... 42 
12.2 Case Report Forms ........................................................................................................................................ 42 
12.3 Source Documents ......................................................................................................................................... 42 
12.4 Data and Safety Monitoring Plan .................................................................................................................. 42 
12.5 Sponsor or FDA Monitoring ......................................................................................................................... 43 
12.6 Record Retention ........................................................................................................................................... 43 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ............ 43 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 44 
13.1 Study Design/Description .............................................................................................................................. 44 
13.2 Randomization/Stratification ......................................................................................................................... 45 
13.3 Accrual and Feasibility .................................................................................................................................. 45 
13.4 Primary Objective, Endpoint(s), Analysis Plan ............................................................................................. 45 
13.5 Secondary Objectives, Endpoints, Analysis Plans ........................................................................................ 45 
13.6 Reporting and Exclusions .............................................................................................................................. 46 
13.7 Evaluation of Toxicity ................................................................................................................................... 46 
13.8 Evaluation of Response ................................................................................................................................. 46 
13.9 Interim Analysis ............................................................................................................................................ 46 
13.10 Ancillary Studies ........................................................................................................................................... 46 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 46 
14.1 Form FDA 1572 ............................................................................................................................................ 46 
14.2 Other Required Documents ........................................................................................................................... 46 
14.3 Institutional Review Board Approval ............................................................................................................ 47 
14.4 Informed Consent .......................................................................................................................................... 47 
14.5 Submission of Regulatory Documents .......................................................................................................... 47 
14.6 Other .............................................................................................................................................................. 48 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ................................................................... 48 
REFERENCES ........................................................................................................................................... 49 
CONSENT FORM ...................................................................................................................................... 52 
APPENDIX A ............................................................................................................................................. 66 
APPENDIX B ............................................................................................................................................. 67 
APPENDIX C ............................................................................................................................................. 68 
APPENDIX D ............................................................................................................................................. 72 
APPENDIX E ............................................................................................................................................. 76 
APPENDIX F.............................................................................................................................................. 86 


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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
To evaluate the effect of a simvastatin intervention versus placebo on the change in secretin-stimulated 
peak bicarbonate concentration in the pancreatic fluid at 6 months post-treatment in patients with a 
history of at least two episodes of acute pancreatitis in the past 12 months. 
 
1.2 
Secondary Objectives  
 
To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline (Study Visit 
1) on:  
(1)  Change in the endoscopic ultrasound score (EUS);  
(2)  Change in serum and pancreatic fluid levels of cytokines, chemokines, and adhesion 
molecules;  
(3)  Change in pancreatitis-related readmissions; and 
(4) Change in quality of life score as measured by the QLQ-C30 and QLQ-PAN28(CP). 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Pancreatic cancer is the fourth leading cause of cancer death in the US, and it has an extremely high 
fatality rate [1]. The incidence for pancreatic cancer in the US has been increasing for more than a decade, 
in parallel with the rates of pancreatitis, and both are driven by the epidemic of obesity and diabetes [2]. 
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, characterized by chronic 
pancreatic inflammation and scarring, irreversibly damaging the pancreas and resulting in loss of exocrine 
and endocrine function. The primary symptoms of CP are abdominal pain, maldigestion, and steatorrhea 
[3]. Chronic pancreatitis, which results from repeated episodes of acute pancreatitis, is the strongest 
identified risk factor for pancreatic cancer and increases the risk by at least 13.3 fold [4]. Pancreatitis and 
pancreatic cancer exist in a disease continuum; patients with an episode of acute pancreatitis have a 20-
30% likelihood of one or more recurrent episodes, with progression to chronic pancreatitis in an estimated 
10% of the recurrent cases [2, 5, 6]. Interventions that have the ability to prevent the development of 
pancreatic cancer in this high-risk population would therefore address a currently unmet major public 
health problem and would have a high clinical impact. Despite this need, and the associated high impact 
potential, few studies have investigated the effectiveness of a chemopreventive strategy for pancreatic 
cancer.  
 
2.2 
Study Agent 
Simvastatin (butanoic acid, see Figure 1) is a lipid-lowering agent that is 
derived synthetically from a fermentation product of Aspergillus terreus. 
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed 
to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-
3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes 
the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in 
the biosynthesis of cholesterol. The empirical formula of simvastatin is 
C25H38O5 and its molecular weight is 418.57. Simvastatin USP is a white to 
off-white powder that is practically insoluble in water; freely soluble in 
chloroform, in methanol and in alcohol; sparingly soluble in propylene 
glycol; very slightly soluble in hexane.  
 
Figure 1. Molecular 
structure of simvastatin 


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Simvastatin tablets for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg 
simvastatin and the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, 
hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and 
titanium dioxide. Butylated hydroxyanisole is added as a preservative. 
 
Simvastatin is the most commonly prescribed HMG-CoA reductase inhibitor, which has a widely 
accepted tolerability profile with few serious side effects [7]. Potential, but uncommon side effects 
include muscle, liver, and kidney problems. Elevated levels of creatine kinase and rhabdomyolysis occur 
in <1% of consumers. In a clinical trial database in which 41,413 patients were treated with simvastatin, 
60% of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of 
myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of 
myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses [8].  
 
Simvastatin is prescribed for primary and secondary prevention of cardiovascular disease and thus is 
indicated for long-term use. We propose to administer simvastatin 40 mg daily for 6 months in this trial. 
 
2.3 
Rationale 
 
Hypotheses:   
1)  Participants randomized to simvastatin will experience a greater increase from baseline (Study Visit 
1) in peak bicarbonate concentration measured at 6 months after initiation of the intervention 
compared to the placebo group. 
 
2)  Compared to the placebo group, participants randomized to simvastatin will experience  
 (a)  A greater reduction from baseline in EUS score;  
 (b) A greater decrease in pro-inflammatory markers and a greater increase in anti-inflammatory 
markers;  
 (c)  Fewer episodes of pancreatitis-related readmissions; and  
 (d) Improvement in quality of life score. 
 
Pancreatic cancer is amenable to a chemoprevention strategy. The progression from acute pancreatitis to 
chronic pancreatitis to pancreatic cancer is characterized by a progressive desmoplastic reaction and an 
associated inflammatory injury to pancreatic cells, induced by factors such as a high fat diet, smoking, 
and alcohol. Both fibrotic and inflammatory processes involve paracrine cross-talk between the 
extracellular matrix (ECM), pancreatic epithelial cells and non-epithelial cells, including fibroblasts, 
stellate cells, and immune cells [9]. Of particular importance is the pancreatic stellate cell which, when 
activated by pro-fibrogenic mediators [10], in turn produces excess i.e., desmoplasia-associated ECM, 
growth factors, such as transforming growth factor-β [TGF-β], and inflammatory factors, including IL-1β 
and IL-6. These factors collectively promote proliferation and invasion via triggering the epithelial-to-
mesenchymal transition [EMT] [11], which gives rise to cancer cells with stem-like properties, leading to 
formation of a localized cancer to metastatic disease [9, 12]. Emerging literature shows that microRNAs, 
such as miR-217, may also play a role in this pathogenic process by activating EMT [13]. Several 
cytokines and C-reactive protein (CRP) are increased in the blood during moderate to severe acute 
pancreatitis. Serum IL-6 is an established pro-inflammatory marker in acute pancreatitis [14-19], and it 
also predicts disease severity and duration [20-23]. Levels of IL-6 increase early and remain elevated in 
severe acute pancreatitis [20-23]. In contrast, IL-10 is an anti-inflammatory cytokine that increases later in 
the disease process and remains elevated with protracted disease [20-23]. IL-10 is thus associated with 
resolution of acute inflammation [15, 24-27].. Circulating biomarkers associated with chronic pancreatitis 
are not as established. However, there are two studies showing that chronic pancreatitis patients have 
increased levels of TGF-β1 [28, 29]. Individual studies report increases in  tumor necrosis factor-α (TNF-
α) [28], and soluble fractalkine [29]. 


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Exocrine insufficiency and endoscopic pancreatic function test (ePFT). Pancreatic inflammation and 
fibrosis that result from unresolved pancreatitis directly cause a decrease in exocrine function, reflected in 
a reduced secretion of bicarbonate and pancreatic enzymes [30]. Although fibrosis, inflammation, and 
loss of parenchymal tissue are best measured by tissue-based histology, an invasive biopsy procedure can 
cause pancreatitis [31] and is therefore not an option for biological measurement. The current gold 
standard for diagnosing chronic pancreatitis is the endoscopic pancreatic function test (ePFT) which 
measures secretin-stimulated production of bicarbonate ion from pancreatic ductal cells during an 
endoscopic ultrasound procedure (EUS) [3, 32]. Clinically, ePFT-based peak bicarbonate levels can 
distinguish mild and severe chronic pancreatitis, and is correlated with the extent of histologically 
determined fibrosis (r=-0.57) [33]. Because ePFT is based on an endoscope-guided collection of pure 
pancreatic fluid, it provides a direct measurement of pancreatic function that is superior to indirect 
measurements in stool i.e., fecal elastase [34]. Endoscope-based specimen collection will also allow for 
measurement of immune cytokines and other potential biomarkers in the pancreatic fluid. Pancreatic fluid 
cytokine levels have been shown to discriminate chronic pancreatitis from milder disease and pancreatic 
cancer from normal pancreas [35, 36].  
 
Statins and the prevention of recurrent pancreatitis. Because of the paracrine and self-perpetuating 
nature of the desmoplastic process in the promotion of pancreatic carcinogenesis, it constitutes a key 
process whose early disruption is a logical target for preventing pancreatic cancer. HMG-CoA reductase 
inhibitors, commonly known as statins, are cardioprotective drugs that also have immunomodulatory 
properties relevant to pancreatic carcinogenesis. Animal models of pancreatitis demonstrate that statins 
decrease pancreatitis in association with a reduction in pro-inflammatory factors [37, 38]. Following 
induction of chronic pancreatitis in rats, 10 mg/kg/day of pravastatin substantially attenuated the 
progression of pancreatic inflammation, fibrosis, and exocrine dysfunction [37]. Increased levels of the 
anti-inflammatory cytokine, IL-10, and decreased levels of the pro-inflammatory cytokine, TNF-α, in the 
intervention group compared to the control group suggests that pravastatin may mediate early 
inflammatory reactions.  
 
Biochemically, statins directly bind leukocyte function antigen-1 (LFA-1), resulting in reduced leukocyte 
adhesion to sites of injury, and subsequent suppression of the inflammatory response [39]. A carboxylic 
moiety of statins also bind to the catalytic site of histone deacetylase (HDAC) protein 2 [40], leading to 
attenuation of HDAC-mediated inflammation [41], and may also downregulate HDAC-mediated 
epithelial to mesenchymal transition [42], which plays an important role in invasion and metastases of 
cancer cells. Indirectly, inhibition of HMG-CoA reductase also results in reduced production of isoprenyl 
groups that directly modify key small GTPase proteins (i.e., RhoA, Ras) involved in inflammation and 
fibrogenesis [43, 44]. Taken together, these studies demonstrate that statins inhibit, either directly or 
indirectly, several signaling pathways implicated in pancreatic carcinogenesis. Coupled with the fact that 
statins have been used clinically for a long time, and have a very favorable toxicity profile, these studies 
support the hypothesis that statins may effectively prevent or reduce the risk of pancreatic cancer.  
 
Consistent with this notion, we have recently reported that patients taking simvastatin, the most 
commonly prescribed statin, experience a dramatic reduction in pancreatitis incidence. Simvastatin was 
independently associated with a 70% reduced risk of pancreatitis, with a rate ratio of 0.29 (95% CL 0.27, 
0.31) after adjustment for age, sex, race/ethnicity, gallstone disorders, hypertriglyceridemia, and alcohol 
and tobacco use [45]. While our investigation suggests that statins may attenuate pancreatitis and 
pancreatitis-associated carcinogenesis, this needs to be rigorously tested in the context of a prospective 
clinical trial. We hypothesize that statins will improve pancreatic function in high-risk patients, as defined 
by those with two or more episodes of acute pancreatitis. Our multi-disciplinary research team will 
randomize pancreatitis patients with recurrent pancreatitis to simvastatin versus placebo, and will evaluate 
the impact of statin treatment on pancreatic function and inflammation implicated in pancreatic 


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carcinogenesis. Measures will include pancreatic exocrine function (secretin-stimulated peak bicarbonate 
concentration; the primary endpoint), endoscopic ultrasound measures of pancreatitis, inflammation-
associated cytokines, chemokines, and adhesion molcules (serum and pancreatic secretion), and clinical 
recurrence. Our randomized trial will elucidate pathophysiological pathways of pancreatitis, and is 
designed to provide badly needed new prevention strategies for those at high risk for pancreatic cancer. 
 
3. 
SUMMARY OF STUDY PLAN 
 
We will conduct a randomized double-blinded, placebo-controlled Phase II trial of statin to evaluate the 
impact of statin treatment on pancreatic function and inflammation in patients diagnosed with recurrent 
pancreatitis who are undergoing treatment at four study sites: Cedars-Sinai Medical Center (CSMC), 
Kaiser Southern California Permanente Medical Group (KPMC), the University of Pittsburgh (UP), and 
Stanford University (SU). Thirty patients will be randomized to simvastatin or placebo (20 in the 
simvastatin arm, 10 in the control). Assuming that ~20% of the study participants drop-out, we expect to 
have data on a final sample of 24 men and women (16 simvastatin, 8 control) completing the 6-month 
follow-up period. Clinical and research measurements will be taken at Baseline (Study Visit 1), Month 3 
(Study Visit 2), and Month 6 (Study Visit 3). Three and 6 months were chosen, given that patients have 
variable recovery times in the order of months after an acute pancreatitis event [46]. Therefore, the 
repeated measures at 3 and 6 months will be essential for determining the trajectory of change in the 
clinical and research measurements during the recovery period. 
 
Patients with at least two episodes of acute pancreatitis in the past 12 months will be recruited for the 
study. We will recruit study participants among several pools of patients: patients hospitalized for acute or 
chronic pancreatitis at the study sites, patients who have an upcoming appointment scheduled with a study 
gastroenterologist, patients referred by other physicians or staff through outpatient clinics, and patients 
who self-refer. All patients will receive their usual care under the guidance of their physician.  
 
Pre-Screen Eligibility Review – Initial determination of eligibility and recruitment  
Inpatients and outpatients at study sites. The clinical research staff at each site will review the medical 
records of patients hospitalized for pancreatitis to determine if they have had at least one previous episode 
of acute pancreatitis in the past 12 months; have a history of use, adverse effects and/or contraindications 
to statin medication (e.g., current systemic use of gemfibrozil, cyclosporine, danazol, or strong CYP3A4 
inhibitors); and to rule out medical contraindications and prohibited concomitant medications specified in 
the eligibility criteria. The medical records of patients who have an upcoming appointment with one of 
the study gastroenterologists, and the medical records of patients who are referred by other physicians at 
the institution, will also be reviewed for eligibility. The research staff will notify one of the trial 
gastroenterologists that a patient is potentially eligible for the trial based on the pre-screen evaluation. 
 
Potentially eligible patients who are hospitalized will be approached by one of the trial gastroenterologists 
or a study team member. After describing the trial and answering the patient's questions, patients who 
express an interest in participating in the trial will be given a study information packet that includes the 
IRB-approved study consent form and HIPAA authorization, and IRB-approved recruitment materials 
(e.g., introductory letter, study brochure; each participating site will choose what materials to include). 
Patients will be encouraged to review the consent documents with family, friends, and/or other 
physicians. 
 
Clinical research staff will prepare and mail the study information packet to potentially eligible patients 
who are outpatients (e.g., patients who have an upcoming appointment with a study gastroenterologist, 
patients hospitalized for pancreatitis who are discharged before the study team has an opportunity to 
approach them, referrals from other physicians). One of the study gastroenterologists or clinical research 


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staff will call potentially eligible patients within 14 days after the packet is mailed to introduce the study 
and answer questions. 
 
Referrals from physicians at outside institutions and self-referrals (medical records not available). 
Additional recruitment strategies such as leaflets placed in outpatient clinics, study announcements sent to 
physicians at outside institutions, flyers and half-page ads posted at outside institutions and at community 
clinics, and video bulletins displayed on screens at the study sites and outside institutions, will be 
employed to increase awareness of the trial and aid in our recruitment goals. The recruitment materials 
will contain contact information for the study. A member of the study team will field questions from 
patients who respond to direct advertisement and outside referrals who call to request more information. 
Staff will describe the study and review the eligibility criteria with the patient using an IRB-approved 
phone script to assess potential eligibility. If the patient is potentially eligible and interested in the trial, 
they will be mailed the study information packet including the consent form and HIPAA authorization. 
Patients who are interested in participating in the study will be scheduled for a visit to sign the study 
consent documents. Clinical research staff will follow-up with a phone call to potentially eligible patients 
who are undecided within 14 days after the packet is mailed to evaluate interest in study participation and 
answer additional questions. Patients who want to volunteer for the study will be scheduled come to the 
clinic to sign the study consent documents. 
 
Screen 1 – Consent and Secondary determination of eligibility. One of the trial gastroenterologists 
will review the study details and consent documents with interested pre-screen eligible patients after all 
clinical options have been presented to the patient. After the patient's questions have been answered, the 
gastroenterologist will obtain signatures on the study consent form and HIPAA authorization. Copies of 
each form will be given to the patient and placed in the medical record. The patient will be told that the 
decision to join or not join the study will not affect the medical treatment that s/he receives, and that s/he 
can withdraw from the study at any time. Written consent will be obtained before any research related 
procedures are initiated. 
 
After consent has been obtained, a secondary assessment of eligibility will be conducted. If not available 
at the study site, the clinical research staff will retrieve medical records from other institutions for 
pancreatitis history. One of the trial gastroenterologists will review the patient’s pancreatitis history and 
confirm the diagnosis of recurrent pancreatitis (at least two episodes of acute pancreatitis in the past 12 
months) using the Atlanta Classification. The diagnosis of acute pancreatitis will be confirmed by any two 
of the following three features: (1) Typical upper abdominal pain often radiating to the back; (2) 
Elevation in serum amylase or lipase ≥3 times upper limit of normal; (3) Features of acute pancreatitis on 
cross-sectional imaging [47]. The gastroenterologist will also review the patient’s computed tomography 
(CT) and magnetic resonance imaging (MRI) results from the past 12 months. Patients with evidence of 
advanced chronic pancreatitis by CT or MRI will be excluded. 
 
Screen 2 – Final determination of eligibility. Consented patients who are eligible after Screen 1 will 
undergo an endoscopic ultrasound (EUS) and endoscopic pancreatic function test (ePFT) within 8 weeks 
after consent to rule out advanced chronic pancreatitis. Patients will also have a physical exam, vital signs 
assessment, symptom assessment, ECOG performance status, and a blood draw to confirm eligibility.  
 
We will exclude patients with advanced chronic pancreatitis as determined by the following criteria:  
a) EUS score greater than or equal to 6,  
b) calcifications in combination with atrophy and/or dilation of ≥5 mm, or  
c) evidence of advanced chronic pancreatitis by computed tomography (CT) or magnetic resonance 
imaging (MRI) results in the past 12 months. 
 
Diagnosis of advanced chronic pancreatitis is based on satisfying one or more of the following criteria 


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[3]:  
a) Intra-ductal or pancreatic parenchymal calcification(s) on cross-sectional imaging;  
b) 6 or more standard criteria for chronic pancreatitis on endoscopic ultrasound (EUS) (Table 1);  
Table 1. EUS criteria for chronic pancreatitis 
Ductal Features 
Parenchymal Features 
Duct well echogenicity 
Echogenic foci 
Side branch dilation 
Cysts (>3 mm in size) 
Calculi 
Accentuation of the lobular pattern 
Irregular pancreatic duct margins 
Focal regions of reduced echogenicity 
Main duct (dilation and narrowing) 
 
 
c) Findings on MRI/MRCP: major duct abnormalities (Cambridge Classification 3 or greater) (Table 2). 
Table 2. Cambridge classification for chronic pancreatitis 
Grade 
Main pancreatic duct 
Side branches 
Normal (Grade 0) 
Normal  
Normal  
Equivocal (Grade I) 
Normal  
<3 Abnormal 
Mild (Grade II) 
Normal  
≥3 Abnormal 
Moderate (Grade III) Abnormal 
>3 Abnormal 
Severe (Grade IV) 
Abnormal with at least one of the following: 
>3 Abnormal 
 
Large cavity >10 mm 
 
 
Duct obstruction 
 
 
Intraductal filling defect 
 
 
Severe dilatation or irregularity 
 
 
Because statins are known to be teratogenic, women of child-bearing potential will be required to have a 
pregnancy test during Screen 2. Women who are pregnant will be excluded from the trial. Patients with 
lab results outside the eligibility range will also be excluded. 
 
Screen 2 eligible/consented patients will be registered and randomized to the study drug (either 
simvastatin or placebo). The Screen 2 EUS and ePFT results will be used as Study Visit 1 baseline 
measurements. 
 
Study Visits 
Study Visit 1 (Baseline measurements and initiation of the intervention). The first study visit will occur 0-
14 days after Screen 2. The following procedures will be performed during this visit:  
a) Review of medical history, medications, and laboratory test results; vital signs assessment, 
symptom assessment, and ECOG performance status 
b) Blood collection for clinical labs and research 
c) Collection of a fecal specimen (self-collected at home) 
d) Interviewer-administered comprehensive questionnaire (demographics, risk factor and clinical 
assessment (Appendix E) 
e) Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
(Appendix D) 
f) Review of inclusion /exclusion criteria 
g) Dispense study drug and review instructions for how to take it 
h) Dispense study diary and review instructions for how to complete it 
 


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Study Visit 2. The first follow-up visit will occur 3 months (± 1 month) after initiation of the intervention. 
The following procedures will be performed during this visit:  
a) Review of medical history, medications, and laboratory test results; physical exam, vital signs 
assessment, symptom assessment, and ECOG performance status 
b) Blood collection for clinical labs and research 
c) Endoscopic pancreatic function test (ePFT) and simultaneous esophagogastroduodenoscopy 
(EGD) 
d) Collection of a fecal specimen (self-collected at home) 
e) Pregnancy test for women of child-bearing potential 
f) Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
g) Review of conformance with inclusion /exclusion criteria 
h) Dispense study drug and review instructions for how to take it 
i) Review study drug diary and assess medication compliance and adverse events 
 
Study Visit 3. The final visit will occur 6 months (± 1 month) after initiation of the intervention. The 
following procedures will be performed during this visit:  
a) Review of medical history, medications, and laboratory test results; physical exam, vital signs 
assessment, symptom assessment, and ECOG performance status 
b) Blood collection for clinical labs and research 
c) Endoscopic pancreatic function test (ePFT) and simultaneous endoscopic ultrasound (EUS) 
d) Collection of a fecal specimen (self-collected at home) 
e) Pregnancy test for women of child-bearing potential 
f) Interviewer-administered follow-up questionnaire to obtain information about changes in 
exposures and behaviors since the baseline visit (Appendix F) 
g) Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
h) Compliance assessment (pill count) and collection of study agent and study diary 
i) Assess adverse events 
 
Post-intervention follow-up. Clinical research staff will make follow-up telephone calls to study 
participants on days 30 ± 7, 60 ± 7, and 90 ± 7 after completion of Study Visit 3 to assess symptoms and 
adverse events. 
 
Accrual will occur within 24 months with an expected accrual rate of 1-2 subjects per month across four 
study sites. We anticipate that all evaluable participants will have completed all study procedures within 
three years. 
 
Study Measurements 
 
Physician assessment. Study subjects will have an assessment by a gastroenterologist at the time of 
screening and enrollment, and at the subsequent planned study visits at Months 3 and 6. Each assessment 
will include an interval symptom history; vital signs, including blood pressure, heart rate, respiratory rate, 
and temperature; and measurement of weight. Height will be measured at Study Visit 1 only. 
 
Baseline and follow-up questionnaires. A structured interview (Appendix E), developed for this 
investigation and including risk factor and clinical assessment, will be administered by the staff at Study 
Visit 1. The questionnaire will obtain information regarding date of birth; detailed race/ethnicity; and 
education; medical history, including pancreatic diseases and diabetes; medications, including analgesics 
and antibiotics; physical activity; history of alcoholic beverage consumption; tobacco smoking history; 
and anthropometry. A shorter questionnaire (Appendix F) will be administered at the 6-month visit to 
assess alcohol use and surgical procedures that will impact the risk of recurrent pancreatitis. 
 


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Quality of life and pain assessment. We will measure quality of life and pain level using the QLQ-C30 
and QLQ-PAN28(CP) (Appendix D). The European Organization for Research and Treatment of Cancer 
(EORTC) QLQ-C30 is a 30-item measure developed to assess the quality of life of cancer patients [48]. 
The measure includes three scales: global health status, functional status (physical, role, emotional, 
cognitive, and social), and physical symptoms. The EORTC QLQ-PAN26 is a 26-item measure 
specifically for patients with pancreatic cancer that assesses pain, dietary changes, disease symptoms, and 
emotional problems related to pancreatic cancer [49]. The QLQ-PAN28(CP) is a modified version of the 
QLQ-PAN26 for patients with chronic pancreatitis [50]. Participants will self-administer the QLQ-C30 
and QLQ-PAN28(CP) assessments. 
 
Endoscopic pancreatic function test (ePFT) and simultaneous endoscopic ultrasound (EUS) and 
fasting pancreatic fluid. Patients will be instructed to fast overnight (8 hours) before the endoscopic 
testing. Pancreatic fluid through the ePFT will be collected at Screen 2 (will be used as Study Visit 1 
baseline measurement), Month 3 (Study Visit 2), and Month 6 (Study Visit 3) to measure secretin-
stimulated peak bicarbonate concentration; cytokines, , chemokines, and adhesion molecules. EUS will be 
performed at Screen 2 and at Study Visit 3. Esophagogastroduodenoscopy (EGD), a simpler endoscopic 
procedure without the ultrasound imaging, will be performed at Study Visit 2. 
 
Fecal specimen. A fecal specimen will be collected from participants at Study Visits 1, 2, and 3 for 
measurement of fecal elastase. A stool collection kit and instructions will be provided to the participant 
before the scheduled visit. The specimen will be self-collected at home and brought to the study visit. 
 
Blood specimen. A blood specimen (approximately 10 mL) will be collected from patients at the Screen 
2 visit for blood tests to confirm eligibility. A Complete Blood Count and Automated Differential 
(CBDF) [for hemoglobin, leukocytes, neutrophils, and platelets] and a Comprehensive Metabolic Panel 
(CMPL) [for total bilirubin, liver enzymes (AST/ALT), and creatinine] will be done to confirm that 
laboratory levels for acceptable organ, hepatic, and renal function are within the eligibility requirements. 
Alkaline phosphatase and glucose are also required at this visit to establish baseline levels but are not 
necessary for eligibility verification. See Appendix A for Clinical Laboratory Minimum Test 
Requirements. If a patient’s lab results within 35 days before the Screen 2 visit are available in the 
medical record and are within eligibility range, their blood will not be drawn at the Screen 2 visit. 
Otherwise, the patient’s blood will be drawn to confirm eligibility. 
 
A blood specimen (approximately 36 mL) will be collected from each participant at Study Visits 1, 2, and 
3. Approximately 10 mL of blood will be drawn for laboratory blood tests to monitor for potential 
adverse effects of the intervention and to confirm that laboratory levels meet the eligibility requirements 
for continuation in the trial. A Lipid Panel will be done at all study visits; a CBDF and a CMPL will be 
done at Study Visits 2 and 3; hemoglobin A1C will be measured at Study Visits 1 and 3; and creatine 
phosphokinase (CPK) will be measured at Study Visit 1 only. See Appendix A for Clinical Laboratory 
Minimum Test Requirements. Twenty-six mL of blood will be collected for research purposes. Six mL of 
blood will be drawn for measurement of serum concentrations of protocol-specific biomarkers (cytokines, 
chemokines, and adhesion molecules), and 20 mL of blood will be drawn for DNA extraction and use in 
future studies. 
 
Pregnancy test. Because statins are known to be teratogenic, women of child-bearing potential will be 
required to have a confirmed negative pregnancy test prior to enrollment and at Study Visits 2 and 3. 
Women who have had a hysterectomy, both ovaries removed, or a tubal ligation will not be required to 
have a pregnancy test. 
 
4. 
PARTICIPANT SELECTION 
 


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4.1 
Inclusion Criteria 
 
4.1.1  At least two episodes of acute pancreatitis in the past 12 months. Acute pancreatitis is defined as 
any 2 of the following: (1) Typical upper abdominal pain; (2) Elevation in serum amylase or lipase ≥3 
times upper limit of normal; (3) Features of acute pancreatitis on cross-sectional imaging.  
 
4.1.2 
Age ≥18 years. 
 
4.1.3 
ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix B). 
 
4.1.4 
Participants must have acceptable organ, hepatic and renal function as defined below: 
Leukocytes 
≥2,500/microliter 
Absolute neutrophil count 
≥1,500/microliter 
Platelets 
≥100,000/microliter 
Hemoglobin 
>10 g/dL 
Total bilirubin 
≤3 × institutional upper limit of normal (ULN) 
AST (SGOT)/ALT (SGPT) 
≤1.5 × institutional ULN 
Creatinine 
<1.5 mg/dL 
 
Patients whose lab levels meet the inclusion criteria by Screen 2 will be included in the trial. 
 
4.1.5 
Women of child-bearing potential must have a confirmed negative pregnancy test result prior to 
enrollment. 
 
4.1.6 
The effects of simvastatin on the developing human fetus at the recommended therapeutic dose 
are unknown. For this reason and because statins are known to be teratogenic, women of child-bearing 
potential must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her study 
physician immediately. It is not known whether simvastatin is excreted into human milk; however, a 
small amount of another drug in this class does pass into breast milk. Because statins have the potential 
for serious adverse reactions in nursing infants, women who receive treatment with simvastatin should not 
breastfeed their infants. 
 
4.1.7  Ability to understand and the willingness to sign a written informed consent document and 
medical release. 
 
4.1.8  Willing and able to comply with trial protocol and follow-up. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Prior or current use of statin medication, or current systemic use of gemfibrozil, cyclosporine, 
danazol, lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, or strong 
CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease 
inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-
containing products). 
 
4.2.2 
History of chronic myopathy 
 
4.2.3 
Current use of any other investigational agents 
 


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4.2.4 
History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar 
chemical or biologic composition to simvastatin (i.e., other statin medications). 
 
4.2.5 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
4.2.6 
Women who are pregnant or breastfeeding. Pregnant women are excluded from this study 
because simvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with simvastatin, breastfeeding should be discontinued if the mother is treated 
with simvastatin. 
 
4.2.7 
Presence of gallstones or hypertriglyceridemia (level greater than 800 mg/dl) that requires 
medical or surgical intervention. Note: We will include patients who had an independent episode of 
pancreatitis after a cholecystectomy, but exclude patients who are candidates for cholecystectomy.  
 
4.2.8 
History of pancreatic adenocarcinoma (at any time) 
 
4.2.9 
History of active malignancy in the past 2 years (excluding basal/squamous cell skin cancer or 
prostate cancer with a Gleason score 6 or less) 
 
4.2.10 Known active infection with HIV 
 
4.2.11 Concurrent illness, such as known psychiatric disorders or substance abuse (i.e., average alcohol 
consumption of more than 5 drinks per day), which in the opinion of the investigators would compromise 
either the patient or the integrity of the data 
 
4.2.12 Lab results do not meet inclusion criteria 4.1.4 by Screen 2. 
 
4.2.13 Recurrent pancreatitis episode is iatrogenic (endoscopic retrograde cholangiopancreatography 
(ERCP) induced) 
 
4.2.14 Advanced chronic pancreatitis as determined by the following criteria: EUS score greater than or 
equal to 6, calcifications in combination with atrophy and/or dilation of ≥5 mm, or evidence of advanced 
chronic pancreatitis by computed tomography (CT) or magnetic resonance imaging (MRI) results in the 
past 12 months. 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
4.4 
Recruitment and Retention Plan 
 
Patients with recurrent pancreatitis will be recruited for the study from the CSMC Pancreatic and Biliary 
Diseases Program, the KPMC Center for Pancreatic Care, the SU Gastroenterology and Digestive Health 
Clinic, and Presbyterian/Montefiore and Shadyside Hospitals at the UP Medical Center. 
Gastroenterologists at the four institutions jointly treat approximately 1,600 patients with acute 
pancreatitis annually, of whom approximately 600 (38%) are recurrent acute pancreatitis cases. We 
estimate that 40% (240) will not be eligible because they have not had at least two episodes of pancreatitis 
in the past 12 months, and that 40% will not be eligible due to current or prior statin use, presence of 


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gallstones, or other medical contraindications. We project that 120 potentially eligible patients will be 
approached for consent annually across four study sites (240 patients during the 24-month accrual 
period). Based on this patient population and the importance of our objectives to the gastroenterology 
community, our recruitment goal of 30 patients with two or more episodes of pancreatitis in the past 12 
months is highly feasible. The sample size of 30 will include an estimated 14 women (10 white, 2 black, 2 
Asian) and 16 men (11 white, 3 black, 2 Asian) with confirmed recurrent pancreatitis. Each of the 
investigators has substantial experience with patient recruitment and/or clinical trials of pancreatic 
diseases and will insure that our recruitment goals are met. Neither the repeated endoscopies nor the ePFT 
are considered barriers to recruitment as there is minimal risk (minor pain, discomfort, and few other 
sequelae) associated with the procedure. Healthy subjects have been subjected to cross-over studies of 
endoscopic and Dreiling tube pancreatic function tests, performed in tandem with a 1-week washout, and 
no procedure- or medication-related complications were reported [51]. Trial gastroenterologists will work 
closely with their gastroenterology teams in the recruitment effort.  
 
Patients who are eligible for the trial based on the pre-screen eligibility review by the clinical research 
staff (initial determination of eligibility) will be provided with a study information packet that includes 
the IRB-approved study informed consent form and HIPAA authorization, and IRB-approved recruitment 
materials (each participating site will choose what materials to include). Patients will be encouraged to 
review the consent documents with family, friends, and/or other physicians. One of the trial 
gastroenterologists will review the study details and consent documents with interested pre-screen eligible 
patients after all clinical options have been presented to the patient. After the patient's questions have 
been answered, the gastroenterologist will obtain signatures on the consent documents. Written consent 
will be obtained before any research related procedures are initiated. After consent has been obtained, 
Screen 1, the secondary assessment of eligibility, will be conducted by trial gastroenterologists (review of 
computed tomography (CT) and magnetic resonance imaging (MRI) results and confirmation of recurrent 
pancreatitis). Consented patients who are eligible after Screen 1 will undergo Screen 2 (final 
determination of eligibility to rule out advanced chronic pancreatitis and pregnancy) within 8 weeks after 
consent. Screen 2 eligible/consented patients will be registered and randomized to the study drug. Study 
Visit 1 (Baseline measurements), the beginning of the intervention (study agent dispensed), will occur 0-
14 days after Screen 2. 
 
Research visits, scheduled at the participating clinic, will coincide whenever practicable with usual care to 
reduce travel time and increase compliance with the study protocol. Participants will receive $50 when 
they complete the Screen 2 testing and $150 at the time they complete each study visit for their time, 
transportation, parking, and other expenses related to the study. Participants who complete the entire 
study – the Screen 2 testing, and three study visits – will receive $500. 
 
Compensation schedule  
Screen 2 
Study Visit 1 Study Visit 2 Study Visit 3 
$50 
$150 
$150 
$150 
 
Study visits will be scheduled at 3 months (± 1 month) and 6 months (± 1 month) to avoid protocol 
violations. A day or two prior to the scheduled follow-up visit, the participant will be contacted by 
telephone to confirm or reschedule his/her visit. Patients who develop intercurrent pancreatitis will 
receive usual medical care by their gastroenterologist, and their next study visit will be rescheduled if 
necessary. The study coordinator will have a database which tracks active participants who do not have a 
scheduled visit or who have missed their targeted visit date. Study visits will be rescheduled for up to 2 
months until the participant is considered lost to follow-up.  
 
5. 
AGENT ADMINISTRATION 


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Intervention will be administered on an outpatient basis. Reported adverse events (AEs) and potential 
risks are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
Thirty participants with recurrent pancreatitis will be randomized into one of 2 groups: 20 participants 
will receive 40 mg simvastatin per day and 10 participants will receive a placebo identical in color, 
consistency, and appearance to simvastatin 40 mg. Simvastatin and placebo will be provided as over-
encapsulated tablets. Dosing will extend for 6 months. 
 
• 
Agent(s): Simvastatin and placebo 
• 
Daily dose(s) and regimen(s) for each agent: One 40 mg capsule per day 
• 
Duration for each agent: Daily treatment for 6 months 
 
The usual recommended dose of simvastatin is 10-40 mg/day, and the toxicity and tolerability are 
comparable for 20 mg and 40 mg [8]. 
 
5.2 
Study Agent Administration 
 
Patients will self-administer the 40 mg capsule of simvastatin or placebo daily in the evening. Patients 
will be instructed to take the study agent at bedtime or with an evening meal. Each participant will be 
given 1 bottle of 120 capsules at Study Visit 1 and 1 bottle of 120 capsules at Study Visit 2 (Month 3). 
 
5.3 
Run-in Procedures  
 
None. 
 
5.4 
Contraindications 
 
Patients are advised not to consume any form of grapefruit (e.g., juice, fruit, grapefruit seed extract, 
dietary supplements containing grapefruit) while on simvastatin as grapefruit may increase the blood 
levels of simvastatin [52]. Participants enrolled in the study will be instructed to avoid all forms of 
grapefruit. 
 
The combined use of simvastatin with systemic formulations of gemfibrozil, cyclosporine, danazol, 
lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, or strong CYP3A4 
inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, 
boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing 
products) is contraindicated due to an increased risk for myopathy. Patients will be screened for 
contraindications to simvastatin prior to enrollment in the study. Patients with known active infection 
with HIV will be excluded from the study. Patients will be advised not to use contraindicated medications 
during the study and will be excluded if systemic use of any contraindicated medication is unavoidable. 
Concomitant medications will be reviewed at study visits and during follow-up telephone calls. 
Participants will be closely monitored for symptoms and side effects to the study drug and will be 
instructed to call the study doctor immediately if they have a serious adverse reaction. 
 
5.5 
Concomitant Medications 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include: 1) start and 


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stop date, dose and route of administration, and indication. Medications taken for a procedure (e.g., 
biopsy) should also be included. 
 
5.6 
Dose Modification 
 
No dose modifications are planned. The study agent will be stopped in the event of an AE ≥ grade 3 
considered possibly, probably, or definitely related to the study agent. The study agent will be restarted 
after resolution. One of the common side effects of statin medication is myalgia (muscle pain with normal 
creatine phosphokinase (CPK) level), and rarely this is associated with statin myopathy (muscle weakness 
or other muscle injury with or without elevation in CPK level). In randomized controlled trials of standard 
dose statin therapy, the risk is very low (<1%). We will measure levels of CPK in the blood drawn at the 
first study visit to establish a patient-specific reference for this indicator of muscle toxicity. During the 
trial, if the participant reports unexplained muscle pain or weakness, CPK will be tested again to check 
for elevation. The study agent will be temporarily discontinued in subjects experiencing grade 1 or greater 
myopathy (unexplained muscle symptoms and creatine phosphokinase (CPK) > 2.5 times institutional 
ULN) or hepatotoxicity (ALT or AST > 1.5 times institutional ULN) that is considered possibly, 
probably, or definitely related to the study agent. Resolution of myopathy or hepatotoxicity will be 
evaluated with follow-up laboratory blood tests 4 weeks after the elevated levels occur. If the lab test 
results are still elevated after 4 weeks, the study agent will be discontinued permanently and the 
participant’s primary care physician will be notified of the abnormal tests. If the lab test results return to 
normal levels, participant will go back on the study agent. 
 
Because dose modification could lead to lack of dose homogeneity that may impair the research 
objectives, we will stop the intervention in patients who initiate drugs that require dose modifications of 
simvastatin below 40 mg: lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, or 
ranolazine. 
 
5.7 
Adherence/Compliance 
 
Compliance will be measured by pill counts and patient diaries. Compliance is defined as 80% of the total 
dose with all doses of the study agent taken during the week before Study Visit 2 and Study Visit 3 (final 
visit). A patient diary will be used to monitor daily compliance (Appendix C). Participants will be 
instructed to record the time the study drug was taken each day in the diary, as well as any potential side 
effects. 
 
Phone calls will be made to study participants every four weeks (± 7 days) to monitor compliance. 
Participants will be asked if they missed any doses of medication, and the dates of all missed doses will 
be recorded. The study agent diary will be reviewed with participants at every visit. Participants who 
report having taken < 80% of the study drug doses between phone calls, or whose pill count at a study 
visit reveals < 80% compliance, will be called every two weeks (± 3 days) to monitor compliance. 
 
The participant will be asked at registration if they would like to receive reminder emails or text messages 
regarding the study medication. Messages will be sent daily for the first week; in following weeks, 
messaging will be targeted to participants having difficulty remembering their dose. Since agent 
compliance is very important during the final week of the intervention, text/email messages will be sent to 
all study participants who opt to receive these reminders. In addition, phone calls will be made to all study 
participants during the week before their final visit (Visit 3) to remind them to take the study drug every 
day until the last study visit when the final endoscopic procedure will be performed. Participants will also 
be reminded to bring any leftover study drugs and the study diary with them to each visit. 
 




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6.3  
Availability 
 
Simvastatin and matching placebo are investigational agents supplied to investigators by NCI/DCP 
through MRIGlobal. 
 
Simvastatin 40 mg and matching placebo will be supplied as overencapsulated tablets for oral 
administration. Simvastatin and matching placebo will be packaged with 120-count 40 mg 
overencapsulated tablets/bottle. Each participant will receive one bottle at Study Visit 1 and one bottle at 
Study Visit 2 (Month 3). 
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of IRB approval of the DCP-approved 
protocol and consent is provided to DCP and the collection of all Essential Documents is complete (see 
DCP website for description of Essential Documents).  
 
NCI, DCP-supplied agents may be requested by the Investigator (or their authorized designees) at each 
Organization. DCP guidelines require that the agent be shipped directly to the institution or site where the 
agent will be prepared and administered. DCP does not permit the transfer of agents between institutions 
(unless prior approval from DCP is obtained). DCP does not automatically ship agents; the site must 
make a request. Agents are requested by completing the DCP Clinical Drug Request form (NIH-986) (to 
include complete shipping contact information) and faxing or mailing the form to the DCP agent 
repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116   
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP using the NCI Drug Accountability Record 
Form (DARF). The Investigator is required to maintain adequate records of receipt, dispensing, and final 
disposition of study agent. This responsibility has been delegated to the study pharmacists: Annie Yi, 
Pharm.D., Investigational Drug Pharmacist at Cedars-Sinai Medical Center; Joseph Chang, Pharm.D., 
Pharmacy Manager at Kaiser Southern California Permanente Medical Group; Linda Gibson, R.Ph., 
Investigational Pharmacist at the University of Pittsburgh; and Scott Mayeda, Diem Tran, and Khanh 
Nguyen, Pharmacists at Stanford University. The receipt record will include from whom the agent was 
received and to whom study agent was shipped, date, quantity and batch or lot number. The dispensing 
record will note quantities and dates study agent was dispensed to and returned by each participant. The 
study agent will be dispensed to the subject at Study Visit 1 and Study Visit 2.  
 
6.6 
Packaging and Labeling 
 
Simvastatin and placebo will be packaged and labeled by NCI DCP. 
 


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Each bottle will be labeled with a one-part label identifying study specific information, such as Study 
title, DCP protocol number, dosing instructions, recommended storage conditions, the name and address 
of the distributor, randomization number, and a caution statement indicating that the agent is limited by 
United States law to investigational use only and the agent should be kept out of reach of children. 
 
6.7 
Storage 
 
The DCP Drug Repository, MRIGlobal, will distribute the study agent directly to each participating site. 
Study agents will be stored in a safe, secure, temperature monitored limited access drug storage area 
specifically for research medication at the Research Pharmacy at each site. Study agents shall be 
maintained at a controlled room temperature [between 15-30°C] by the Research Pharmacy at each site 
and once dispensed, the subjects will be instructed to store the drug in their homes protected from light, 
heat, and moisture. MRIGlobal will be notified in the event of a temperature excursion below 15°C or 
above 30°C for 24 hours continuously. MRIGlobal will evaluate the temperature excursions on a case-by-
case basis. 
 
6.8 
Registration/Randomization 
 
The Lurie Cancer Center Clinical Trials Management System (CTMS) will be the database of record. The 
study coordinator must upload (via CTMS), a signed and complete informed consent along with HIPAA 
authorization and a completed registration form for each participant identified as eligible to be entered 
into the study.  
 
All participants must be registered in CTMS Monday-Friday between the hours of 9:30 a.m. and 5:00 
p.m., Central Time (CT). Participants must not start protocol treatment prior to registration in CTMS.  
 
After registration, participants will be randomized by a member of the Quality Assurance Team of the 
Northwestern University Lurie Cancer Center (NU) to treatment with the study agent or placebo. 
Investigators and participants will be blinded as to the result of randomization. The following people will 
be un-blinded: the study statistician at Northwestern University (NU); the quality assurance team at NU; 
and the investigational pharmacists at CSMC, KPMC, UP, and SU. Full unblinded randomization 
information will be emailed to the investigational pharmacist at each study site. The study statistician will 
set up randomization blocks.  
 
The clinical research coordinators at CSMC, KPMC, UP, and SU will receive a blinded Participant ID 
code for the patient via email. 
 
Randomization procedures are also provided in Section 13. 
 
6.9 
Blinding and Unblinding Methods 
 
The research pharmacist will manage the investigational agent. The blind will be maintained through the 
effort of the research pharmacist, and the pharmacy. Unblinding will only occur when it is deemed 
medically necessary, and will only take place after consultation with the NCI, DCP Task Order Monitor. 
If the NCI Task Order Monitor cannot be reached and the participant requires emergency care, the Study 
Chairman may authorize the site PI to break the blind. The date and reason for breaking the blind must be 
submitted by the site PI to the Study Chairman and the NCI Task Order Monitor as soon as possible. 
 
DCP Medical/Task Order Monitor  
Luz Maria Rodriguez, MD, FACS  
NCI/Division of Cancer Prevention  


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9609 Medical Center Dr.  
Rm 5E-228  
Bethesda, MD 20892 
Telephone (240) 276-7039  
Fax (240) 276-7848  
Email: rodrigul@mail.nih.gov 
 
6.10 
Agent Destruction/Disposal 
 
At the completion of investigation, all unused study agent will be destroyed according to local 
institutional procedures. Destruction records must be provided to MRIGlobal at the end of the study.  
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
Procedure 
Pre-
Screen1 
Screen 
12 
Screen 
23 
Study 
Visit 14 
Months 
1–3 
Study 
Visit 25 
Months 
4-6 
Study 
Visit 36 
Follow-
Up 
Assess eligibility 
X 
X 
X 
 
 
 
 
 
 
Informed consent form and 
HIPAA authorization 
 
X 
 
 
 
  
 
  
 
Registration and randomization to 
simvastatin or placebo 
 
 
X 
 
 
 
 
 
Review medical history, 
medications, and lab test results 
 
X 
X 
X 
 
X 
 
X 
 
Review CT and MRI results 
 
X 
 
 
 
 
 
 
 
Blood Hematology: Complete 
Blood Count with Differential 
(CBDF) 
 
 
X 
 
 
X 
 
X 
 
Blood Chemistry: Comprehensive 
Metabolic Panel (CMPL) 
 
 
X 
 
 
X 
 
X 
 
Pancreatic fluid via endoscopic 
pancreatic function test (ePFT)  
 
 
X 
 
 
X 
 
X 
 
Endoscopic ultrasound (EUS)  
 
 
X 
 
 
 
 
X 
 
Esophagogastroduodenoscopy 
(EGD) 
 
 
 
 
 
X 
 
 
 
Urine pregnancy test7 
 
 
X 
 
 
X 
 
X 
 
Demographics (date of birth, race, 
ethnicity, education) 
 
 
 
X 
 
  
 
  
 
Physical exam  
 
 
X 
 
 
X 
 
X 
 
Vital signs assessment, measure 
weight, symptom assessment, and 
ECOG performance status 
 
 
X 
X 
 
X 
 
X 
 
Blood test: Lipid Panel 
 
 
 
X 
 
X 
 
X 
 
Blood test: Hemoglobin A1C 
(HbA1C) 
 
 
 
X 
 
 
 
X 
 
Blood test: Creatine 
phosphokinase (CPK) 
 
 
 
X 
 
 
 
 
 
Collect blood specimen for 
 
 
 
X 
 
X 
 
X 
 


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Procedure 
Pre-
Screen1 
Screen 
12 
Screen 
23 
Study 
Visit 14 
Months 
1–3 
Study 
Visit 25 
Months 
4-6 
Study 
Visit 36 
Follow-
Up 
research8 
Fecal specimen (self-collected) 
 
 
 
X 
 
X 
 
X 
 
Risk factor questionnaire 
 
 
 
X 
 
 
 
X 
 
QLQ-C30 and QLQ-PAN28(CP) 
 
 
 
X 
 
X 
 
X 
 
Imaging studies, as needed 
 
 
 
X 
 
X 
 
X 
 
Review eligibility criteria 
 
 
 
X 
 
X 
 
 
 
Dispense study agent and diary 
 
 
 
X 
 
X 
 
 
 
Collect study agent and diary 
 
 
 
 
 
X 
 
X 
 
Review study diary 
 
 
 
 
 
X 
 
X 
 
Assess compliance 
 
 
 
 
X 
X 
X 
X 
 
Assess adverse events 
 
 
 
 
X 
X 
X 
X 
X 
Telephone contact9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Pre-Screen eligibility review by clinical research staff to determine initial eligibility. Research staff will review 
medical records of patients hospitalized for pancreatitis, and of patients who have an upcoming appointment with a 
study gastroenterologist. For patients who respond to direct advertisement and outside referrals who call to request more 
information (whose medical records are not available), research staff will describe the study, field questions, and assess 
potential eligibility using an IRB-approved phone script.  
2 Consent and secondary determination of eligibility by trial gastroenterologists. Review of patient’s CT and MRI results 
from past 12 months and confirmation of recurrent pancreatitis (at least two episodes of acute pancreatitis in the past 12 
months) using the Atlanta Classification. The diagnosis of acute pancreatitis requires two of the following three features: 
(1) abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating 
to the back); (2) serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal; 
and (3) characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT). Patients with 
CT or MRI evidence of advanced chronic pancreatitis will be excluded from the trial. 
3 Consented patients who are eligible after Screen 1 will undergo an endoscopic ultrasound (EUS) and endoscopic 
pancreatic function test (ePFT), clinical labs, and pregnancy test (for women of child-bearing potential) within 8 weeks 
after consent. Patients with EUS evidence of advanced chronic pancreatitis, patients with lab results outside the 
eligibility range, and women who are pregnant will be excluded from the trial. 
4 Screen 2 eligible/consented patients will be registered and randomized. Study Visit 1 (baseline measurements and 
initiation of the intervention) will occur 0-14 days after Screen 2. The Screen 2 EUS and ePFT results will be used as 
Visit 1 measurements. 
5 Study Visit 2 will occur 3 months (± 1 month) after the initiation of the intervention. 
6 Study Visit 3 (last day of study drug) will occur 6 months (± 1 month) after initiation of the intervention. 
7 Pregnancy test for women of child-bearing potential at the Screen 2 visit and at Study Visits 2 and 3. Women who have 
had a hysterectomy, both ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
8 Blood collection for research (26 mL): 6 mL for measurement of protocol-specific biomarkers and 20 mL banked for 
DNA extraction and future studies 
9 Telephone contact with patients during the screening period to assess eligibility, introduce the study, answer questions, 
and schedule pre-study evaluations. Telephone contact every four weeks (± 7 days) during the intervention to assess 
compliance and adverse events. Follow-up telephone contact on days 30 ± 7, 60 ± 7, and 90 ± 7 after completion of 
Study Visit 3 to assess adverse events. 
 
7.2 
Pre-Study Evaluation and Baseline Testing 
 
7.2.1  Pre-Screen Eligibility Review – Initial determination of eligibility and recruitment  
 
Inpatients and outpatients at study sites. The medical records of patients hospitalized for acute or chronic 
pancreatitis will be reviewed by the clinical research staff to determine initial eligibility as specified in the 


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inclusion and exclusion criteria. The medical records of patients who have an upcoming appointment with 
one of the study gastroenterologists, and the medical records of patients who are referred by other 
physicians at the institution, will also be reviewed for eligibility. The following information will be 
reviewed: 
1. History of acute pancreatitis in the past 12 months 
2. History of use and/or adverse effects to statin medication, and contraindications to statin use 
3. Medical contraindications and medications that impact inclusion in the study 
 
Potentially eligible patients who are hospitalized will be approached by one of the trial gastroenterologists 
or a study team member. After describing the trial and answering the patient's questions, patients who 
express an interest in participating in the trial will be given a study information packet that includes the 
IRB-approved study informed consent form and HIPAA authorization, and IRB-approved recruitment 
materials (e.g., introductory letter, study brochure; each participating site will choose what materials to 
include). Patients will be encouraged to review the consent documents with family, friends, and/or other 
physicians. 
 
Clinical research staff will prepare and mail the study information packet to potentially eligible patients 
who are outpatients (e.g., patients who have an upcoming appointment with a study gastroenterologist, 
patients hospitalized for pancreatitis who are discharged before the study team has an opportunity to 
approach them, referrals from other physicians). One of the study gastroenterologists or clinical research 
staff will call potentially eligible patients within 14 days after the packet is mailed to introduce the study 
and answer questions. 
 
Referrals from physicians at outside institutions and self-referrals (medical records not available). 
Additional recruitment strategies such as leaflets placed in outpatient clinics, study announcements sent to 
physicians at outside institutions, flyers and half-page ads posted at outside institutions and at community 
clinics, and video bulletins displayed on screens at the study sites and outside institutions, will be 
employed to increase awareness of the trial and aid in our recruitment goals. The recruitment materials 
will contain contact information for the study. A member of the study team will field questions from 
patients who respond to direct advertisement and outside referrals who call to request more information. 
Staff will describe the study and review the eligibility criteria with the patient using an IRB-approved 
phone script to assess potential eligibility. If the patient is potentially eligible and interested in the trial, 
they will be mailed the study information packet including the consent form and HIPAA authorization. 
Patients who are interested in participating in the study will be scheduled for a visit to sign the study 
consent documents. Clinical research staff will follow-up with a phone call to potentially eligible patients 
who are undecided within 14 days after the packet is mailed to evaluate interest in study participation and 
answer additional questions. Patients who want to volunteer for the study will be scheduled come to the 
clinic to sign the study consent documents. 
 
7.2.2  Screen 1 – Consent and Secondary determination of eligibility 
 
Interested pre-screen eligible patients will be recruited and consented into the trial. One of the trial 
gastroenterologist will review the study details and consent documents with potentially eligible patients 
after all clinical options have been presented to the patient. After the patient's questions have been 
answered, the gastroenterologist will obtain signatures on the study consent form and HIPAA 
authorization. Copies of each form will be given to the patient and placed in the medical record. Written 
consent will be obtained before any research related procedures are initiated. 
 
After consent has been obtained, a secondary assessment of eligibility will be conducted. 


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1. If not available at the study site, the clinical research staff will retrieve medical records from 
other institutions for pancreatitis history.  
2. Trial gastroenterologists will review the patient’s pancreatitis history and confirm the diagnosis of 
recurrent pancreatitis (at least two episodes of acute pancreatitis in the past 12 months) using the 
Atlanta Classification. They will also review the patient’s computed tomography (CT) and 
magnetic resonance imaging (MRI) results from the past 12 months. 
 
Patients with CT or MRI evidence of advanced chronic pancreatitis will be excluded from the trial. 
 
7.2.3  Screen 2 – Final determination of eligibility, Registration, and Randomization 
 
Consented patients who are eligible after Screen 1 will undergo the following procedures within 8 weeks 
after consent to rule out advanced chronic pancreatitis and pregnancy. Patients will be instructed to fast 
overnight (8 hours) before the endoscopic testing.  
1. Clinical labs for a Complete Blood Count with Differential (CBDF) and a Comprehensive 
Metabolic Panel (CMPL) will be done to confirm that laboratory levels for acceptable organ, 
hepatic, and renal function are within the eligibility requirements. See Appendix A for Clinical 
Laboratory Minimum Test Requirements. If a patient’s lab results within 35 days before the 
Screen 2 visit are available in the medical record and are within eligibility range, their blood will 
not be drawn at the Screen 2 visit. Otherwise, the patient’s blood will be drawn to confirm 
eligibility. 
2. Pregnancy test for women of child-bearing potential. Women who have had a hysterectomy, both 
ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
3. Physical exam including vital signs assessment, symptom assessment, and ECOG performance 
status 
4. Endoscopic ultrasound (EUS) 
5. Endoscopic pancreatic function test (ePFT) 
 
Based on Screen 2 results, patients with EUS evidence of advanced chronic pancreatitis, patients with lab 
results outside the eligibility range, and women who are pregnant will be excluded from the trial. Patients 
with EUS evidence of advanced chronic pancreatitis will not undergo the ePFT. See Section 3. Summary 
of Study Plan for advanced chronic pancreatitis diagnostic criteria.  
 
Consented patients who qualify for the study after the Screen 2 eligibility evaluations will be registered 
and randomized to the study drug (simvastatin or placebo). The Screen 2 EUS and ePFT results will be 
used as Study Visit 1 baseline measurements. The pancreatic fluid will be used to measure secretin-
stimulated peak bicarbonate concentration;  cytokines, chemokines, and adhesion molecules.  
 
7.2.4  Study Visit 1 – Baseline Testing and Initiation of the Statin Intervention 
 
Study Visit 1 (Baseline measurements) will occur 0-14 days after Screen 2. Participants will be told to 
fast for 8 hours before the study visit. Fasting instructions will be provided to participants prior to their 
study visit, and participants will receive a phone call reminder the day before the visit to fast overnight. 
The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Measure height and weight and symptom assessment 
3. Vital signs assessment: blood pressure, heart rate, respiratory rate, and oral temperature 
4. ECOG performance status 


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5. Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a Lipid Panel, hemoglobin A1C, and creatine phosphokinase (CPK) to establish baseline levels 
prior to initiating the study agent. CBDF and CMPL lab results from the Screen 2 eligibility visit 
will be used to establish patient-specific references prior to initiation of therapy. If blood tests 
were not done at the Screen 2 visit for a CBDF and CMPL; and lab results within 30 days prior to 
this visit for these tests are not available in the medical record, a CBDF and CMPL will be done 
at this visit. See Appendix A for Clinical Laboratory Minimum Test Requirements.  
6. Blood collection for research purposes (26 mL): 6 mL will be collected for measurement of 
protocol-specific biomarkers (serum concentrations of cytokines, chemokines, and adhesion 
molecules), and 20 mL will be banked for DNA extraction and future studies.  
7. Fecal specimen for measurement of fecal elastase. A stool collection kit and instructions will be 
provided to the participant before the scheduled visit. The specimen will be self-collected at 
home. The participant will receive a phone call reminder the day before the visit to collect the 
fecal specimen and bring it to the study visit. 
8. Interviewer-administered questionnaire to obtain demographic information (date of birth, detailed 
race and ethnicity, education); medical history, including pancreatic diseases and diabetes; 
medications, including analgesics and antibiotics; physical activity; history of alcoholic beverage 
consumption; tobacco smoking history; and anthropometry 
9. Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
10. Review of inclusion /exclusion criteria 
11. Dispense study agent and review instructions for how to take the study drug. Each participant will 
be given a 3-month supply of the study agent (1 bottle of 120 capsules). 
12. Dispense study diary and review instructions for how to complete it 
 
7.3 
Evaluation During Study Intervention 
 
7.3.1  Study Visit 2 
 
Study Visit 2 will occur 3 months (± 1 month) after the initiation of the intervention. Participants will be 
told to fast for 8 hours before the study visit. Fasting instructions will be provided to participants prior to 
their study visit, and participants will receive a phone call reminder the day before the visit to fast 
overnight. The following procedures/evaluations will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Physical exam including measurement of weight and symptom assessment 
3. Vital signs assessment: blood pressure, heart rate, respiratory rate, and oral temperature 
4. ECOG performance status 
5. Pregnancy test for women of child-bearing potential. Women who have had a hysterectomy, both 
ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
6. Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a Complete Blood Count and Automated Differential (CBDF), a Complete Metabolic Panel 
(CMPL), and a Lipid Panel to monitor for potential adverse effects of the intervention and to 
confirm that laboratory levels meet the eligibility requirements for continuation in the trial (See 
Appendix A). If lab results within 30 days prior to this visit for any of these tests are available in 
the medical record, the blood test(s) will not be done.  
7. Blood collection for research purposes (26 mL): 6 mL will be collected for measurement of 
protocol-specific biomarkers (serum concentrations of cytokines, chemokines, and adhesion 
molecules), and 20 mL will be banked for DNA extraction and future studies. 


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8. Fecal specimen for measurement of fecal elastase. A stool collection kit and instructions will be 
provided to the participant before the scheduled visit. The specimen will be self-collected at 
home. The participant will receive a phone call reminder the day before the visit to collect the 
fecal specimen and bring it to the study visit. 
9. Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
10. Review of conformance with inclusion /exclusion criteria 
11. Collect study agent and diary 
12. Assess compliance (pill count) 
13. Review study diary  
14. Assess adverse events 
15. Dispense study agent and diary. Each participant will be given a 3-month supply of the study 
agent (1 bottle of 120 capsules). 
16. Endoscopic pancreatic function test (ePFT) and simultaneous esophagogastroduodenoscopy 
(EGD) and fasting pancreatic fluid to measure secretin-stimulated peak bicarbonate 
concentration; cytokines, chemokines, and adhesion molecules. 
 
7.3.2 
Telephone Calls and Email/Text Messages 
 
Study participants will be followed during intervention via telephone calls every four weeks (± 7 days) by 
the clinical research staff to assess compliance and adverse events. Participants who report having taken < 
80% of the study drug doses between phone calls, or whose pill count at a study visit reveals < 80% 
compliance, will be called every two weeks (± 3 days) to monitor compliance. In addition, participants 
will receive a phone call the day before each scheduled study visit to remind them to fast overnight and to 
collect a fecal specimen and bring it to the study visit. Participants will also be reminded to bring any 
leftover study drugs and the study diary with them to the visit. Study participants will also be called 
during the week before their final visit (Visit 3) to remind them to take the study drug every day until the 
visit appointment. 
 
Participants who opt to receive reminders for study medication intake via email or text messages will be 
contacted by the study staff during the first week of study and further as needed. The study staff will send 
emails or text messages on cellular phone; participants will be encouraged to respond to these messages 
indicating if the study drug has been taken. These responses will be used to assess compliance and will be 
reviewed at weekly phone contact. For participants who miss more than one dose in a week, the 
email/text reminders will continue further into dosing period. Since agent compliance is very important 
during the final week of the intervention, text/email messages will be sent to all study participants who 
opt to receive these reminders. 
 
The following information with be collected during the telephone calls: 
1. Medication compliance review. Participants will be asked if they missed any doses of medication, 
and the dates of all missed doses will be recorded. 
2. Concomitant medication review 
3. Adverse events. Participants will be asked if they have experienced any of the following 
symptoms to assess adverse events:  
a. Upper respiratory infections  
b. Headache 
c. Abdominal pain 
d. Constipation 
e. Nausea / Vomiting 


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4. Additional symptoms experienced by participants will be recorded to assess adverse events  
 
7.4 
Evaluation at Completion of Study Intervention 
 
7.4.1  Study Visit 3 
 
The final study visit will occur 6 months (± 1 month) after initiation of the intervention. Participants will 
be told to fast for 8 hours before the study visit. Fasting instructions will be provided to participants prior 
to their study visit, and participants will receive a phone call reminder the day before the visit to fast 
overnight. The following procedures will be performed during this visit: 
1. Review medical history, medications, and laboratory test results 
2. Physical exam including measurement of weight and symptom assessment 
3. Vital signs assessment: blood pressure, heart rate, respiratory rate, and oral temperature 
4. ECOG performance status 
5. Pregnancy test for women of child-bearing potential. Women who have had a hysterectomy, both 
ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
6. Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a Complete Blood Count and Automated Differential (CBDF), a Complete Metabolic Panel 
(CMPL), a Lipid Panel, and hemoglobin A1C to monitor for potential adverse effects of the 
intervention and to confirm that laboratory levels meet the eligibility requirements for 
continuation in the trial (See Appendix A). If lab results within 30 days prior to this visit for any 
of these tests are available in the medical record, the blood test(s) will not be done. 
7. Blood collection for research purposes (26 mL): 6 mL will be collected for measurement of 
protocol-specific biomarkers (serum concentrations of cytokines, chemokines, and adhesion 
molecules), and 20 mL will be banked for DNA extraction and future studies. 
8. Fecal specimen for measurement of fecal elastase. A stool collection kit and instructions will be 
provided to the participant before the scheduled visit. The specimen will be self-collected at 
home. The participant will receive a phone call reminder the day before the visit to collect the 
fecal specimen and bring it to the study visit. 
9. Interviewer-administered follow-up questionnaire to obtain information about changes in 
exposures and behaviors since the baseline visit, and to assess alcohol use and surgical 
procedures that will impact the risk of recurrent pancreatitis 
10. Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level 
11. Collect study agent and diary 
12. Assess compliance (pill count) 
13. Review study diary  
14. Assess adverse events 
15. Endoscopic pancreatic function test (ePFT) and simultaneous endoscopic ultrasound (EUS) and 
fasting pancreatic fluid to measure secretin-stimulated peak bicarbonate concentration; 
inflammatory cytokines, chemokines, and adhesion molecules 
 
7.5 
Post-intervention Follow-up Period 
 
Clinical research staff will make follow-up telephone calls to study participants on days 30 ± 7, 60 ± 7, 
and 90 ± 7 after completion of Study Visit 3 to assess symptoms and adverse events.  
 
7.6 
Methods for Clinical Procedures 


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Endoscopic pancreatic function test (ePFT) and simultaneous endoscopic ultrasound (EUS) and 
fasting pancreatic fluid. Patients will be instructed to fast overnight (8 hours) before the endoscopic 
testing. Instructions regarding preparing for the ePFT and the simultaneous EUS will be provided to the 
participants before each study measurement at Screen 2 and Study Visit 3 (6 months). 
Esophagogastroduodenoscopy (EGD), a simpler endoscopic procedure without the ultrasound imaging, 
will be performed at Study Visit 2 (3 months) in tandem with an ePFT. The ePFT/EUS (or ePFT/EGD) 
requires intravenous sedation with propofol that has a demonstrated safety profile [53]. A 6-mm 
ultrasound-adapted endoscope will be passed into the stomach and the duodenum. Experienced 
endoscopists will visualize the pancreas to determine the presence or absence of nine ductal and 
parenchymal criteria for chronic pancreatitis: hyperechoic foci, hyperechoic strands, cysts, lobularity, 
calcifications, hyperechoic duct margins, visual side branches, main pancreatic duct dilation, and main 
pancreatic duct irregularity, which sum to a score ranging from 0 to 9  (secondary endpoint) [32]. As soon 
as the EUS is completed, one of the trial gastroenterologists will perform the ePFT. The 
gastroenterologists are experienced with ePFT, and Drs. Afghani (CSMC) and Wu (KPMC) have written 
review articles on its validity and utility [32, 54]. Briefly, the ultrasound-adapted endoscope will be 
replaced with a standard endoscope and fluid from the stomach and duodenum will be removed by 
aspiration. A test dose of ChiRhoStim® human synthetic secretin 0.2 mcg (0.1 mL) is injected 
intravenously to test for possible allergies. After one minute, if there are no signs of allergic reaction, 
ChiRhoStim® at a dose of 0.2 mcg/kg of body weight is injected intravenously over 1 minute. Pancreatic 
fluid will be collected at five time points over one hour (at 0-10 minutes, 10-20 minutes, 20-30 minutes, 
30-45 minutes, and 45-60 minutes). Each collection will contain at least 3 mL of fluid, which is sufficient 
for analysis of peak bicarbonate concentration (primary endpoint) and cytokine concentrations (secondary 
endpoint). For each time point, 1.0 mL of pancreatic fluid will be placed into a plastic collection vial 
without preservatives and placed in wet ice. The samples will be transported to the designated processing 
lab for bicarbonate analysis. The remainder of the pancreatic fluid specimen will be stored for later assays 
of cytokines, chemokines, and adhesion markers (secondary endpoints). [55]. Immediately upon receipt 
of the pancreatic fluid, lab personnel will process the specimen as specified in the Laboratory Manual. 
Processed specimens will be stored in a -80o C freezer awaiting batch analysis. 
 
Fecal specimen. A stool collection kit and instructions regarding the collection of the fecal specimen will 
be provided to participants prior to their study visit. The fecal specimen will be self-collected at home and 
brought to the study visit. Participants will receive a phone call reminder the day before the visit to collect 
the fecal specimen and bring it to the study visit. The fecal specimen will be processed as specified in the 
Laboratory Manual and stored at -80oC.  
 
Blood specimen. A blood specimen (approximately 10 mL) will be collected from each participant at the 
Screen 2 visit for blood tests to confirm eligibility. A Complete Blood Count (CBC) and a 
Comprehensive Metabolic Panel (CMPL) will be done to confirm that laboratory levels for acceptable 
organ, hepatic, and renal function are within the eligibility requirements. See Appendix A for Clinical 
Laboratory Minimum Test Requirements. If a patient’s lab results within 35 days before the Screen 2 visit 
are available in the medical record and are within eligibility range, their blood will not be drawn at the 
Screen 2 visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. 
 
Approximately 36 mL of blood will be collected from each participant at Study Visits 1, 2, and 3 using a 
standard phlebotomy protocol. Fasting instructions will be provided to participants prior to their study 
visit, and participants will receive a phone call reminder the day before the visit to fast overnight (8 
hours). The date and time of the blood draw and of the participant’s last meal will be recorded.  
 
Approximately 10 mL of blood will be drawn for laboratory blood tests to monitor for potential adverse 
effects of the intervention and to confirm that laboratory levels meet the eligibility requirements for 
continuation in the trial. A fasting Lipid Panel will be done at all study visits. A CBDF and a CMPL will 


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be done at Study Visits 2 and 3. Fasting hemoglobin A1C will be measured at Study Visits 1 and 3. 
Creatine phosphokinase (CPK) will be measured at Study Visit 1. See Appendix A for Clinical 
Laboratory Minimum Test Requirements. 
 
The CMPL and CBDF test results will be utilized to screen for any issues that could be related to an 
adverse event or affect eligibility for the trial. CBDF and CMPL lab results from the Screen 2 eligibility 
visit will be used to establish patient-specific references prior to initiation of therapy. If blood tests were 
not done at the Screen 2 visit for a CBDF and CMPL; and lab results within 30 days prior to Study Visit 1 
for these tests are not available in the medical record, a CBDF and CMPL will be done at Study Visit 1. 
The Lipid Panel includes tests for cholesterol, high density lipoprotein cholesterol, low density 
lipoprotein cholesterol, and triglycerides. Since the study agent is a cholesterol lowering agent, we feel 
that it is important to establish baseline lipid levels prior to initiating the study agent (Study Visit 1) and 
to monitor lipids at subsequent study visits. Hemoglobin A1C is used to assess glucose control in insulin-
dependent diabetics whose glucose levels are very labile and in whom single blood glucose measurements 
may not accurately reflect the level of control present over the preceding few weeks. Glucose and 
hemoglobin A1C will be used to establish a baseline (Study Visit 1) for monitoring adverse events 
(incident diabetes) during the trial. CPK will be tested to establish a baseline for monitoring myopathy, a 
rare complication associated with the study agent (<1%). CPK will be measured at Study Visit 1 to 
establish a patient-specific reference for this indicator of muscle toxicity. If the participant reports 
unexplained muscle pain or weakness during the trial, CPK will be tested again to check for elevation. 
 
Twenty-six mL of blood will be collected for research purposes. Six mL of blood will be drawn into a red 
top serum vacutainer tube for measurement of protocol-specific biomarkers (cytokines, chemokines, and 
adhesion molecules). Twenty mL of blood will be drawn into three vacutainer tubes, including one 6 mL 
red top serum tube and two 7 mL lavender top EDTA tubes, for DNA extraction and use in future studies. 
The blood will be collected and processed as specified in the Laboratory Manual. Processed specimens 
will be stored at -80oC. 
 
Biomarkers. Pancreatic fluid will be analyzed for secretin-stimulated peak bicarbonate levels. Study 
assays for blood and pancreatic fluid concentrations of cytokines, chemokines, and adhesion 
moleculeswill be performed in Dr. Pandol’s laboratory at CSMC. Inflammatory cytokines will be 
measured in pancreatic fluid collected 30 minutes after secretin stimulation and in serum samples 
collected at each visit using our Luminex-based MAGPIX multiplexing analysis system in Dr. Pandol’s 
lab using methods previously described [36].  
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
The overall objective of this trial is to examine the effect of simvastatin use versus placebo at 6 months 
from baseline (Study Visit 1) on pancreatic function and inflammatory mediators in patients with 
recurrent acute pancreatitis (at least two episodes of acute pancreatitis in the past 12 months). Participants 
will be on the study drug from Study Visit 1 until the last study visit (Study Visit 3 at 6 months) when the 
final endoscopic procedure will be performed. Primary and secondary endpoints are measured in 
specimen samples taken after 8 hours of fasting. 
 
8.1 
Primary Endpoint 
 
Primary: To measure changes in pancreas exocrine function (secretin-stimulated peak bicarbonate 
concentration in the pancreatic fluid) as measured by the endoscopic pancreatic function test (ePFT). We 
hypothesize that participants randomized to simvastatin will experience a greater increase from baseline 
in peak bicarbonate concentration measured at 6 months from baseline compared to the placebo group. 
 


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8.2 
Secondary Endpoints 
 
8.2.1  To measure changes in endoscopic ultrasound score (EUS), a measure of pancreatitis. We 
hypothesize that compared to the placebo group participants randomized to simvastatin will experience a 
greater reduction from baseline in EUS score. 
 
8.2.2  To measure changes in serum and pancreatic secretions of the following targets: interleukins (IL; 
1α, 1β, 1RΑ, 2, 4, 5, 6, 7, 8, 9, 10, 12p40, 12p70, 13, 15, 17A, 17F, 18, 21, 22, 27, 23, 31), 
BDNF, CD40L, EGF, ENA78, Eotaxin, FASL, FGFβ,  GCSF, GMCSF, GROA, HGF, ICAM1, 
IFNα, IFNβ, IFNγ, IP10, LIF, Leptin, MCP1, MCP3, MCSF, MIG, MIP1α, MIP1β, PDGFβ, PIGF1, 
NGF, Rantes, Resistin, PAI1, SCF, SDF1α, TGFα, TGFβ,  TNFα, TNFβ, TRAIL, VCAM1, 
VEGF, VEGFD. . We hypothesize that participants randomized to simvastatin will experience a greater 
decrease in pro-inflammatory markers and a greater increase in anti-inflammatory markers. 
 
8.2.3  To assess changes in pancreatitis-related readmissions. We hypothesize that participants 
randomized to simvastatin will experience fewer episodes of pancreatitis-related readmissions. A 
pancreatitis-related readmission will be defined as a hospital readmission that is due to complications 
from the previous pancreatitis episode, as determined by a physician; or an independent episode of acute 
pancreatitis defined by at least two of the following 1) Typical upper abdominal pain; 2) Elevation in 
serum amylase or lipase ≥3 times ULN; 3) Features of acute pancreatitis on cross-sectional imaging. 
Source documents include: 1) lipase or amylase levels; 2) physician notes; 3) imaging results. 
 
8.2.4 
To assess changes in quality of life measures using the QLQ-C30 and QLQ-PAN28(CP). We 
hypothesize that participants randomized to simvastatin will experience improvement in quality of life 
scores.  
 
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, noncompliance, 
concomitant medications, or medical contraindication. Participants who experience complications of 
pancreatitis or develop intercurrent pancreatitis during the study will be instructed to continue taking the 
study agent unless they are unable to take oral medications. The study agent will be resumed as soon as 
they are able to tolerate oral medications. Participants will continue to be followed, if possible, for safety 
reasons and in order to collect endpoint data according to the schedule of events.  
 
As described in section 7.5, clinical research staff will make follow-up telephone calls to the participants 
on days 30 ± 7, 60 ± 7, and 90 ± 7 after the participant discontinues the study agent to assess symptoms 
and adverse events. Standard of care data (medical history, laboratory test results, concomitant 
medications, imaging results) will continue to be collected via review of the participant’s electronic 
medical record at the time points specified in the Schedule of Time and Events. If feasible, we will 
conduct a research visit to collect final measurements for participants who permanently discontinue the 
study agent early. An end-of-study research visit will be conducted 6 months after initiation of the statin 
intervention (Study Visit 3). The blood collections for clinical labs and banked samples future research, 
and the follow-up risk questionnaire will not be done. The following procedures will be performed during 
the end-of-study visit: 
1. Review medical history, medications, and laboratory test results 
2. Vital signs assessment, measurement of weight, and symptom assessment 
3. ECOG performance status 


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4.  Pregnancy test for women of child-bearing potential. Women who have had a hysterectomy, both 
ovaries removed, or a tubal ligation will not be required to have a pregnancy test. 
5.  Blood collection for measurement of protocol-specific biomarkers (6 mL): serum concentrations 
of the following targets: interleukins (IL; 1α, 1β, 1RΑ, 2, 4, 5, 6, 7, 8, 9, 10, 12p40, 12p70, 
13, 15, 17A, 17F, 18, 21, 22, 27, 23, 31), BDNF, CD40L, EGF, ENA78, Eotaxin, FASL, 
FGFβ,  GCSF, GMCSF, GROA, HGF, ICAM1, IFNα, IFNβ, IFNγ, IP10, LIF, Leptin, 
MCP1, MCP3, MCSF, MIG, MIP1α, MIP1β, PDGFβ, PIGF1, NGF, Rantes, Resistin, 
PAI1, SCF, SDF1α, TGFα, TGFβ,  TNFα, TNFβ, TRAIL, VCAM1, VEGF, VEGFD. 
6. Fecal specimen for measurement of fecal elastase. A stool collection kit and instructions will be 
provided to the participant before the scheduled visit. The specimen will be self-collected at 
home. 
7. Self-administered QLQ-C30 and QLQ-PAN28(CP) to assess quality of life and pain level. 
8. Endoscopic pancreatic function test (ePFT) and simultaneous endoscopic ultrasound (EUS) and 
fasting pancreatic fluid to measure secretin-stimulated peak bicarbonate concentration; and 
concentrations of the following targets: interleukins (IL; 1α, 1β, 1RΑ, 2, 4, 5, 6, 7, 8, 9, 10, 
12p40, 12p70, 13, 15, 17A, 17F, 18, 21, 22, 27, 23, 31), BDNF, CD40L, EGF, ENA78, 
Eotaxin, FASL, FGFβ,  GCSF, GMCSF, GROA, HGF, ICAM1, IFNα, IFNβ, IFNγ, IP10, 
LIF, Leptin, MCP1, MCP3, MCSF, MIG, MIP1α, MIP1β, PDGFβ, PIGF1, NGF, Rantes, 
Resistin, PAI1, SCF, SDF1α, TGFα, TGFβ,  TNFα, TNFβ, TRAIL, VCAM1, VEGF, 
VEGFD. 
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons:  
 
Adverse Event 
 
Death  
 
Disease Progression 
 
Lost to follow-up/Participant Withdrawal 
 
Participant Refused Follow-up 
 
Physician Decision 
 
Protocol Defined Follow-up Completed 
 
Protocol Violation   
 
Study Complete  
 
Ineligible 
 
Other  
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
Endoscopic pancreatic function test: The current gold standard for diagnosing chronic pancreatitis is the 
endoscopic pancreatic function test (ePFT) which measures secretin-stimulated production of bicarbonate 
ion from pancreatic ductal cells during an endoscopic ultrasound procedure (EUS) [3, 32]. Clinically, 
ePFT-based peak bicarbonate levels can distinguish mild and severe chronic pancreatitis, and is correlated 
with the extent of histologically determined fibrosis (r=-0.57) [33]. Because ePFT is based on an 
endoscope-guided collection of pure pancreatic fluid, it provides a direct measurement of pancreatic 


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function that is superior to indirect measurements in stool i.e., fecal elastase [34]. 
 
Endoscopic ultrasound: The endoscopic ultrasound is an imaging tool for evaluating the presence or 
absence of nine ductal and parenchymal criteria for chronic pancreatitis: hyperechoic foci, hyperechoic 
strands, cysts, lobularity, calcifications, hyperechoic duct margins, visual side branches, main pancreatic 
duct dilation, and main pancreatic duct irregularity, which sum to a score ranging from 0 to 9 [32]. It is 
the current standard of care imaging method for determining the extent of chronic pancreatitis.  
 
Immunological cytokines and C-reactive protein: A panel of immunological cytokines will be measured 
to evaluate the effect of statin on immune profiling markers in the pancreatic fluid and in the blood. We 
will use the MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel- Immunology 
Multiplex to measure interleukins (IL; 1α, 1β, 1RΑ, 2, 4, 5, 6, 7, 8, 9, 10, 12p40, 12p70, 13, 15, 
17A, 17F, 18, 21, 22, 27, 23, 31), BDNF, CD40L, EGF, ENA78, Eotaxin, FASL, FGFβ,  GCSF, 
GMCSF, GROA, HGF, ICAM1, IFNα, IFNβ, IFNγ, IP10, LIF, Leptin, MCP1, MCP3, MCSF, MIG, 
MIP1α, MIP1β, PDGFβ, PIGF1, NGF, Rantes, Resistin, PAI1, SCF, SDF1α, TGFα, TGFβ,  
TNFα, TNFβ, TRAIL, VCAM1, VEGF, and VEGFD. 
 
9.2 
Comparable Methods 
 
Proposed methods represent standard technology for measuring the study biomarkers. 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
1) Study blood tests will be done for a Complete Blood Count and Automated Differential (CDF), a 
Complete Metabolic Panel (CMPL), a Lipid Panel, hemoglobin A1C, and creatine phosphokinase 
(CPK) at the clinical laboratories at each study site; or the blood tests will be done at an external 
CLIA-certified clinical laboratory as required by the participant’s health insurance carrier.  
 
2) Measurement of bicarbonate concentrations in pancreatic fluid will be performed by Cedars-Sinai 
Department of Pathology and Laboratory Medicine. 
 
3) Study assays for blood and pancreatic fluid concentrations of interleukins (IL; 1α, 1β, 1RΑ, 2, 4, 5, 
6, 7, 8, 9, 10, 12p40, 12p70, 13, 15, 17A, 17F, 18, 21, 22, 27, 23, 31), BDNF, CD40L, 
EGF, ENA78, Eotaxin, FASL, FGFβ,  GCSF, GMCSF, GROA, HGF, ICAM1, IFNα, IFNβ, 
IFNγ, IP10, LIF, Leptin, MCP1, MCP3, MCSF, MIG, MIP1α, MIP1β, PDGFβ, PIGF1, 
NGF, Rantes, Resistin, PAI1, SCF, SDF1α, TGFα, TGFβ,  TNFα, TNFβ, TRAIL, 
VCAM1, VEGF, and VEGFDwill be performed in the Stanford Human Immune Monitoring 
Core (HIMC). The lab is equipped with a Luminex MAGPIX multiplexing system which will be 
used in combination with specific antibody based magnetic bead assays to measure each of the 
analytes.  
 
10.2 
Collection and Handling Procedures 
 
Research study staff at participating study sites will receive specific instructions for collection, 
processing, and shipment of specimens.  
 
Endoscopic pancreatic function test (ePFT) for collection of fasting pancreatic fluid.  
Instructions regarding the endoscopic procedures (Esophagogastroduodenoscopy (EGD) or endoscopic 


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ultrasound (EUS)) and the collection of fasting pancreatic fluid will be given to participants prior to their 
study visit. Subjects will be instructed to fast overnight (8 hours) before the testing. Briefly, the 
ultrasound-adapted endoscope will be replaced with a standard endoscope and fluid from the stomach and 
duodenum will be removed by aspiration. A test dose of ChiRhoStim® human synthetic secretin 0.2 mcg 
(0.1 mL) is injected intravenously to test for possible allergies. After one minute, if there are no signs of 
allergic reaction, ChiRhoStim® at a dose of 0.2 mcg/kg of body weight is injected intravenously over 1 
minute. Pancreatic fluid will be aspirated from the descending duodenum at five time points over one 
hour (at 0-10 minutes, 10-20 minutes, 20-30 minutes, 30-45 minutes, and 45-60 minutes) following 
hormonal stimulation. Each collection will contain at least 3 mL of pancreatic fluid, which is sufficient 
for analysis of peak bicarbonate concentration (primary endpoint) and cytokine, chemokine, adhesion 
molecule concentrations (secondary endpoint). For each time point, 1.0 mL of pancreatic fluid will be 
placed into a plastic collection vial without preservatives and placed in wet ice. The samples will be 
transported to the designated processing lab for bicarbonate analysis. The remainder of the pancreatic 
fluid specimen will be stored for later assays of cytokines, chemokines, and adhesion molecules. 
Immediately upon receipt of the pancreatic fluid, lab personnel will process the specimen as specified in 
the Laboratory Manual. Processed specimens will be stored in a -80o C freezer awaiting batch analysis. 
 
Fecal specimen. A stool collection kit that includes instructions and supplies for collecting the fecal 
sample at home will be provided to participants prior to their study visit. The fecal specimen will be self-
collected at home and brought to the study visit. Participants will receive a phone call reminder the day 
before the visit to collect the fecal specimen and bring it to the study visit. The fecal specimen will be 
processed as specified in the Laboratory Manual and stored at -80oC. .  
 
Blood specimen. A blood specimen (approximately 10 mL) will be collected from each participant at the 
Screen 2 visit for blood tests to confirm eligibility. A Complete Blood Count (CBC) and a 
Comprehensive Metabolic Panel (CMPL) will be done to confirm that laboratory levels for acceptable 
organ, hepatic, and renal function are within the eligibility requirements. See Appendix A for Clinical 
Laboratory Minimum Test Requirements. If a patient’s lab results within 35 days before the Screen 2 visit 
are available in the medical record and are within eligibility range, their blood will not be drawn at the 
Screen 2 visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. 
 
Approximately 36 mL of blood will be collected from each participant at Study Visits 1, 2, and 3 using a 
standard phlebotomy protocol. Fasting instructions will be provided to participants prior to their study 
visit, and participants will receive a phone call reminder the day before the visit to fast overnight (8 
hours). The date and time of the blood draw and of the participant’s last meal will be recorded.  
 
Approximately 10 mL of blood will be drawn for laboratory blood tests to monitor for potential adverse 
effects of the intervention and to confirm that laboratory levels meet the eligibility requirements for 
continuation in the trial. A fasting Lipid Panel will be done at all study visits. A CBDF and a CMPL will 
be done at Study Visits 2 and 3. If blood tests were not done at the Screen 2 visit for a CBDF and CMPL; 
and lab results within 30 days prior to Study Visit 1 for these tests are not available in the medical record, 
a CBDF and CMPL will also be done at Study Visit 1. Fasting Hemoglobin A1C will be measured at 
Study Visits 1 and 3. Creatine phosphokinase (CPK) will be measured at Study Visit 1. See Appendix A 
for Clinical Laboratory Minimum Test Requirements. 
 
Twenty-six mL of blood will be collected for research purposes. Six mL of blood will be drawn into a red 
top serum vacutainer tube for measurement of protocol-specificinterleukins (IL; 1α, 1β, 1RΑ, 2, 4, 5, 
6, 7, 8, 9, 10, 12p40, 12p70, 13, 15, 17A, 17F, 18, 21, 22, 27, 23, 31), BDNF, CD40L, EGF, 
ENA78, Eotaxin, FASL, FGFβ,  GCSF, GMCSF, GROA, HGF, ICAM1, IFNα, IFNβ, IFNγ, IP10, 
LIF, Leptin, MCP1, MCP3, MCSF, MIG, MIP1α, MIP1β, PDGFβ, PIGF1, NGF, Rantes, Resistin, 


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PAI1, SCF, SDF1α, TGFα, TGFβ,  TNFα, TNFβ, TRAIL, VCAM1, VEGF, and VEGFD. Twenty 
mL of blood will be drawn into three vacutainer tubes, including one 6 mL red top serum tube and two 7 
mL lavender top EDTA tubes, for DNA extraction and use in future studies. The blood will be collected 
and processed as specified in the Laboratory Manual. Processed specimens will be stored at -80oC for 
later measurement of cytokine concentrations, DNA extraction, and use in future studies. 
 
10.3 
Shipping Instructions 
 
Blood samples for laboratory blood tests (Complete Blood Count and Automated Differential (CBDF), 
Complete Metabolic Panel (CMPL), Lipid Panel, hemoglobin A1C, and creatine phosphokinase (CPK)) 
will be transported to the clinical laboratories at each study site for processing; or the blood will be drawn 
and processed at an external CLIA-certified clinical laboratory as required by the participant’s health 
insurance carrier. 
 
Blood samples for research, pancreatic fluid samples, and fecal specimens collected at CSMC, UP, and 
SU will be transported to the designated laboratories at the respective study site for processing. All 
samples collected at KPMC will be delivered via courier to CSMC immediately after collection for 
processing. KPMC research blood samples may be processed at KPMC or at CSMC. If processed at 
KPMC, the processed aliquots will be couriered to CSMC with the pancreatic fluid samples and fecal 
specimens. 
 
CSMC Laboratories 
Blood samples collected for research will be transported to the Cedars Sinai Clinical and Translational 
Research Center (CTRC) Laboratory for processing. 
Clinical and Translational Research Center (CTRC) Laboratory 
Steven Spielberg Building, Room 280 
8723 Alden Drive 
Los Angeles, CA 90048 
Telephone: 310-423-7445 
 
Pancreatic fluid samples and fecal specimens collected at CSMC and KPMC will be transported to Dr. 
Pandol’s laboratory at CSMC. Personnel in the Pandol Laboratory will prepare all samples for analyses.  
Pandol Laboratory, Attn: Richard Waldron, Ph.D. 
Cedars-Sinai Medical Center 
110 N. George Burns Rd. 
Davis Building, Room 3096 
Los Angeles, CA 90048 
Telephone: 310-423-4731 
E-mail: Richard.Waldron@cshs.org 
 
The Pandol Laboratory will aliquot pancreatic fluid samples for measurement of bicarbonate levels. The 
pancreatic fluid samples will be transported to the Cedars Sinai Clinical Laboratory for bicarbonate 
analysis. 
Cedars-Sinai Department of Pathology and Laboratory Medicine 
8700 Beverly Blvd., Room 8725 
Los Angeles, CA 90048  
Telephone: 310-423-5431 
  
The Pandol Laboratory will package and ship serum and pancreatic fluid samples to the Stanford Human 
Immune Monitoring Center (HIMC) for assays of cytokines, chemokines, and adhesion molecules.  
Holden T. Maecker, PhD 


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Director, Human Immune Monitoring Center (HIMC) 
phone: +1.650.723.1671 
email: maecker@stanford.edu 
Stanford School of Medicine 
Fairchild Science Bldg, D039 
299 Campus Drive 
Stanford, CA 94305-5124 
fax: +1.650.498.7495 
 
UP Research Laboratory  
Kim Stello, Lab Manager and Sample Processing 
841 Scaife Hall 
3550 Terrace Street 
Pittsburgh, PA 15261 
Telephone: 412-648-8060 
 
SU Research Laboratory  
Peili Hsu, Acting Manager 
Clinical and Translational Research Unit (CTRU) lab 
Freidenrich Center for Translational Research 
800 Welch Road 
Palo Alto, CA 94305 
Telephone: 650-724-1175 
 
All leftover research blood samples, pancreatic fluid samples, and fecal samples collected and processed 
at UP and SU will be shipped to CSMC at end of trial. Shipping address for CSMC specimen manager: 
Geoffrey Houghton, MSc. 
Clinical Research Specialist, Prevention and Control 
Samuel Oschin Comprehensive Cancer Institute 
Cedars-Sinai Medical Center 
Davis Building, Room 3096 
8700 Beverly Blvd. 
Los Angeles, CA 90048 
Telephone: 310-423-9670 
Cellular: 310-384-8281 
E-mail: Geoffrey.Houghton@cshs.org 
 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. Cedars-Sinai will send a quarterly manifest of specimens collected and/or 
received to the Northwestern Cancer Prevention Consortium (NCPC).  
 
10.4 
Tissue Banking 
 
Leftover pancreatic fluid, tissue, and fecal samples will be stored and maintained for future research. 
Banked samples for use in future research will include blood (20 mL collected from the participant at 
each visit), and surplus pancreatic fluid, tissue, and fecal samples leftover after all study analyses are 
completed. Future research may include: 1) studies to identify genes and/or biomarkers and proteins that 
influence an individual’s risk of getting pancreatitis, pancreatic cancer, or other diseases; 2) studies to 
identify specific pathways and mechanisms that promote pancreatic cancer. All banked specimens will be 
coded with the unique Biobank subject identifier and stored in -80°C freezers located in the Shuman 
Basement of the Davis Research Building at CSMC.  


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Appropriate administrative, physical, and technical safeguards are in place to ensure the confidentiality, 
integrity, and security of the banked specimens. Investigators with future IRB approved studies who are 
approved to receive specimens will not be given access to any information that can establish the identity 
of the donor. All data and specimens sent to approved investigators will be coded and de-identified, and 
will contain no direct identifiers. The data will always be published using aggregate statistics and no 
participant will be identified in any reports or publications. 
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course 
of the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.  
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported 
as AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up 
further for a final determination, if possible. 
 
A list of AEs that have occurred or might occur can be found in §6.2 Reported Adverse Events and 
Potential Risks, as well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and Study Visit 1 (baseline) assessments are 
completed must be recorded on the AE CRF (paper and/or electronic) whether or not related to study 
agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for adverse event reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a serious adverse event (SAE) 


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• 
Whether or not the subject dropped due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
 
 
11.1.3.1 Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive terminology 
(MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE can be found 
at http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
AEs will be assessed according to the grade associated with the CTCAE AE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the adverse event is related to study agent will be classified as one of the following: 
not related, unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such. Adverse Events which occur in 
participants who are screened but not enrolled in the study will be followed for one week.  
 
11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 


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• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital abnormality or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization should also be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require intervention to prevent one of the 
other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE 
Report Form found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 
11.2.2.2 Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.  
 
DCP Medical/Task Order Monitor  
Luz Maria Rodriguez, MD, FACS  
NCI/Division of Cancer Prevention  
9609 Medical Center Dr.  
Rm 5E-228  
Bethesda, MD 20892 
Telephone (240) 276-7039  
Fax (240) 276-7848  
Email: rodrigul@mail.nih.gov 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug and expectedness 
 
11.2.2.3 The Lead Organization and all Participating Organizations will email written SAE reports to 
the following within 48 hours of learning of the event using the fillable PDF SAE Report Form.  
• 
DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com 
• 
NCI DCP Medical Monitor, Dr. Luz Rodriguez (rodrigul@mail.nih.gov) 
• 
Northwestern Cancer Prevention Consortium (ncpc@northwestern.edu) 
  
11.2.2.4 The DCP Medical Monitor and CCSA regulatory staff will determine which SAEs require 
FDA submission as IND safety reports. 
 


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11.2.2.5 The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.3 Follow-up of SAE 
 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available. All SAEs will be followed according to standard 
of care. SAEs possibly, probably, or definitely related to the study agent will be followed until resolved.  
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
Data will be managed by the study statistician, Dr. Jovanovic, according to standard operating procedures, 
which meet the guidelines of DCP Requirements for Data Management and which follow the Data 
Management Plan that Northwestern University has on file with the Division of Cancer Prevention, NCI. 
Source data verification will be performed by the Northwestern Cancer Prevention Consortium. The 
Consortia 2012 Data Management Plan, submitted as part of a contract agreement with the NCI 
(HHSN261201200035I), was approved.  
 
Clinical data will be reported to Northwestern University through the Lurie Cancer Center Clinical Trials 
Management System (CTMS), which will be the database of record.  
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRFs) developed from the 
standard set of DCP Chemoprevention CRF Templates and utilizing NCI-approved Common Data 
Elements (CDEs). The approved CRFs will be used by Northwestern University to create the electronic 
CRFs (e-CRFs) screens in the CTMS-RDC application. Site staff will enter data into the e-CRFs for 
transmission to DCP according to DCP standards and procedures. 
 
All specimen results that are batch analyzed will be collected and stored on excel spreadsheets. The excel 
spreadsheets will constitute the database of record.  
 
12.3 
Source Documents 
 
All source documents will be collected and stored by the research staff at the site of accrual. Any data 
recorded directly in CTMS that constitute no prior written or electronic record of data, will be specifically 
identified as source data. Quality of Life questionnaires completed in person may be completed on the 
paper and entered into CTMS.  
 
12.4 
Data and Safety Monitoring Plan 
 
A comprehensive Data Safety and Monitoring Plan has been submitted by Northwestern University, 
approved by the DCP, and is on file there. Any future changes will be forwarded for review.  
 
This trial is subject to review by the Lurie Cancer Center Data Monitoring Committee (DMC). Semi-
Annual reports, SAEs, and protocol deviations will be reviewed by the DMC at bi-weekly meetings. This 
trial is also subject to possible annual audits by the Lurie Cancer Center Clinical Trials Audit Committee 
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12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New 
Drug Application (NDA). For NCI/DCP, records will be retained for at least three years after the 
completion of the research. NCI will be notified prior to the planned destruction of any materials. The 
records should be accessible for inspection and copying by authorized persons of the Food and Drug 
Administration. If the study is done outside of the United States, applicable regulatory requirements for 
the specific country participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
The agent(s) supplied by DCP, NCI, used in this protocol, is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as Collaborator(s)) and the NCI Division of Cancer Prevention. Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator@ 
contained within the terms of award, apply to the use of Agent(s) in this study: 
 
12.7.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational agents contain confidential 
information and should not be shared or distributed without the permission of the NCI. If a patient 
participating on the study or participant’s family member requests a copy of this protocol, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from the DCP 
website. 
 
12.7.2 For a clinical protocol where there is an Investigational Agent used in combination with (an) 
other investigational Agent(s), each the subject of different collaborative agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-party Data”). 
 
12.7.3 NCI must provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination protocol, 
and the existence of any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 


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12.7.4 Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational agent. 
 
12.7.5 Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational agent. 
 
12.7.6 Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. All data made 
available will comply with HIPAA regulations. 
 
12.7.7 When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators of Collaborator's wish to contact them. 
 
12.7.8 Any manuscripts reporting the results of this clinical trial must be provided to DCP for immediate 
delivery to Collaborator(s) for advisory review and comment prior to submission for publication. 
Collaborator(s) will have 30 days (or as specified in the CTA) from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in 
order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to DCP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to DCP prior to release. Copies of any 
manuscript, abstract, and/or press release/ media presentation should be sent to the Protocol Information 
Office at NCI DCP PIO@mail.nih.gov.  
 
 
 
 
The Protocol Information Office will forward manuscripts to the DCP Project Officer for distribution to 
the Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
This is a phase II randomized, double-blinded, placebo-controlled trial of statin to evaluate the impact of 
statin treatment on pancreatic function and inflammation implicated in pancreatic carcinogenesis in 
patients with recurrent acute pancreatitis. The primary objective of this study will be to demonstrate that 
statins will improve pancreatic function in high-risk patients, as defined by those with two or more 
episodes of acute pancreatitis in the past 12 months. 
 
The primary outcome for this study is change from baseline (Study Visit 1) at 6 months of peak 
bicarbonate concentration as measured by ePFT. Sample size calculations follow from computations 
PASS 11 (www.ncss.com). Means and standard deviations of peak bicarbonate concentrations are derived 
from the literature on the validity and utility of ePFT for diagnosis of chronic pancreatitis [56, 57]. We 
expect baseline peak bicarbonate levels to be 60 mEq/L in these patients with recurrent pancreatitis, with 
a standard deviation of 13 mEq/L. We expect the peak bicarbonate levels to increase in both simvastatin 
and placebo groups as the groups recover from the acute pancreatitis event, with the simvastatin group 
showing a greater increase to full recovery compared to the placebo group. An analytic sample size of 24 
(after 20% drop out) will have 82% power to detect a statistically significant one-sided difference of 15 
mEq/L (25 vs. 10 mEq/L) at an alpha level of 0.05. The anticipated changes are well within the range of 


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peak bicarbonate levels of patients with mild to severe pancreatitis [56, 57] whose median peak 
bicarbonate levels range from 40 mEq/L to 100 mEq/L.  
 
13.2 
Randomization/Stratification  
 
Patients will be randomized by the study statistician at Northwestern University. Randomization will be 
carried out among consented patients meeting the Screen 2 eligibility criteria at each study site with a 2:1 
ratio for simvastatin and placebo assignment. 
 
13.3 
Accrual and Feasibility 
 
Sample size: Intervention = 30 (20:10) randomized sample; after 20% drop out = 24 (16:8) analytic sample. 
The expected accrual rate is 1-2 participants per month across four study sites, and the planned recruitment 
duration is 24 months. We anticipate that all evaluable participants will have completed all study procedures 
within three years. Power and precision arguments are provided below. 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary outcome for this study is change from baseline (Study Visit 1) at 6 months of peak 
bicarbonate concentration as measured by ePFT. For the primary endpoint, we will consider differences 
D(T) and D(P) for D=After-Before, for Treatment and Placebo (Control) groups respectively. Then we 
will use a nonparametric two-sample Wilcoxon-Mann-Whitney test to address the hypothesis H0: mean 
[D (T)] =mean [D (P)] versus H1: mean[D(T)] > mean[D(P)], and report a one-sided p-value, as 
presented in Table 3. If p<0.05 we will consider this to be evidence of activity in the simvastatin group. 
Table 3. Numeric Results for Mann-Whitney Test (Uniform Distribution) 
Power 
N1 
N2 
Ratio 
Alpha 
Beta 
Mean1 
Mean2  
S1 
S2 
0.82 
16 
8 
0.5 
0.05 
0.18 
25 
10 
13 
13 
Null Hypothesis: Mean1=Mean2. Alternative Hypothesis: Mean1>Mean2. 
The standard deviations were assumed to be equal at 13 mEq/L. 
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
For secondary endpoints, we will consider D(T) and D(P) as well as percent change relative to baseline as 
well, namely, D (T)/B (T) and D (P)/B (P). For all secondary variables, we will use descriptive statistics 
and graphics at 3 months and at 6 months, as well as study random effects regression trends along the 
timeline Baseline  3 months  6 months for further hypotheses generation. In particular, we will look 
into cytokines, chemokines, and adhesion molecules and quality of life scores from the QLQ-C30 and 
QLQ-PAN28(CP) assessment after possible log-transformation of continuous data. In particular, we will 
be interested in the relation between a) pairs of secondary variables and differences D=After-Before in 
pairs of secondary variables in the Treatment group, b) same as a) but in the control group, c) comparing 
pairwise changes between the Treatment and the Control groups, and d) relationship of secondary 
outcomes with recurrent pancreatitis. In this way, we will be able to study co-dependence among various 
secondary variables and their possible relationship with recurrent pancreatitis. We will thus fit various 
regression models, estimate relevant parameters (e.g., intercept, slope) and explore the apparent 
magnitudes of change in these parameters in the treatment and the control group.  
 
Analyses will be performed with Stata software. All analyses will be conducted on an intention to treat 
basis (all randomized participants will be included in the assigned group) and will begin with univariate 
cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step 
to possible model building. We will not control for overall Type I error due to small number of 


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observations and the preliminary nature of the study. 
 
13.6 
Reporting and Exclusions 
 
We anticipate some contamination from the simvastatin intervention to placebo due to non-compliance. 
We do not expect cross-over from the placebo to statin group as participants will be aware that they might 
be on statins already and would not want to jeopardize their safety and care. However, new clinical 
guidelines for prescription of statins may also influence drop-outs among participants who wish to reduce 
the risk of cardiovascular disease [58]. These guidelines recommend targeting men and women with 
cardiovascular disease, LDL cholesterol ≥ 190 mg/dL, and persons 40-75 years with diabetes or a 10-year 
cardiovascular disease risk ≥ 7.5%. Most of these people would not meet the eligibility criteria for study 
participation. The drop-out rate is expected to be 4 subjects in the treatment arm and 2 subjects in the 
placebo arm at 6 months follow-up. 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of simvastatin. 
 
13.8 
Evaluation of Response 
 
Changes in peak bicarbonate concentration as measured by ePFT will be evaluated for all randomized 
participants. 
 
13.9 
Interim Analysis 
 
There will be no planned interim analyses.  
 
13.10 Ancillary Studies 
 
N/A 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) 
will provide a signed Form FDA 1572 stating that the study will be conducted in compliance with 
regulations for clinical investigations and listing the investigators, at each site that will participate in the 
protocol. All personnel directly involved in the performance of procedures required by the protocol and 
the collection of data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 


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14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all 
Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form 
FDA 1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by 
the IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. 
The investigator will explain all aspects of the study in lay language and answer all questions regarding 
the study. If the participant decides to participate in the study, he/she will be asked to sign and date the 
Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document 
or may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for 
Research is available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
the Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior 
to initiation. 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for 
completeness and accuracy. Once the Consortia Lead Organization has received complete and accurate 
documents from a participating organization, the Consortium Lead Organization will forward the 
regulatory documents to DCP’s Regulatory Contractor: 


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Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place, Suite 350 West 
 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the 
Consortium Lead Organization for review, which will then be electronically forwarded to DCP’s 
Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
All research related costs associated with participating in this study will be paid for, and will not be the 
responsibility of the participant. Individuals will receive $50 for completing the Screen 2 testing and $150 
at the completion of each visit for their time, transportation, parking, and other expenses related to the 
study. Subjects who complete the entire study – the Screen 2 testing, baseline testing (Study Visit 1), and 
two follow-up visits (Study Visits 2 and 3) – will receive $500. Subjects will be paid only for the visits 
they complete.  
 
It is possible that a research injury or illness may result from participating in this study. Subjects being 
treated for a research injury or illness will not pay for the costs of care provided by Cedars-Sinai Medical 
Center (CSMC); Kaiser Southern California Permanente Medical Group (KPMC); the University of 
Pittsburgh (UP); or Stanford University (SU); or in any emergency room provided that they are being 
treated for a research injury or illness. If a subject chooses to obtain non-emergency care elsewhere, the 
costs of that care will be the responsibility of the study participant and/or their health insurance carrier. 
Losses such as lost wages will not be paid. 
 


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41. Shakespear MR, Halili MA, Irvine KM, et al. Histone deacetylases as regulators of inflammation and 
immunity. Trends Immunol 2011;32(7):335-43. 
42. von Burstin J, Eser S, Paul MC, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and 
is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 2009;137(1):361-
71, 371 e1-5. 
43. Bolomini-Vittori M, Montresor A, Giagulli C, et al. Regulation of conformer-specific activation of 
the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat Immunol 2009;10(2):185-
94. 
44. Jaster R, Brock P, Sparmann G, et al. Inhibition of pancreatic stellate cell activation by the 
hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin. Biochem Pharmacol 
2003;65(8):1295-303. 
45. Wu BU, Pandol SJ, Amy Liu IL. Simvastatin is associated with reduced risk of acute pancreatitis: 
findings from a regional integrated healthcare system. Gut 2014; 10.1136/gutjnl-2013-306564. 


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46. Uomo G, Gallucci F, Madrid E, et al. Pancreatic functional impairment following acute necrotizing 
pancreatitis: long-term outcome of a non-surgically treated series. Dig Liver Dis 2010;42(2):149-52. 
47. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of the 
Atlanta classification and definitions by international consensus. Gut 2013;62(1):102-11. 
48. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst 1993;85(5):365-76. 
49. Fitzsimmons D, Kahl S, Butturini G, et al. Symptoms and quality of life in chronic pancreatitis 
assessed by structured interview and the EORTC QLQ-C30 and QLQ-PAN26. Am J Gastroenterol 
2005;100(4):918-26. 
50. European Organisation for Research and Treatment of Cancer (EORTC). Pancreatic Cancer (EORTC 
QLQ-PAN26). April 23, 2015. http://groups.eortc.be/qol/pancreatic-cancer-eortc-qlq-pan26. 
51. Stevens T, Conwell DL, Zuccaro G, Jr., et al. A randomized crossover study of secretin-stimulated 
endoscopic and dreiling tube pancreatic function test methods in healthy subjects. Am J Gastroenterol 
2006;101(2):351-5. 
52. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum 
concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol 
Ther 1998;64(5):477-83. 
53. Cohen LB, Dubovsky AN, Aisenberg J, et al. Propofol for endoscopic sedation: A protocol for safe 
and effective administration by the gastroenterologist. Gastrointest Endosc 2003;58(5):725-32. 
54. Wu BU, Banks PA. Clinical management of patients with acute pancreatitis. Gastroenterology 
2013;144(6):1272-81. 
55. Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of 
pancreatic cancer. JAMA 2014;311(4):392-404. 
56. Ketwaroo G, Brown A, Young B, et al. Defining the accuracy of secretin pancreatic function testing 
in patients with suspected early chronic pancreatitis. Am J Gastroenterol 2013;108(8):1360-6. 
57. Stevens T, Conwell DL, Zuccaro G, Jr., et al. A prospective crossover study comparing secretin-
stimulated endoscopic and Dreiling tube pancreatic function testing in patients evaluated for chronic 
pancreatitis. Gastrointest Endosc 2008;67(3):458-66. 
58. Stone NJ, Robinson JG, Lichtenstein AH, et al. Treatment of blood cholesterol to reduce 
atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of 
Cardiology/American Heart Association cholesterol guideline. Ann Intern Med 2014;160(5):339-43. 
 
 
 


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CONSENT FORM 
 
 (Insert Institution name) 
Consent Form 
Study Title for Study Participants: A Study Testing Simvastatin to Prevent Pancreatic 
Cancer in People with Recurrent Pancreatitis 
Protocol Title: NWU2014-04-01, Statin Therapy to Reduce the Risk of Recurrent Pancreatitis 
Principal Investigator: Marc T. Goodman, Ph.D., M.P.H. 
Sponsored By: National Cancer Institute (NCI)  
 
 
Introduction 
You are being asked to take part in a research study. This document has important information 
about the reason for the study, what you will do if you choose to be in this research study, and 
the way we would like to use information about you and your health. 
 
What is the usual approach to my recurrent pancreatitis (pancreatitis that occurs more 
than once)? 
You are being asked to take part in this study because you have recurrent pancreatitis and are at 
increased risk for pancreatic cancer. People who are at increased risk and choose not to 
participate in a study are usually followed closely by their doctor to watch for the development 
of cancer. 
 
What are my other choices if I do not take part in this study? 
• You may choose to have the usual approach described above; 
• You may choose to take part in a different study, if one is available; or 
• You may choose to do nothing. 
 
Why is this study being done? 
The purpose of this study is to compare the safety and effects of simvastatin in people with 
recurrent pancreatitis who are at an increased risk for pancreatic cancer. In this study, you will 
get either simvastatin or placebo, a pill that looks like the study drug but contains no medication. 
Simvastatin is approved by the U.S. Food and Drug Administration (FDA) to reduce the risk for 
heart attack, stroke, and chest pain in patients who have heart disease or risk factors for heart 
disease such as smoking, high blood pressure, low high-density lipoprotein (HDL), or family 
history of early heart disease. It is also approved to lower the risk for heart attack or stroke in 
patients with type 2 diabetes and risk factors such as diabetic eye or kidney problems, smoking, 
or high blood pressure. However, simvastatin is not approved by the FDA to decrease the risk of 
recurrent pancreatitis. Studies show that simvastatin lowers the risk of heart disease not only by 
decreasing cholesterol, but also by decreasing inflammation. We believe that this anti-
inflammatory effect of simvastatin may help patients with pancreatitis. There will be about 30 
people taking part in this study at Cedars-Sinai Medical Center (CSMC); Kaiser Southern 
California Permanente Medical Group (KPMC); the University of Pittsburgh (UP); and Stanford 


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University (SU). 
 
What are the study groups? 
This study has two study groups. Group 1 will receive the study drug simvastatin and Group 2 
will receive a placebo, a pill that looks like the study drug but contains no medication. There will 
be 20 people in Group 1 and 10 people in Group 2. 
 
A computer will randomly put you in a study group—like a coin toss—to decide what group you 
get placed into. This is done because no one knows if one study group is better, the same, or 
worse than the other group. Once you are put in a group, you cannot switch to the other group. 
 
Neither you nor your doctor will know if you are receiving simvastatin or placebo. Your doctor 
cannot choose which group you will be in.  
 
 
 
 
 
 
 
 
 
How long will I be in this study? 
Your participation in the study will last 9 months. You will receive the study drug for 6 months, 
and your doctor will continue to watch you for side effects and follow your condition for 3 
months after you stop taking the study drug. If you stop taking the study drug early, your doctor 
will continue to watch you for side effects for 3 months. 
 
What extra tests and procedures will I have if I take part in this study? 
If you agree to participate in this study, you will be required to sign this consent form before you 
have any tests or procedures that are done only for this study. Most of the exams, tests, and 
procedures you will have are part of the usual approach for your condition. However, there are 
some extra tests and procedures that you will need to have if you take part in this study, 
including review of your medical history and medications, blood tests, endoscopic tests of your 
gastrointestinal tract, collection of stool samples, completion of questionnaires, and pregnancy 
tests (only for women who are able to become pregnant). These extra tests and procedures are 
described in further detail below. 
 
There are 4 main parts to this study: Screening, Baseline Testing, Intervention, and Follow-up 
after Completion of Study Intervention. 
 
Screening (Screening 1 and 2) 
Screening is a period during which tests and exams will be done to determine if you are eligible 
to participate in the study. Some of the tests and exams may have been recently done by one of 
your doctors and might not need to be repeated. You may be required to provide a medical 
You agree to take 
part in the study 
Randomize  
(The computer will 
randomly put you in a 
study group) 
Group 1 
Simvastatin 
(20 people will receive this) 
Group 2 
Placebo 
(10 people will receive this) 


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release to obtain medical records from clinical centers other than (Insert institution name) to 
review your pancreatitis history. 
 
 Screening 1 
After you sign the consent form, you will need to have the following to determine if you 
are eligible for the study:  
• Review of your medical records and pancreatitis history by the study doctor to 
confirm that you have recurrent pancreatitis 
• Review of your computed tomography (CT) and magnetic resonance imaging (MRI) 
results in the past 12 months. If previous CT or MRI results show that you have 
advanced chronic pancreatitis, you will not be eligible for the study. 
 
 Screening 2 
If you are still eligible after Screening 1, the following will occur: 
• Physical exam and vital signs assessment (blood pressure, heart rate, respiratory rate, 
and oral temperature)  
• Blood draw (about 2 teaspoons or 10 mL of your blood will be collected) for lab tests 
to check for a low blood count or clotting problems and to check your liver and 
kidneys 
• Endoscopic ultrasound (EUS) and endoscopic pancreatic function test (ePFT). These 
tests allow the doctor to see your upper gastrointestinal tract and check the function of 
your pancreas. You will be asked to fast overnight (8 hours) before the endoscopic 
testing. 
• Pregnancy test (for women who are able to become pregnant) 
 
Endoscopic ultrasound (EUS) is a test that lets a doctor see your upper gastrointestinal tract. 
The doctor uses a long, flexible, lighted tube called an endoscope that has a video camera, as 
well as additional ultrasound tubes to visualize the digestive tract by sound waves. Images of 
the inside of the patient's body can be seen on a screen. Before the EUS is administered, a 
medicine will be sprayed into your mouth to prevent you from coughing or gagging when the 
endoscope is inserted. An intravenous (IV) needle will be inserted into your arm, and you 
will be given medicine through the IV to make you relaxed and sleepy. You should feel no 
pain. When you are sleepy, the endoscope will be guided through your mouth and throat, 
then through the esophagus, stomach, and duodenum (first part of the small intestine). This 
will allow the doctor to examine the inside of these organs.  
 
The endoscopic pancreatic function test (ePFT) is a test that checks on the function of your 
pancreas. It is done after the EUS. Fluid from your stomach and duodenum will be removed 
when the endoscope is in place. Then secretin will be administered through your IV. Secretin 
is a digestive hormone that stimulates secretions by the liver and pancreas. A small dose of 
secretin will be administered first to observe and make sure you do not have strong adverse 
reactions to it before the full dose is administered. After the secretin is administered, 
pancreatic fluid will be collected at five time points over one hour (at 0-10 minutes, 10-20 
minutes, 20-30 minutes, 30-45 minutes, and 45-60 minutes). Each collection will contain at 
least 3 mL (about 1/2 teaspoon) of fluid.  
 


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When EUS and ePFT testing is finished, the doctor will slowly remove the endoscope. The 
EUS and ePFT will be done by a highly trained, experienced doctor. The EUS will take about 
30 minutes and the ePFT will take about one hour. The Screening 2 visit, including the EUS 
and ePFT, will last approximately 3-4 hours. 
 
If the EUS results show that you have advanced chronic pancreatitis, if your lab test results 
are unacceptable, or if you are pregnant, you will not be eligible for the study. 
 
Baseline Testing (Study Visit 1) 
If the Screening 2 exams and tests show that you can take part in the study, and you choose to, 
then you will be randomized to a study group. You will also need the following extra procedures. 
These are not part of the usual approach for your condition. The baseline testing will take place 
at (site specific clinic and address) 0-14 days after the Screening 2 tests. You will be asked to 
fast overnight (8 hours) before the testing. The baseline testing will take approximately 2 hours.  
• Review of your medical history, medications, and laboratory test results, and a vital signs 
assessment (blood pressure, heart rate, respiratory rate, and oral temperature) 
• Blood tests (about 7 teaspoons or 36 mL of blood will be collected) to check your organ 
function, and for research purposes 
• Collection of a stool sample for research purposes. A stool collection kit and instructions 
for collecting the sample at home will be provided before the scheduled visit. You will 
collect your stool sample at home and bring it to the baseline testing. 
• Completion of a questionnaire that asks about your background (birthplace, race, 
education, marital status), health habits, physical activity, and tobacco and alcohol use. The 
questionnaire will be administered by a research staff person, who will ask you the 
questions and record the answers.  
• Completion of a questionnaire that asks about your pain level and quality of life. This is a 
self-administered questionnaire. 
 
The blood and stool samples are required in order for you to take part in this study because the 
research on the samples is an important part of the study. You will receive a phone call the day 
before the visit to remind you to fast overnight and to collect the stool sample and bring it to the 
baseline testing. 
 
The study drug (either simvastatin or placebo) will be provided to you at the baseline testing. 
Study staff will review instructions for how and when to take the study drug. You will be given a 
study diary to fill out and record each dose of study drug that you take. You should mark any 
missed or skipped doses in this diary, as well as any side effects that you are experiencing.  
 
Intervention (Study Visits 2 and 3) 
During the Intervention portion of this study, you will be asked to take the study drug every day 
for 6 months and participate in 2 study visits. Research staff will contact you approximately 
every four weeks by phone to check on your progress and answer any questions regarding the 
study drug. You will also be asked questions about potential side effects of the study drug. These 
phone calls will last approximately 10 minutes.  
  
Reminders to take your study drug: You will have the option of receiving email or text messages 


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from research staff to remind you about the study drug during the first week of the intervention 
period. We encourage you to respond to indicate if the dose has been taken. If you are having 
trouble remembering, these reminders can be extended beyond the first week. It is important that 
you stay on the study drug until the last study visit 6 months after you start intervention with the 
study drug. You will receive a phone call from research staff to remind you to stay on the study 
drug during the last week of the study intervention, as it is very important that you not miss any 
dose during this week so that we are able to fully use all data collected. Reminder messages to 
take the study drug will also be sent to you. 
 
 Study Visit 2 
You will need to come to (site specific clinic and address) for a study visit 3 months after 
you start intervention with the study drug. You will be asked to fast overnight (8 hours) 
before this visit. The following procedures will be done during the visit: 
• Review of your medical history, medications, and laboratory test results, and a 
physical exam and vital signs assessment (blood pressure, heart rate, respiratory 
rate, and oral temperature) 
• Review of your study diary and side effects of the study drug you may be 
experiencing 
• Blood tests (about 7 teaspoons or 36 mL of blood will be collected)  
• Pregnancy test (for women who are able to become pregnant) 
• Collection of a stool sample for research purposes. A stool collection kit and 
instructions for collecting the sample at home will be provided before the 
scheduled visit. You will collect your stool sample at home and bring it to the 
study visit. 
• Completion of a self-administered questionnaire that asks about your pain level and 
quality of life 
• Esophagogastroduodenoscopy (EGD) and endoscopic pancreatic function test 
(ePFT) 
 
Esophagogastroduodenoscopy (EGD) is a test that lets a doctor see your upper 
gastrointestinal tract. EGD is a simpler procedure than the EUS performed in Screening 2 
in that while it does involve an imaging scope, it will not require additional ultrasound 
probes to visualize the digestive tract using sound waves. ePFT will be performed after 
the EGD. The two procedures will take about 90 minutes. 
 
This visit, including the EGD and ePFT, will last approximately 4 hours. You will 
receive a phone call the day before the visit to remind you to fast overnight and to collect 
the stool sample and bring it to the study visit. We will also remind you to bring your 
study diary and any leftover study drugs to the visit. 
 
 Study Visit 3 
You will need to come to (site specific clinic and address) for a final study visit 6 months 
after you start intervention with the study drug. You will be asked to fast overnight (8 
hours) before this visit. The following procedures will be done during the visit: 
• Review of your medical history, medications, and laboratory test results, and a 
physical exam and vital signs assessment (blood pressure, heart rate, respiratory 


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rate, and oral temperature) 
• Review of your study diary and side effects of the study drug you may be 
experiencing. The study diary and all unused study medication will be collected at 
this visit. 
• Blood tests (about 7 teaspoons or 36 mL of blood will be collected) 
• Pregnancy test (for women who are able to become pregnant) 
• Collection of a stool sample for research purposes. A stool collection kit and 
instructions for collecting the sample at home will be provided before the 
scheduled visit. You will collect your stool sample at home and bring it to the 
study visit. 
• Completion of a questionnaire that asks about changes in your health habits, 
physical activity, and tobacco and alcohol use since your baseline testing. The 
questionnaire will be administered by a research staff person. 
• Completion of a self-administered questionnaire that asks about your pain level 
and quality of life 
• Endoscopic ultrasound (EUS) and endoscopic pancreatic function test (ePFT) 
 
The endoscopic ultrasound (EUS) and endoscopic pancreatic function test (ePFT) are the 
same tests as those performed during Screening 2.  
 
The final study visit, including the EUS and ePFT, will last approximately 4 hours. You 
will receive a phone call the day before the visit to remind you to fast overnight and to 
collect the stool sample and bring it to the study visit. We will also remind you to bring 
your study diary and any leftover study drugs to the visit. 
 
Follow-up after Completion of Study Intervention 
We will continue to follow your condition for 3 months after you stop taking the study drug. 
Research staff will contact you by phone to check on potential symptoms and side effects you 
may be experiencing, and to answer any questions you may have. These phone calls will last 
approximately 10 minutes. You will be contacted approximately 30 days, 60 days, and 90 days 
after you complete the study. 
 
What possible risks can I expect from taking part in this study?  
Your involvement in this study may involve the following risks: 
 
Risks associated with simvastatin 
The study drug simvastatin used in this study may affect how different parts of your body work, 
such as your liver and kidneys. Simvastatin is not safe for people with active liver disease. You 
will have blood tests before and during the study to monitor your liver and kidney function. The 
study doctor will let you know if changes occur that may affect your health.  
 
There is also a risk that you could have side effects.  
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 


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• Some side effects may go away soon, some may last a long time, or some may never go 
away.  
• Some side effects may be serious and may even result in death 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
 
The tables below show the most common side effects that we know about simvastatin, some of 
which may be serious. There might be other side effects that we do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
 
OCCASIONAL  
(out of every 100 people receiving simvastatin, from 4 to 20 may experience): 
• Upper respiratory infections  
• Headache 
• Abdominal pain 
• Constipation 
• Nausea 
• Myalgia (muscle aches) 
• Dry skin 
 
RARE, SOME MAY BE SERIOUS  
(out of every 100 people receiving simvastatin, 3 or fewer may experience): 
• Feeling weak and having no energy  
• Confusion, forgetfulness, or memory problems 
• Liver failure (signs and symptoms: fatigue, weight loss, yellowing of the 
skin or eyes) 
• Rhabdomyolysis (a breakdown of muscle tissue), a rare condition that may 
cause kidney damage (signs and symptoms: muscle pain, tenderness, or 
weakness; dark colored urine) 
• Elevations in blood glucose 
 
Food and medication interactions: 
Grapefruit and grapefruit juice may interact with simvastatin and lead to potentially dangerous 
effects. Do not consume grapefruit products (grapefruit, grapefruit juice, grapefruit seed extract, 
or dietary supplements containing grapefruit) during the intervention portion of this study.  
 
Simvastatin interacts with many other medications in ways that can increase or decrease the 
amount of medication in your blood. The interactions could result in increased levels that can be 


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dangerous, or decreased levels so that drugs don’t work. Simvastatin also interacts with some 
medications in a way that increases the risk of muscle injury called myopathy (symptoms: 
unexplained muscle weakness or pain). Simvastatin should not be taken by people who are also 
taking the antibiotics erythromycin, clarithromycin, or telithromycin; the antidepressant 
nefazodone; the antifungal drugs itraconazole, ketoconazole, posaconazole, or voriconazole; the 
immunosuppressant cyclosporine; the endometriosis drug danazol; HIV protease inhibitors; the 
Hepatitis C protease inhibitors boceprevir or telaprevir; lomitapide (a drug used to treat high 
cholesterol that runs in families); or the cardiovascular drugs gemfibrozil, diltiazem, 
dronedarone, amiodarone, amlodipine, ranolazine, or verapamil (medications used to treat high 
cholesterol, high blood pressure, angina (chest pain), or heart rhythm problems). Oral 
formulations (i.e., tablets or capsules) of these medications should not be used during the 
intervention portion of this study. Topical formulations, including creams, shampoos, foams, and 
gels applied to the skin, are acceptable. Tell the study doctor immediately if you use any of these 
medications, or if any of these medications is prescribed for you during the study. 
 
Alcohol consumption 
Simvastatin should be used with caution in patients who consume more than 5 drinks per day of 
alcohol as simvastatin may cause liver injury. We will monitor your liver function every three 
months and inform you if your test results are abnormal.  
 
Reproductive risks 
Women who are pregnant or may become pregnant should not use simvastatin. When taken 
during pregnancy, simvastatin may cause harm to a developing baby. Women who are pregnant, 
attempting to become pregnant or breastfeeding may not participate in the study. Women of 
child-bearing potential will be required to have a pregnancy test before the study and at the 
follow-up visits, and must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of study participation. Let the 
study doctor know immediately if you believe you might be pregnant. 
 
Esophagogastroduodenoscopy (EGD), endoscopic ultrasound (EUS), and endoscopic pancreatic 
function testing (ePFT)  
You may experience an infection, possibly somewhere along the path of the endoscope; piercing 
or tearing of an organ that could require subsequent surgery; or bleeding more than normally 
expected. There is a small risk of complications related to the sedative (medicine given to relax 
you during the procedure) such as an allergic reaction, nausea, or irregular heartbeats. During the 
ePFT procedure, secretin will be administered through your intravenous (IV) line. Secretin is a 
digestive hormone that stimulates secretions by the liver and pancreas. There is a small risk of 
complications related to the EGD, EUS, ePFT, or the secretin administration, such as nausea, 
flushing, abdominal pain, or vomiting. Secretin has the potential to cause a serious allergic 
reaction, which may include rash, low blood pressure, wheezing, shortness of breath, or swelling 
of the face or throat. A small dose of secretin will be administered first to observe and make sure 
you do not have strong adverse reactions to it before the full dose is administered. You should 
not drive after an EGD, EUS, or ePFT, and you should arrange transportation after the study 
visits where the EGD, EUS, or ePFT will be performed. The study doctor will discuss the risks 
of possible complications before your EGD, EUS, and ePFT procedures. 
 


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Blood Collection 
There may be pain, swelling, or bruising around the vein where your blood is collected. You may 
feel faint. There is a small risk of infection at the place on your body from which the blood is 
collected. The blood will be drawn by a person trained to collect blood using sterile (clean) 
equipment, and a very small needle will be used for drawing your blood to minimize discomfort. 
The blood draw will be done after you haven't eaten for 8 hours. You may feel weak, light-
headed, dizzy, and have palpitations. 
 
Questionnaires 
You may feel uncomfortable answering some of the questions you will be asked. If you feel 
uncomfortable answering any question, you can choose not to answer it. 
 
What possible benefits can I expect from taking part in this study? 
You should not expect to benefit from taking part in this research study. The results from this 
study will provide information that will help scientists to better understand how pancreatitis 
develops, and to learn whether simvastatin will improve pancreatic function in individuals with 
recurrent pancreatitis. This knowledge could help prevent pancreatic cancer in the future. 
 
Can I stop taking part in this study? 
Your participation in this research study is voluntary so you may decline to participate or to stop 
being in this study at any time. If you decide to stop for any reason, it is important to let the 
study doctor know as soon as possible so you can stop safely. If you choose not to participate in 
this study or decide to stop participating, you will not suffer any loss of benefits to which you 
would be entitled outside of the study. Choosing not to participate will not negatively affect the 
care you receive or any present or future medical treatment.  
 
You will be told about any new information or changes in the study that could affect your health 
or your willingness to continue in the study. 
 
Your participation in this study may be ended without your consent by the principal investigator 
or the study doctor for the following reasons: 
• If you develop a dangerous side effect; 
• If you become pregnant; 
• If your health changes;  
• If the study is no longer in your best interest; 
• If you do not follow the study rules; 
• If the study is stopped early for any reason by the sponsor, IRB, or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. If you choose to be in this study, you have the right to be treated with respect, including 
respect for your decision whether or not you wish to continue or stop being in the study.  
 
If you want to speak with someone who is not directly involved in this research, or have 
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Institutional Review Board or other site specific entity). You can call them at (insert phone 
number) or contact them by email at (insert email address). The (site specific entity) has been 
established to protect the rights and welfare of research participants. You may also contact the 
(site specific entity) if you want to offer input or obtain information regarding the study. 
 
What are the costs of taking part in this study? 
There will be tests and procedures that are done only for this study and other tests and 
procedures that are part of your routine medical care (not part of the research). 
 
The simvastatin and placebo will be supplied at no charge while you take part in this study. The 
cost of study-specific exams, tests, and any other procedures performed for research purposes 
will be paid for by the study. 
 
Some costs associated with your care may be considered standard of care, and will be billed to 
you or your insurance company. You will have to pay for any costs (including deductibles and 
co-payments) not covered by your health insurer. You should check with your health plan or 
insurance company to find out what they will pay for. 
 
Will I receive payment for taking part in this study? 
You will receive $50 for completing Screening 2 and $150 at the completion of each visit (Study 
Visit 1, Study Visit 2, and Study Visit 3) to reimburse you for your time, transportation, parking, 
and other expenses related to the study, as summarized in the table below. The total amount you 
will receive if you complete the whole study – Screening 2 and Study Visits 1, 2, and 3 – is 
$500. If you do not complete the entire research study, you will only be paid for those visits you 
do complete. 
Research 
Visit 
Covered (done for research purposes 
at no cost to you) 
Not covered (routine 
medical care, billed to 
you or your insurance) 
Payment to you 
when you finish 
the visit 
Screening 2  Medical records and medications 
review, vital signs assessment, blood 
tests, pregnancy test, EUS and ePFT 
Physical exam 
$50  
Study Visit 1 Medical history and medications 
review, vital signs assessment, blood 
tests, stool collection, questionnaires 
 
$150 
Study Visit 2 Medical history and medications 
review, vital signs assessment, blood 
tests, stool collection, pregnancy test, 
questionnaire, EGD and ePFT 
Physical exam 
$150 
Study Visit 3 Medical history and medications 
review, vital signs assessment, blood 
tests, stool collection, pregnancy test, 
questionnaires, EUS and ePFT 
Physical exam 
$150 
 
You may be required to complete a W-9 Form in order to receive payment. The W-9 Form will 
be maintained by our accounting department at (Insert institution name). If total payment is $600 


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–62– 
or more from (Insert institution name) in a calendar year, a 1099 Form will be filed with the IRS 
in accordance with federal tax law. If you are a (Insert institution name) employee, you should 
provide your employee identification number to the research team so that your payment can be 
appropriately processed through Payroll. For your own protection and to comply with tax laws, 
your payment for participation will be reported to the IRS together with other compensation you 
receive from (Insert institution name). 
 
What happens if I am injured or hurt because I took part in this study? 
If you feel you have been injured or hurt as a result of taking part in the study, it is important that 
you contact your study doctor immediately: (Insert site specific study doctor's name and 
telephone number). If it is a medical emergency, call 911 or go to an emergency room. You will 
get medical treatment if you are injured or hurt as a result of taking part in this research study. 
 
Who will see my medical information? 
Your privacy is very important to us and we will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, we will do our best to 
make sure that any information that is released will not be able to identify you. Some of your 
health information, and information about your specimens, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private. Some of these organizations are:  
• The study sponsor, the National Cancer Institute (NCI)  
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the US. 
• The National Cancer Institute will obtain information for this clinical trial under data 
collection authority Title 42 U.S.C. 285. 
 
Where can I get more information? 
You may visit the NCI website at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to 
get the same information at: 1-800-4-CANCER (1-800-422-6237).  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor (insert name of site-specific study 
doctor(s) at (insert telephone number). 
 
 


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This section is about optional studies you can choose to take part in. 
 
Optional Sample Collections for Biobanking for Possible Future Studies 
 
Researchers are trying to learn more about cancer and other health problems. Much of this 
research is done using samples from your biopsies, blood, or other fluids. Through these studies, 
researchers hope to find new ways to prevent, detect, treat, or cure health problems. Some of 
these studies may be about genes. Genes carry information about features that are found in you 
and in people who are related to you. Researchers are interested in the way that genes affect how 
your body responds to treatment. 
 
The researchers would like to ask your permission to store left over samples and health 
information obtained during your participation in this study for future medical research. Storing 
samples for future studies is called biobanking. If you agree, the blood, tissue, pancreatic fluid, 
and stool samples, and information collected about you during the study will be coded and kept 
at (Insert institution name). 
 
The research that may be done is unknown at this time. Future research may include: 1) studies 
to identify genes and/or biomarkers and proteins that influence an individual’s risk of getting 
pancreatitis, pancreatic cancer, or other diseases; 2) studies to identify specific pathways and 
mechanisms that promote cancer. A biomarker is a biological molecule found in blood, other 
body fluids, or tissues that may be a sign of a condition or disease. 
 
What is involved? 
Your samples and some related information may be stored in the NCI Biobank, along with 
samples and information from other people who take part. These are not additional samples that 
will be collected, but will consist of any material (blood, tissue, pancreatic fluid, and stool 
samples) that remains after the tests described for this study have been conducted. The samples 
will be kept until they are used up. 
 
Qualified researchers can submit a request to use the materials stored in the NCI Biobank. A 
research committee at (Insert institution name) will review each request. There will also be an 
ethics review to ensure that the request is necessary and proper. You will not be notified if/when 
research is conducted using your samples. 
 
What are the possible risks? 
1) There is a risk that an unauthorized person could obtain the personal information in your 
medical records or other information we have stored about you. 
2) There is a potential risk from collecting genetic information about you. Even without 
your name or other identifiers, your genetic information is unique to you. The researchers 
believe the chance that someone will identify you is very small, but the risk may change 
in the future as people come up with new ways of tracing information. 
3) There are laws against the misuse of genetic information, but they may not give full 
protection. New health information about inherited traits that might affect you or your 
blood relatives could be found during a study. The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
 


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–64– 
A new Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law generally will protect you 
in the following ways: 
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
 
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of 
your employment. All health insurance companies and group health plans must follow this law 
by May 21, 2010. All employers with 15 or more employees must follow this law as of 
November 21, 2009. 
 
Be aware that this new Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you (such as 
your name or birth date) will be sent. Samples will be identified by a unique study code 
only.  
2) The list that links the unique code to your name will be kept separate from your sample 
and health information. Any NCI Biobank and (Insert institution name) staff with access 
to the list must sign an agreement to keep your identity confidential. 
3) Researchers to whom (Insert institution name) sends your sample and information will 
not know who you are. They must also sign an agreement that they will not try to find out 
who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) The results from research on your samples will not be put in your medical record. 
6) If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits? 
You will not benefit from taking part. The study of your samples and data will help us to learn 
about the biological markers and mechanisms that influence an individual’s risk of pancreatitis, 
cancer, and other diseases. We hope that studying the samples and data may, in the future, help 
to prevent or cure these diseases and result in new treatments.  
 
Are there any costs or payments?  
There will be no cost to you or your insurance company for storage of your samples. Your blood, 
tissue, pancreatic fluid, and stool samples will be used only for research and will not be sold. 
You will not be paid for allowing your leftover samples to be used in research. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 


NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–65– 
profits. 
 
What if I change my mind?  
If you decide you no longer want your samples to be used, you can call (insert name and phone 
number) who will let the researchers know. Then, any sample that remains in the bank will no 
longer be used. Samples or related information that have already been given to or used by 
researchers will not be returned. 
 
What if I have more questions?  
If you have questions about the use of your samples for research, contact the principal 
investigator, Dr. Marc T. Goodman, at 310-423-6188. 
 
Samples for future research studies 
My samples and related information may be kept in the NCI Biobank for use in future health 
research. 
Please circle one: 
YES 
 
NO 
 
I agree that my study doctor, or their representative, may contact me or my physician to see if I 
wish to participate in other research in the future. 
Please circle one: 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
Consent Summary 
I have read this consent form and the research study has been explained to me. I have been given 
time to ask questions, and have been told whom to contact if I have more questions. I agree to be 
in the research study described above. I will be given a signed copy of this form. I agree to take 
part in the main study and any additional studies where I circled ‘yes’.    
 
 
 
 
 
 
Name (printed) and Signature of Research Participant 
Date of Signature 
 
 
 
 
 
 
Name (printed) and Signature of Person Obtaining Consent 
Date of Signature 
 
 
 
 
 
 


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Protocol Version 3.8,  January 9, 2020 
 
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APPENDIX A 
 
Clinical Laboratory Minimum Test Requirements 
 
Clinical labs must include at least the following tests. It is acceptable to do additional tests if they are 
included in the blood panels at your institution. 
 
Blood Hematology: 
Complete Blood Count 
and Differential 
Blood Chemistry: 
Comprehensive Metabolic 
Panel 
Lipid Panel * 
Other Blood Tests 
Hemoglobin 
Platelet count 
White blood cell count 
(WBC, leukocytes), total 
Neutrophil count, absolute 
Alanine aminotransferase 
(ALT (SGPT)) 
Aspartate aminotransferase 
(AST (SGOT)) 
Alkaline phosphatase (ALP) 
Bilirubin, total 
Creatinine 
Glucose 
Total cholesterol 
High density lipoprotein 
(HDL) cholesterol 
Low density lipoprotein 
(LDL) cholesterol 
Triglycerides 
Hemoglobin A1C 
(HbA1C) † 
Creatine phosphokinase 
(CPK) § 
* Lipid panels will be done at Study Visits 1, 2, and 3. 
† Hemoglobin A1C will be measured at Study Visits 1 and 3. 
§ Creatine phosphokinase (CPK) will be measured at Study Visit 1 to establish a patient-specific reference 
for this indicator of muscle toxicity. If the patient reports unexplained muscle pain or weakness during the 
trial, CPK will be tested again to check for elevation. 
 
 
 


NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
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APPENDIX B 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 










NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
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APPENDIX D 
Participant ID:       
 
 
Date:       
 
 
 
Statin Therapy to Reduce the Risk of Recurrent Pancreatitis 
 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential.  
 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2.  Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3.  Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
4.  Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5.  Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
6.  Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7.  Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8.  Were you short of breath? 
1 
2 
3 
4 
9.  Have you had pain? 
1 
2 
3 
4 
10.  Did you need to rest? 
1 
2 
3 
4 
11.  Have you had trouble sleeping? 
1 
2 
3 
4 
12.  Have you felt weak? 
1 
2 
3 
4 
13.  Have you lacked appetite? 
1 
2 
3 
4 
14.  Have you felt nauseated? 
1 
2 
3 
4 
15.  Have you vomited? 
1 
2 
3 
4 
16.  Have you been constipated? 
1 
2 
3 
4 
Please go on to the next page 
 
 
 
 
 
 


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–73– 
 
During the past week: 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
17.  Have you had diarrhea? 
1 
2 
3 
4 
18.  Were you tired? 
1 
2 
3 
4 
19.  Did pain interfere with your daily activities? 
1 
2 
3 
4 
20.  Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21.  Did you feel tense? 
1 
2 
3 
4 
22.  Did you worry? 
1 
2 
3 
4 
23.  Did you feel irritable? 
1 
2 
3 
4 
24.  Did you feel depressed? 
1 
2 
3 
4 
25.  Have you had difficulty remembering things? 
1 
2 
3 
4 
26.  Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27.  Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28.  Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best applies to 
you. 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
 
 
 
 
 
Excellent 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0  
 
 
 
 
Please continue to the next page 


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Protocol Version 3.8,  January 9, 2020 
 
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Participant ID:       
 
 
Date:       
 
 
 
Statin Therapy to Reduce the Risk of Recurrent Pancreatitis 
 
EORTC QLQ- PAN28(CP) 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week.  
During the past week: 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
31.  Have you had abdominal discomfort? 
1 
2 
3 
4 
32.  Did you have a bloated feeling in your abdomen? 
1 
2 
3 
4 
33.  Have you had back pain? 
1 
2 
3 
4 
34. Did you have pain during the night? 
1 
2 
3 
4 
35. Did you find it uncomfortable in certain positions 
(e.g. lying down)? 
1 
2 
3 
4 
36. Were you restricted in the types of food you can eat 
as a result of your disease or treatment? 
1 
2 
3 
4 
37.  Were you restricted in the amounts of food you can eat 
as a result of your disease or treatment? 
1 
2 
3 
4 
38.  Did food and drink taste different from usual? 
1 
2 
3 
4 
39.  Have you had indigestion? 
1 
2 
3 
4 
40.  Were you bothered by gas (flatulence)? 
1 
2 
3 
4 
41.  Have you worried about your weight being too low? 
1 
2 
3 
4 
42.  Did you feel weak in your arms and legs? 
1 
2 
3 
4 
43.  Did you have a dry mouth? 
1 
2 
3 
4 
44.  Have you had itching? 
1 
2 
3 
4 
45. To what extent was your skin yellow? 
1 
2 
3 
4 
46. Did you have frequent bowel movements? 
1 
2 
3 
4 
47. Did you feel the urge to move your bowels quickly? 
1 
2 
3 
4 
48. Have you felt physically less attractive as a result of 
your disease and treatment? 
1 
2 
3 
4 
Please go on to the next page 
 
 
 
 
 
 


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Protocol Version 3.8,  January 9, 2020 
 
–75– 
 
 
During the past week: 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
49.  Have you found it difficult to avoid drinking alcohol? 
Not applicable 
1 
2 
3 
4 
50.  Have you felt guilty or embarrassed about drinking alcohol? 
Not applicable 
1 
2 
3 
4 
51.  Have you been dissatisfied with your body? 
1 
2 
3 
4 
52.  To what extent have you been troubled with side 
effects from your treatment? 
1 
2 
3 
4 
53.  Were you worried about your health in the future? 
1 
2 
3 
4 
54.  Were you limited in planning activities, for example 
meeting friends, in advance? 
1 
2 
3 
4 
55.  Have you received adequate support from your health 
care professionals? 
1 
2 
3 
4 
56.  Has the information given about your physical condition 
and treatment been adequate? 
1 
2 
3 
4 
57.  Have you felt less interest in sex? 
1 
2 
3 
4 
58.  Have you felt less sexual enjoyment? 
1 
2 
3 
4 
 
 
 
\\soton.ac.uk\ude\personalfiles\users\cdj\mydocuments\pan26\pan28(cp)\qlqpan28(cp).doc 
DO NOT USE OR COPY WITHOUT PERMISSION 
 
 
 
 
 
 
 
 
 
 
  
_ 
 
 
Participant's Signature 
Date 
 


NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–76– 
APPENDIX E 
 
 
 
Participant ID:        
 
Date:       
 
 
 
 
 
 
 
Statin Therapy to Reduce the Risk of Recurrent Pancreatitis 
 
 
 
 
Baseline Questionnaire 
 
 
 
 
 
We appreciate the time you are taking to complete this questionnaire. Please try to 
answer each question as completely as you can, even if you are unsure about the answer. 
If you feel uncomfortable answering any question, you can choose not to answer it. All 
answers will be kept confidential. 
 








NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–80– 
3. Has a doctor or health care provider ever told you that you had diabetes? 
1 
 Yes 
0 
 No → If NO Go to Question # 7 
 
4. How old were you when a doctor first told you that you had diabetes?       years old  
 
5. Did you do any of the following to monitor or treat your diabetes? 
Check Yes or No for each item. 
Yes 
No 
a. Use a home glucose test to monitor your insulin level? 
1 
 
0 
 
b. Change your diet? 
1 
 
0 
 
c. Take medication by mouth?* 
1 
 
0 
 
d. Take insulin by injection?* 
1 
 
0 
 
*IF RESPONDENT TOOK MEDICATION BY MOUTH OR INSULIN BY INJECTION, ASK: 
6. Have you ever taken (type 
of drug) for one year or 
longer? Repeat for each 
drug. If Yes, ask additional 
details. Use continuation 
sheet if needed. 
Yes   No 
What was the 
name of the 
medication? 
Show Hand Card 
How old 
were you 
when 
you first 
took 
(drug)? 
How old 
were you 
when 
you last 
took 
(drug)? 
Was there a period of 
one month or more 
when you did not take 
(drug)? If Yes, ask: 
How many months? 
 Yes    No 
a. Oral agent for diabetes   
1 
  0 
       
 
      
      
1 
  0 
 
      
b. 2nd oral agent for 
diabetes    
1 
  0 
       
 
      
      
1 
  0 
 
      
c. Insulin injection agent 
1 
  0 
       
 
      
      
1 
  0 
 
      
d. 2nd insulin injection 
agent 
1 
  0 
       
 
      
      
1 
  0 
 
      
e. Other injectable for 
diabetes 
1 
  0 
       
 
      
      
1 
  0 
 
      
f. 2nd injectable for 
diabetes 
1 
  0 
       
 
      
      
1 
  0 
 
      
g. Inhalable powder for 
diabetes 
1 
  0 
       
 
      
      
1 
  0 
 
      
 
7. Have you ever taken (type 
of drug) for one year or 
longer? Repeat for each 
drug. If Yes, ask additional 
details. Use continuation 
sheet if needed. 
Yes   No 
What was the 
name of the 
medication? 
Show Hand Card 
How old 
were you 
when 
you first 
took 
(drug)? 
How old 
were you 
when 
you last 
took 
(drug)? 
Was there a period of 
one month or more 
when you did not take 
(drug)? If Yes, ask: 
How many months? 
 Yes    No 
a. A prescription drug to 
control high blood 
pressure   
1 
  0 
       
 
      
      
1 
  0 
 
      
b. 2nd drug to control high 
blood pressure    
1 
  0 
       
 
      
      
1 
  0 
 
      
c. Anti-depressant    
1 
  0 
       
 
      
      
1 
  0 
 
      
d. 2nd anti-depressant   
1 
  0 
       
 
      
      
1 
  0 
 
      
 
 


NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–81– 
8. Over the past year, have you taken an antibiotic for any reason? 
1 
 Yes 
0 
 No → If NO Go to Question # 9 
a. What was the name of the antibiotic(s) you took?       
 
 
b. When was the last time you took antibiotics?      /      (Month/Year) 
 
c. Over the past year, how many courses of antibiotics have you taken? A course usually lasts about one 
week, and does not count refills. 
      courses of antibiotics 
 
9. Have you ever used over-the-counter probiotic supplements such as Acidophilus, Accuflora, Align, Culturelle, 
Spirulina, or Phillips’ Colon Health? 
1 
 Yes 
0 
 No → If NO Go to Question # 10 
a. What was the name of the probiotic supplement(s)?       
  
 
b. How old were you the last time you took probiotics?       years old 
 
10. Have you ever taken aspirin (Bayer, Bufferin, Excedrin, etc.) at least 4 days per week for 3 months or longer? 
This doesn't include acetaminophen (Tylenol), ibuprofen (Advil, Motrin) or naproxen (Aleve). 
1 
 Yes 
0 
 No → If NO Go to Section D. PHYSICAL ACTIVITY 
 
11. For what reason do/did you take aspirin? Check all boxes that apply. 
1 
 To treat an existing condition such as arthritis, heart disease, or stroke  
2 
 To prevent heart attacks, stroke, or cancer 
3 
 To treat chronic pain or headaches 
4 
 Other reason (please describe):       
 
 
12. How old were you when you started taking aspirin at least 4 days per week?       years old 
 
13. Do you take aspirin at least 4 days per week now? 
1 
 Yes 
0 
 No 
 
14. Please tell me about the 
type(s) of aspirin you have 
used. Repeat for each type. 
If Yes, ask additional details. 
How often do/did you 
take (type of aspirin)? 
How many 
tablets did you 
take at a time? 
Over your lifetime, about 
how long did you take 
(aspirin type)? Write in a 
number and check one box. 
a. Low-dose or baby aspirin 
(81 mg per tablet) 
0 
 I don’t use it 
1 
 Every day 
2 
 4-6 days a week 
3 
 2-3 days a week 
4 
 Once a week or less 
1 
 1 
2 
 2 
3 
 3 or more 
      
2 
 Weeks 
3 
 Months 
4 
 Years 
b. Regular strength aspirin 
(325 mg per tablet) 
0 
 I don’t use it 
1 
 Every day 
2 
 4-6 days a week 
3 
 2-3 days a week 
4 
 Once a week or less 
1 
 1 
2 
 2 
3 
 3 or more 
      
2 
 Weeks 
3 
 Months 
4 
 Years 
c. Extra strength aspirin 
(500 mg per tablet)   
0 
 I don’t use it 
1 
 Every day 
2 
 4-6 days a week 
3 
 2-3 days a week 
4 
 Once a week or less 
1 
 1 
2 
 2 
3 
 3 or more 
      
2 
 Weeks 
3 
 Months 
4 
 Years 
d. Other type of aspirin 
      
  
Dose:      mg per tablet 
1 
 Every day 
2 
 4-6 days a week 
3 
 2-3 days a week 
4 
 Once a week or less 
1 
 1 
2 
 2 
3 
 3 or more 
      
2 
 Weeks 
3 
 Months 
4 
 Years 








NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–85– 
 
INTERVIEWER'S REMARKS 
 
1. Participant ID       
 
 
2. Visit Number 
1 
 First 
 
3. Interviewer 
        (Initials) 
 
4. Date of Interview 
Month       Day       Year        
 
5. Interview Start Time 
        :          (Hour: Minutes [24-hour time]) 
 
6. Interview End Time 
        :          (Hour: Minutes [24-hour time]) 
 
7. The interview included: (Check all boxes that apply.) 
1 
 The participant only 
2 
 A spouse or partner 
3 
 Another family member 
4 
 Another person (please specify)       
  
 
8. The participant's cooperation was: (Check one box only.) 
1 
 Excellent 
2 
 Very Good 
3 
 Good 
4 
 Fair 
5 
 Poor 
 
9. The quality of the interview is: (Check one box only.) 
1 
 Excellent 
2 
 Generally reliable 
3 
 Questionable 
4 
 Unreliable 
 
 
 
 
  
_ 
 
 
Signature of Clinical Research Staff who administered questionnaire 
Date 
 
 
 


NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–86– 
APPENDIX F 
 
 
 
 
Participant ID:        
 
Date:       
 
 
 
 
 
 
 
Statin Therapy to Reduce the Risk of Recurrent Pancreatitis 
 
 
 
 
Follow-Up Questionnaire – Study Visit 3 (6-Month Visit) 
 
 
 
 
 
Thank you for continuing to participate in our study. We appreciate the time you are 
taking to complete this questionnaire. This questionnaire focuses on any changes that 
may have occurred since your first research visit for this study on       (date of baseline 
visit). Please try to answer each question as completely as you can, even if you are unsure 
about the answer. If you feel uncomfortable answering any question, you can choose not 
to answer it. All answers will be kept confidential. 




NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–88– 
5. Since your first research visit for this study on 
      (date of baseline visit), have you had 
surgery to remove your (type of tissue)? 
Repeat for each type of tissue. If Yes, ask 
question about surgery date. 
Yes 
No 
When did you 
have this surgery? 
Month/Day/Year 
a. Appendix 
1 
 
0 
 
   /   /     
b. Gall Bladder 
1 
 
0 
 
   /   /     
c. Gall Stones 
1 
 
0 
 
   /   /     
d. Stomach or part of your stomach 
1 
 
0 
 
   /   /     
e.  Colon or rectum 
1 
 
0 
 
   /   /     
WOMEN ONLY: 
 
 
 
f. Breast (mastectomy) 
1 
 
0 
 
   /   /     
g. Uterus (hysterectomy) 
1 
 
0 
 
   /   /     
h. Ovaries (oophorectomy) 
1 
 
0 
 
   /   /     
 
6. Since your first research visit for this study 
on       (date of baseline visit), have you 
taken (type of drug)? Repeat for each drug. 
If Yes, ask additional details. Use 
continuation sheet if needed. 
Yes 
No 
What was the name of 
the medication? 
Show Hand Card 
When did you 
last take 
(drug)? 
a. Oral agent for diabetes   
1 
 
0 
       
 
   /   /     
b. 2nd oral agent for diabetes    
1 
 
0 
       
 
   /   /     
c. Insulin injection agent 
1 
 
0 
       
 
   /   /     
d. 2nd insulin injection agent 
1 
 
0 
       
 
   /   /     
e. Other injectable for diabetes 
1 
 
0 
       
 
   /   /     
f. 2nd injectable for diabetes 
1 
 
0 
       
 
   /   /     
g. Inhalable powder for diabetes 
1 
 
0 
       
 
   /   /     
h. A prescription drug to control high blood 
pressure 
1 
 
0 
       
 
   /   /     
i. 2nd drug to control high blood pressure    
1 
 
0 
       
 
   /   /     
j. Anti-depressant    
1 
 
0 
       
 
   /   /     
k. 2nd anti-depressant   
1 
 
0 
       
 
   /   /     
l. Antibiotic 
1 
 
0 
       
 
   /   /     
m.  2nd antibiotic 
1 
 
0 
       
 
   /   /     
 
 






NWU2014-04-01 
Protocol Version 3.8,  January 9, 2020 
 
–91– 
 
INTERVIEWER'S REMARKS 
 
1. Participant ID       
 
 
2. Visit Number 
3 
 Third 
 
3. Interviewer 
        (Initials) 
 
4. Date of This Visit 
Month       Day       Year        
 
5. Date of Baseline Visit 
Month       Day       Year        
 
6. Interview Start Time 
        :          (Hour: Minutes [24-hour time]) 
 
7. Interview End Time 
        :          (Hour: Minutes [24-hour time]) 
 
8. The interview included: (Check all boxes that apply.) 
1 
 The participant only 
2 
 A spouse or partner 
3 
 Another family member 
4 
 Another person (please specify)       
  
 
9. The participant's cooperation was: (Check one box only.) 
1 
 Excellent 
2 
 Very Good 
3 
 Good 
4 
 Fair 
5 
 Poor 
 
10. The quality of the interview is: (Check one box only.) 
1 
 Excellent 
2 
 Generally reliable 
3 
 Questionable 
4 
 Unreliable 
 
 
 
 
  
_ 
 
 
Signature of Clinical Research Staff who administered questionnaire 
Date