Simvastatin in Reducing Pancreatitis in Patients With Recurrent, Acute or Chronic Pancreatitis

PRIMARY OBJECTIVES:

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 change in the endoscopic ultrasound score (EUS). II. To evaluate the effect of a
simvastatin intervention versus placebo at 6 months from baseline (study visit

1) on change in fecal elastase. III. To evaluate the effect of a simvastatin intervention
versus placebo at 6 months from baseline (study visit

1) on change in serum and pancreatic fluid levels of CRP, IL-6, IL-10, TGFbeta1, MMP-9,
TNF-alpha, and soluble (s)-fractalkine.

IV. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline (study visit 1) on change in pancreatic fluid levels of EMT markers, e-cadherin and
vimentin.

V. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline (study visit 1) on change in pancreatitis-related readmissions. VI. To evaluate the
effect of a simvastatin intervention versus placebo at 6 months from baseline (study visit

1) on change in KRAS gene mutations in pancreatic fluid. VII. To evaluate the effect of a
simvastatin intervention versus placebo at 6 months from baseline (study visit

1) on change in quality of life score as measured by the quality of life questionnaire core
30 (QLQ-C30) and quality of life questionnaire pancreatic modification (QLQ-PAN28) 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.

Inclusion Criteria:

- At least two episodes of acute pancreatitis in the past 12 months; acute pancreatitis
is defined 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

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Leukocytes >= 2,500/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Hemoglobin > 10 g/dL

- Total bilirubin =< 3.0 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 x institutional ULN; patients whose AST/ALT levels normalize by screen 2 after
an abnormal test will be included in the trial

- Creatinine < 1.5 mg/dL

- Women of child-bearing potential must have a confirmed negative pregnancy test result
prior to enrollment

- Women of child-bearing potential and men 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; women who receive treatment with simvastatin should not breastfeed their
infants

- Ability to understand and the willingness to sign a written informed consent document
and medical release

- Willing and able to comply with trial protocol and follow-up

Exclusion Criteria:

- Prior or current use of statin medication, or current use of gemfibrozil,
cyclosporine, danazol, lomitapide, verapamil, diltiazem, dronedarone, amiodarone,
amlodipine, ranolazine, or strong cytochrome P450, family 3, subfamily A, polypeptide
4 (CYP3A4) inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole,
human immunodeficiency virus [HIV] protease inhibitors, boceprevir, telaprevir,
erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing
products)

- History of chronic myopathy

- Current use of any other investigational agents

- History of adverse effects, intolerance, or allergic reactions attributed to compounds
of similar chemical or biologic composition to simvastatin (i.e., other statin
medications)

- 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

- Women who are pregnant or breastfeeding; breastfeeding should be discontinued if the
mother is treated with simvastatin

- Presence of gallstones and 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

- History of pancreatic adenocarcinoma (at any time)

- 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)

- Known active infection with HIV

- 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

- Laboratory (lab) results do not meet inclusion criteria

- Recurrent pancreatitis episode is iatrogenic (endoscopic retrograde
cholangiopancreatography [ERCP] induced)

- Advanced chronic pancreatitis as determined by the following criteria: EUS score
greater than 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