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

Study Overview
=================
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.

Official Title
-----------------
Statin Therapy to Reduce the Risk of Recurrent Pancreatitis

Conditions
-----------------
Acute Pancreatitis

Intervention / Treatment
-----------------
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Simvastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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 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; 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 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; 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (simvastatin)<br>Patients receive simvastatin PO QD for 6 months. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Simvastatin<br>* Given PO<br>* Other names: Zocor;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for 6 months. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peak Bicarbonate Concentration, Measured Using Endoscopic Pancreatic Function Test (ePFT) | Change in peak bicarbonate level (mmol/l) from baseline up to 6 months. Decreased peak bicarbonate concentration indicates worsening pancreatic function. | Baseline to up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Endoscopic Ultrasound Score (EUS) | Change in EUS score (0-96) from baseline to up to 6 months. EUS Score is a measure of pancreatitis by the presence or absence of nine ductal and parenchymal criteria for CP: 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 96. Presence of 6 or more standard criteria indicates advanced chronic pancreatitis. A positive score indicates an improvement. A negative score indicates a reduction. | Baseline to up to 6 months | 
| Serum and Pancreatic Secretions | Expression of three biomarkers, HGF (hepatocyte growth factor), Resistin, and FASL (Fas ligand) in fluorescent intensity (arbitrary units), as an estimate of immune analyte concentration. | Baseline and 6 months | 
| Pancreatitis-related Readmissions | Number of participants with pancreatitis-related hospital readmissions. | Baseline to up to 6 months | 
| Change in Health-related Quality of Life. | Change in health-related quality of life scores (1-100) from baseline to up to 6 months measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-PAN28(CP) scores. A positive value indicates improvement and a negative value indicates reduction. | Baseline to up to 6 months |