The following datasets contain the data available for EPPT NWU2014-04-01. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 35 datasets contain the raw form data received, excluding PII.

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Trial 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.

Patients are randomized to 1 of 2 treatment arms:

• Arm I (Simvastatin): Patients receive Simvastatin orally (PO) once daily (QD) for 6 months.
• Arm II (placebo): Patients receive placebo PO QD for 6 months.

Enrollment Statistics

Target Enrollment: 30

Actual Enrollment: 8

Actual Registration: 8

• 8 people randomized
  • 6 in Arm I: Simvastatin
    • 6 completed the study
  • 2 in Arm II: Placebo
    • 1 completed the study
    • 1 lost to follow-up

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

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Thirty-eight recurrent acute pancreatitis (RAP) patients were prescreened as eligible for the trial and were approached; however, 30 patients (79%) were not enrolled. Six RAP patients (4 women, 2 men) were randomized to simvastatin and 2 patients (2 men) to the placebo control between 2016 and 2019. The trial was closed for failure to recruit a minimum 50% of the recruitment goal. The resulting sample size was too small to draw conclusions regarding the study endpoints. Barriers to recruitment included stringent eligibility criteria and high prevalence of statin use in the adult population of the United States. Gallstone disease, continued chronic alcohol abuse, and concern about the complex study procedures were important barriers to recruitment.

Mean peak bicarbonate levels did not differ significantly between the simvastatin and placebo groups (P = 0.29) in intention-to-treat analysis (Table 1). After adjustment for treatment, visit, and treatment × visit interaction (P for interaction, 0.07), the difference remained nonsignificant. Although none of the results achieved statistical significance, the peak bicarbonate concentration (mmol/L) between the baseline and 6-month visit tended to decrease in the simvastatin group (mean [standard deviation], −8.2 [22.7]) but increase in the placebo group (mean [standard deviation], 5.5 [0.7]) (Table 1). The expression of 3 biomarkers, hepatocyte growth factor, resistin, and Fas ligand were differentially expressed (P < 0.05) between the simvastatin and placebo groups (Table 1).

This feasibility study provides important insight regarding the design of future trials in subjects with RAP. The selection of endoscopic pancreatic function test (ePFT) as a primary outcome measure should be avoided. Alternative study endpoints that are less invasive and more likely to attract patient interest in participation need to be considered. To complement health-related quality-of-life outcomes like pain alleviation, the use of validated imaging or molecular markers of progression, such as circulating cell-free mitochondrial DNA,7 must be further developed. Attainability of recruitment goals is an important consideration in future trials.