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.
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The Enhanced Person dataset contains all relevant information from every dataset received (except adverse dataset). Each record represents one participant and contains updated variable names, formats, and labels. All information coming from non-person-based datasets has been converted into a person-based format.
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The Adverse Events dataset contains adverse event information, including onset date, grade of severity, attribution to the study agent, and outcome. This version of the dataset includes updated variable names, formats, and labels.
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.
Schema Description
Medical records were checked for pre-screening eligibility. Next patients went through a screening evaluation to check other eligibility requirements. They signed an informed consent form and went through a physical exam, lab tests, x-ray imaging, medical imaging, and an eligibility screening. Patients were then randomized and either got Simvastatin (40mg) or a placebo identical in color, consistency, and appearance to Simvastatin daily for 6 months. Next patients had 3 visits, baseline, month 3 plus or minus 1 month, and month 6 plus or minus 1 month. Patients went through a physical exam, had vital signs and a medical history take, lab tests and results, QLQ-C30, QLQ-PAN28(CP), and compliance and adverse events forms. Follow-up telephone calls to assess adverse events were done after the trial ended.
Biospecimen Report
Endoscopic pancreatic function test (ePFT) for collection of fasting pancreatic fluid
Instructions regarding the endoscopic procedures (Esophagogastroduodenoscopy (EGD) or endoscopic 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. Processed specimens will be stored in a -80°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 -80°C.
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. 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.
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 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. TwentymL of blood will be drawn into three vacutainer tubes, including one 6 mL red top serum tube and two 7mL lavender top EDTA tubes, for DNA extraction and use in future studies. The blood will be collected and processed. Processed specimens will be stored at -80°C for later measurement of cytokine concentrations, DNA extraction, and use in future studies.
Number of Biospecimen Vials/Slides Collected Per Person
Material
Visit 1
Visit 2
Visit 3
Plasma (36 mL)
1
1
1
Serum (6 mL)
1
1
1
Buffy Coat (7 mL)
2
2
2
RBC (36 mL)
1
1
1
Blood Clot
1
1
1
Secretin
1
1
Stool
1
1
1
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.
