Acute Pancreatitis
Conditions
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo Administration
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
DRUGSimvastatin
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Bicarbonate Concentration, Measured Using Endoscopic Pancreatic Function Test (ePFT) | Baseline to up to 6 months | Change in peak bicarbonate level (mmol/l) from baseline up to 6 months. Decreased peak bicarbonate concentration indicates worsening pancreatic function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Endoscopic Ultrasound Score (EUS) | Baseline to up to 6 months | 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. |
| Serum and Pancreatic Secretions | Baseline and 6 months | 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. |
| Pancreatitis-related Readmissions | Baseline to up to 6 months | Number of participants with pancreatitis-related hospital readmissions. |
| Change in Health-related Quality of Life. | Baseline to up to 6 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Simvastatin) Patients receive simvastatin PO QD for 6 months.
Laboratory Biomarker Analysis: Correlative studies
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies
Simvastatin: Given PO | 6 |
| Arm II (Placebo) Patients receive placebo PO QD for 6 months.
Laboratory Biomarker Analysis: Correlative studies
Placebo Administration: Given PO
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies | 2 |
| Total | 8 |
Baseline characteristics
| Characteristic | Arm I (Simvastatin) | Total | Arm II (Placebo) |
|---|---|---|---|
| Age, Continuous | 46.0 years STANDARD_DEVIATION 12.9 | 43.3 years STANDARD_DEVIATION 12.8 | 35.0 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 8 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 2 Participants |
| Region of Enrollment United States | 6 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 5 / 6 | 2 / 2 |
| serious Total, serious adverse events | 5 / 6 | 1 / 2 |
Outcome results
Primary
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.
Time frame: Baseline to up to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Simvastatin) | Change in Peak Bicarbonate Concentration, Measured Using Endoscopic Pancreatic Function Test (ePFT) | -8.20 mmol/l | Standard Deviation 22.7 |
| Arm II (Placebo) | Change in Peak Bicarbonate Concentration, Measured Using Endoscopic Pancreatic Function Test (ePFT) | 5.50 mmol/l | Standard Deviation 0.707 |
Secondary
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.
Time frame: Baseline to up to 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Physical Functioning | 5.6 score on a scale | Standard Deviation 6.6 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Fatigue | -22.2 score on a scale | Standard Deviation 35.1 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Cognitive Functioning | 2.8 score on a scale | Standard Deviation 6.8 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Pain | -8.3 score on a scale | Standard Deviation 36.1 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Role Functioning | 30.6 score on a scale | Standard Deviation 35.6 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Social Functioning | 22.2 score on a scale | Standard Deviation 36 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Overall | 19.4 score on a scale | Standard Deviation 19.5 |
| Arm I (Simvastatin) | Change in Health-related Quality of Life. | Insomnia | -22.2 score on a scale | Standard Deviation 50.2 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Overall | 33.3 score on a scale | Standard Deviation 0 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Physical Functioning | 6.7 score on a scale | Standard Deviation 9.4 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Role Functioning | 25.0 score on a scale | Standard Deviation 35.4 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Cognitive Functioning | 16.7 score on a scale | Standard Deviation 23.6 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Social Functioning | 8.3 score on a scale | Standard Deviation 35.4 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Fatigue | -50.0 score on a scale | Standard Deviation 39.3 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Pain | -25.0 score on a scale | Standard Deviation 35.4 |
| Arm II (Placebo) | Change in Health-related Quality of Life. | Insomnia | -33.3 score on a scale | Standard Deviation 47.1 |
Secondary
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.
Time frame: Baseline to up to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Simvastatin) | Change in the Endoscopic Ultrasound Score (EUS) | 0.500 score on a scale | Standard Deviation 1.38 |
| Arm II (Placebo) | Change in the Endoscopic Ultrasound Score (EUS) | 0.500 score on a scale | Standard Deviation 0.707 |
Secondary
Pancreatitis-related Readmissions
Number of participants with pancreatitis-related hospital readmissions.
Time frame: Baseline to up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Simvastatin) | Pancreatitis-related Readmissions | 5 Participants |
| Arm II (Placebo) | Pancreatitis-related Readmissions | 1 Participants |
Secondary
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.
Time frame: Baseline and 6 months
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | Baseline HGF | 5.72 median fluorescent intensity |
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | 6 month HGF | 5.76 median fluorescent intensity |
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | Baseline Resistin | 13.79 median fluorescent intensity |
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | 6 month Resistin | 12.94 median fluorescent intensity |
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | Baseline FASL | 4.99 median fluorescent intensity |
| Arm I (Simvastatin) | Serum and Pancreatic Secretions | 6 month FASL | 4.83 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | Baseline FASL | 4.83 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | Baseline HGF | 7.13 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | 6 month Resistin | 12.45 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | 6 month HGF | 5.99 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | 6 month FASL | 4.82 median fluorescent intensity |
| Arm II (Placebo) | Serum and Pancreatic Secretions | Baseline Resistin | 12.39 median fluorescent intensity |