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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02743364
• Collaborator: (none)
• Enrollment: 8
• Locations: 5
• Arms: 2
• Patients Per Site: 1.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Pancreatitis	Other: Laboratory Biomarker Analysis; Other: Placebo Administration; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Simvastatin	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Statin Therapy to Reduce the Risk of Recurrent Pancreatitis
• Actual Study Start Date: Sep 19, 2016
• Actual Primary Completion Date: Oct 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (simvastatin) Patients receive simvastatin PO QD for 6 months.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies; Drug: Simvastatin; Given PO; Other Names: MK 733 Synvinolin Zocor
Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 6 months.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo Administration; Given PO; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Pancreatitis-related Readmissions [Baseline to up to 6 months]

   Number of participants with pancreatitis-related hospital readmissions.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
2	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
3	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
4	Southern California Permanente Medical Group	Pasadena	California	United States	91188
5	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Marc T Goodman, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 9, 2020

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02743364
• Other Study ID Numbers: NCI-2016-00437; NCI-2016-00437; N01-CN-2012-00035; NCI2014-04-01; NWU2014-04-01; N01CN00035; P30CA060553
• First Posted: Apr 19, 2016
• Last Update Posted: Jan 4, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Pancreatitis; Simvastatin

Study Results

Participant Flow

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	6	2
COMPLETED	6	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	6	2	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.0 (12.9)	35.0 (11.3)	43.3 (12.8)
Sex: Female, Male (Count of Participants)
Female	4 66.7%	0 0%	4 50%
Male	2 33.3%	2 100%	4 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	2 100%	8 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 16.7%	0 0%	1 12.5%
White	5 83.3%	2 100%	7 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%	2 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Change in Peak Bicarbonate Concentration, Measured Using Endoscopic Pancreatic Function Test (ePFT)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	6	2
Mean (Standard Deviation) [mmol/l]	-8.20 (22.7)	5.50 (0.707)

2. Secondary Outcome

Title	Change in the Endoscopic Ultrasound Score (EUS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	6	2
Mean (Standard Deviation) [score on a scale]	0.500 (1.38)	0.500 (0.707)

3. Secondary Outcome

Title	Serum and Pancreatic Secretions
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	6	2
Baseline HGF	5.72	7.13
6 month HGF	5.76	5.99
Baseline Resistin	13.79	12.39
6 month Resistin	12.94	12.45
Baseline FASL	4.99	4.83
6 month FASL	4.83	4.82

4. Secondary Outcome

Title	Pancreatitis-related Readmissions
Description	Number of participants with pancreatitis-related hospital readmissions.
Time Frame	Baseline to up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	6	2
Count of Participants [Participants]	5 83.3%	1 50%

5. Secondary Outcome

Title	Change in Health-related Quality of Life.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Simvastatin)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	6	2
Physical Functioning	5.6 (6.6)	6.7 (9.4)
Role Functioning	30.6 (35.6)	25.0 (35.4)
Cognitive Functioning	2.8 (6.8)	16.7 (23.6)
Social Functioning	22.2 (36.0)	8.3 (35.4)
Fatigue	-22.2 (35.1)	-50.0 (39.3)
Pain	-8.3 (36.1)	-25.0 (35.4)
Insomnia	-22.2 (50.2)	-33.3 (47.1)
Overall	19.4 (19.5)	33.3 (0)

Adverse Events

Time Frame	AEs collected from the time informed consent was signed and baseline procedures were completed through 90 days post-intervention. In total AEs collected for a period of 9 months.
Arm/Group Title	Arm I (Simvastatin)		Arm II (Placebo)
Arm/Group Description	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		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
All Cause Mortality
	Arm I (Simvastatin)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/2 (0%)
Serious Adverse Events
	Arm I (Simvastatin)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		1/2 (50%)
Gastrointestinal disorders
Pancreatitis	5/6 (83.3%)	12	1/2 (50%)	1
Abdominal Pain	0/6 (0%)	0	1/2 (50%)	1
Infections and infestations
Urinary Tract Infection	1/6 (16.7%)	1	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Simvastatin)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		2/2 (100%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	2/2 (100%)	2
Gastrointestinal disorders
Abdominal Pain	5/6 (83.3%)	15	2/2 (100%)	3
Constipation	4/6 (66.7%)	5	1/2 (50%)	1
Nausea	3/6 (50%)	5	1/2 (50%)	1
Vomiting	3/6 (50%)	4	0/2 (0%)	0
Dyspepsia	1/6 (16.7%)	3	0/2 (0%)	0
Investigations
Alanine aminotransferase increased	1/6 (16.7%)	2	1/2 (50%)	1
Aspartate aminotransferase increased	1/6 (16.7%)	1	1/2 (50%)	1
Metabolism and nutrition disorders
Anorexia	1/6 (16.7%)	1	1/2 (50%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.