Statin Therapy in Primary Sclerosing Cholangitis (PSC): a Multi-omics Study

Sponsor

Stanford University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05912387

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

PSC is a liver disease that has no medical cure. Patients with PSC are at a greatly increased risk of cancer and infection. Additionally, many patients require a liver transplant. Progress towards a cure has been severely limited by an incomplete understanding of why patients develop PSC. The investigators aim to close this gap by conducting a pilot human study in patients with PSC, using statin therapy as a model

Condition or Disease	Intervention/Treatment	Phase
Primary Sclerosing Cholangitis Inflammatory Bowel Diseases	Drug: Rosuvastatin	Early Phase 1

Detailed Description

Database studies have suggested that use of statins is associated with lower mortality in patients with PSC. Statins are also safe, widely used medications for the treatment of high cholesterol. This track record of safety makes repurposing statins for use in PSC an attractive option.

This study will evaluate the impact of bile acid profile and the microbiome. Rosuvastatin induced changes in cell signaling pathways in the body, as well as its impact of bacterial gene expression in the microbiome will be evaluated. The investigators anticipate that this study will provide key insights into the biologic basis of PSC, which may aid in the development of drugs for the treatment of PSC.

This research study will enroll patients with PSC. The study will be conducted in 3 phases:

baseline measurements, study period (treatment with rosuvastatin), and follow-up (follow-up after completing statin treatment). All patients will receive the study drug, and no patients will receive placebo treatment. Rosuvastatin is FDA approved for treatment of high cholesterol, but its use in this trial is off label.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

The Effect of Statin Therapy on Bile Acid Physiology and the Microbiome in Primary Sclerosing Cholangitis (PSC): a Multi-omics Study

Actual Study Start Date :

May 31, 2023

Anticipated Primary Completion Date :

May 31, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rosuvastatin therapy Participants will receive rosuvastatin for 12 weeks followed by a 2 week washout period prior to the final follow-up visit. All patients will receive the study drug, and will serve as their own control. No participants will receive placebo. Rosuvastatin is FDA approved for treatment of high cholesterol, but its use in this trial is off label.	Drug: Rosuvastatin Rosuvastatin 20 mg tablet once daily by mouth

Arm

Intervention/Treatment

Experimental: Rosuvastatin therapy

Participants will receive rosuvastatin for 12 weeks followed by a 2 week washout period prior to the final follow-up visit. All patients will receive the study drug, and will serve as their own control. No participants will receive placebo. Rosuvastatin is FDA approved for treatment of high cholesterol, but its use in this trial is off label.

Drug: Rosuvastatin

Rosuvastatin 20 mg tablet once daily by mouth

Outcome Measures

Primary Outcome Measures

Change in bile acid (BA) profile: total bile acid [Baseline and week 12]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio [Baseline and week 12]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio [Baseline and week 12]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in pathogen density in the duodenum [Baseline and week 12]
Measure impact of statin therapy upon pathogen density (ratio of good bacteria to pathogenic bacteria) within the microbial community of the duodenum.
Change in bacterial gene expression profile in the duodenum [Baseline and week 12]
This outcome aims to develop an understanding of the profile of microbial metabolic pathways in the duodenum and changes to the profile in response to statin therapy; gene sequencing with be done using shotgun metagenomics followed by pathway analysis.

Secondary Outcome Measures

Change in bile acid (BA) profile: total bile acid [Baseline, week 4, week 14]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio [Baseline, week 4, week 14]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio [Baseline, week 4, week 14]
BA profile of biliary aspirate and feces in response to statin therapy.
Change in pathogen density in the duodenum [Baseline, week 4, week 14]
Measure impact of statin therapy upon pathogen density (ratio of good bacteria to pathogenic bacteria) within the microbial community of the duodenum.
Change in bacterial gene expression profile in the duodenum [Baseline, week 4, week 14]
This outcome aims to develop an understanding of the profile of microbial metabolic pathways in the duodenum and changes to the profile in response to statin therapy; gene sequencing with be done using shotgun metagenomics followed by pathway analysis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Males and females, greater than or equal to 18 years of age
Established diagnosis of PSC, defined by either appropriate cholangiographic findings or supportive liver biopsy plus an established diagnosis of inflammatory bowel disease (IBD - Crohn's disease or ulcerative colitis) per American College of Gastroenterology (ACG) guidelines for the PSC-IBD arm
Hypercholesterolemia with BMI < 25.0 for the comparison arm

Exclusion Criteria:

Diagnosis of PSC-autoimmune hepatitis overlap syndrome
Woman who are pregnant, nursing, or expect to be pregnant
The presence of any comorbidity known to cause secondary sclerosing cholangitis, including: immunoglobulin G-4 (IgG4), associated cholangitis, recurrent bacterial cholangitis, recurrent pyogenic cholangitis, ischemic cholangiopathy, surgical biliary trauma, cholangiocarcinoma, and portal hypertensive biliopathy
Diagnosis of a serious medical condition (unless approved in writing by a physician)
Patients taking statin therapy prior to study initiation
Patients with known clinically allergy to statin therapy
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5 times the upper limit of normal
Bilirubin greater than 3.0 mg/dL
Recent use of antibiotics (within the last 90 days)
Concurrent use of any immunosuppressive medications (such as any calcineurin inhibitor, steroids at a dose greater than 10 mg of prednisone-equivalents per day)
Actively using a fibrate drug
Actively using a ritonavir containing drug
Familial hypercholesterolemia or other inherited disorder of lipid metabolism
Recent myocardial infarction or cerebrovascular accident
Body mass index > 25.0 for the comparison arm
Chronic kidney disease stage 5 or end-stage renal disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Stanford	California	United States	94305

Sponsors and Collaborators

Stanford University

Investigators

Principal Investigator: Chiraag Kulkarni, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Chiraag Kulkarni, Principal Investigator, Stanford University

ClinicalTrials.gov Identifier:

NCT05912387

Other Study ID Numbers:

67292

First Posted:

Jun 22, 2023

Last Update Posted:

Jun 22, 2023

Last Verified:

Jun 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Keywords provided by Chiraag Kulkarni, Principal Investigator, Stanford University

Statin

Additional relevant MeSH terms:

Inflammatory Bowel Diseases

Cholangitis

Cholangitis, Sclerosing

Rosuvastatin Calcium

Study Results

No Results Posted as of Jun 22, 2023