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

• ClinicalTrials.gov Identifier: NCT05912387
• Recruitment Status: Recruiting
• First Posted: June 22, 2023
• Last Update Posted: March 21, 2024
• Sponsor: Stanford University
• Information provided by (Responsible Party): Sidhartha Ranjit Sinha, Stanford University

Tracking Information

• First Submitted Date: June 1, 2023
• First Posted Date: June 22, 2023
• Last Update Posted Date: March 21, 2024
• Actual Study Start Date: May 31, 2023
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2024)

• Change in bile acid (BA) profile: total bile acid [ Time Frame: Baseline and week 12 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio [ Time Frame: Baseline and week 12 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio [ Time Frame: Baseline and week 12 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in pathogen density in the small intestine [ Time Frame: 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 small intestine [ Time Frame: 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.

Original Primary Outcome Measures (submitted: June 12, 2023)

• Change in bile acid (BA) profile: total bile acid [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline and week 12 ]
  BA profile of biliary aspirate and feces in response to statin therapy.
• Change in pathogen density in the duodenum [ Time Frame: 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 [ Time Frame: 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.

Current Secondary Outcome Measures (submitted: March 19, 2024)

• Change in bile acid (BA) profile: total bile acid [ Time Frame: Baseline, week 4, week 14 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio [ Time Frame: Baseline, week 4, week 14 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio [ Time Frame: Baseline, week 4, week 14 ]
  BA profile of biliary/intestinal aspirate and/or feces in response to statin therapy.
• Change in pathogen density in the small intestine [ Time Frame: 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 small intestine [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: June 12, 2023)

• Change in bile acid (BA) profile: total bile acid [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline, week 4, week 14 ]
  BA profile of biliary aspirate and feces in response to statin therapy.
• Change in pathogen density in the duodenum [ Time Frame: 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 [ Time Frame: 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Primary Sclerosing Cholangitis
• Inflammatory Bowel Diseases

Intervention

Drug: Rosuvastatin

Rosuvastatin 20 mg tablet once daily by mouth

Study Arms

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.

Intervention: Drug: Rosuvastatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 12, 2023): 15
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Touran Fardeen; (650) 725-5890; tfardeen@stanford.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05912387
• Other Study ID Numbers: 67292
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual participant data will not be shared

• Current Responsible Party: Sidhartha Ranjit Sinha, Stanford University
• Original Responsible Party: Chiraag Kulkarni, Stanford University, Principal Investigator
• Current Study Sponsor: Stanford University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sidhartha Sinha, MD; Stanford University

• PRS Account: Stanford University
• Verification Date: March 2024