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

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

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
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Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05912387


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

Locations
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United States, California
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Touran Fardeen       tfardeen@stanford.edu   
Sponsors and Collaborators
Stanford University
Investigators
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Principal Investigator: Sidhartha Sinha, MD Stanford University
More Information
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Responsible Party: Sidhartha Ranjit Sinha, Principal Investigator, Stanford University
ClinicalTrials.gov Identifier: NCT05912387    
Other Study ID Numbers: 67292
First Posted: June 22, 2023    Key Record Dates
Last Update Posted: March 21, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared

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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
Keywords provided by Sidhartha Ranjit Sinha, Stanford University:
Statin
Additional relevant MeSH terms:
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Inflammatory Bowel Diseases
Cholangitis
Cholangitis, Sclerosing
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Gastroenteritis
Bile Duct Diseases
Biliary Tract Diseases
 Rosuvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors