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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Primary Sclerosing Cholangitis, Inflammatory Bowel Diseases

Intervention / Treatment
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* Drug: Rosuvastatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rosuvastatin therapy<br>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<br>* Rosuvastatin 20 mg tablet once daily by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in bile acid (BA) profile: total bile acid | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline and week 12 | 
| Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline and week 12 | 
| Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline and week 12 | 
| Change in pathogen density in the duodenum | Measure impact of statin therapy upon pathogen density (ratio of good bacteria to pathogenic bacteria) within the microbial community of the duodenum. | Baseline and week 12 | 
| Change in bacterial gene expression profile in the duodenum | 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. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in bile acid (BA) profile: total bile acid | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline, week 4, week 14 | 
| Change in bile acid (BA) profile: secondary bile acids:primary bile acids ratio | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline, week 4, week 14 | 
| Change in bile acid (BA) profile: conjugated:unconjugated BAs ratio | BA profile of biliary aspirate and feces in response to statin therapy. | Baseline, week 4, week 14 | 
| Change in pathogen density in the duodenum | Measure impact of statin therapy upon pathogen density (ratio of good bacteria to pathogenic bacteria) within the microbial community of the duodenum. | Baseline, week 4, week 14 | 
| Change in bacterial gene expression profile in the duodenum | 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. | Baseline, week 4, week 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Statin