Statin Therapy for Primary Sclerosing Cholangitis

Recruiting in Palo Alto (17 mi)

Overseen by Sidhartha Sinha, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Stanford University

Must not be taking: Statins, Immunosuppressants, Fibrates, Ritonavir

Disqualifiers: Pregnancy, Autoimmune hepatitis, Cholangiocarcinoma, others

No Placebo Group

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial uses Rosuvastatin, a cholesterol-lowering drug, to treat patients with PSC, a severe liver disease. The study aims to see if the drug can change cell communication and gut bacteria behavior to help understand and treat PSC. Rosuvastatin is effective in lowering LDL cholesterol and is well tolerated in various dosages.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including statins, immunosuppressive drugs, fibrate drugs, and ritonavir-containing drugs. If you are on any of these, you would need to discontinue them to participate.

What data supports the effectiveness of the drug Rosuvastatin for treating primary sclerosing cholangitis?

There is increasing evidence that statins, like Rosuvastatin, can benefit patients with chronic liver diseases, and a study in Sweden suggests that statin use is associated with improved outcomes for patients with primary sclerosing cholangitis. ^{1 2 3 4 5}

Is statin therapy safe for humans?

Statins, including Rosuvastatin (also known as Crestor or Rosuvastatin calcium), are generally considered safe for humans and have been used to reduce the risk of colorectal cancer and cholangiocarcinoma (a type of bile duct cancer) in patients with primary sclerosing cholangitis. ^{6 7 8 9 10}

How does the drug Rosuvastatin differ from other treatments for primary sclerosing cholangitis?

Rosuvastatin is unique because it is primarily used to lower cholesterol levels and reduce inflammation, which may offer a novel approach to managing primary sclerosing cholangitis, a condition with no proven effective medical treatments. Unlike traditional treatments like ursodeoxycholic acid, which focus on improving bile flow, Rosuvastatin's potential benefits could stem from its effects on cholesterol and inflammation. ^{1 2 3 11 12}

Research Team

Sidhartha Sinha, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for adults over 18 with Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease. Participants must not be pregnant, have PSC-autoimmune hepatitis overlap, secondary sclerosing cholangitis conditions, serious medical issues without physician approval, or a history of statin use or allergy to it. They should also meet certain blood test criteria and not be on specific medications.

Inclusion Criteria

I have high cholesterol and my BMI is under 25.

I have been diagnosed with PSC and IBD according to ACG guidelines.

I am 18 years old or older.

Exclusion Criteria

I have been taking statin medication before starting this study.

Patients with known clinically allergy to statin therapy

I am currently taking medication that contains ritonavir.

Trial Timeline

Baseline Measurements

Initial measurements of bile acid profile and microbiome before treatment

2 weeks

1 visit (in-person)

Treatment

Participants receive rosuvastatin for 12 weeks to evaluate its impact on bile acid profile and microbiome

12 weeks

3 visits (in-person) at baseline, week 4, and week 14

Washout

A 2-week period without treatment to observe changes post-treatment

2 weeks

No visits

Follow-up

Participants are monitored for changes in bile acid profile and microbiome after treatment

2 weeks

1 visit (in-person) at the end of the washout period

Treatment Details

Interventions

• Rosuvastatin (HMG-CoA Reductase Inhibitor)

Trial Overview The study tests the effects of Rosuvastatin, a cholesterol-lowering drug (statin), in patients with PSC. It aims to understand how this treatment might help manage PSC by monitoring changes through various health markers collected from participants.

Participant Groups

Group I: Rosuvastatin therapy Experimental Treatment 1 Intervention

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.

Rosuvastatin is already approved in Canada, Japan for the following indications:

Approved in Canada as Crestor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in Japan as Crestor for:

• Hypercholesterolemia
• Familial hypercholesterolemia

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Dr. Richard A. Miller

Stanford University

Chief Executive Officer since 2023

Stanford University, MD

Dr. Robert Schott

Stanford University

Chief Medical Officer since 2021

University of Michigan, MD

Findings from Research

Ursodeoxycholic acid (UDCA) is the most promising treatment for primary sclerosing cholangitis, as it improves biliary secretion and may reduce the risk of colorectal and bile duct cancers, although its effects on liver histology and survival remain unclear.

Endoscopic treatment of dominant stenoses in patients with primary sclerosing cholangitis has been shown to improve cholestasis and extend survival, highlighting the importance of managing complications associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary sclerosing cholangitis. Rost, D., Kulaksiz, H., Stiehl, A.[2020]

Primary sclerosing cholangitis (PSC) is a progressive liver disease with no effective treatments currently available, and it often leads to serious complications like cirrhosis and bile duct cancer over a long period, typically a decade or more.

Management of PSC focuses on symptom relief and addressing complications, with options like balloon dilatation for strictures and liver transplantation for advanced cases, while experimental therapies such as immunosuppressive and choleretic agents are being tested in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Fifth Carlos E. Rubio Memorial Lecture. Sclerosing cholangitis: pathogenesis, pathology, and practice. Larusso, NF.[2018]

In a study of 219 patients with primary sclerosing cholangitis, a higher dose of ursodeoxycholic acid did not show a statistically significant benefit on survival or prevention of liver transplantation compared to placebo over 5 years.

Despite some trends towards lower liver transplantation rates and decreased liver enzyme levels in the ursodeoxycholic acid group, there were no significant differences in symptoms or quality of life between the treatment and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Olsson, R., Boberg, KM., de Muckadell, OS., et al.[2022]

In a study of 2914 patients with primary sclerosing cholangitis (PSC) in Sweden, statin use was linked to a significant reduction in all-cause mortality (hazard ratio of 0.68) and the risk of death or liver transplantation (hazard ratio of 0.50).

Azathioprine also showed similar benefits in reducing mortality and the need for liver transplantation, while ursodeoxycholic acid did not demonstrate any impact on mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin Use Is Associated With Improved Outcomes of Patients With Primary Sclerosing Cholangitis. Stokkeland, K., Höijer, J., Bottai, M., et al.[2021]

In a study of 22 patients with primary sclerosing cholangitis (PSC), common symptoms included fatigue, dark urine, and weight loss, with significant biochemical abnormalities observed at admission, such as elevated alkaline phosphatase and bilirubin levels.

Treatment with ursodeoxycholic acid (UDCA) did not show a statistically significant improvement in patient outcomes compared to those not receiving UDCA, indicating that while some patients improved, the therapy may not enhance prognosis overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical and pathological analysis of 22 cases of primary sclerosing cholangitis]. Liu, HH., Fu, JL., Luo, SQ., et al.[2018]

There is currently no proven medical therapy that alters the progression of primary sclerosing cholangitis (PSC), although ursodeoxycholic acid can improve liver biochemistry without affecting long-term survival outcomes.

Emerging treatments, such as fecal microbiota transplantation and synthetic bile acids, show promise in clinical trials, while balloon dilatation is a safer option than stent insertion for managing biliary strictures in PSC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Therapeutics in Primary Sclerosing Cholangitis. Tan, N., Lubel, J., Kemp, W., et al.[2023]

In a study of 21 patients with primary sclerosing cholangitis (PSC) treated with 9 mg of oral budesonide daily for one year, there was a slight improvement in liver enzyme levels, but overall benefits were minimal.

The treatment was associated with significant bone mass loss, indicating a risk of osteoporosis, and two patients required evaluation for liver transplantation, suggesting potential safety concerns with budesonide in PSC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral budesonide in the treatment of primary sclerosing cholangitis. Angulo, P., Batts, KP., Jorgensen, RA., et al.[2015]

Immunosuppressive agents (IAs) do not significantly reduce the risk of mortality or the need for liver transplantation in patients with primary sclerosing cholangitis (PSC), based on an analysis of 266 patients from 7 studies.

While IAs may lead to some improvement in liver function markers, they are associated with adverse events such as diarrhea and abdominal pain, indicating that their use may not be beneficial overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis. Peng, X., Luo, X., Hou, JY., et al.[2018]

Primary sclerosing cholangitis is a rare autoimmune disease with no current treatment options, leading to high rates of severe liver disease and the need for transplants.

Recent advances in understanding the disease's genetics and natural history have paved the way for targeted drug development, with new treatments entering clinical trials, offering hope for patient-specific therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision medicine in primary sclerosing cholangitis. Maurice, JB., Thorburn, D.[2020]

In a randomized controlled trial involving 161 patients with primary sclerosing cholangitis (PSC), the oral medication norursodeoxycholic acid (norUDCA) significantly reduced serum alkaline phosphatase (ALP) levels in a dose-dependent manner over 12 weeks, with reductions of up to 26% compared to placebo.

The safety profile of norUDCA was excellent, showing no significant difference in serious adverse events compared to the placebo group, which supports further investigation in a phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. Fickert, P., Hirschfield, GM., Denk, G., et al.[2018]

In a 30-month pilot trial involving 12 patients with primary sclerosing cholangitis, daily administration of 10 mg/kg ursodeoxycholic acid significantly reduced serum cholesterol and liver enzyme levels, indicating improved liver function during treatment periods.

Patients experienced relief from symptoms like fatigue, itching, and diarrhea while on ursodiol, with benefits persisting for up to 2 years, suggesting its potential as a long-term treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. O'Brien, CB., Senior, JR., Arora-Mirchandani, R., et al.[2019]

Currently, there are no effective treatments that can slow down or reverse the progression of primary sclerosing cholangitis (PSC), a chronic liver disease characterized by bile duct fibrosis.

High-dose ursodeoxycholic acid shows potential as a treatment option, but further large-scale trials are necessary to determine its impact on the health outcomes of patients with PSC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The management of primary sclerosing cholangitis. Mitchell, SA., Chapman, RW.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of primary sclerosing cholangitis. [2020]

2. Puerto Rico pubmed.ncbi.nlm.nih.gov

The Fifth Carlos E. Rubio Memorial Lecture. Sclerosing cholangitis: pathogenesis, pathology, and practice. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Statin Use Is Associated With Improved Outcomes of Patients With Primary Sclerosing Cholangitis. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[A clinical and pathological analysis of 22 cases of primary sclerosing cholangitis]. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Current Therapeutics in Primary Sclerosing Cholangitis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Oral budesonide in the treatment of primary sclerosing cholangitis. [2015]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis. [2018]

9. Australia pubmed.ncbi.nlm.nih.gov

Precision medicine in primary sclerosing cholangitis. [2020]

10. Netherlands pubmed.ncbi.nlm.nih.gov

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

The management of primary sclerosing cholangitis. [2019]