Rosuvastatin for Liver Cirrhosis

(LCN RESCU Trial)

Recruiting at 12 trial locations

Overseen By Crystal Santillanes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Statins, Amiodarone, Methotrexate, others

Disqualifiers: Hepatocellular carcinoma, Portal thrombosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 96 weeks

256 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of rosuvastatin, a medication typically used for cholesterol, in individuals with compensated cirrhosis (a type of liver damage). The study will compare rosuvastatin to a placebo (a non-active pill) over two years. Individuals with a clinical diagnosis of cirrhosis due to nonalcoholic steatohepatitis, alcohol-related liver disease, or treated viral hepatitis, who do not currently have severe symptoms like fluid buildup or confusion, may be suitable candidates. Participants should not be on statins or have had recent serious heart or liver issues. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as statins, and some others that could interfere with the study. If you're on any of these, you may need to stop them before joining the trial.

Is there any evidence suggesting that rosuvastatin is likely to be safe for humans?

Research has shown that rosuvastatin is generally well-tolerated by most people. One study found that the risk of liver failure for those taking rosuvastatin is very low, about 1 in a million, similar to the risk for people not taking any statins. However, rare cases of serious liver problems have occurred. Most people taking rosuvastatin do not experience these issues.

For individuals with chronic liver disease, using strong statins like rosuvastatin has been linked to a lower risk of death, suggesting potential benefits for those with liver conditions.

In summary, rosuvastatin appears safe for most people, but like any medication, it carries some risks. Always consult a doctor about possible side effects before starting any new treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cirrhosis?

Researchers are excited about rosuvastatin for liver cirrhosis because it offers a unique approach compared to standard treatments like lifestyle changes, antiviral treatments, and other medications that mainly manage symptoms or underlying causes. Rosuvastatin is a statin, which is typically used to lower cholesterol, but it also has anti-inflammatory and antifibrotic properties that could directly benefit liver function. This dual action not only addresses cholesterol-related issues but also targets the liver's inflammation and scarring, potentially offering a new way to slow or even reverse the progression of cirrhosis. This makes rosuvastatin a promising candidate for changing how liver cirrhosis is treated.

What evidence suggests that rosuvastatin might be an effective treatment for liver cirrhosis?

Research has shown that rosuvastatin might help people with liver problems. In this trial, participants will receive either rosuvastatin or a placebo. For those with long-term liver disease, strong statins like rosuvastatin are linked to a lower risk of death. Statins do more than lower cholesterol; they also help the liver by reducing scarring, swelling, and damage from harmful molecules. Other studies found that rosuvastatin doesn't significantly change in the bodies of people with mild liver disease, suggesting it can be used safely in these cases. ^{1 3 4 6 7}

Who Is on the Research Team?

Jody Ciolino

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

Adults aged 18-75 with compensated cirrhosis due to nonalcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, or cryptogenic causes. Participants must have a clinical diagnosis of cirrhosis confirmed by biopsy or other criteria and cannot be on statins or have conditions like uncontrolled diabetes, recent serious cardiovascular events, active substance abuse, certain infections or cancers.

Inclusion Criteria

I have been diagnosed with cirrhosis caused by fatty liver, alcohol, viral hepatitis, or unknown reasons.

My liver disease is stable without severe symptoms.

My cirrhosis has been confirmed by a doctor using tests or imaging.

Exclusion Criteria

I have chronic hepatitis B or C that has not been treated.

I experience significant muscle pain or tenderness.

Alcohol Use Disorder Identification Test (AUDIT) score of ≥8

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

Open-label active run-in phase to evaluate initial safety and adherence to rosuvastatin

4 weeks

1 visit (in-person)

Treatment

Participants receive either rosuvastatin or placebo for 96 weeks

96 weeks

Regular visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Rosuvastatin

Trial Overview The trial is testing the safety and effectiveness of rosuvastatin versus a placebo in patients with compensated cirrhosis over two years. It's a phase 2 study where neither the participants nor the researchers know who receives the actual medication (double-blind).

How Is the Trial Designed?

Group I: Active Experimental Treatment 1 Intervention

Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry) rosuvastatin by mouth once daily, followed by a period of 96 weeks rosuvastatin 20 mg daily (10 mg daily for participants of East-Asian ancestry).

Group II: Placebo Placebo Group 1 Intervention

Open-label lead-in period of 4 weeks on 20 mg (10 mg for participants of East ancestry) rosuvastatin by mouth once daily, followed by a period of 96 weeks placebo.

Rosuvastatin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Crestor for:

• High cholesterol
• Hyperlipoproteinemia
• Prevention of cardiovascular disease

Approved in European Union as Crestor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

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?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

The Cleveland Clinic

Collaborator

Trials

1,072

Recruited

1,377,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

University of Miami

Collaborator

Trials

976

Recruited

423,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

University of California, San Diego

Collaborator

Trials

1,215

Recruited

1,593,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

In a study involving 12,400 patients over 12,212 patient-years, rosuvastatin was found to have a safety profile similar to other statins, with adverse events occurring in 57.4% of patients, comparable to 56.8% in the placebo group.

Serious side effects like myopathy and significant liver or muscle enzyme elevations were very rare (less than 0.03% for myopathy), indicating that rosuvastatin is well tolerated among patients with dyslipidemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of rosuvastatin. Shepherd, J., Hunninghake, DB., Stein, EA., et al.[2015]

Statins, commonly used for lowering cholesterol, are safe for patients with chronic liver disease and cirrhosis, and they may even reduce mortality and the risk of liver complications.

The review highlights that statins can help decrease complications in liver cirrhosis by addressing issues like portal hypertension, sepsis, and the risk of liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety and Benefit of Statins in Liver Cirrhosis: a Review. Souk, K., Al-Badri, M., Azar, ST.[2015]

Rosuvastatin (Crestor) is more effective than other statins in lowering low-density lipoprotein cholesterol (LDL-C), showing greater reductions across doses of 5-40 mg/day, and also increases high-density lipoprotein cholesterol while significantly reducing triglycerides.

In clinical trials, rosuvastatin was well tolerated with a low incidence of adverse events, demonstrating a safety profile similar to other statins, although long-term safety and effectiveness in preventing coronary events have not been established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin: a high-potency HMG-CoA reductase inhibitor. Lopez, LM.[2019]

In a study of 502 patients with primary hypercholesterolemia, rosuvastatin (5 mg and 10 mg) significantly reduced LDL cholesterol levels by 42% and 49%, respectively, outperforming pravastatin and simvastatin, which reduced LDL-C by 28% and 37%.

Rosuvastatin 10 mg achieved National Cholesterol Education Program (NCEP) treatment goals in 87% of patients, demonstrating its superior efficacy compared to pravastatin (53%) and simvastatin (64%), while all treatments were well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study. Paoletti, R., Fahmy, M., Mahla, G., et al.[2019]

Rosuvastatin is a highly potent statin that effectively inhibits cholesterol synthesis, showing up to a 65% reduction in LDL cholesterol in hypercholesterolemic patients during early-phase studies.

The drug selectively targets liver cells with minimal uptake in nonhepatic tissues, and it has low potential for metabolic interactions, making it a safe option for lipid-lowering therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the pharmacology of statins: characteristics of rosuvastatin. Chapman, MJ., McTaggart, F.[2019]

In the JUPITER trial, rosuvastatin significantly reduced the occurrence of major cardiovascular events in healthy individuals aged ≥60 years (women) or ≥50 years (men) with normal LDL-C levels but elevated hsCRP levels, demonstrating its efficacy in primary prevention of cardiovascular disease.

Rosuvastatin was well tolerated, with most side effects being mild to moderate, and it effectively lowered both LDL-C and hsCRP levels, although the exact mechanism of its benefits remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin: a review of its use in the prevention of cardiovascular disease in apparently healthy women or men with normal LDL-C levels and elevated hsCRP levels. Carter, NJ.[2015]

Statins, or HMG-CoA reductase inhibitors, have been shown to be effective in managing dyslipidemia and improving liver function in patients with chronic liver diseases like nonalcoholic fatty liver disease and hepatitis C, based on a review of studies from 2005 to 2011.

Despite concerns about potential liver damage, clinical trials indicated that statin therapy did not lead to significant adverse effects and often resulted in improved liver enzyme levels and lipid profiles in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor use in chronic liver disease: a therapeutic controversy. Tzefos, M., Olin, JL.[2022]

Rosuvastatin, currently in phase III clinical trials, shows promise in significantly lowering total cholesterol and LDL cholesterol levels in patients with high cholesterol, potentially more effectively than other statins.

However, there is not enough evidence to assess the safety of rosuvastatin or its impact on heart-related health outcomes, indicating that further research is needed to fully understand its benefits and risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin: do we need another statin? Ho, C.[2010]

Rosuvastatin is an effective statin that significantly improves lipid profiles in patients with dyslipidemias, outperforming other statins like atorvastatin, pravastatin, and simvastatin in achieving LDL-C goals after 12 weeks of treatment.

The treatment is generally well tolerated, with low incidences of serious side effects, such as myopathy and elevated CPK levels, making rosuvastatin a safe first-line option for managing cholesterol in both low- and high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin: a review of its use in the management of dyslipidemia. Scott, LJ., Curran, MP., Figgitt, DP.[2018]

Rosuvastatin is a potent statin that significantly reduces LDL cholesterol by 52-63% at doses of 10-40 mg, outperforming other statins like atorvastatin and simvastatin in lowering LDL levels.

It is well tolerated and has a safety profile similar to other statins, making it a suitable option for patients with dyslipidemia, including those with hypertriglyceridemia or diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosuvastatin--a highly effective new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor: review of clinical trial data at 10-40 mg doses in dyslipidemic patients. Schuster, H.[2017]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK548620/

Rosuvastatin - LiverTox - NCBI Bookshelf - NIH In the clinically apparent liver injury attributed to rosuvastatin, recovery is usually complete within 1 to 2 months. Recurrence of injury with ...

2. ahajournals.org ahajournals.org/doi/10.1161/JAHA.122.028310

High‐Intensity Statin Reduces the Risk of Mortality Among ... Among patients with CLD with atherosclerotic cardiovascular disease, high‐intensity statin was significantly associated with a lower risk of mortality.

3. bmjgroup.com bmjgroup.com/new-study-sheds-light-on-long-term-effectiveness-and-safety-of-two-widely-used-statins/

New study sheds light on long term effectiveness and ... The researchers found no discernible differences between the two groups for all cause death (2.6% in the rosuvastatin group v 2.3% in the atorvastatin group), ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7967963/

A systematic review on pharmacokinetics, cardiovascular ... Rosuvastatin and pitavastatin showed minimal PK changes in Child–Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0753332224016925

Statins and non-alcoholic fatty liver disease: A concise review Statins show beneficial effects beyond lipid lowering by improving fibrosis, inflammation, oxidative stress and microcirculation in NAFLD/NASH.

6. crestor.com crestor.com/hcp/about-crestor/safety-tolerability

Safety and Tolerability Information | For HCPs There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury ...

7. bmcgastroenterol.biomedcentral.com bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-021-01704-w

A systematic review on pharmacokinetics, cardiovascular ... Rosuvastatin and pitavastatin showed minimal PK changes in Child–Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study.