Simvastatin for Liver Cirrhosis

(SACRED Trial)

Not currently recruiting at 11 trial locations

Overseen By David E Kaplan, MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must not be taking: CYP34A4 inhibitors

Disqualifiers: Statin use, Hepatocellular carcinoma, ASCVD, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether simvastatin, a common cholesterol-lowering medication, can prevent liver cirrhosis from worsening in U.S. Veterans with liver scarring but no symptoms. The study compares simvastatin to a placebo (a pill with no active medicine) to determine if it reduces the risk of developing symptoms. It also examines how genes might influence simvastatin's effectiveness and safety, along with any changes in quality of life. Veterans with liver cirrhosis from causes like chronic hepatitis or alcohol use, but without symptoms, might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you need to take certain medications that interact with simvastatin. These include some antibiotics, antifungals, and heart medications, among others.

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

Research has shown that simvastatin, a drug often used to lower cholesterol, might help people with liver problems. Studies have found that it can reduce high blood pressure in the liver and may decrease death rates in patients with severe liver issues after bleeding incidents. Some reports also suggest that simvastatin can improve survival and reduce new liver problems.

However, in rare cases, simvastatin has caused serious liver damage, leading to liver failure and even death. These cases are uncommon, and most people recover within a few months if they experience any issues.

Overall, simvastatin is usually well-tolerated, especially since it is already approved for treating high cholesterol. But like any medication, it's important to weigh the potential risks and benefits. ^{1 2 3 4 5}

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

Simvastatin is unique because it targets liver cirrhosis by potentially reducing liver inflammation and fibrosis, which is different from the standard treatments that focus mainly on managing symptoms and complications. Most current treatments, like diuretics or beta-blockers, do not address the underlying liver damage. Simvastatin, by lowering cholesterol and providing anti-inflammatory effects, could offer a new approach by directly impacting liver health. Researchers are excited because it might slow disease progression and improve liver function, offering hope for a condition with limited treatment options.

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

Research has shown that simvastatin, which participants in this trial may receive, might help lower the risk of liver problems in people with cirrhosis. Studies have found that simvastatin can reduce high blood pressure in the liver and lower the risk of death in patients who have experienced severe liver bleeding. Some evidence also suggests that simvastatin may improve survival rates in certain groups of cirrhosis patients. Although results vary, these studies offer a hopeful outlook on simvastatin's potential benefits for managing cirrhosis. ^{1 2 3 5 6}

Who Is on the Research Team?

David E Kaplan, MD MSc

Principal Investigator

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Are You a Good Fit for This Trial?

This trial is for U.S. Veterans aged 18-80 with compensated cirrhosis, indicated by specific liver conditions and test results. Participants must not have had certain complications like overt ascites or hepatic encephalopathy recently, no history of hepatocellular carcinoma, and should not be on conflicting medications or have other severe health issues.

Inclusion Criteria

I am at high risk for my liver condition getting worse.

I have cirrhosis caused by hepatitis, alcohol, or fatty liver disease.

My liver disease is stable with specific health criteria met.

Exclusion Criteria

I have had liver cancer in the past.

Patients with life expectancy < 3 years due to comorbid conditions

My liver disease is severe (CTP Score > 9).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

Participants trial 20mg simvastatin once at bedtime for two weeks to determine tolerability prior to randomization

2 weeks

Treatment

Participants receive simvastatin 40mg/day or placebo for up to 24 months

24 months

Regular visits for monitoring liver enzyme levels and other health parameters

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Simvastatin

Trial Overview The study tests if Simvastatin (40mg), a drug normally used to lower cholesterol, can prevent worsening symptoms in patients with high-risk compensated cirrhosis compared to a placebo. It's randomized and double-blind, meaning neither the researchers nor participants know who gets the real medicine.

How Is the Trial Designed?

Group I: Simvastatin Experimental Treatment 1 Intervention

Simvastatin 40mg PO once at bedtime for up to 24 months. Note: all enrolled subjects will trial 20mg once at bedtime for two weeks as lead-in to determine tolerability prior to randomization.

Group II: Placebo Placebo Group 1 Intervention

Placebo 40mg PO once at bedtime for up to 24 months. Note: all enrolled subjects will trial 20mg once at bedtime for two weeks as lead-in to determine tolerability prior to randomization.

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

Approved in European Union as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in United States as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in Canada as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Approved in Japan as Zocor for:

• Hypercholesterolemia
• Cardiovascular disease

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a study of 30 patients with decompensated cirrhosis, simvastatin treatment for one year significantly reduced cirrhosis severity, particularly in patients who improved from Child-Pugh class B to A, indicating its potential efficacy in managing cirrhosis.

Patients who responded positively to simvastatin also experienced improved health-related quality of life and fewer hospitalizations for cirrhosis complications, suggesting that simvastatin may have beneficial anti-inflammatory effects in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients. Muñoz, AE., Pollarsky, F., Marino, M., et al.[2023]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8422958/

SACRED: Effect of simvastatin on hepatic decompensation ... Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage ...

2. journals.lww.com journals.lww.com/ajg/fulltext/9900/simvastatin_addition_to_standard_of_care_improves.1870.aspx

Simvastatin Addition to Standard of Care Improves Long- ... Simvastatin may be associated with improved survival in selected patients with cirrhosis after variceal bleed and reduced incidence of new onset ...

3. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2829933

Simvastatin and Rifaximin in Decompensated Cirrhosis Simvastatin plus rifaximin had no effect on transplant or death or incidence of other complications of cirrhosis. The rate of adverse events was ...

4. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00363-3/fulltext

Age-specific protective effects of statins against cirrhosis in ... Borderline to significant protection against cirrhosis was achieved with a daily dose of ≥6961 mg simvastatin-equivalent for at least 245 days ...

5. esmed.org esmed.org/MRA/mra/article/view/6958

Treatment of Decompensated Cirrhosis Patients with ... Baseline severity and Inflammation would influence the effect of simvastatin on clinical outcomes in cirrhosis patients. Dig Dis Sci. 2023 ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK548720/

Simvastatin - LiverTox - NCBI Bookshelf - NIH In most cases, however, recovery occurs within 1 to 3 months. Rare cases of acute liver failure and death have been attributed to simvastatin.