Atorvastatin for Liver Cancer Risk in Fibrosis

(TORCH Trial)

Recruiting at 1 trial location

Overseen By Yujin Hoshida, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Raymond Chung

Must not be taking: Statins

Disqualifiers: HIV, Untreated HCV, Uncontrolled HBV, others

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

Compensation: Varies

Number of Visits: 4

Duration: 48 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether atorvastatin, a medication typically used to lower cholesterol, can help prevent liver cancer in individuals with advanced liver scarring, known as fibrosis. Participants will take either atorvastatin or a placebo (a non-active pill) for 48 weeks to determine if it reduces their cancer risk. Suitable candidates have advanced liver fibrosis or cirrhosis (severe liver scarring) and are at high risk for developing liver cancer, but do not have certain other liver conditions. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but if you are taking a statin, you must stop it and undergo a 90-day washout period before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that atorvastatin, a type of statin, is generally safe and may benefit liver health. Statins are typically used to lower cholesterol, but they also appear to aid with liver issues. Studies have found that people who regularly take statins have a lower risk of liver disease and are 28% less likely to die from liver-related problems.

Atorvastatin, in particular, might offer extra protection for the liver. It has been shown to lower the risk of liver cancer and cirrhosis, which is scarring of the liver. This makes it a promising option for people with liver fibrosis who are at risk of developing liver cancer.

While atorvastatin is safe for most people, it is important to note that, like any medication, it can have side effects. Most people tolerate it well, but some might experience muscle pain or digestive issues. Always consult a healthcare provider if there are any concerns. ^{1 2 3 4 5}

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

Unlike the standard treatments for reducing liver cancer risk, such as lifestyle changes or surveillance, atorvastatin works by targeting cholesterol levels, which may play a role in liver health. Researchers are excited because atorvastatin is primarily a cholesterol-lowering medication, and its potential impact on fibrosis and liver cancer risk offers a novel approach to managing these conditions. This could mean a dual benefit for patients who need both cardiovascular and liver disease management.

What evidence suggests that atorvastatin might be an effective treatment for liver cancer risk in fibrosis?

Research has shown that atorvastatin, a type of medication called a statin, might reduce the risk of liver cancer. One study found that people taking statins had a 33% lower chance of developing liver cancer. Another study linked statin use to a 28% lower risk of dying from liver-related problems. In this trial, participants in Group A will receive atorvastatin, which has demonstrated strong results in lowering the risk of liver cancer. These findings suggest that atorvastatin may help prevent liver cancer, particularly in individuals with serious liver conditions like fibrosis. ^{1 2 3 5 6}

Who Is on the Research Team?

Raymond Chung, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults over 18 with advanced liver fibrosis or cirrhosis at high risk for developing liver cancer (HCC) can join. They must be able to take medication as directed and complete study visits. Women who can have children must use birth control, and participants need recent liver imaging. People with other major illnesses, certain chronic liver diseases, uncontrolled infections like HIV or hepatitis B, a history of drug abuse, or those on statins recently cannot join.

Inclusion Criteria

I can follow the medication schedule and attend all study visits.

The subject must be able to comply with the instructions for taking the study drug and be able to complete the study schedule of assessments.

My scans show a liver condition with increased blood pressure in the portal vein.

Exclusion Criteria

ALT > 10 x ULN

Known positivity for HIV infection

I have been diagnosed with a chronic liver disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atorvastatin or placebo daily for 48 weeks to assess chemopreventive impact on HCC risk

48 weeks

Regular visits every 4 weeks, with additional visits at weeks 12, 24, 36, and 48

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a 5-year observational study to examine HCC incidence

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Atorvastatin
• Placebo

Trial Overview

The trial is testing if Atorvastatin (20 mg daily pill) prevents liver cancer better than a placebo in people with serious scarring of the liver due to disease. It's a controlled test where neither doctors nor patients know who gets the real medicine versus a fake pill to ensure unbiased results.

How Is the Trial Designed?

Group I: Group A: Atorvastatin 20 mg Experimental Treatment 1 Intervention

Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

Group II: Group B: Placebo to Match (PTM) Placebo Group 1 Intervention

PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

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

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

Raymond Chung

Lead Sponsor

Trials

3

Recruited

100+

University of Texas Southwestern Medical Center

Collaborator

Trials

1,102

Recruited

1,077,000+

Published Research Related to This Trial

Statins, while generally well tolerated, can cause idiosyncratic liver injury in 1.9%-5.5% of patients, particularly with atorvastatin and simvastatin, which have over 50 reported cases of liver damage.

Most patients who experience liver injury from statins recover after stopping the medication, although there have been rare cases leading to severe outcomes like liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatotoxicity of statins and other lipid-lowering agents. Björnsson, ES.[2022]

In a study of 1,036 patients with stage I or II hepatocellular carcinoma (HCC), those using statins had a longer median survival of 23.9 months compared to 18.9 months for nonusers, suggesting a potential benefit.

However, after adjusting for various biases and confounding factors, statin use was not significantly associated with improved survival rates, indicating that statins do not enhance survival in elderly patients with early-stage liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin Use and Survival with Early-Stage Hepatocellular Carcinoma. Jeon, CY., Goodman, MT., Cook-Wiens, G., et al.[2017]

In a study involving 94 cases of hepatocellular carcinoma (HCC) and 468 matched controls, statin use was found to be significantly associated with a reduced risk of developing HCC, with an odds ratio of 0.32.

The protective effect of statins against HCC was consistent regardless of the duration of use, indicating that even short-term use may be beneficial in lowering HCC risk in low-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin use and risk of hepatocellular carcinoma in a U.S. population. McGlynn, KA., Divine, GW., Sahasrabuddhe, VV., et al.[2021]

In a study of 9,135 patients with chronic hepatitis C, statin use was linked to a 44% reduction in the development of cirrhosis and a 49% reduction in hepatocellular carcinoma (HCC), indicating significant protective effects against liver disease progression.

The effectiveness of statins was dose-dependent, with atorvastatin and fluvastatin showing the most pronounced antifibrotic effects, suggesting that higher doses may provide greater benefits in managing fibrosis and reducing cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Simon, TG., Bonilla, H., Yan, P., et al.[2022]

Atorvastatin effectively reduced serum cholesterol levels in mice but did not decrease the size or number of chemically induced liver tumors, indicating it does not inhibit hepatocellular carcinoma (HCC) growth.

The study challenges the idea that long-term atorvastatin use may protect against HCC, as it showed no beneficial effects on tumor growth despite changes in drug uptake transporters in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemically induced mouse liver tumors are resistant to treatment with atorvastatin. Braeuning, A., Bucher, P., Hofmann, U., et al.[2022]

Statins, known for lowering cholesterol, also have beneficial effects in cirrhosis patients, including anti-inflammatory properties and potential to reduce the risk of liver complications and mortality, based on retrospective studies.

Ongoing clinical trials are expected to provide more insights into the safety and effectiveness of statins in treating cirrhosis, which could influence future treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC. Sharpton, SR., Loomba, R.[2023]

In a study of 16,668 adults with chronic hepatitis B or C, lipophilic statin users had a significantly lower 10-year risk of developing hepatocellular carcinoma (HCC) compared to nonusers, with a risk reduction of 4.8 percentage points.

Both lipophilic and hydrophilic statin users experienced lower 10-year mortality rates, but only lipophilic statins showed a strong association with reduced HCC incidence, suggesting they may be more effective in preventing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Simon, TG., Duberg, AS., Aleman, S., et al.[2021]

Lipophilic statins, especially atorvastatin, significantly reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis by suppressing high-risk liver gene patterns associated with cancer development.

Atorvastatin uniquely inhibits key pathways (YAP and AKT) involved in liver cancer progression, making it a promising candidate for HCC chemoprevention in patients with liver diseases like hepatitis C and nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Kim, MH., Kim, MY., Salloum, S., et al.[2022]

In a study of 42 patients with nonalcoholic steatohepatitis treated with atorvastatin for 12 months, significant improvements were observed in liver injury markers and metabolic profiles, including decreased liver transaminases and triglycerides, and increased beneficial adiponectin levels.

Atorvastatin's effectiveness in improving disease activity is linked to its ability to lower tumor necrosis factor-α levels, suggesting a mechanism by which it alleviates inflammation associated with nonalcoholic steatohepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property. Hyogo, H., Yamagishi, S., Maeda, S., et al.[2022]

In a study of over 73,000 patients with newly diagnosed cirrhosis, higher cholesterol levels were linked to better liver function and lower mortality rates, suggesting that hyperlipidemia may have protective effects in these patients.

Each additional year of statin use was associated with an 8.0%-8.7% reduction in mortality for patients with cirrhosis, indicating that statins can be beneficial and should not be avoided due to concerns about liver toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis. Kaplan, DE., Serper, MA., Mehta, R., et al.[2019]

In a study of 1,072 patients with nonalcoholic steatohepatitis (NASH) and advanced liver fibrosis, those with bridging fibrosis (F3) showed no cases of hepatocellular carcinoma (HCC) during follow-up, indicating a low risk for this group.

Among patients with cirrhosis (F4), the annual incidence of HCC was 1.90 per 100 person-years, and statin use was associated with a significantly lower risk of developing HCC, with a 23.6% reduction in risk for each additional year of statin use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis. Pinyopornpanish, K., Al-Yaman, W., Butler, RS., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4351398/

Statin Use and Risk of Primary Liver Cancer in the Clinical ...

Statin use was associated with a statistically significantly reduced risk of liver cancer (ORadj = 0.55, 95% CI = 0.45 to 0.69), especially among current users ...

2.

jamanetwork.com

jamanetwork.com/journals/jamanetworkopen/fullarticle/2806370

Statin Use and Risk of Liver Disease, Hepatocellular ...

Regular use of statins was associated with a 15% lower hazard ratio of new-onset liver disease and a 28% lower hazard ratio for liver-related deaths compared ...

3.

cardi-oh.org

cardi-oh.org/resources/current-52--statins-reduce-liver-cancer-and-decompensation-risk-in-patients-with-chronic-liver-disease

Statins Reduce Liver Cancer and Decompensation Risk in ...

Further, multivariable analysis demonstrated a 33% risk reduction for hepatocellular carcinoma among statin users, with a reduced risk also ...

4.

thelancet.com

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

Age-specific protective effects of statins against cirrhosis in ...

In adjusted models, baseline statin use was significantly associated with a reduced risk of cirrhosis over 10 years (HR 0.74 [95% confidence ...

5.

medicalnewstoday.com

medicalnewstoday.com/articles/certain-type-statins-may-help-decrease-liver-cancer-risk

Certain type of statins may help decrease liver cancer risk

Participants in this study who used lipophilic (fat-soluble) statins like atorvastatin and simvastatin had the greatest outcomes for liver cancer.

6.

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.