Lisinopril for Non-Alcoholic Fatty Liver Disease

Not currently recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: ACE inhibitors, ARBs, Lithium

Disqualifiers: Decompensated liver disease, Alcoholic liver disease, Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well lisinopril, a medication typically used for high blood pressure, can prevent the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD occurs when fat accumulates in the liver and can lead to liver cancer. The trial aims to determine if lisinopril can stop liver damage and reduce cancer risk. Individuals diagnosed with non-alcoholic steatohepatitis (a type of NAFLD) through body imaging or liver biopsy, who have not used similar medications in the past six months, might be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you have not used an ACE inhibitor or ARB within 24 weeks before joining. If you're taking vitamin E or anti-diabetic medications, you must be on a stable dose for a certain period before and during the study. If you're taking lithium, you cannot participate.

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

Research has shown that lisinopril is generally well-tolerated and often treats high blood pressure. Studies have found that some people might experience mild side effects like dizziness or a dry cough while taking lisinopril.

In rare cases, lisinopril has caused temporary liver issues, such as slight increases in liver proteins in the blood. However, serious liver problems remain very uncommon.

This trial is in the second phase, focusing on lisinopril's safety specifically for liver conditions. Its common use for blood pressure suggests it is usually safe for many people. ^{1 2 3 4 5}

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

Unlike the standard treatments for non-alcoholic fatty liver disease, which often focus on lifestyle changes and managing associated conditions like diabetes or high cholesterol, lisinopril is being explored for its potential benefits directly on the liver. Lisinopril, a medication traditionally used to treat high blood pressure, may have a unique impact by reducing liver stiffness and fat content, thanks to its ability to improve blood flow and reduce inflammation. Researchers are excited because this approach could offer a new pathway to directly target liver health, potentially leading to better outcomes for patients with this condition.

What evidence suggests that lisinopril might be an effective treatment for NAFLD?

Studies have shown that lisinopril, a medication typically used for high blood pressure, might aid in treating non-alcoholic fatty liver disease (NAFLD). Research suggests that lisinopril may reduce liver fibrosis, a condition where scar tissue forms in the liver and can lead to damage. While not yet proven for liver disease, its potential benefits stem from its ability to protect blood vessels and reduce inflammation. Early findings indicate it could slow the progression of NAFLD, potentially lowering the risk of liver cancer in affected individuals. Participants in this trial will receive lisinopril to further investigate these potential benefits. ^{1 2 4 6 7}

Who Is on the Research Team?

Ju Dong Yang

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

Adults diagnosed with nonalcoholic steatohepatitis (NASH) and liver fibrosis, who have not used certain blood pressure medications recently, can join this trial. They must have a stable blood count, kidney function, and be willing to use contraception if of childbearing potential. Exclusions include pregnant or breastfeeding women, those with severe liver disease or recent weight reduction surgery, heavy drinkers, and individuals on unstable doses of certain supplements or diabetes medication.

Inclusion Criteria

Clinical diagnosis of nonalcoholic steatohepatitis (NASH) assessed by the presence of body imaging criteria (ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]), or liver biopsy up to six months prior to enrollment without suspicious nodules or cancer

Absolute neutrophil count >= 1,500/microliter

Platelets >= 75,000/microliter

Exclusion Criteria

You have had allergic reactions to drugs that are similar to lisinopril.

You have a history of serious liver problems, such as fluid buildup in the abdomen (ascites), confusion caused by liver damage (hepatic encephalopathy), or bleeding from swollen blood vessels in the esophagus (variceal bleeding).

You are currently taking lithium medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive lisinopril orally once daily for 24 weeks. Patients undergo transient elastography and blood sample collection on study. Optional PDFF MRI and MRE may be conducted.

24 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

1-2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Lisinopril

Trial Overview The RELIEF-NAFLD study is testing whether the blood pressure medication Lisinopril can prevent worsening of non-alcoholic fatty liver disease (NAFLD) and reduce the risk of developing liver cancer. Participants will undergo various assessments including questionnaires, imaging tests like MRI and ultrasonography for fat in the liver as well as biospecimen collection to monitor effects.

How Is the Trial Designed?

Group I: Prevention (lisinopril) Experimental Treatment 7 Interventions

Patients receive lisinopril PO QD for 24 weeks in absence of unacceptable toxicity. Patients undergo transient elastography during screening and on study. Patients also undergo blood sample collection on study and may undergo a PDFF MRI and MRE on study.

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

Approved in United States as Lisinopril for:

• High blood pressure
• Heart failure
• Survival following a heart attack

Approved in European Union as Lisinopril for:

• Hypertension
• Heart failure
• Acute myocardial infarction

Approved in Canada as Lisinopril for:

• Hypertension
• Heart failure
• Post-myocardial infarction

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving 29 rabbits, the ACE-inhibitor ramipril significantly reduced the development of key features of non-alcoholic fatty liver disease (NAFLD), including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, compared to a placebo.

Ramipril also significantly decreased the progression to non-alcoholic steatohepatitis (NASH), indicating its potential as a preventive treatment for NAFLD in conditions associated with high cholesterol diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits. Sturzeneker, MCS., de Noronha, L., Olandoski, M., et al.[2020]

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, and currently, there are no effective pharmacologic treatments available, with management primarily focused on lifestyle changes.

Emerging evidence suggests that targeting the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may be a promising therapeutic approach for NAFLD, but more robust randomized controlled trials are needed to confirm their efficacy in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. Paschos, P., Tziomalos, K.[2022]

Three middle-aged men developed hepatitis after taking ramipril, with symptoms appearing between 3 to 8 weeks after starting the medication, indicating a potential risk of liver injury associated with this drug.

Liver biopsies revealed unique findings such as duct necrosis and bile extravasation, and prolonged cholestasis was observed in one patient, suggesting that liver function should be monitored in patients prescribed ramipril.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramipril-associated hepatotoxicity. Yeung, E., Wong, FS., Wanless, IR., et al.[2021]

Patients with metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) require careful selection of antihypertensive medications due to the liver's role in drug metabolism.

The article highlights the importance of angiotensin-converting enzyme (ACE) inhibitors, discussing their pharmacological properties and potential benefits for patients with these comorbid conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CURRENT ISSUES IN THE CHOICE OF ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH METABOLIC SYNDROME AND RELATED NON-ALCOHOLIC FATTY LIVER DISEASE]. Morozova, TE., Rykova, SM., Shmarova, DG.[2018]

A 61-year-old woman developed acute liver injury after starting aliskiren, an antihypertensive medication, with significant increases in liver enzymes indicating hepatocellular damage.

Upon stopping aliskiren, the patient's liver enzyme levels rapidly normalized, suggesting a direct link between the drug and the liver injury, which is supported by reports of 117 suspected cases of aliskiren-related hepatotoxicity in pharmacovigilance databases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases. Crepin, S., Godet, B., Carrier, P., et al.[2019]

In a study of over 7.7 million patients, those with non-alcoholic fatty liver disease (NAFLD) were more likely to be prescribed specific antidiabetic drugs, such as SGLT2 inhibitors and thiazolidinediones, compared to those without NAFLD, indicating a targeted approach in managing diabetes in these patients.

Patients with NAFLD also showed higher prescription rates for certain antihypertensive and lipid-lowering medications, such as angiotensin II receptor antagonists and fibrates, suggesting that comorbid conditions influence treatment choices, although the differences in prescription rates were not substantial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. Machida, T., Obara, T., Miyazaki, M., et al.[2022]

Lisinopril, an ACE inhibitor commonly used for hypertension and diabetic nephropathy, can cause rare but severe liver injury, as demonstrated in a case of fulminant hepatic cholestasis in a 59-year-old woman.

Despite being well-tolerated in most patients, this case highlights that lisinopril can lead to life-threatening hepatotoxicity, emphasizing the need for monitoring liver function in patients taking this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisinopril-Induced Liver Injury: An Unusual Presentation and Literature Review. Al-Rifaie, A., Khan, MA., Ali, A., et al.[2022]

A 6-month study involving 20 patients with metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) showed that the combination of amlodipine, lisinopril, and rosuvastatin significantly reduced blood pressure and improved liver enzyme levels, indicating effective management of both hypertension and liver health.

The therapy led to normalization of liver enzymes (ALT and AST) in all patients, and significant reductions in LDL cholesterol and insulin resistance, demonstrating both safety and efficacy in this high cardiovascular risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Efficacy of Amlodipine, Lisinopril and Rosuvastatin Therapy in Patients With Metabolic Syndrome and Nonalcoholic Fatty Liver Disease]. Baranova, EI., Berezina, AV., Melioranskaya, EI., et al.[2019]

Telmisartan and olmesartan, both angiotensin II receptor blockers, significantly improved insulin resistance and liver injury markers in patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CH-C), suggesting their potential as therapeutic options.

The study found that telmisartan had more pronounced effects on improving insulin sensitivity and liver function compared to olmesartan, indicating that it may be particularly beneficial for patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. Enjoji, M., Kotoh, K., Kato, M., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04550481

Study Details | NCT04550481 | Role of Lisinopril in ... This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD).

2. clinicaltrials.cedars-sinai.edu clinicaltrials.cedars-sinai.edu/view/EIIT2021-NOUREDDIN-NAFLD

Role of Lisinopril in Preventing the Progression of ... This study focuses on individuals who have a higher-than-average risk of developing liver cancer (hepatocellular carcinoma) due to their diagnosis.

3. prevention.cancer.gov prevention.cancer.gov/clinical-trials/clinical-trials-search/nct04550481

Role of Lisinopril in Preventing the Progression of Non ... This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD).

4. trialx.com trialx.com/clinical-trials/listings/253642/role-of-lisinopril-in-preventing-the-progression-of-non-alcoholic-fatty-liver-disease-relief-nafld-study/

Role of Lisinopril in Preventing the Progression of Non- ... This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10562311/

Non-Alcoholic Fatty Liver Disease (NAFLD) and risk of new ... Accumulating evidence suggests an association between NAFLD and heart failure (HF), but large-scale data analyses from Germany are scarce.

6. mountsinai.org mountsinai.org/clinical-trials/role-of-lisinopril-in-preventing-progression-of-non-alcoholic-fatty-liver-disease-relief-nafld-study

Role of Lisinopril in Preventing the Progression of Non- ... This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD).

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK548860/

Lisinopril - LiverTox - NCBI Bookshelf - NIH Lisinopril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury that can be ...