Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease, RELIEF-NAFLD Study

Study Overview
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Brief Summary
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This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD is a condition where there is an accumulation of fatty cells in the liver. NAFLD increases a person's risk of developing liver cancer. Liver fibrosis is the common finding of chronic liver diseases leading to reduced liver function. Lisinopril is a medication that is commonly used to treat high blood pressure. Lisinopril may help to decrease liver fibrosis. The purpose of this trial is to find out what effect, if any, lisinopril has on a patient's risk of developing liver cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine if NAFLD patients with advanced fibrosis will demonstrate a change in PRO-C3, a marker of liver fibrosis, following 24 weeks of treatment with lisinopril. SECONDARY OBJECTIVES: I. Noninvasive measures of fibrosis and steatosis: Ia. Change from baseline in PC3X (cross-linked multimeric PRO-C3); Ib. Change from baseline in steatosis, as measured by controlled attenuation parameter (CAP), determined with transient elastography (Fibroscan); Ic. Change from baseline in liver stiffness as measured with magnetic resonance elastography (MRE); Id. Change from baseline in liver stiffness as measured with transient elastography (Fibroscan); Ie. Changes from baseline in Fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS); If. Change in inflammatory markers (caspase cleaved cytokeratin 18 [CK-18], NF-kappaB, TGF-beta, TNF-alpha, IL6 and IL8). OUTLINE: Patients receive lisinopril orally (PO) once daily (QD) for 24 weeks in absence of unacceptable toxicity. Patients undergo transient elastography (Fibroscan) during screening and on study. Patients also undergo blood sample collection on study and may undergo a proton density fat fraction (PDFF) magnetic resonance imaging (MRI) and MRE on study. Patients are followed up at 32 weeks after the start of study medication.

Official Title
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Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD): Relief-NAFLD

Conditions
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Hepatocellular Carcinoma, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Drug: Lisinopril
* Procedure: Liver Ultrasonographic Elastography
* Procedure: Magnetic Resonance Elastography
* Procedure: Magnetic Resonance Imaging
* Procedure: Proton Density Fat Fraction
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects >= 18 years of age 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 Screening transient elastography (Fibroscan) liver stiffness >= 12 kPa (which correlates with F3 fibrosis and more) and < 25 kPa. Historic transient elastography (Fibroscan) within 0-4 weeks prior to the date of the screening visit is acceptable Controlled attenuation parameter score of >= 270 dB/m or historic liver biopsy within 0-6 months prior to the date of the screening visit consistent with NASH (defined as the presence of steatosis, inflammation, and ballooning), with stage 3-4 fibrosis according to the NASH Clinical Research Network classification (or equivalent) Leukocytes >= 3,000/microliter Absolute neutrophil count >= 1,500/microliter Platelets >= 75,000/microliter Total bilirubin within normal institutional limits unless the patient has Gilbert's syndrome Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 8 x institutional upper limit of institutional limits Glomerular filtration rate > 30 ml/min International normalized ratio (INR) =< 1.3 unless the patient is on a therapeutic medication Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) The effects of lisinopril has been shown to be teratogenic in animal models. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand and the willingness to sign a written informed consent document. If a participant has impaired decision-making capacity (IDMC), their legal representative may replace them in this process Systolic blood pressure >= 90 and =< 160 mm/Hg. Diastolic blood pressure >= 60 and =< 110 mm/Hg Exclusion Criteria: Prior or current use of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor antagonist (ARB) within 0-24 weeks prior to enrollment Glomerular filtration rate =< 30 ml/min (for both male and female participants) History of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding History of other causes of liver disease, including but not limited to alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (primary biliary cholangitis, primary sclerosing cholangitis, or autoimmune hepatitis), drug-induced hepatotoxicity, Wilson's disease, iron overload, or alpha-1-antitryspin deficiency History of liver transplantation History of hepatocellular carcinoma (HCC) diagnosis History of weight reduction surgery in the past 2 years or planned during the study Within 6 months prior to the date of the screening visit, there must be no history of the following cardiac events: unstable angina; myocardial infarction, coronary artery bypass surgery or coronary angioplasty; transient ischemic attack or cerebrovascular accident; emergency room visit or hospitalization for confirmed cardiovascular disease Participants taking vitamin E >= 800 IU/day must be on a stable dose, defined as no changes in prescribed dose, new vitamin E-containing medications, or discontinuation for at least 180 days prior to the date of the screening visit and throughout study participation Participants taking anti-diabetic medications must be on a stable dose for at least 90 days prior to the date of the screening visit and in the period between the date of the screening visit and enrollment Current alcohol consumption > 21 oz/week for males or > 14 oz/week for females (1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, 4 oz/120 mL glass of wine, and a 1oz/30 mL measure of 40 proof [20%] alcohol) Participants may not be receiving any other investigational agents, at the time of the screening visit, or in the prior 30 days, or within 5 half-lives of the prior investigational agent (whichever is longer) History of allergic reactions attributed to compounds of similar chemical or biologic composition to lisinopril Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements History of human immunodeficiency virus (HIV) infection. HIV patients may develop fatty liver as well as advanced fibrosis due to many causes including metabolic syndrome, hyperuricemia, HIV-related lipodystrophy, genetic polymorphisms, medications, and HIV itself. As the natural history of fatty liver in this population is largely unknown, these patients will be excluded from this study Women who are pregnant or breastfeeding. Pregnant women are excluded from this study because lisinopril is an ACE Inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with lisinopril. Breastfeeding should be discontinued if the mother is treated with lisinopril Systolic blood pressure >= 161 mm/Hg. Diastolic blood pressure >= 111 mm/Hg Participants taking lithium

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (lisinopril)<br>Patients receive lisinopril PO QD for 24 weeks in absence of unacceptable toxicity. Patients undergo transient elastography (Fibroscan) during screening and on study. Patients also undergo blood sample collection on study and may undergo a PDFF MRI and MRE on study. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Lisinopril<br>* Given PO<br>* Other names: Zestril;Procedure: Liver Ultrasonographic Elastography<br>* Undergo transient elastography (Fibroscan)<br>* Other names: Vibration-Controlled Transient Elastrography;Procedure: Magnetic Resonance Elastography<br>* Undergo PDFF MRE<br>* Other names: MRE;Procedure: Magnetic Resonance Imaging<br>* Undergo PDFF MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Proton Density Fat Fraction<br>* Undergo PDFF MRI/MRE<br>* Other names: PDFF;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PRO-C3 values | Descriptive statistics will be used to summarize changes and values at each time point. The primary analysis will be performed using a paired t-test to compare the pre- to post-treatment changes in PRO-C3 levels. PRO-C3 levels will be log-transformed to satisfy the normality assumption. If log-transformation does not satisfy the normality assumption, a signed rank test will be used. | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PC3X (cross-linked multimeric PRO-C3) |  | Baseline to 24 weeks | 
| Change in steatosis | Measured by controlled attenuation parameter, determined with transient elastography (Fibroscan). Changes in categorical variables will be analyzed using the Stuart-Maxwell test of marginal homogeneity. Linear regression models will be used to identify baseline characteristics that are associated with biomarker changes. Model selection will be conducted according to the purposeful model selection approach (REF) to a parsimonious set of predictors. Model fit will be assessed using standard regression diagnostics. Changes in categorical outcomes from pre- to post-treatment will also be categorized as improvement vs. no improvement (i.e. no change or worsening in steatosis grade), and logistic regression models will be used to examine association with baseline characteristics. | Baseline to 24 weeks | 
| Change liver stiffness | Measured with magnetic resonance elastography. Changes in categorical variables will be analyzed using the Stuart-Maxwell test of marginal homogeneity. Linear regression models will be used to identify baseline that are associated with biomarker changes. Model selection will be conducted according to the purposeful model selection approach (REF) to a parsimonious set of predictors. Model fit will be assessed using standard regression diagnostics. Changes in categorical outcomes from pre- to post-treatment will also be categorized as improvement vs. no improvement (i.e. no change or worsening in steatosis grade), and logistic regression models will be used to examine association with baseline characteristics. | Baseline to 24 weeks | 
| Change liver stiffness | Measured with transient elastography (Fibroscan). Changes in categorical variables will be analyzed using the Stuart-Maxwell test of marginal homogeneity. Linear regression models will be used to identify baseline characteristics that are associated with biomarker changes. Model selection will be conducted according to the purposeful model selection approach (REF) to a parsimonious set of predictors. Model fit will be assessed using standard regression diagnostics. Changes in categorical outcomes from pre- to post-treatment will also be categorized as improvement vs. no improvement (i.e. no change or worsening in steatosis grade), and logistic regression models will be used to examine association with baseline characteristics. | Baseline to 24 weeks | 
| Change in non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) | Changes in categorical variables will be analyzed using the Stuart-Maxwell test of marginal homogeneity. Linear regression models will be used to identify baseline characteristics that are associated with biomarker changes. Model selection will be conducted according to the purposeful model selection approach (REF) to a parsimonious set of predictors. Model fit will be assessed using standard regression diagnostics. Changes in categorical outcomes from pre- to post-treatment will also be categorized as improvement vs. no improvement (i.e. no change or worsening in steatosis grade), and logistic regression models will be used to examine association with baseline characteristics. | Baseline to 24 weeks | 
| Change in Fibrosis-4 score | Changes in categorical variables will be analyzed using the Stuart-Maxwell test of marginal homogeneity. Linear regression models will be used to identify baseline characteristics that are associated with biomarker changes. Model selection will be conducted according to the purposeful model selection approach (REF) to a parsimonious set of predictors. Model fit will be assessed using standard regression diagnostics. Changes in categorical outcomes from pre- to post-treatment will also be categorized as improvement vs. no improvement (i.e. no change or worsening in steatosis grade), and logistic regression models will be used to examine association with baseline characteristics. | Baseline to 24 weeks | 
| Change in inflammatory markers (caspase cleaved cytokeratin 18, NF-kappaB, TGF-beta, TNF-alpha, IL6 and IL8) | Descriptive statistics, including means, 95% confidence intervals, or median and inter-quartile range, will be used to summarize changes as well as biomarker values at each time point. To determine whether changes in these biomarkers occurred following treatment, paired t-test will be used as described for the analysis of the primary endpoint. Biomarker values may be transformed to satisfy the normality assumption. If no suitable transformation can be found, a signed rank test will be used. For the analysis of inflammatory biomarkers, tests will be adjusted for multiple comparisons to control the false discovery rate using the method of Romano. | Baseline to 24 weeks |