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

Hepatocellular Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04550481
• Other study ID #: NCI-2020-06905
• Secondary ID: NCI-2020-06905NC
• Status: Recruiting
• Phase: Phase 2
• Start date: May 11, 2021
• Est. completion date: October 30, 2024

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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) or liver ultra-sound attenuation (LiSA), determined with transient elastography:

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; 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: October 30, 2024
• Est. primary completion date: October 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 liver stiffness >= 12 kPa (which correlates with F3 fibrosis and more) and < 25 kPa. Historic transient elastography within 0-4 weeks prior to the date of the screening visit is acceptable. Patients with liver stiffness >= 10 and < 12 kPA with clinical evidence of cirrhosis based on any of the following criteria would also be eligible.

• Imaging diagnosis of nodular liver with splenomegaly or recanalized umbilical vein

• MRE >= 5 kPa

• Fibrosis (FIB)-4 > 2.67 or platelet count < 150,000 mL

• Liver biopsy < 5 years with meta-analysis of histological data in viral hepatitis (METAVIR) stage 4 or Ishak stage 5-6

• Controlled attenuation parameter score or liver steatosis analysis (LiSA) of >= 260 dB/m and any single component of metabolic syndrome (ATP3 criteria) or historic liver biopsy within 0 - 6 months prior to the date of the screening visit consistent with nonalcoholic steatohepatitis (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 high-risk variceal bleeding

• NOTE: Trace ascites documented by radiology is permitted

• 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

Related Conditions & MeSH terms

• Fatty Liver
• Hepatocellular Carcinoma
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection

Drug:
• Lisinopril
Given PO

Procedure:
• Liver Ultrasonographic Elastography
Undergo transient elastography
• Magnetic Resonance Elastography
Undergo PDFF MRE
• Magnetic Resonance Imaging
Undergo PDFF MRI
• Proton Density Fat Fraction
Undergo PDFF MRI/MRE

Other:
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Mount Sinai Hospital	New York	New York
United States	Mayo Clinic in Rochester	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in steatosis	Measured by magnetic resonance imaging-proton density fat fraction. 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 versus (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
Other	Change in markers of liver injury and function: alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase		Baseline to 24 weeks
Other	Change in homeostatic assessment of glycosylated hemoglobin		Baseline to 24 weeks
Other	Change in serum lipid profiles		Baseline to 24 weeks
Other	Change in systolic and diastolic blood pressure		Baseline to 24 weeks
Other	Changes in microbiome and metabolomics and genomics	Collect urine, stool, serum/plasma, and genomic deoxyribonucleic acid.	Baseline to 24 weeks
Primary	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	Change in PC3X (cross-linked multimeric PRO-C3)		Baseline to 24 weeks
Secondary	Change in steatosis	Measured by controlled attenuation parameter or liver steatosis analysis, determined with transient 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 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
Secondary	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
Secondary	Change liver stiffness	Measured with transient 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 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
Secondary	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
Secondary	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
Secondary	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