Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk

Study Overview
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Brief Summary
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Prospective randomized, multi-center, double blind placebo-controlled trial to assess the chemopreventive impact of atorvastatin (20 mg oral) vs placebo in up to 60 adults with advanced fibrosis at high risk of developing HCC.

Detailed Description
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The study objective is to investigate the chemopreventive efficacy of atorvastatin (20 mg) on HCC risk compared to placebo in adults with advanced fibrosis (i.e. METAVIR fibrosis stage 3-4) and high-risk PLSec (defined by pre-randomization blood-based assay). HCC risk will be measured by changes in prognostic liver secretome signature (PLSec) risk score after oral administration of atorvastatin for 1 year with up to 5 years post-treatment of chart monitoring.

Official Title
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Multi-center Double Blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Long-term Atorvastatin (20 mg/Day) v. Placebo on HCC Risk in Individuals With Advanced Liver Fibrosis

Conditions
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Liver Fibroses, Cirrhosis

Intervention / Treatment
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* Drug: Atorvastatin 20mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent Male or female age > 18 years at time of consent Clinically or histologically diagnosed advanced liver fibrosis or cirrhosis, as defined by one or more of the following: Liver biopsy demonstrating advanced fibrosis or cirrhosis (METAVIR 3-4) Fibroscan or MR elastography consistent with advanced fibrosis or cirrhosis Imaging showing cirrhotic-appearing liver with signs of portal hypertension Advanced fibrosis or cirrhosis documented clinically by a treating physician High-risk for HCC at screening according to the FIB-4 index High PLSec score measured in screening blood sample from the FIB-4-high individuals. Liver imaging within 6 months of Day 1 is required in cirrhotic subjects only, to exclude HCC Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception Willing and able to undergo protocol blood sampling Subject must be able to comply with dosing instructions for study drug administration and able to complete study schedule of assessments Exclusion Criteria: Diagnosis of any of the following forms of chronic liver disease: - primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Autoimmune hepatitis, alpha-1-antitrypsin (A1AT) deficiency, Wilson disease, hemochromatosis, iron overload, prior known or suspected drug-induced liver injury (DILI) Current or prior history of any of the following: - Clinically significant illness or any other major medical disorder that in the opinion of the investigator, may interfere with subject treatment, assessment or compliance with the protocol Known positivity for HIV infection Active, untreated HCV infection - Patients with prior history of HCV who achieved sustained virologic response (SVR) >12 from Day 1 may be included in the study Uncontrolled chronic HBV - Patients with well controlled disease with >12 months of stable medication use (or no medication use, in those persons for whom anti-HBV therapy is not indicated) Clinical hepatic decompensation, defined as Child's Pugh class B or C cirrhosis (see History of biliary diversion Solid organ transplant Malignancy within the 5 years prior to screening, with the exception of specific cancers that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible Pregnant or Nursing Females (a negative serum pregnancy test is required at screening for WOCBP) Life threatening SAE during the screening period Subjects having the following laboratory parameters at screening ALT > 10 x ULN AST > 10 x ULN Hemoglobin < 8.5 g/dl Serum creatinine > 2.0 mg/dL CK > 3x ULN Females who may wish to become pregnant and/or plan to undergo egg harvesting during the study and up to 30 days of the last dose of study drug WOCBP must abstain from breastfeeding and be willing to use effective birth control during through the week 4 post treatment follow-up visit Clinically relevant alcohol or drug abuse within 12 months of screening Use of any prohibited concomitant medications as described in Section 9.1.1 Use of a statin medication within 90 days of Day 1 visit - Subjects who are on a current statin at time of consent must be willing to undergo a 90-day washout period prior to randomization Known hypersensitivity to Atorvastatin Current or planned participation in an investigational new drug (IND) trial from 30-days prior to randomization through the week 4 post treatment follow-up visit

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Atorvastatin 20 mg<br>Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis. | Drug: Atorvastatin 20mg<br>* Oral administration of atorvastatin 20 mg<br>* Other names: Lipitor;|
| Placebo Comparator: Group B: Placebo to Match (PTM)<br>PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis. | Drug: Placebo<br>* Oral administration of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduced magnitude of high-risk PLSec after treatment vs before treatment | The primary objective (primary endpoint) of this study is to determine the effect of atorvastatin compared with placebo on HCC risk level measured by change in serum-based prognostic liver secretome signature (PLSec) score (delta-PLSec). High-risk for HCC is indicated by a PLSec score of 4 or greater. Low-risk for HCC is indicated by a PLSec score below 4. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete adverse event profile | Minimized toxicity in response to treatment based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5 at least every 4 weeks to week 12 and at weeks 24, 36, and 48. | 48 weeks | 
| Complete profile of change in quality of life for patients | The investigators will assess the subjects' quality of life while on treatment using the Chronic Liver Disease Questionnaire (CLDQ). A Likert scale response format will be used for all items (n=29), and the overall CLDQ score will be obtained by adding scores for each item and dividing by the total number of items (n=29). The score ranges from 1 (most impairment) to 7 (least impairment). | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, Atorvastatin, Liver Disease, Chemoprevention