Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk

Overview

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.

Description

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.

Eligibility

Inclusion Criteria:

1. Willing and able to provide informed consent
2. Male or female age > 18 years at time of consent
3. 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
4. High-risk for HCC at screening according to the FIB-4 index
5. High PLSec score measured in screening blood sample from the FIB-4-high individuals.
6. Liver imaging within 6 months of Day 1 is required in cirrhotic subjects only, to exclude HCC
7. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
8. Willing and able to undergo protocol blood sampling
9. Subject must be able to comply with dosing instructions for study drug administration and able to complete study schedule of assessments

Exclusion Criteria:

1. 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)
2. 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
3. Known positivity for HIV infection
4. 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
5. 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)
6. Clinical hepatic decompensation, defined as Child's Pugh class B or C cirrhosis (see
7. History of biliary diversion
8. Solid organ transplant
9. 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
10. Pregnant or Nursing Females (a negative serum pregnancy test is required at screening for WOCBP)
11. Life threatening SAE during the screening period
12. 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
13. 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

14. WOCBP must abstain from breastfeeding and be willing to use effective birth control during through the week 4 post treatment follow-up visit
15. Clinically relevant alcohol or drug abuse within 12 months of screening
16. Use of any prohibited concomitant medications as described in Section 9.1.1
17. 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
18. Known hypersensitivity to Atorvastatin
19. 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