Clinical trial NCT05028829: Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Liver Fibroses
Cirrhosis
Keywords: Liver Disease
Chemoprevention
HCC
Atorvastatin
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: University of Texas Southwestern Medical Center
First posted: 2021-08-31
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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 criteria: 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. PLSec score ≥ 3 measured in screening blood samples 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:

   * alpha-1-antitrypsin (A1AT) deficiency, Wilson disease, hemochromatosis, iron overload, prior known or suspected drug-induced liver injury (DILI)
   * Patients with PBC, PSC, AIH, or stable hemochromatosis may be included if their liver disease etiology overlaps with that of steatotic liver disease (SLD)
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 \>B7 or C cirrhosis

   - Patients with Child's Pugh score of 7, class B, may be included in the study
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

Primary outcomes:
measure: Reduced magnitude of high-risk PLSec after treatment vs before treatment
timeFrame: 48 weeks
Secondary outcomes:
measure: Complete adverse event profile
timeFrame: 48 weeks
measure: Complete profile of change in quality of life for patients
timeFrame: 48 weeks
Other outcomes:
measure: Exploratory Endpoint: Modulation of high-risk Prognostic Liver Signature (PLS) after treatment vs before treatment
timeFrame: 48 weeks
measure: Exploratory Endpoint: Assessment of Pharmacokinetic (PK) Biomarkers of Atorvastatin
timeFrame: 48 weeks
measure: Exploratory Endpoint: Assessment of Pharmacodynamic (PD) Biomarkers of Atorvastatin
timeFrame: 48 weeks
measure: Exploratory Endpoint: Assess the difference in HCC incidence rate between treatment groups
timeFrame: 288 weeks
measure: Exploratory Endpoint: Assessment of Immunohistochemical Markers of Pre/Neoplastic Foci
timeFrame: 48 weeks
measure: Exploratory Endpoint: Assessment of change in the proportion of high-risk patients defined by Prognostic Liver Secretome Signature (PLSec) score
timeFrame: 48 weeks
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: Massachusetts General Hospital
name: Raymond Chung, MD
role: PRINCIPAL_INVESTIGATOR
References: