Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk

Cirrhosis Clinical Trial

— TORCH  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05028829
• Other study ID #: 21-444
• Status: Recruiting
• Phase: Phase 2
• Start date: May 10, 2023
• Est. completion date: March 1, 2031

Study information

• Verified date: July 2023
• Source: Massachusetts General Hospital
• Contact: Raymond Chung, MD
• Phone: 617-724-7526
• Email: chung.raymond[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: March 1, 2031
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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

Related Conditions & MeSH terms

• Cirrhosis
• Fibrosis
• Liver Cirrhosis
• Liver Fibroses

Intervention

Drug:
• Atorvastatin 20mg
Oral administration of atorvastatin 20 mg
• Placebo
Oral administration of placebo

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Texas Southwestern Medical Center	Dallas	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Raymond Chung	University of Texas Southwestern Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory Endpoint: Modulation of high-risk Prognostic Liver Signature (PLS) after treatment vs before treatment	The investigators will assess the significant magnitude of modulation in PLS-based HCC risk level calculated as the Combined Enrichment Score (CES) jointly measuring suppression of high-risk-associated genes and induction of low-risk-associated genes in the PLS.; A negative CES indicates reduction of HCC risk level. The Mean CES between the treatment arms will be compared by using a two-sample t-test.	48 weeks
Other	Exploratory Endpoint: Assessment of Pharmacokinetic (PK) Biomarkers of Atorvastatin	The investigators will assess the PK biomarkers of atorvastatin in serum from baseline and week 48. Serum atorvastatin concentration (ng/mL) will be measured between the atorvastatin group and placebo group.	48 weeks
Other	Exploratory Endpoint: Assessment of Pharmacodynamic (PD) Biomarkers of Atorvastatin	The investigators will assess the PD biomarkers of atorvastatin in serum from baseline and week 48. Serum Low-Density Lipoprotein, or LDL (mg/mL) and total cholesterol concentration (mg/mL) will be measured between the atorvastatin group and placebo group.	48 weeks
Other	Exploratory Endpoint: Assess the difference in HCC incidence rate between treatment groups	After subjects complete their on-treatment period, the study team will conduct a 5-year post-treatment observational study to examine the incidence rate of HCC between the atorvastatin group and the placebo group.	288 weeks
Other	Exploratory Endpoint: Assessment of Immunohistochemical Markers of Pre/Neoplastic Foci	The investigators will assess the immunohistochemical markers of pre/neoplastic foci in formalin-fixed pre-treatment paraffin-embedded (FFPE) liver biopsy tissues. The investigators will measure the intensity of TAP cytoplasmic and nuclear staining by NIH ImageJ Software.	48 weeks
Other	Exploratory Endpoint: Assessment of change in the proportion of high-risk patients defined by Prognostic Liver Secretome Signature (PLSec) score	In addition to the delta-PLSec assessed in the primary outcome, the investigators will assess the change in the proportion of subjects with high-risk PLSec (= 4) to low-risk PLSec (< 4) following treatment to be compared between the atorvastatin and placebo arms.; The range of the PLSec score is 0 to 8. A higher PLSec score indicates a higher risk for hepatocellular carcinoma (HCC).	48 weeks
Primary	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	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
Secondary	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