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Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk (TORCH)

Primary Purpose

Liver Fibroses, Cirrhosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Atorvastatin 20mg
Placebo
Sponsored by
Raymond Chung
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Liver Fibroses focused on measuring Liver Disease, Chemoprevention, HCC, Atorvastatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

    1. Liver biopsy demonstrating advanced fibrosis or cirrhosis (METAVIR 3-4)
    2. Fibroscan or MR elastography consistent with advanced fibrosis or cirrhosis
    3. FIB-4 score > 3.25
    4. Imaging showing cirrhotic-appearing liver with signs of portal hypertension
    5. Advanced fibrosis or cirrhosis documented clinically by a treating physician
  4. PLSec score consistent with high-risk profile

    a. PLSec profile will be measured from screening blood sampling and must indicate a high-risk profile

  5. High-risk for HCC at screening according to the HCC Risk Calculator model
  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:

    a. 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:

    a. 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

    a. 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

    a. 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
  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

    1. ALT > 10 x ULN
    2. AST > 10 x ULN
    3. Hemoglobin < 8.5 g/dl
    4. Serum creatinine > 2.0 mg/dL
    5. 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
  17. Use of a statin medication within 90 days of Day 1 visit

    a. 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

Sites / Locations

  • Massachusetts General HospitalRecruiting
  • University of Texas Southwestern Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Group A: Atorvastatin 20 mg

Group B: Placebo to Match (PTM)

Arm Description

Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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).

Full Information

First Posted
August 25, 2021
Last Updated
July 25, 2023
Sponsor
Raymond Chung
Collaborators
University of Texas Southwestern Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT05028829
Brief Title
Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 10, 2023 (Actual)
Primary Completion Date
March 1, 2026 (Anticipated)
Study Completion Date
March 1, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Raymond Chung
Collaborators
University of Texas Southwestern Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Fibroses, Cirrhosis
Keywords
Liver Disease, Chemoprevention, HCC, Atorvastatin

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A: Atorvastatin 20 mg
Arm Type
Experimental
Arm Description
Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.
Arm Title
Group B: Placebo to Match (PTM)
Arm Type
Placebo Comparator
Arm Description
PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin 20mg
Other Intervention Name(s)
Lipitor
Intervention Description
Oral administration of atorvastatin 20 mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral administration of placebo
Primary Outcome Measure Information:
Title
Reduced magnitude of high-risk PLSec after treatment vs before treatment
Description
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.
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Complete adverse event profile
Description
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.
Time Frame
48 weeks
Title
Complete profile of change in quality of life for patients
Description
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).
Time Frame
48 weeks
Other Pre-specified Outcome Measures:
Title
Exploratory Endpoint: Modulation of high-risk Prognostic Liver Signature (PLS) after treatment vs before treatment
Description
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.
Time Frame
48 weeks
Title
Exploratory Endpoint: Assessment of Pharmacokinetic (PK) Biomarkers of Atorvastatin
Description
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.
Time Frame
48 weeks
Title
Exploratory Endpoint: Assessment of Pharmacodynamic (PD) Biomarkers of Atorvastatin
Description
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.
Time Frame
48 weeks
Title
Exploratory Endpoint: Assess the difference in HCC incidence rate between treatment groups
Description
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.
Time Frame
288 weeks
Title
Exploratory Endpoint: Assessment of Immunohistochemical Markers of Pre/Neoplastic Foci
Description
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.
Time Frame
48 weeks
Title
Exploratory Endpoint: Assessment of change in the proportion of high-risk patients defined by Prognostic Liver Secretome Signature (PLSec) score
Description
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).
Time Frame
48 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Raymond Chung, MD
Phone
617-724-7526
Email
chung.raymond@mgh.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raymond Chung, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Raymond Chung, MD
Email
Chung.Raymond@mgh.harvard.edu
First Name & Middle Initial & Last Name & Degree
Raymond Chung, MD
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yujin Hoshida, MD
Email
Yujin.Hoshida@UTSouthwestern.edu
First Name & Middle Initial & Last Name & Degree
Yujin Hoshida, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Dr. Raymond T. Chung. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
IPD Sharing Time Frame
1/2025-1/2026
IPD Sharing Access Criteria
Researchers accessing IPD must be approved and have a data use agreement in place with Mass General Brigham to access the data.

Learn more about this trial

Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk

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