Safety and Efficacy of Atorvastatin v. Placebo on HCC Risk (TORCH)
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT05028829 |
Recruitment Status :
Recruiting
First Posted : August 31, 2021
Last Update Posted : July 28, 2023
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Liver Fibroses Cirrhosis | Drug: Atorvastatin 20mg Drug: Placebo | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 60 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Prevention |
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 |
Actual Study Start Date : | May 10, 2023 |
Estimated Primary Completion Date : | March 1, 2026 |
Estimated Study Completion Date : | March 1, 2031 |
Arm | Intervention/treatment |
---|---|
Experimental: Group A: Atorvastatin 20 mg
Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.
|
Drug: Atorvastatin 20mg
Oral administration of atorvastatin 20 mg
Other Name: Lipitor |
Placebo Comparator: Group B: Placebo to Match (PTM)
PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.
|
Drug: Placebo
Oral administration of placebo |
- Reduced magnitude of high-risk PLSec after treatment vs before treatment [ Time Frame: 48 weeks ]
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.
- Complete adverse event profile [ Time Frame: 48 weeks ]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 [ Time Frame: 48 weeks ]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).
- Exploratory Endpoint: Modulation of high-risk Prognostic Liver Signature (PLS) after treatment vs before treatment [ Time Frame: 48 weeks ]
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.
- Exploratory Endpoint: Assessment of Pharmacokinetic (PK) Biomarkers of Atorvastatin [ Time Frame: 48 weeks ]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.
- Exploratory Endpoint: Assessment of Pharmacodynamic (PD) Biomarkers of Atorvastatin [ Time Frame: 48 weeks ]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.
- Exploratory Endpoint: Assess the difference in HCC incidence rate between treatment groups [ Time Frame: 288 weeks ]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.
- Exploratory Endpoint: Assessment of Immunohistochemical Markers of Pre/Neoplastic Foci [ Time Frame: 48 weeks ]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.
- Exploratory Endpoint: Assessment of change in the proportion of high-risk patients defined by Prognostic Liver Secretome Signature (PLSec) score [ Time Frame: 48 weeks ]
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).
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05028829
Contact: Raymond Chung, MD | 617-724-7526 | chung.raymond@mgh.harvard.edu |
United States, Massachusetts | |
Massachusetts General Hospital | Recruiting |
Boston, Massachusetts, United States, 02114 | |
Contact: Raymond Chung, MD Chung.Raymond@mgh.harvard.edu | |
Principal Investigator: Raymond Chung, MD | |
United States, Texas | |
University of Texas Southwestern Medical Center | Not yet recruiting |
Dallas, Texas, United States, 75390 | |
Contact: Yujin Hoshida, MD Yujin.Hoshida@UTSouthwestern.edu | |
Principal Investigator: Yujin Hoshida, MD |
Principal Investigator: | Raymond Chung, MD | Massachusetts General Hospital |
Responsible Party: | Raymond Chung, Director of Hepatology, MGH, Massachusetts General Hospital |
ClinicalTrials.gov Identifier: | NCT05028829 |
Other Study ID Numbers: |
21-444 |
First Posted: | August 31, 2021 Key Record Dates |
Last Update Posted: | July 28, 2023 |
Last Verified: | July 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
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. |
Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) |
Time Frame: | 1/2025-1/2026 |
Access Criteria: | Researchers accessing IPD must be approved and have a data use agreement in place with Mass General Brigham to access the data. |
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 |
Liver Disease Chemoprevention HCC Atorvastatin |
Liver Cirrhosis Fibrosis Pathologic Processes Liver Diseases Digestive System Diseases Atorvastatin Anticholesteremic Agents |
Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors |