The Regression of Liver Fibrosis and Risk for Hepatocellular Carcinoma (ROLFH) Study

Chronic Hepatitis B Clinical Trial

— ROLFH  

Official title:

The Regression of Liver Fibrosis and Risk for Hepatocellular Carcinoma (ROLFH) Study

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01831037
• Other study ID #: 137855
• Status: Withdrawn
• Phase: N/A
• First received: April 2, 2013
• Last updated: January 27, 2015
• Start date: July 2015
• Est. completion date: December 2019

Study information

• Verified date: January 2015
• Source: University of Arkansas
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

This study aims to demonstrate that patients with chronic hepatitis C (CHC) and B (CHB) experiencing regression of liver cirrhosis after effective antiviral therapy have decreased risk for hepatocellular carcinoma (HCC). Primary aim is to determine the incidence of HCC in patients with cirrhosis secondary to CHC and CHB, after treatment is provided, and to identify the magnitude of the decreased risk for HCC in patients experiencing regression of fibrosis. As a secondary aim, environmental risk factors for HCC development will be sought, in order to determine a subset of patients in whom it will be safe to stop surveillance.

Description:

Cirrhosis is the final pathway of chronic liver disease, and up to 30% of patients develop hepatocellular carcinoma (HCC) within 5 years of diagnosis of cirrhosis. Worldwide, chronic hepatitis C (CHC) and B (CHB) account for the majority of cases of cirrhosis. Successful antiviral treatment results in regression of fibrosis in the majority of patients. Surveillance programs for early detection of HCC mandate the use of imaging (ultrasound/CT-scan) every 6 months. It has been shown in CHC and CHB that the risk of HCC is greatly reduced after viral disease is eradicated/inactive. However, the impact that regression of fibrosis and other factors could have in abating the incidence of HCC has not been systematically investigated. Currently, all patients with eradicated/inactive viral disease continue to be enrolled in HCC surveillance programs, generating anxiety in patients and very high costs to our healthcare system. Fibrotest (FT) and transient elastography (TE) are noninvasive tools proven to be useful for serial assessment of liver fibrosis.

OBJECTIVES: The proposed hypothesis is that patients with regression of liver fibrosis have decreased risk for HCC. Primary aim is to determine the incidence of HCC in patients with cirrhosis secondary to CHC and CHB, during the 3-7 years after treatment is provided, and to identify the magnitude of the decreased risk for HCC in patients experiencing regression of fibrosis. As a secondary aim, environmental risk factors for HCC development will be sought, in order to determine a subset of patients in whom it will be safe to stop surveillance.

METHODS: Patients 18-70 year-old with cirrhosis will be identified from hepatology clinics in 4 academic centers in North America. FT/TE will be obtained before the start of antivirals and yearly thereafter (prospective arm). A retrolective arm of all patients treated no earlier than Jan/2009 will also be included. In this group, baseline FT/TE will be performed off treatment (CHC) or after initial phase of therapy (CHB), and yearly thereafter. During baseline and yearly visits other factors possibly affecting HCC development will be investigated (family history, comorbidities, BMI, diet, etc.). Patients will be classified as having or having not undergone regression of fibrosis after a 3-year follow up, depending on FT and TE evolution. During follow up, all patients will undergo 6-month imaging as part of their routine HCC surveillance. Based on power calculations, enrollment should stop after 924 patients have been recruited. Kaplan-Meier and Cox regression models will be used to analyze data.

PATIENT OUTCOMES: ROLFH study uses state-of-the-art noninvasive markers of liver fibrosis to test whether reversed fibrosis decreases the risk of HCC. We believe this study will lead to a better understanding of HCC risk factors, improved patient counseling and decision making, optimized screening and allocation of health resources, and decreased healthcare costs.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Age 18-70

• Chronic liver disease due to CHC or CHB.

• Starting of disease-specific treatment no earlier than January of 2010. Treatment could consist of:

• combination therapy with peginterferon and ribavirin, with or without a direct-acting viral agent in CHC;

• single or combination therapy containing peginterferon, entecavir, or tenofovir in CHB.

• Established cirrhosis on liver biopsy (METAVIR F4) obtained before starting disease-specific treatment.

• In patients without liver biopsy, any of the following criteria will be used as a surrogate to define cirrhosis:

• History of spleen >13 cm, bilirubin >2, albumin <3.5, INR >1.5 (2 of 3 criteria).

• History of APRI ([AST/ULN]/platelets x 100) >2, and esophageal varices or ascites.

• History of Fibrotest/Fibrosure >0.74, and TE >12.5 kPa (M-probe) or >10 kPa (XL-probe).

Exclusion Criteria:

• Known diagnosis of hepatocellular carcinoma or portal vein thrombosis

• Conditions limiting Fibrotest/Fibrosure read: hemolysis, Gilbert's syndrome, autoimmune disease.

• Conditions limiting TE read: ascites, heart failure with retrograde vascular congestion, extrahepatic cholestasis.

• Pregnancy or implantable active medical device (such as pacemaker or defibrillator).

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Chronic Hepatitis B
• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Other:
• Regression of fibrosis
Regression of fibrosis will be defined by assessing yearly evolution of noninvasive markers in patients who received antiviral therapy before start of the study, and by comparing baseline markers before start of antiviral therapy to those on subsequent yearly visits in patients prospective recruited (>50% of cases).
• Specific risk factors related to hepatocellular carcinoma
Such as: family history of liver cancer; body mass index; alcohol, smoking and recreational drug use status; dietary habits, including use of caffeinated drinks; comorbidities such as type 2 diabetes mellitus; use of medications for other chronic diseases such as statins and angiotensin-converting enzyme inhibitors.

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary	Alberta
Canada	University of Toronto	Toronto	Ontario
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas

Sponsors (4)

Lead Sponsor	Collaborator
University of Arkansas	University of Calgary, University of North Carolina, Chapel Hill, University of Toronto

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (8)

Barritt AS 4th, Fried MW. Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. Gastroenterology. 2012 May;142(6):1314-1323.e1. doi: 10.1053/j.gastro.2012.02.013. Review. — View Citation

Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020-2. doi: 10.1002/hep.24199. — View Citation

Duarte-Rojo A, Altamirano JT, Feld JJ. Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. Ann Hepatol. 2012 Jul-Aug;11(4):426-39. Review. — View Citation

El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012 May;142(6):1264-1273.e1. doi: 10.1053/j.gastro.2011.12.061. Review. — View Citation

European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012 Apr;56(4):908-43. doi: 10.1016/j.jhep.2011.12.001. Erratum in: J Hepatol. 2012 Jun;56(6):1430. — View Citation

Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Beaton M, Levstik M, Duarte-Rojo A, Wong D, Crotty P, Elkashab M. Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe. J Hepatol. 2012 Mar;56(3):564-70. doi: 10.1016/j.jhep.2011.10.007. Epub 2011 Oct 23. — View Citation

Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Duarte-Rojo A, Wong D, Beaton M, Levstik M, Crotty P, Elkashab M. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology. 2012 Jan;55(1):199-208. doi: 10.1002/hep.24624. Epub 2011 Nov 18. — View Citation

van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, Duarte-Rojo A, Heathcote EJ, Manns MP, Kuske L, Zeuzem S, Hofmann WP, de Knegt RJ, Hansen BE, Janssen HL. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012 Dec 26;308(24):2584-93. doi: 10.1001/jama.2012.144878. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Regression of liver fibrosis	According to Fibrotest/Fibrosure and transient elastography	Change from baseline to 3 years	No
Primary	Hepatocellular carcinoma	According to standard imaging surveillance protocol, and confirmatory CT/MRI/biopsy	3 years	No
Secondary	Risk factors for hepatocellular carcinoma	Positive family history of liver cancer, BMI, active/previous smoking, active/previous alcohol consumption, caffeine consumption in diet, diabetes mellitus, use of drugs for chronic medical conditions	Change from baseline to 3 years	No
Secondary	Profile with lowest risk for hepatocellular carcinoma	Composite of regression of fibrosis plus other specific conditions decreasing incidence of hepatocellular carcinoma to <1.5% / year	Change from baseline to 3 years	No