Antiviral Therapy in Hepatitis B Virus (HBV)-Related Advanced Liver Disease Patients

A Randomized, Open Label, Phase IV, Multicenter Study for Efficacy and Safety of Lamivudine Versus Entecarvir Therapy in HBV-related Advanced Liver Disease Patients With High Viral Load and Normal or Slightly Elevated Transaminase

This is a randomized, open label, phase IV, multicenter study for efficacy and safety of lamivudine versus entecarvir therapy in HBV-related advanced liver disease patients with high viral load and normal or slightly elevated transaminase.

Study Overview

• Status: Unknown
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Entecavir; Drug: Lamivudine

Detailed Description

Currently, treatment guidelines for the management of chronic hepatitis B (CHB) recommend that patients with serum HBV DNA > 105 copies/ml and elevated ALT levels greater than two times the upper limit of normal (ULN) are obvious candidates for antiviral therapy. Guidelines also suggest that antiviral therapy be considered in CHB patients with high viral load, if a biopsy shows significant liver disease despite ALT ≤ 2× ULN. Data from recent trials in hepatitis B patients who present with normal to minimally elevated ALT (≤ 2× ULN) indicate that significant hepatic pathology could still be found. Serum ALT level may not accurately predict activity of liver damage. ALT is a poor predictor of outcome and therefore is not a suitable criterion for antiviral therapy in chronic hepatitis B infection. Also, a recent large randomized controlled clinical trial comparing lamivudine maintenance and placebo in advanced fibrosis (Ishak fibrosis score ≥ 4) suggests that sustained viral suppression with antiviral therapy is linked to reduced risk for disease progression. (Liaw YF et al. NEJM 2004;351:1521-1531)

• Study Type: Interventional
• Enrollment (Anticipated): 462
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Male and female, 18 years of age or older
• HBsAg positive for more than 6 months
• Serum HBV DNA > 2,000 IU/ml
• Serum ALT < 2 X ULN on two consecutive occasions at least 3 months apart
• Naïve to nucleoside or nucleotide therapy
• On liver biopsy, fibrosis score ≥ 3 according to METAVIR scoring system (within 2 years of Day 0)

• If liver biopsy is not available, subjects must have two of the following items

  • Overt findings of cirrhosis by radiologic evidence (MRI, CT, US)
  • Gastrointestinal varices
  • Platelet count < 100,000,Splenomegaly (Spleen size - 12cm)
• The patient who is willing and able to provide written informed consent to participate in this study

Exclusion criteria

• A history of SBP, variceal bleeding, HEP, HCC
• Decompensated liver disease (Child-Pugh score > 10)
• Co-infected with HCV or HIV
• History of any other forms of liver disease.
• Patient who is pregnant or breastfeeding
• Treatment with immunosuppressive, immunomodulatory agents or antiviral agents within 6 months prior to study entry
• A history of liver transplantation or planned for liver transplantation
• A history of any other medical disease or condition that would make the patients unsuitable for the study.
• Patient is currently abusing alcohol or illicit drugs or has a history of alcohol abuse or illicit substance abuse within the preceding 2 years.
• Patient is enrolled or plans to enroll in another clinical trial of an investigational agent while participating in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; entecavir 0.5 mg QD	Drug: Entecavir; entecavir 0.5 mg QD; Other Names: Baraclude 0.5mg
Active Comparator: B; lamivudine 100 mg QD	Drug: Lamivudine; lamivudine 100 mg QD; Other Names: Zeffix 100mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to disease progression as defined by the first occurrence of any of the cirrhosis compolications	5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients achieving either HBV DNA level ≤ 60 IU/mL Proportion of patients with ALT normalization Proportion of patients with HBeAg loss and seronconversion Proportion of patients with virologic breakthrough	at months 12, 24, 36, 48, and 60

Collaborators and Investigators

• Sponsor: Yonsei University
• Collaborators: Bristol-Myers Squibb; Pusan National University Hospital; Korea University Anam Hospital; Korea University; Kyungpook National University Hospital; Inje University; Hanyang University; The Catholic University of Korea; Kangbuk Samsung Hospital; Severance Hospital; Soonchunhyang University Hospital; Hallym University Medical Center; Chung-Ang University; Konkuk University Hospital; Inha University Hospital; Keimyung University; Ajou University
• Investigators: Study Chair: Kwnag-Hyub Han, MD, Yonsei Univsersity College of Medicine; Study Director: Jun Yong Park, MD, Yonsei Univsersity College of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Anticipated): July 1, 2014
• Study Completion (Anticipated): July 1, 2015

Study Registration Dates

• First Submitted: January 14, 2009
• First Submitted That Met QC Criteria: January 14, 2009
• First Posted (Estimate): January 15, 2009

Study Record Updates

• Last Update Posted (Estimate): December 16, 2010
• Last Update Submitted That Met QC Criteria: December 15, 2010
• Last Verified: January 1, 2009

More Information

Terms related to this study

• Keywords: Lamivudine; Chronic hepatitis B; Entecavir; Advanced fibrosis
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Liver Diseases; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Entecavir; Lamivudine
• Other Study ID Numbers: 4-2008-0296