Clinical trial NCT00823550: Antiviral Therapy in Hepatitis B Virus (HBV)-Related Advanced Liver Disease Patients
Official title: 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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Keywords: Chronic hepatitis B
Advanced fibrosis
Lamivudine
Entecavir
Lead sponsor: Yonsei University
Sponsor class: OTHER
Collaborators: name: Severance Hospital
name: Kangbuk Samsung Hospital
name: Konkuk University Hospital
name: Chung-Ang University
name: Ajou University
name: Inha University Hospital
name: Soonchunhyang University Hospital
name: The Catholic University of Korea
name: Hallym University Medical Center
name: Kyungpook National University Hospital
name: Keimyung University
name: Korea University Anam Hospital
name: Korea University
name: Hanyang University
name: Inje University
name: Pusan National University Hospital
name: Bristol-Myers Squibb
First posted: 2009-01-15
Enrollment: 462
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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)

Eligibility criteria: 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.

Primary outcomes:
measure: Time to disease progression as defined by the first occurrence of any of the cirrhosis compolications
timeFrame: 5 years
Secondary outcomes:
measure: 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
timeFrame: at months 12, 24, 36, 48, and 60
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
Study officials:
affiliation: Yonsei Univsersity College of Medicine
name: Kwnag-Hyub Han, MD
role: STUDY_CHAIR
affiliation: Yonsei Univsersity College of Medicine
name: Jun Yong Park, MD
role: STUDY_DIRECTOR
References: