A Phase IIIb Study to Compare Entecavir Plus Tenofovir vs. Adefovir Added to Continuing Lamivudine Therapy in Adult Patients With Lamivudine-Resistant Hepatitis B Infection

A Comparative Study of the Antiviral Efficacy and Safety of Entecavir Plus Tenofovir Versus Adefovir Added to Continuing Lamivudine in Adults With Lamivudine- Resistant Chronic Hepatitis B Virus Infection

The purpose of this clinical research study is to find out whether a combination of entecavir (ETV) plus tenofovir (TNF) works better against Hepatitis B virus than adefovir (ADV) added to continuing lamivudine (LVD) therapy in patients whose Hepatitis B virus (HBV) is resistant against lamivudine. The safety of this treatment will also be studied.

Study Overview

• Status: Terminated
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Entecavir + Tenofovir; Drug: Adefovir + continuing Lamivudine

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Local Institution
  • Leuven, Belgium, 3000
    • Local Institution
• Germany
  • Berlin, Germany, 13353
    • Local Institution
  • Bonn, Germany, 53105
    • Local Institution
  • Duesseldorf, Germany, 40237
    • Local Institution
  • Mainz, Germany, 55131
    • Local Institution
• Italy
  • Messina, Italy, 98124
    • Local Institution
  • Modena, Italy, 41100
    • Local Institution
  • Naples, Italy, 80135
    • Local Institution
  • Padova, Italy, 35128
    • Local Institution
  • San Giovanni Rotondo, Italy, 71013
    • Local Institution
• Poland
  • Chorzow, Poland, 41-500
    • Local Institution
  • Krakow, Poland, 31-531
    • Local Institution
  • Lublin, Poland, 20-089
    • Local Institution
• Turkey
  • Ankara, Turkey, 06620
    • Local Institution
  • Ankara, Turkey, 06010
    • Local Institution
  • Istanbul, Turkey, 34093
    • Local Institution
  • Istanbul, Turkey, 34098
    • Local Institution
  • Istanbul, Turkey, 34360
    • Local Institution
  • Istanbul, Turkey, 34460
    • Local Institution
  • Istanbul, Turkey, 34722
    • Local Institution
  • Izmir, Turkey, 35100
    • Local Institution
  • Kocaeli, Turkey, 41380
    • Local Institution
  • Sihhiye Ankara, Turkey, 06100
    • Local Institution
  • Trabzon, Turkey, 61080
    • Local Institution
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • San Francisco, California, United States, 94118
      • Kaiser Permanente Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • New York
    • New York, New York, United States, 10025
      • Local Institution

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:

• Chronic HBV infection
• History of lamivudine (LVD) treatment, and lamivudine resistance (LVDr), receiving LVD at screening visit
• Compensated liver function
• HBV DNA ≥ 172,000 IU/mL
• Hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative

Exclusion Criteria:

• Evidence of decompensated cirrhosis
• Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV)
• Recent history of pancreatitis
• Serum alpha fetoprotein > 100 ng/mL
• Except lamivudine, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B

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: 1	Drug: Entecavir + Tenofovir; Tablets, Oral Entecavir 1 mg + Tenofovir 300 mg, once daily, 100 weeks; Other Names: Baraclude
Experimental: 2	Drug: Adefovir + continuing Lamivudine; Tablets, Oral, Adefovir 10 mg + Lamivudine, 100 mg, once daily, 100 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Achieved an Hepatitis B Virus DNA (HBV DNA) Level < 50 IU/mL at Week 48	using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay, by Polymerase Chain Reaction (PCR); HBV DNA < 50 IU/mL = approximately 300 copies/mL	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 96	by PCR, using the Roche COBAS®TaqMan - HPS assay; HBV DNA < 50 IU/mL = approximately 300 copies/mL.	Week 96
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or is an important medical event.	Day 1 through end of treatment (Week 100 +/- 5 days)
Number of Participants Who Achieved HBV DNA < the Lower Limit of Detection (LLD) at Weeks 48 and 96	by PCR, using the Roche for the Roche COBAS® TaqMan - HPS assay. LLD = 4.8 IU/mL (approximately 28 copies/mL)	Week 48, Week 96
HBV DNA Values at Weeks 48 and 96	Number of Participants with HBV DNA <LLD (4.8); LLD to <50; 50 to <172; 172 to <1,720; 1,720 to <17,200; and ≥17,200 IU/mL (<LLD (28); 28 to <300; 300 to <1,000; 1,000 to <10,000; 10,000 to <100,000; and ≥100,000 copies/mL by PCR, using the Roche COBAS®TaqMan - HPS assay	Weeks 48, Week 96
Mean log10 Reduction From Baseline in HBV DNA at Weeks 48 and 96	by PCR, using the Roche COBAS®TaqMan - HPS assay	Week 48, Week 96
Number of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieved ALT Normalization (≤ 1 x ULN) at Weeks 48 and 96		Week 48, Week 96
Number of Participants Who Were Hepatitis B E-antigen (HBeAg)-Positive at Baseline With Loss of HBeAg at Weeks 48 and 96	HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication.	Baseline, Week 48, Week 96
Number of Participants Who Were HBeAg-positive at Baseline With HBe Seroconversion at Weeks 48 and 96	HBe seroconversion = HBeAg loss and presence of hepatitis B e-antibody (HBeAb)	Baseline, Week 48, Week 96
Number of Participants With Hepatitis-B-Virus Surface Antigen of the (HBsAg) Loss at Weeks 48 and 96	Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection	Week 48, Week 96
Number of Participants With HBs Seroconversion (HBsAg Loss and Presence of HBsAb) at Weeks 48 and 96	Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAb = HBsAg antibodies. HBs Seroconversion = HBsAg loss and presence of HBseAb	Week 48, Week 96
Number of Participants With Genotypic Resistance Based on Analysis of Samples From Participants With HBV DNA ≥ 50 IU/mL at Weeks 48 and 96	HBV DNA ≥ 50 IU/mL = approximately 300 copies/mL	Week 48, Week 96

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: January 18, 2008
• First Submitted That Met QC Criteria: January 30, 2008
• First Posted (Estimate): January 31, 2008

Study Record Updates

• Last Update Posted (Estimate): November 23, 2010
• Last Update Submitted That Met QC Criteria: November 15, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, 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; Tenofovir; Entecavir; Lamivudine; Adefovir
• Other Study ID Numbers: AI463-137