A Study in Korea of Entecavir Versus Lamivudine in Adults With Chronic Hepatitis B Infection

A Phase IV Study of the Antiviral Activity and Safety of Entecavir Versus Lamivudine in Adults With Chronic Hepatitis B Infection Who Are Negative for Hepatitis B e Antigen in Korea

Entecavir, 0.5 mg daily, will have clinical efficacy (assessed as an undetectable hepatitis B DNA, <300 copies/mL, by Roche Comprehensive Bio-Analytical System Amplicor polymerase chain reaction assay) that is comparable (noninferior) and potentially superior to lamivudine, 100 mg once daily, in adults with hepatitis B e antigen-negative chronic hepatitis B virus infection.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Entecavir; Drug: Lamivudine Placebo; Drug: Lamivudine; Drug: Entecavir Placebo

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bucheon, Korea, Republic of, 420-717
    • Local Institution
  • Busan, Korea, Republic of, 602-739
    • Local Institution
  • Chuncheon, Korea, Republic of, 200-704
    • Local Institution
  • Daegu, Korea, Republic of, 700-721
    • Local Institution
  • Daegu, Korea, Republic of, 705-030
    • Local Institution
  • Daejeon, Korea, Republic of, 301-721
    • Local Institution
  • Guri, Korea, Republic of, 471-020
    • Local Institution
  • Jeonju, Korea, Republic of, 561-180
    • Local Institution
  • Seoul, Korea, Republic of, 135-710
    • Local Institution
  • Seoul, Korea, Republic of, 136-705
    • Local Institution
  • Seoul, Korea, Republic of, 130-702
    • Local Institution
  • Seoul, Korea, Republic of, 135-270
    • Local Institution
  • Seoul, Korea, Republic of, 138-040
    • Local Institution
  • Seoul, Korea, Republic of, 150-950
    • Local Institution
  • Seoul, Korea, Republic of, 152-050
    • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Nucleoside and nucleotide-naive subjects with chronic HBV infection
• Hepatitis B Surface antigen(HBsAg)-positive ≥6 months
• Detectable HBsAg
• HBV DNA ≥ 105 copies/mL by PCR
• ALT 1.3 to 10 x the ULN
• HBeAg negative, anti-hepatitis B Virus E antigen antibody (anti-HBeAb) positive status

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Entecavir + Lamivudine placebo (0-96 weeks) Entecavir (96-240 weeks)	Drug: Entecavir; Tablets, Oral, 0.5 mg, once daily (0-96 weeks) and (96-240 weeks); Other Names: Baraclude; BMS-200475; Drug: Lamivudine Placebo; Capsules, Oral, 0 mg, once daily (0-96 weeks)
Active Comparator: Arm B; Lamivudine + Entecavir placebo (0-96 weeks) Lamivudine (96-240 weeks)	Drug: Lamivudine; Capsules, Oral, 100 mg, once daily (0-96 weeks) Tablets, Oral, 100 mg, once daily (96-240 weeks); Drug: Entecavir Placebo; Tablets, Oral, 0 mg, once daily (0-96 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved a Virologic Response at Week 24	Virologic response=Hepatitis B virus DNA <300 copies/mL by polymerase chain reaction assay.	At Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hepatitis B Virus (HBV) DNA <10^3, <10^4, or < 10^5 Copies/mL by Polymerase Chain Reaction (PCR) Assy at Weeks 24, 48, and 96	The number and percentage of participants achieving the following endpoints will be tabulated at each visit through Week 240 by treatment group: HBV DNA <300 copies/mL by PCR assay; HBV DNA <10^3, <10^4, or < 10^5 copies/mL by PCR assay. Treatment comparisons will be assessed using the same method as the primary endpoint.	At Weeks 24, 48, and 96
Mean Log10 Reduction From Baseline in Hepatitis B Virus (HBV) DNA at Weeks 24, 48, 96, 144, 192, and 240	Mean log10 reduction from Baseline in HBV DNA virus by the Roche Comprehensive Bio-Analytical System Amplicor polymerase chain reaction (PCR) assay at Week 24. The extent of the decrease was estimated by comparing HBV DNA levels of all participants in each group with a linear regression model with covariates of treatment and baseline HBV DNA by PCR assay.	At Weeks 24, 48, 96, 144, 192, and 240
Mean Laboratory Test Values for Alanine Aminotransferase (ALT) at Week 24	Mean ALT values from baseline by laboratory test. .	At Week 24
Number of Participants With Normalization of Serum Alanine Aminotransferase (ALT) Levels at Weeks 24, 48, and 96	Normalization of serum ALT= ≤*institutional upper limit of normal.	At Weeks 24, 48, and 96
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Most Common AEs, and Grade 3/4 AEs at Week 24	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Most common AEs=AEs affecting ≥3 participants. Grade 3 (Severe)/Grade 4 (Very Severe)AEs per World Health Organization (WHO) criteria.Serious adverse events/deaths reported for enrolled patients regardless of treatment status.	Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to end of 24-week follow-up period
Number of Participants With Elevations in Alanine Transaminase (ALT) and Aspartate Aminoaminase (AST) Levels, Elevations in ALT and AST Levels,Simultaneous Elevations in ALT and Total Bilirubin Levels, and ALT Flares at Week 24	ALT flares=ALT>2*Baseline and 10*upper limit of normal. Serious adverse events/deaths reported for enrolled patients regardless of treatment status.	Start of dosing (Day 1) until end of treatment (24 weeks) + 5 days and to end of 24-week follow-up period
Number of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results by World Health Organization (WHO) Criteria at Week 24	ULN=upper limit of normal; ALT=alanine transaminase. WHO criteria: Grade 3=Severe (inability to carry out usual activity); Grade 4=Very severe (debilitating or significantly incapacitating patient despite symptomatic treatment).	Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to the end of the 24-week follow-up period
Number of Participants With Clinically or Statistically Significant Changes in Vital Sign Measurements at Week 24	Vital signs assessed included blood pressure, heart rate, body temperature, and respiration rate.	Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to end of 24-week follow-up period
Number of Participants With Virologic Rebound at Week 24	Virologic rebound was defined as a confirmed ≥1 log10 increase in hepatitis B virus (HBV) DNA from nadir on blinded treatment (as determined by 2 sequential HBV DNA measurements or last on-treatment measurement).	At Week 24
Percentage of Participants With a Virologic Response as Defined by Undetectable Hepatitis B Virus DNA at Weeks 48, 96, 144, 192, and 240	Undetectable HBV DNA= <300 copies/mL by polymerase chain reaction assay	At Weeks 48, 96, 144, 192, and 240
Number of Participants With Viral Rebound and Drug-resistant Hepatitis B Virus (HBV) DNA Mutations at Week 96	Virologic rebound was defined as a confirmed ≥1 log10 increase in HBV DNA from nadir on blinded treatment (as determined by 2 sequential HBV DNA values or last on-treatment measurement).	At 96 weeks
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Most Common AEs, and Grade 3/4 AEs at Week 240	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.	Start of dosing (Day 1) until end of treatment (Week 240) + 5 days
Number of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results by World Health Organization (WHO) Criteria at Week 96	ULN=upper limit of normal; ALT=alanine transaminase. WHO criteria: Grade 3=Severe (inability to carry out usual activity); Grade 4=Very severe (debilitating or significantly incapacitating patient despite symptomatic treatment).	Start of dosing (Day 1) until Week 96

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: October 26, 2006
• First Submitted That Met QC Criteria: October 26, 2006
• First Posted (Estimate): October 27, 2006

Study Record Updates

• Last Update Posted (Estimate): November 26, 2014
• Last Update Submitted That Met QC Criteria: November 6, 2014
• Last Verified: November 1, 2014

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; Entecavir; Lamivudine
• Other Study ID Numbers: AI463-105