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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Entecavir
* Drug: Lamivudine Placebo
* Drug: Lamivudine
* Drug: Entecavir Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |