Suboptimal Responders to Adefovir Switching to Entecavir

Study Overview
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Brief Summary
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Switching to Entecavir will result in superior antiviral efficacy as compared to continuing with Adefovir in patients with a suboptimal response to Adefovir

Official Title
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A Comparative Study of the Week 12 Antiviral Efficacy and Safety of Switching to Entecavir vs. Continuing Adefovir Treatment in Adults With Chronic Hepatitis B and Suboptimal Response to Adefovir

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Entecavir
* Drug: Adefovir/Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic infection with hepatitis B virus (HBV)(detectable hepatitis B surface antibody (HBsAg) at screening and at least 24 weeks prior to screening, or detectable HBsAg for <24 weeks and negative for immunoglobulin M core antibody) Documentation of hepatitis B e antigen (HBeAg) positive or negative status Naive to nucleoside/nucleotide analogues, with the exception of adefovir Suboptimal response to adefovir treatment No lamivudine/telbivudine, entecavir, or adefovir resistance-associated substitutions at screening Male or female gender, aged 16 years and older Compensated liver function Serum alanine aminotransferase level <10*upper limit of normal at screening Exclusion Criteria: Women who are pregnant or breastfeeding Evidence of decompensated cirrhosis Coinfection with HIV, hepatitis C virus, or hepatitis D virus Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication) Chronic renal insufficiency, defined as a creatinine clearance <50 mL/min Current abuse of illegal drugs or alcohol, sufficient in the investigator's opinion to prevent adequate compliance with study therapy or to increase the risk of hepatotoxicity or pancreatitis Other serious medical conditions that might preclude completion of this study or that require chronic administration of prohibited medications Serum creatinine level >1.5 mg/dL; hemoglobin level <10.0 g/dL; platelet count <70,000/mm^3; absolute neutrophil count <1500 cells/mm^3; serum alpha fetoprotein level >100 ng/mL Except adefovir, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B (eg, lamivudine, entecavir), or any other experimental anti-HBV antiviral, or any China Traditional Medicine Therapy with interferon, thymosin alpha, or other immunostimulators within 24 weeks of randomization Required chronic administration of medications that cause immunosuppression, that are associated with a high risk of nephrotoxicity or hepatotoxicity, or that affect renal excretion.

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entecavir, 0.5 mg QD<br> | Drug: Entecavir<br>* Tablets, Oral, 0.5 mg, once daily (QD), 52 weeks<br>* Other names: BMS-200475;|
| Other: Adefovir, 10 mg QD/Entecavir, 0.5 mg QD<br>Control | Drug: Adefovir/Entecavir<br>* Tablets, Oral, 10-mg adefovir QD for 12 weeks followed by 0.5-mg entecavir QD for a maximum of 52 weeks<br>* Other names: BMS-200475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing | HBV DNA Level <50 IU/mL=approximately 300 copies/mL. | At Week 12 from Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing | HBV=hepatitis B virus. HBV DNA Level <50 IU/mL=approximately 300 copies/mL. | At Week 48 from Day 1 | 
| Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | HBV=hepatitis B virus | At Weeks 12 and 48 from Day 1 | 
| Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | ULN=upper limit of normal. ALT normalization= ≤1*ULN, among participants with baseline ALT >1*ULN | At Weeks 12 and 48 from Day 1 | 
| Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion |  | At Weeks 12 and 48 from Day 1 | 
| Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion |  | At Weeks 12 and 48 from Day 1 | 
| Number of Participants With Genotypic Resistance to Entecavir |  | At Week 48 from Day 1 | 
| Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | 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. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study drug. | Continually from Day 1 through Week 48, and through 24-week follow-up period | 
| Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Hematology testing assessed levels of hemoglobin, white blood cells, platelets, neutrophils, international normalized ration, red blood cells, lymphocytes, and monocytes. | Day 1 through Week 48 |