Suboptimal Responders to Adefovir Switching to Entecavir

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

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

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Entecavir; Drug: Adefovir/Entecavir

• Study Type: Interventional
• Enrollment (Actual): 228
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100011
      • Local Institution
  • Guizhou
    • Guiyang, Guizhou, China, 550004
      • Local Institution
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Local Institution
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Local Institution
  • Jilin
    • Changchun, Jilin, China, 130021
      • Local Institution
  • Liaoning
    • Shenyang, Liaoning, China, 110004
      • Local Institution
  • Shanghai
    • Shanghai, Shanghai, China, 200235
      • Local Institution
    • Shanghai, Shanghai, China
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Entecavir, 0.5 mg QD	Drug: Entecavir; Tablets, Oral, 0.5 mg, once daily (QD), 52 weeks; Other Names: Baraclude; BMS-200475
OTHER: Adefovir, 10 mg QD/Entecavir, 0.5 mg QD; Control	Drug: Adefovir/Entecavir; Tablets, Oral, 10-mg adefovir QD for 12 weeks followed by 0.5-mg entecavir QD for a maximum of 52 weeks; Other Names: Baraclude; BMS-200475

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: July 17, 2008
• First Submitted That Met QC Criteria: July 18, 2008
• First Posted (ESTIMATE): July 21, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): February 11, 2013
• Last Update Submitted That Met QC Criteria: January 4, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis B, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Entecavir; Adefovir
• Other Study ID Numbers: AI463-171