Safety and Antiviral Activity of Entecavir in Participants With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01438424
First received: September 16, 2011
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

The purpose of this study is to provide entecavir to participants who have completed another entecavir trial without achieving virologic response or who relapsed during postdosing follow-up.


Condition Intervention Phase
Hepatitis B Virus
HBV
Drug: Entecavir
Drug: Lamivudine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Preliminary Assessment of Safety and Antiviral Activity of Open-label Entecavir in Subjects With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Overall Study: Number of Participants With Death As Outcome, Any Adverse Event (AE), Grade 3-4 AEs, Serious Adverse Events (SAEs), and Discontinuations Due to AEs [ Time Frame: Continuously from Day 1 through Week 240 ] [ Designated as safety issue: Yes ]
    An AE is a new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not be causally related to treatment. An SAE is an unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine transaminase; ULN=upper limit of normal.

  • Overall Study: Number of Participants With Normal Hematology Values at Baseline and Abnormalities in Hematology Laboratory Test Results Through Week 240 [ Time Frame: Day 1 of treatment through Week 240 ] [ Designated as safety issue: Yes ]
    Hemoglobin (g/dL): Grade (Gr) 1=9.5-11.0; Gr 2=8.0-<9.5; Gr 3=6.5-<8.0; Gr 4=<6.5 White blood cells (cells/mm^3): Gr 1=2,500-<4,000; Gr 2=1,000-<2,500; Gr 3=800-<1,000; Gr 4=<800. Neutrophils (cells/mm^3): Gr 1=1000-<1500; Gr 2=750-<1000; Gr 3=500-<750; Gr 4=<500. Platelets (cells/mm^3): Gr 1=75,000-99,000; Gr 2=50,000-<75,000; Gr 3=20,000-<50,000; Gr 4=<20,000. Prothrombin time (seconds): Gr 1=1.01-<1.26*ULN; Gr 2=1.26-<1.51 *ULN; Gr 3=1.51-3*ULN; Gr 4=>3*ULN. INR: Gr 1=1.24-1.5; Gr 2=1.5-2; Gr 3=2-3; Gr 4=>3. INR=international normalized ratio; ULN=upper limit of normal. .

  • Overall Study: Number of Participants With Normal Pancreatic Enzyme and Renal Function Values at Baseline and Abnormalities in Pancreatic Enzyme and Renal Function Laboratory Test Results at End of Dosing [ Time Frame: Day 1 of treatment through Week 240 ] [ Designated as safety issue: Yes ]
    Amylase: Grade 1=1.10-<1.40*ULN; Grade 2=1.40-< 2.10*ULN; Grade 3=2.10-5.00*ULN; Grade 4=>5.00*ULN. Lipase: Grade 1.1-<1.4*ULN; Grade 2=1.4-<2.1*ULN; Grade 3=2.1-5.0*ULN; Grade 4=>5.0*ULN. Creatinine: Grade 1=1.10-< 1.60*ULN; Grade 2=1.60-<3.10*ULN; Grade 3=3.10-6.00*ULN; Grade 4=>6.00*ULN. Blood urea nitrogen (BUN): Grade 1=1.25-<2.60*ULN; Grade 2=2.60-<5.10*ULN; Grade 3=5.10-10*ULN; Grade 4=>10*ULN. ULN=upper limit of normal.

  • Overall Study: Number of Participants With Normal Electrolyte and Fasting Glucose Values at Baseline and Abnormalities in Electrolyte and Fasting Glucose Laboratory Test Results at End of Dosing [ Time Frame: Day 1 of treatment through Week 240 ] [ Designated as safety issue: Yes ]
    Hypochloremia: Grade (Gr) 1=90-93; Gr 2=85-<90; Gr 3=80-<85; Gr 4=40-<80. Hyperchloremia: Gr 1=113-<117; Gr 2=117-<121; Gr 3=121-125; Gr 4>125. Hypocarbia: Gr 1=19-21; Gr 2=15-<19; Gr 3=41-45; Gr 4=>45. Hypercarbia: Gr 1=31-36; Gr 2=37-40; Gr 3=41-45; Gr 4=>45. Hyponatremia: Gr 1=130-132; Gr 2=123-<130; Gr 3=116-<123; Gr 4<116. Hypernatremia: Gr 1=148-<151; Gr 2=151-<158; Gr 3=158-165; Gr 4=>165. Hypokalemia: Gr 1=3-3.4; Gr 2=2.5-<3; Gr 3=2-<2.5; Gr 4=<2. Hyperkalemia: Gr 1=5.6-<6.1; G2=6.1-<6.6; Gr 3=6.6-7; Gr 4=>7. Hypoglycemia: Gr 1=55-64; Gr 2=40-<55; Gr 3=30-< 40; G4=-<30. Hyperglycemia: Gr 1=116-<161; Gr 2=161-<251; Gr 3=251-500; Gr 4>500.

  • Week 144: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results [ Time Frame: Continuously from Day 1 through Week 144 ] [ Designated as safety issue: Yes ]
    An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. AST=aspartate aminotransferase; ULN=upper limit of normal.

  • Week 192: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results [ Time Frame: Continuously from Day 1 through Week 192 ] [ Designated as safety issue: Yes ]
    An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. CTC Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine aminotransferase; ULN=upper limit of normal.

  • Off-treatment Follow-up: Percentage of Participants With Sustained Hepatitis B Virus (HBV) DNA <10,000 Copies by Polymerase Chain Reaction (PCR) Assay (Amendment 11 Cohort) [ Time Frame: End of dosing to Week 48 off-treatment follow-up ] [ Designated as safety issue: No ]
    The Amendment 11 Cohort consisted of participants who were hepatitis B e antigen (HBeAg) negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0*ULN at the end of study drug dosing.ALT=alanine aminotransferase; ULN=upper limit of normal.


Secondary Outcome Measures:
  • Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay [ Time Frame: Study entry to Week 192 ] [ Designated as safety issue: No ]
  • Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay [ Time Frame: Study entry to Week 192 ] [ Designated as safety issue: No ]
  • Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay [ Time Frame: Baseline to Week 192 ] [ Designated as safety issue: No ]
    Observed values.

  • Overall Study: Mean HBV DNA Level by PCR Assay [ Time Frame: Study entry to Week 216 ] [ Designated as safety issue: No ]
  • Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg) [ Time Frame: Study entry to Week 216 ] [ Designated as safety issue: No ]
    Observed values.

  • Overall Study: Percentage of Participants With HBeAg Seroconversion [ Time Frame: Study entry to Week 216 ] [ Designated as safety issue: No ]
    Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody.

  • Overall Study: Mean Alanine Transaminase (ALT) Levels [ Time Frame: Study entry to Week 216 ] [ Designated as safety issue: No ]
    Observed values.

  • Overall Study: Percentage of Participants Who Achieved ALT Normalization [ Time Frame: Study entry to Week 216 ] [ Designated as safety issue: No ]
    ULN=upper limit of normal. ALT normalization=ALT levels ≤1.0*ULN.

  • Week 192: Percentage of Participants With Histologic Improvement (Efficacy Evaluable Cohort) [ Time Frame: Baseline to Week 192 ] [ Designated as safety issue: No ]
    The Knodell Histologic Activity Index scores stage of necrosis and grade of inflammation in liver biopsies. Components are necrosis near the portal vein, intralobular degeneration and focal necrosis, portal inflammation, and fibrosis. The 4 components are scored from 1 to 4 and 1 to 10 (necrosis near the portal vein) and combined for a total score, with 22 being the highest possible score. Higher the score for each component=greater liver damage. Histologic improvement=a ≥2-point reduction in total Knodell score and no worsening in fibrosis. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell necroinflammatory scores ≥2.

  • Week 192: Percentage of Participants With Improvement in Fibrosis (Efficacy Evaluable Cohort) [ Time Frame: Baseline to Week 192 ] [ Designated as safety issue: No ]
    The Ishak Modification for Hepatic Activity Index (HAI) scores necroinflammatory activity in chronic hepatitis. 0=no fibrosis, 1=fibrosis expansion of some portal areas, 2=fibrosis expansion of most portal areas, 3=fibrosis expansion of most portal areas with occasional bridging, 4=fibrosis expansion of portal areas with marked bridging, 5=incomplete cirrhosis, 6=probable or definite cirrhosis. Higher score=more severe necrosis. Improvement in fibrosis=≥1-point reduction in HAI score. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell scores ≥2.

  • Overall Study: Percentage of Participants With a Confirmed ≥1 log10 Increase From Nadir in HBV DNA by PCR Assay [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAG, Seroconversion, and ALT ≤1.0*Upper Limit of Normal (ULN) (Entecavir Continuous Treatment Cohort) [ Time Frame: Baseline to Weeks 48, 96, 144, 192, and 240 ] [ Designated as safety issue: No ]
    The Entecavir Continuous Treatment Cohort consisted of participants from study AI463-022 (NCT00035633) who were nucleoside-naive HBeAg-positive and enrolled in the current study with ≤35 days off treatment between the last dose in AI463-022 and the first dose in the current. This cohort is considered to be on continuous entecavir treatment and permitted assessment of continuous administration of entecavir in AI463-022 and the current study.

  • Percentage of Participants Who Achieved HBV DNA <300 and <10^4 Copies/mL by PCR Assay and ALT ≤1.0*Upper Limit of Normal (ULN) (Entecavir Retreatment Cohort) [ Time Frame: Baseline to Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]
    The Entecavir Retreatment Cohort consisted of participants who were nucleoside-naive, HBeAg-negative and enrolled from BMS study AI463-027 with >60 days off treatment between the last dose in AI463-027 and the first dose in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as retreatment in the current study.

  • Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAg, HBeAg Seroconversion, and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort) [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.

  • Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort) [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.

  • Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort) [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with >60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.

  • Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort) [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with >60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.

  • Off-treatment Follow-up: Percentage of Participants With Sustained HBV DNA <1,000, <300, and <10,000 Copies/mL by PCR Assay and With ALT ≤1*ULN (Amendment 11 Cohort) [ Time Frame: End of dosing to Weeks 48 and 96 off-treatment follow-up ] [ Designated as safety issue: No ]
    The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR Assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0*ULN at the end of study drug dosing. ULN=upper limit of normal.

  • Off-treatment Follow-up: Mean Change in HBV DNA (Amendment 11 Cohort) [ Time Frame: End of dosing to Weeks 48 and 96 off-treatment follow-up ] [ Designated as safety issue: No ]
    The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0*ULN at the end of study drug dosing.


Enrollment: 1053
Study Start Date: January 2001
Study Completion Date: April 2011
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Entecavir, 1.0 mg, with or without lamivudine Drug: Entecavir
Tablets, Oral, 1.0 mg, once daily
Other Name: Baraclude
Drug: Lamivudine
Oral, 100 mg, daily

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key inclusion criteria:

  • Age of 16 years and older
  • Receipt of entecavir or lamivudine in a previous entecavir study.

Participants who were, based on their response to entecavir:

  • Virologic nonresponders at Week 48
  • Partial virologic responders who became nonresponders during the second year of treatment
  • Partial virologic responders at Week 96
  • Complete responders who relapsed during postdosing follow-up

    • Decompensated liver disease in AI463-048 that met 1 or more of the following criteria:
  • Nonresponse to adefovir after at least 24 weeks of treatment
  • Partial response to adefovir after 96 weeks of treatment
  • Complete response to adefovir after relapsing during postdosing follow-up
  • Demonstrated intolerance to adefovir

    • Except for those participants enrolled from AI463-048, compensated liver disease.

Key exclusion criteria:

  • HIV coinfection
  • Receiving nephrotoxic or hepatotoxic agents
  • Ongoing opportunistic infections
  • Hemoglobin level <11.0 g/dL except for those enrolled from AI463-048
  • Platelet count <70,000 mm^3 except for those enrolled from AI463-048
  • Absolute granulocyte count <1,500 cells/mm^3
  • Recent history of pancreatitis (within 24 weeks prior to first dose of therapy)
  • Current evidence of ascites requiring paracentesis, hepatic encephalopathy, or variceal bleeding, except for those enrolled from AI463-048
  • Known history of allergy to nucleoside analogues.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01438424

Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01438424     History of Changes
Other Study ID Numbers: AI463-901
Study First Received: September 16, 2011
Results First Received: June 12, 2012
Last Updated: July 19, 2012
Health Authority: Hong Kong: Department of Health
Indonesia: Departement Kesehatan (Department of Health)
Indonesia: National Agency of Drug and Food Control
Malaysia: Ministry of Health
Philippines: Bureau of Food and Drugs
Philippines: Department of Health
Singapore: Clinical Trials & Epidemiology Research Unit (CTERU)
Singapore: Domain Specific Review Boards
Singapore: Health Sciences Authority
South Korea: Korea Food and Drug Administration (KFDA)
Taiwan: Department of Health
Taiwan: National Bureau of Controlled Drugs
Thailand: Food and Drug Administration
Thailand: Ministry of Public Health
Pakistan: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
Australia: National Health and Medical Research Council
Canada: Health Canada
Czech Republic: State Institute for Drug Control
Poland: Ministry of Health
Poland: Ministry of Science and Higher Education
Poland: National Institute of Medicines
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ethics Committee
Russia: FSI Scientific Center of Expertise of Medical Application
Russia: Ministry of Health of the Russian Federation
Slovakia: Public Health Authority
Turkey: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Germany: Ministry of Health
Switzerland: Swissmedic
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Portugal: National Pharmacy and Medicines Institute
Spain: Spanish Agency of Medicines
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Brazil: National Health Surveillance Agency
Brazil: National Committee of Ethics in Research
Peru: Instituto Nacional de Salud
Mexico: Federal Commission for Sanitary Risks Protection
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Denmark: Danish Dataprotection Agency
Denmark: Danish Medicines Agency
Denmark: The Danish National Committee on Biomedical Research Ethics
Israel: Ministry of Health
Italy: Ministry of Health
Italy: National Bioethics Committee
Italy: National Institute of Health
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Italy: The Italian Medicines Agency
Greece: Ethics Committee
Greece: National Organization of Medicines
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Antiviral Agents
Lamivudine
Entecavir
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on April 17, 2014