Antiviral Activity of Entecavir in Patients Receiving Liver Transplant Due to Chronic Hepatitis B Virus Infection

Study of the Antiviral Activity of Entecavir in Patients Receiving Liver Transplant Due to Chronic Hepatitis B Virus Infection

The purpose of this clinical research study is to learn if the study drug entecavir will prevent the recurrence of hepatitis B virus (HBV) in participants who receive an orthotopic liver transplant (OLT) due to HBV infection.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: entecavir

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1181ACH
    • Local Institution
• Australia
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Local Institution
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution
• Brazil
  • Sao Paulo, Brazil, 01246
    • Local Institution
  • Ceara
    • Fortaleza, Ceara, Brazil, 60430
      • Local Institution
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035
      • Local Institution
• France
  • Clichy Cedex, France, 92118
    • Local Institution
  • Paris Cedex 12, France, 75571
    • Local Institution
  • Villejuif, France, 94800
    • Local Institution
• Italy
  • Bologna, Italy, 40125
    • Local Institution
  • Roma, Italy, 00168
    • Local Institution
  • Roma, Italy, 00133
    • Local Institution
  • Torrette Di Ancona, Italy, 60020
    • Local Institution
• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Local Institution
  • Seoul, Korea, Republic of, 120-752
    • Local Institution
  • Seoul, Korea, Republic of, 135-710
    • Local Institution
  • Seoul, Korea, Republic of, 138-736
    • Local Institution
• Spain
  • Barcelona, Spain, 08035
    • Local Institution
  • Barcelona, Spain, 08036
    • Local Institution
  • Madrid, Spain, 280009
    • Local Institution
  • Valencia, Spain, 46009
    • Local Institution
• Taiwan
  • Kaohsiung, Taiwan, 833
    • Local Institution
  • Taipei, Taiwan, 112
    • Local Institution
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Hospital & Clinic
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Baylor college of medicine

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:

• Patients receiving orthotopic liver transplant (OLT) due to end-stage liver disease because of chronic HBV infection, with HBV-DNA < 172 IU/mL (approximately < 1000 copies/mL) prior to liver transplant
• Must have detectable hepatitis B surface antigen (HBsAg) at screening and for at least 24 weeks prior to screening

Exclusion Criteria:

• Patients with hepatocellular carcinoma with evidence of extrahepatic spread, multiple tumors ≥ 6.5 cm in diameter or there is up to three nodules ≥ 4.5 cm in diameter and total tumor diameter is ≥ 8 cm
• Co-infection with human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) or hepatitis C virus (HCV)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: entecavir	Drug: entecavir; Tablets, Oral, 1 mg, once daily, up to 72 weeks; Other Names: Baraclude; BMS-200475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HBV Deoxyribonucleic Acid (DNA) => 50 IU/mL by Polymerase Chain Reaction (PCR) at Week 72	HBV DNA assessments were performed using the Roche COBAS® TaqMan High+Pure system (HPS) assay. HBV DNA => 50 IU/mL = approximately => 300 copies/mL.	At 72 weeks
Number of Participants With HBV DNA by PCR >= 50 IU/mL Through Week 72	HBV DNA assessments were performed using the Roche COBAS® TaqMan High+Pure system (HPS) assay. HBV DNA => 50 IU/mL = approximately => 300 copies/mL.	At baseline (day 1), week 12, 24, 36, 48, 60, and 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distribution of ALT Levels Through 72 Weeks: Overall	ALT is an enzyme present in serum and various tissues of the body, associated commonly with the liver. Elevated levels of ALT often suggests existence of medical problems which includes viral hepatitis. Normal range varies from laboratory to laboratory. Values of 5-60 U/L is usually considered normal. ALT abnormality = >1.25 x ULN (upper limit of normal).	On Day 1 (baseline) and at week 4, 12, 24, 36, 48, 60, 72
Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at the End of Post-dosing Follow-up	HBV DNA assessments were to be performed using the Roche COBAS® TaqMan AmpliPrep assay. HBV DNA < 50 IU/mL = approximately 300 copies/mL.	At 72 weeks + 24 weeks follow-up
Percentage of Participants With HBeAg Loss at Week 72 (for HBeAg-positive Participants)	HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week.	At week 72
Percentage of Participants With HBeAg Seroconversion at Week 72 (for HBeAg-positive Participants)	HBeAg is a hepatitis B viral protein. HBeAg Seroconversion = HBeAg Loss and Presence of Hepatitis B e Antibody (HBeAb).	At week 72
Percentage of Participants With HBsAg Loss at Week 72	HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg loss = HBsAg-negative at the specified analysis week.	At week 72
Percentage of Participants With HBsAg Seroconversion at Week 72	HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBs seroconversion is defined as HBsAg loss with positive HBsAb.	At week 72
Percentage of Participants With HBsAg Recurrence At Week 72	HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg recurrence is defined as having detectable HBsAg among participants who have already experienced loss of HBsAg on-treatment. HBsAg recurrence = HBsAg-positive at the specified analysis week.	At week 72
Total Bilirubin at Week 72	Bilirubin measures are used to diagnose or monitor liver functioning or diseases that include hepatitis. Viral hepatitis is one of the condition in which bilirubin levels are elevated. Normal range varies from laboratory to laboratory. Bilirubin abnormality : => 1.1 x ULN mg/dL.	At week 72
Prothrombin Time (PT) at Week 72	Prothrombin, a liver protein, plays an important role in the extrinsic pathway of clotting. Increased prothrombin time indicates abnormal liver functioning. Normal prothrombin time varies from laboratory to laboratory. Generally, normal prothrombin time varies between 10 to 13.2 seconds. Abnormal PT: > 1.01 x ULN.	At week 72
Number of Participants With Liver Rejection Through Week 72		Through week 72
Number of Participants With Re-transplantation Through Week 72		Through week 72
Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations From Study Drug Due to AEs (On-treatment [OT] and Off-treatment Follow-up [OF])	AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or an overdose. Toxicity grading by modified WHO grade system. Grade (GR) 2=moderate; GR3=severe; GR4=very severe. OT=from start of dosing to end of dosing+5 days; OF=from end of dosing+6 days to start of other anti-HBV therapy or end of follow-up.	OT:From start of dosing through Week 72 + 5 days; OF:End of OT through 24-weeks follow-up
Number of Participants With Laboratory Abnormalities On-treatment (OT) and Off-Treatment Follow-up(OF): Hematology (All Grades)	Criteria for hematology abnormalities were: Hemoglobin : <11.0 g/dL; White Blood Cells : <4000/mm^3; Neutrophils : <1500/mm^3; Platelets : < 99,000/mm^3; International Normalized Ratio (INR) : increase >= 0.5 from baseline.	OT:From start of dosing through Week 72 + 5 days; OF:End of OT through 24-weeks follow-up
Number of Participants With Laboratory Abnormalities On-treatment (OT) and Off-Treatment (OF) Follow-up: Serum Chemistry (All Grades)	Normal ranges are local lab data and vary according to the site. Criteria for laboratory abnormalities:ALT:>1.25xULN;AST:>1.25xULN;ALP:>1.25xULN;Total Bilirubin:>1.1xULN;Serum Lipase:>1.10xULN;Creatinine:>1.1xULN;Blood Urea Nitrogen:>1.25xULN;Hyperglycemia:>116mg/dL;Hypoglycemia:<64mg/dL;Hyponatremia:<132meq/L;Hypernatremia:>148meq/L;Hypokalemia:<3.4meq/L;hyperkalemia:>5.6meq/L;Hypochloremia:<93meq/L;Hyperchloremia:>113meq/L;Albumin: Decrease >= 1g/dL from baseline and < 3 g/dL. HYPER=value>ULN(upper limit of normal). HYPO=value<LLN (lower limit of normal).	OT:From start of dosing through Week 72 + 5 days; OF:End of OT through 24-weeks follow-up

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: November 1, 2006
• First Submitted That Met QC Criteria: November 1, 2006
• First Posted (Estimate): November 2, 2006

Study Record Updates

• Last Update Posted (Estimate): May 31, 2012
• Last Update Submitted That Met QC Criteria: April 30, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Chronic Hepatitis B Virus, Liver Transplant
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; 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; Virus Diseases; Hepatitis B, Chronic; Hepatitis, Chronic; Herpesviridae Infections; Anti-Infective Agents; Antiviral Agents; Entecavir
• Other Study ID Numbers: AI463-109