A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of Hepatitis Be Antigen (HBeAg) Positive Chronic Hepatitis B

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2011 by Gilead Sciences.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00116805
First received: June 30, 2005
Last updated: October 31, 2011
Last verified: October 2011
  Purpose

This study is designed to evaluate the safety and antiviral activity of tenofovir disoproxil fumarate (TDF, tenofovir DF) compared to adefovir dipivoxil (ADV, Hepsera) for the treatment of HBeAg-positive chronic hepatitis B. Participants will receive either TDF or the approved hepatitis B therapy ADV. After 48 weeks all participants will be switched to open-label (OL) TDF.


Condition Intervention Phase
Chronic Hepatitis B
Drug: tenofovir disoproxil fumarate
Drug: adefovir dipivoxil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Complete response was a composite endpoint defined as histological response and HBV DNA below 400 copies/mL. Histological response was defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).


Secondary Outcome Measures:
  • Percentage of Participants With Histological Response at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Histological response was defined as Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).

  • Percentage of Participants With HBV DNA <400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Percentage of Participants With HBV DNA <400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.

  • Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at the end of blinded treatment.

  • Percentage of Participants With ALT Normalization at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.

  • Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Hepatitis B e-antigen (HBeAg) loss was defined as negative HBeAg result for those subjects with HBeAg-positive result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.

  • Percentage of Participants With HBeAg Loss or Seroconversion at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    HBeAg loss was defined as a negative HBeAg result for those participants with a positive HBeAg result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.

  • Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Hepatitis B s-antigen (HBsAg) loss was defined as negative HBsAg result for those participants with positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.

  • Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    HBsAg loss was defined as a negative HBsAg result for those participants with a positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.

  • Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    Participants evaluated for resistance included those with HBV DNA >/= 400 copies/mL at Week 96 in TDF monotherapy, those who discontinued after Week 48 with HBV DNA >/= 400 copies/mL, and those who added emtricitabine to their open-label TDF regimen and had HBV DNA >/= 400 copies/mL at the time of the addition.


Enrollment: 266
Study Start Date: June 2005
Estimated Study Completion Date: June 2014
Primary Completion Date: June 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Double-blind tenofovir disoproxil fumarate (TDF) 300 mg once daily and then switch to open-label (OL) TDF 300 mg once daily for an additional 336 weeks (TDF-TDF)
Drug: tenofovir disoproxil fumarate
TDF 300 mg once daily for 48 weeks and then open-label TDF 300 mg once daily for an additional 336 weeks
Other Name: Viread
Active Comparator: B
Double-blind adefovir dipivoxil (ADV) 10 mg once daily and then switch to OL TDF 300 mg once daily for an additional 336 weeks (ADV-TDF)
Drug: adefovir dipivoxil
ADV 10 mg once daily for 48 weeks and then open-label TDF 300 mg once daily for an additional 336 weeks
Other Name: Hepsera (first 48 weeks) and then switch to Viread (additional 336 weeks)

Detailed Description:

Efficacy of TDF versus ADV will be evaluated for histologic improvement, reductions in serum HBV DNA, changes in liver enzymes, and the generation of antibody to the virus. Safety will be assessed by evaluating adverse events, laboratory abnormalities and the development of drug-resistant mutations. After 48 weeks, all participants will receive OL TDF, and the efficacy and safety of TDF will be monitored for an additional 336 weeks.

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A patient must meet all of the following inclusion criteria to be eligible for participation in this study.

  • Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for more than 6 months.
  • 18 through 69 years of age, inclusive.
  • Active hepatitis B e-antigen (HBeAg) positive chronic HBV infection, with all of the following:

    • HBeAg positive at screening;
    • Alanine aminotransferase (ALT) levels > 2 × ULN and </= 10 × ULN;
    • Serum HBV DNA > 1 million copies/mL at screening;
    • creatinine clearance >/= 70 mL/min;
    • hemoglobin >/= 8 g/dL;
    • neutrophils >/= 1,000 /mL
  • Knodell necroinflammatory score >/= 3 and a Knodell fibrosis score < 4. However, up to 96 patients with cirrhosis, i.e., a Knodell fibrosis score equal to 4, will be eligible for enrollment.
  • Negative serum β-HCG
  • Nucleotide naïve, i.e., no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks.
  • Nucleoside naïve, i.e., no prior nucleoside (any nucleoside) therapy for greater than 12 weeks.
  • Willing and able to provide written informed consent.
  • Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline.

Exclusion Criteria:

A patient who meets any of the following exclusion criteria is not to be enrolled in this study.

  • Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study.
  • Males and females of reproductive potential who are unwilling to use an "effective" method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used.
  • Decompensated liver disease defined as conjugated bilirubin >1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, platelets < 75,000/mL, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage).
  • Received any nucleoside, nucleotide (TDF or ADV) or interferon (pegylated or not) therapy within 6 months prior to the pre-treatment biopsy.
  • Evidence of hepatocellular carcinoma (HCC), i.e., α-fetoprotein >50 ng/mL.
  • Coinfection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis delta virus (HDV).
  • Significant renal, cardiovascular, pulmonary, or neurological disease.
  • Received solid organ or bone marrow transplantation.
  • Is currently receiving therapy with immunomodulators (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion.
  • Has proximal tubulopathy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00116805

  Hide Study Locations
Locations
United States, California
La Jolla, California, United States, 92067
LaJolla, California, United States, 92067
Los Angeles, California, United States, 90048
Orange, California, United States, 92868
Pasadena, California, United States, 91105
San Diego, California, United States, 92115
San Diego, California, United States, 92123
San Francisco, California, United States, 94115
San Jose, California, United States, 95116
United States, Florida
Cooper City, Florida, United States, 33026
Miami, Florida, United States, 33136
United States, Georgia
Atlanta, Georgia, United States, 30308
United States, Hawaii
Honolulu, Hawaii, United States, 96817
United States, Maryland
Baltimore, Maryland, United States, 21229
College Park, Maryland, United States, 20740
United States, Massachusetts
Boston, Massachusetts, United States, 02215
United States, Michigan
Ann Arbor, Michigan, United States, 48109
Detroit, Michigan, United States, 48202
United States, Missouri
St. Louis, Missouri, United States, 63110
United States, New York
Bronx, New York, United States, 10467
Flushing, New York, United States, 11355
Manhasset, New York, United States, 11030
New York, New York, United States, 10021
New York, New York, United States, 10032
New York, New York, United States, 10029
United States, Tennessee
Memphis, Tennessee, United States, 38103
United States, Texas
Houston, Texas, United States, 77005
San Antonio, Texas, United States, 78229
United States, Virginia
Annandale, Virginia, United States, 22003
Fairfax, Virginia, United States, 22031
Richmond, Virginia, United States, 23249
United States, Washington
Seattle, Washington, United States, 98104
Australia, New South Wales
Camperdown, New South Wales, Australia, 2050
Concord, New South Wales, Australia, 2139
Westmead, New South Wales, Australia, 2145
Australia, Queensland
Herston, Queensland, Australia, 4029
Australia, Victoria
Footscray, Victoria, Australia, 3011
Heidelberg, Victoria, Australia, 3084
Melbourne, Victoria, Australia, 3004
Australia
Perth, Australia, 6001
Bulgaria
Sofia, Bulgaria, 1233
Sofia, Bulgaria, 1431
Varna, Bulgaria, 9010
Canada, Alberta
Calgary, Alberta, Canada, T2N4N1
Canada, British Columbia
Vancouver, British Columbia, Canada, V5Z1H2
Canada, Manitoba
Winnepeg, Manitoba, Canada, R3E3P4
Canada, Ontario
Ottawa, Ontario, Canada, K1H 8L6
Toronto, Ontario, Canada, M5T 2S8
Toronto, Ontario, Canada, M5G 2C4
Czech Republic
Brno, Czech Republic, 62500
Hradec Kralove, Czech Republic
Prague, Czech Republic
Praha 6- Stresovice, Czech Republic, 169 02
France
Clichy, France, 92110
Creteil, France, 94010
Grenoble, France, 38043
Lille, France, 59037
Lyon, France, 69288
Nancy, France, 54500
Paris, France
Paris, France, 75651
Pessac, France, 33600
Strasbourg, France, 67901
Toulouse, France, 31059
Germany
Berlin, Germany, 13353
Berlin, Germany, 10969
Duesseldorf, Germany, 40237
Dusseldorf, Germany, 40225
Essen, Germany, 45122
Frankfurt, Germany, 60590
Hannover, Germany, 30623
Herne, Germany, 44623
Homburg/Saar, Germany, 66421
Kiel, Germany, 24105
Koeln, Germany, 50924
Mainz, Germany, 55131
Mannheim, Germany, 68167
Munchen, Germany, 81377
Tubingen, Germany, 72076
Greece
Athens, Greece, 11526
Thessaloniki, Greece, 56429
Thessaloniki, Greece, 54642
Thessaloniki, Greece
Italy
Palermo, Italy, 90127
Torino, Italy, 10134
Netherlands
Rotterdam, Netherlands, 3015
New Zealand
Auckland, New Zealand
Hamilton, New Zealand
Whakatane, New Zealand
Poland
Bialystok, Poland, 15-540
Bydgoszcz, Poland, 85-030
Chorzow, Poland, 41-500
Kielce, Poland, 25-317
Krakow, Poland, 31-501
Lodz, Poland, 91-437
Warszawa, Poland, 01-201
Wroclaw, Poland, 51-149
Spain
Barcelona, Spain, 08035
Barcelona, Spain, 08025
Barcelona, Spain, 08907
Madrid, Spain, 28007
Madrid, Spain, 28035
Madrid, Spain, 28034
Madrid, Spain, 28006
Santander, Spain, 39008
Valencia, Spain, 46009
Turkey
Ankara, Turkey, 06100
Bursa, Turkey
Istanbul, Turkey
Istanbul, Turkey, 81324
Izmir, Turkey
United Kingdom
Birmingham, United Kingdom, B15 2TH
London, United Kingdom, WC1E 6HX
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Jeffrey D Bornstein, MD Gilead Sciences
  More Information

Additional Information:
No publications provided by Gilead Sciences

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00116805     History of Changes
Other Study ID Numbers: GS-US-174-0103
Study First Received: June 30, 2005
Results First Received: February 11, 2010
Last Updated: October 31, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
tenofovir
adefovir
hepatitis B
HBeAg Positive

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis B
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
Tenofovir disoproxil
Tenofovir
Adefovir
Adefovir dipivoxil
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on September 30, 2014