A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Positive Chronic Hepatitis B
Information source: Gilead Sciences
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Hepatitis B
Intervention: TDF (Drug); ADV (Drug); TDF placebo (Drug); ADV placebo (Drug); FTC/TDF (Drug)
Phase: Phase 3
Status: Active, not recruiting
Sponsored by: Gilead Sciences Official(s) and/or principal investigator(s): Anuj Gaggar, MD, Study Director, Affiliation: Gilead Sciences
Summary
This study is designed to evaluate the safety and antiviral activity of tenofovir disoproxil
fumarate (TDF, tenofovir DF) compared to adefovir dipivoxil (ADV) 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 TDF.
Clinical Details
Official title: A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48
Secondary outcome: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96 Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384 Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, and 384 Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, and 384 Percentage of Participants With Histological Response at Week 48 Percentage of Participants With Histological Response at Week 240 Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48 Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240 Ranked Assessment of Necroinflammation and Fibrosis at Week 48 Ranked Assessment of Necroinflammation and Fibrosis at Week 240 Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 Percentage of Participants With ALT Normalization at Week 96 Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384 Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, and 384 Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, and 384 Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48 Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96 Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48 Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96 Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, and 384 Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance) Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)
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 open-label TDF, and
the efficacy and safety of TDF will be monitored for the remainder of the study.
Eligibility
Minimum age: 18 Years.
Maximum age: 69 Years.
Gender(s): Both.
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 × the upper limit of
the normal range (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, ie, a Knodell fibrosis score equal to 4, will be eligible
for enrollment
- Negative serum β-human chorionic gonadotropin (hCG)
- Nucleotide naïve, ie, no prior nucleotide (TDF or ADV) therapy for > 12 weeks
- Nucleoside naïve, ie, no prior nucleoside (any nucleoside) therapy for > 12 weeks
- Willing and able to provide written informed consent
- 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 (eg, 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), ie, 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 (eg, corticosteroids, etc.),
investigational agents, nephrotoxic agents, or agents susceptible of modifying renal
excretion
- Has proximal tubulopathy
Locations and Contacts
Perth 6001, Australia
Sofia 1431, Bulgaria
Sofia 1233, Bulgaria
Varna 9010, Bulgaria
Brno 62500, Czech Republic
Hradec Kralove, Czech Republic
Prague, Czech Republic
Praha 6- Stresovice 169 02, Czech Republic
Clichy 92110, France
Creteil 94010, France
Grenoble 38043, France
Lille 59037, France
Lyon 69288, France
Nancy 54500, France
Paris 75651, France
Paris, France
Pessac 33600, France
Strasbourg 67901, France
Toulouse 31059, France
Berlin 10969, Germany
Berlin 13353, Germany
Duesseldorf 40237, Germany
Dusseldorf 40225, Germany
Essen 45122, Germany
Frankfurt 60590, Germany
Hannover 30623, Germany
Herne 44623, Germany
Homburg/Saar 66421, Germany
Kiel 24105, Germany
Koeln 50924, Germany
Mainz 55131, Germany
Mannheim 68167, Germany
Munchen 81377, Germany
Tubingen 72076, Germany
Athens 11526, Greece
Thessaloniki 54642, Greece
Thessaloniki 56429, Greece
Thessaloniki, Greece
Palermo 90127, Italy
Torino 10134, Italy
Rotterdam 3015, Netherlands
Auckland, New Zealand
Hamilton, New Zealand
Whakatane, New Zealand
Bialystok 15-540, Poland
Bydgoszcz 85-030, Poland
Chorzow 41-500, Poland
Kielce 25-317, Poland
Krakow 31-501, Poland
Lodz 91-437, Poland
Warszawa 01-201, Poland
Wroclaw 51-149, Poland
Barcelona 08025, Spain
Barcelona 08035, Spain
Barcelona 08907, Spain
Madrid 28006, Spain
Madrid 28007, Spain
Madrid 28034, Spain
Madrid 28035, Spain
Santander 39008, Spain
Valencia 46009, Spain
Ankara 06100, Turkey
Bursa, Turkey
Istanbul, Turkey
Istanbul 81324, Turkey
Izmir, Turkey
Birmingham B15 2TH, United Kingdom
London NW3 2QG, United Kingdom
London WC1E 6HX, United Kingdom
Calgary, Alberta T2N4N1, Canada
Vancouver, British Columbia V5Z1H2, Canada
La Jolla, California 92067, United States
LaJolla, California 92067, United States
Los Angeles, California 90048, United States
Orange, California 92868, United States
Pasadena, California 91105, United States
San Diego, California 92115, United States
San Diego, California 92123, United States
San Francisco, California 94115, United States
San Jose, California 95116, United States
Cooper City, Florida 33026, United States
Miami, Florida 33136, United States
Atlanta, Georgia 30308, United States
Honolulu, Hawaii 96817, United States
Winnepeg, Manitoba R3E3P4, Canada
Baltimore, Maryland 21229, United States
College Park, Maryland 20740, United States
Boston, Massachusetts 02215, United States
Ann Arbor, Michigan 48109, United States
Detroit, Michigan 48202, United States
St. Louis, Missouri 63110, United States
Camperdown, New South Wales 2050, Australia
Concord, New South Wales 2139, Australia
Westmead, New South Wales 2145, Australia
Bronx, New York 10467, United States
Flushing, New York 11355, United States
Manhasset, New York 11030, United States
New York, New York 10021, United States
New York, New York 10029, United States
New York, New York 10032, United States
Ottawa, Ontario K1H 8L6, Canada
Toronto, Ontario M5G 2C4, Canada
Toronto, Ontario M5T 2S8, Canada
Herston, Queensland 4029, Australia
Memphis, Tennessee 38103, United States
Houston, Texas 77005, United States
San Antonio, Texas 78229, United States
Footscray, Victoria 3011, Australia
Heidelberg, Victoria 3084, Australia
Melbourne, Victoria 3004, Australia
Annandale, Virginia 22003, United States
Fairfax, Virginia 22031, United States
Richmond, Virginia 23249, United States
Seattle, Washington 98104, United States
Additional Information
Starting date: June 2005
Last updated: March 30, 2015
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