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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 48

Percentage 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

Page last updated: August 23, 2015

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