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A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of HBeAg Negative Chronic Hepatitis B
This study is ongoing, but not recruiting participants.

First Received on June 30, 2005.   Last Updated on January 5, 2011   History of Changes
Sponsor: Gilead Sciences
Information provided by: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00117676
  Purpose

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


Condition Intervention Phase
Chronic Hepatitis B
 Drug: Tenofovir DF (TDF) 300 mg
Drug: Double-blind adefovir dipivoxil (ADV) 10 mg (switch to open-label TDF 300 mg post Week 48)
 Phase III

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 Presumed Pre-Core Mutant Chronic Hepatitis B

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis B
Drug Information available for: Adefovir Adefovir dipivoxil Tenofovir Tenofovir disoproxil Tenofovir Disoproxil Fumarate Recombinant hepatitis B vaccine Hepatitis B Vaccines Hepatitis A Vaccines
U.S. FDA Resources

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 Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48 [ Time Frame: 48 weeks ] [ 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 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 ]
  • 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 Alanine Aminotransferase (ALT) Normalization at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    ALT normalization was defined as ALT outside the normal range at baseline and within the normal range at the end of blinded treatment.

  • Percentage of Participants With ALT Normalization at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    ALT normalization was defined as ALT outside the normal range at baseline and within the normal range at Week 96.

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

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

  • Number 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 ]

Enrollment: 375
Study Start Date: June 2005
Estimated Study Completion Date: May 2014
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Adefovir dipivoxil (ADV) 10 mg
Double-blind period: Double-blind ADV 10 mg taken once daily through Week 48. Open-label period: Open-label TDF 300 mg taken once daily (through Week 384). For the purpose of results reporting, this arm is labelled "ADV" for the double-blind period, during which participants received ADV monotherapy. For post-Week 48 assessments, this arm is labelled "ADV-TDF" to indicate participants switched from ADV monotherapy for the first 48 weeks to OL TDF for the remainder of the study.
 Drug: Double-blind adefovir dipivoxil (ADV) 10 mg (switch to open-label TDF 300 mg post Week 48)
Adefovir dipivoxil (ADV group) 10 mg once daily for 48 weeks then switch to open-label TDF for an additional 336 weeks (ADV-TDF group)
Other Names:
  • Hepsera (double-blind period)
  • Viread (open-label period)
Experimental: Tenofovir DF (TDF) 300 mg
Double-blind period: Double-blind TDF 300 mg taken once daily through Week 48. Open-label period: Open-label TDF 300 mg taken once daily (through Week 384). For the purpose of results reporting, this arm is labelled "TDF" for the double-blind period, during which participants received TDF monotherapy. For post-Week 48 assessments, this arm is labelled "TDF-TDF" to indicate participants received both double-blind and then OL TDF.
 Drug: Tenofovir DF (TDF) 300 mg
Double-blind TDF 300 mg once daily for 48 weeks (TDF group), then open-label TDF 300 mg once daily for an additional 336 weeks (TDF-TDF group)
Other Name: Viread

Detailed Description:

The efficacy of TDF versus ADV will be evaluated for histologic improvement, reductions in serum hepatitis B virus deoxyribonucleic acid (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 subjects will receive open-label (OL) TDF, and the efficacy and safety of TDF will continue to 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 at least 6 months.
  • 18 through 69 years of age, inclusive.

  • Active hepatitis B e-antigen (HBeAg) negative chronic HBV infection, with all of the following:

    • HBeAg negative and HBeAb positive at screening;
    • Alanine aminotransferase (ALT) levels > the upper limit of normal (ULN) and </= 10 x ULN;
    • Serum HBV DNA > 100,000 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 120 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. However, up to 120 patients with greater than 12 weeks prior lamivudine experience will be eligible.
  • 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:

  • Pregnant women, women who are breast feeding, or women 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.
  • 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)
  • Coinfection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00117676

  Show 113 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Jeffrey D Bornstein, M.D. Gilead Sciences
  More Information

Additional Information:
Related Info  This link exits the ClinicalTrials.gov site
Related Info  This link exits the ClinicalTrials.gov site
Related Info  This link exits the ClinicalTrials.gov site

No publications provided by Gilead Sciences

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011 Jan;140(1):132-43. Epub 2010 Oct 16.
Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55.

Responsible Party: Jeffrey D. Bornstein, MD/ Sr. Director, Clinical Research, Gilead Sciences
ClinicalTrials.gov Identifier: NCT00117676     History of Changes
Other Study ID Numbers: GS-US-174-0102
Study First Received: June 30, 2005
Results First Received: February 11, 2010
Last Updated: January 5, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
tenofovir
adefovir
hepatitis B virus
HBeAg Negative

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
 Adefovir dipivoxil
Adefovir
Tenofovir
Tenofovir disoproxil
Antiviral Agents
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 February 13, 2012



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