A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00117676
First received: June 30, 2005
Last updated: August 21, 2015
Last verified: August 2015
  Purpose

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


Condition Intervention Phase
Chronic Hepatitis B
Drug: TDF
Drug: ADV
Drug: TDF placebo
Drug: ADV placebo
Drug: FTC/TDF
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 Presumed Pre-Core Mutant Chronic Hepatitis B

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • 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 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]

    Complete response was a composite endpoint defined as histological response and HBV DNA < 400 copies/mL. Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.

    A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40.



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 Weeks 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
  • Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384 [ Time Frame: Weeks 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
  • Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, and 384 [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
  • Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, and 384 [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Histological Response at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.

  • Percentage of Participants With Histological Response at Week 240 [ Time Frame: Baseline; Week 240 ] [ Designated as safety issue: No ]
    Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.

  • Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).

  • Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240 [ Time Frame: Baseline; Week 240 ] [ Designated as safety issue: No ]
    The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).

  • Ranked Assessment of Necroinflammation and Fibrosis at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.

  • Ranked Assessment of Necroinflammation and Fibrosis at Week 240 [ Time Frame: Baseline; Week 240 ] [ Designated as safety issue: No ]
    Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.

  • Percentage of Participants With ALT Normalization at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    ALT normalization was defined as ALT > upper limit of normal (ULN) at baseline and within the normal range at the end of blinded treatment. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

  • Percentage of Participants With ALT Normalization at Weeks 96 [ Time Frame: Baseline; Week 96 ] [ Designated as safety issue: No ]
    ALT normalization was defined as ALT > ULN at baseline and within the normal range at Week 96. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

  • Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384 [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
    ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

  • Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, and 384 [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
  • Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, and 384 [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 48. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 48.

  • Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96 [ Time Frame: Baseline; Week 96 ] [ Designated as safety issue: No ]
    HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 96. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 96.

  • Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, and 384 [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ] [ Designated as safety issue: No ]
    HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at the subsequent time point. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at the subsequent time point.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance) [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 48, those with viral breakthrough, and those who discontinued after Week 24 with HBV DNA ≥ 400 copies/mL.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 49 to 95 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 96 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 48 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 97 to 144 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 144 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 96 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 96 and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 145 to 192 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 192 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 144 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 144 and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 193 to 240 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 240 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 192 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 192 and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 241 to 288 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 288 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 240 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 240 and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 289 to 336 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 336 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 288 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 288 and had HBV DNA ≥ 400 copies/mL at the time of the addition.

  • Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 337 to 384 ] [ Designated as safety issue: No ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 384 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 336 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 336 and had HBV DNA ≥ 400 copies/mL at the time of the addition.


Enrollment: 375
Study Start Date: June 2005
Estimated Study Completion Date: January 2016
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TDF-TDF
TDF plus placebo to match ADV (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF fixed dose combination [FDC] tablet) to their treatment regimen in the open-label period.
Drug: TDF
Tenofovir disoproxil fumarate (TDF) 300 mg tablet administered orally once daily
Other Name: Viread®
Drug: ADV placebo
Placebo to match ADV administered orally once daily
Drug: FTC/TDF
Emtricitabine (FTC) 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet administered orally once daily
Other Name: Truvada®
Active Comparator: ADV-TDF
ADV plus placebo to match TDF (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
Drug: TDF
Tenofovir disoproxil fumarate (TDF) 300 mg tablet administered orally once daily
Other Name: Viread®
Drug: ADV
Adefovir dipivoxil (ADV) 10 mg tablet administered orally once daily
Other Name: Hepsera®
Drug: TDF placebo
Placebo to match TDF administered orally once daily
Drug: FTC/TDF
Emtricitabine (FTC) 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet administered orally once daily
Other Name: Truvada®

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 TDF, and the efficacy and safety of TDF will continue to be monitored for the remainder of the study.

  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 the normal range (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, ie, a Knodell fibrosis score equal to 4, will be eligible for enrollment
  • Negative serum β-human chorionic gonadotropin (hCG)
  • Nucleotide naive, ie, no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks
  • Nucleoside naive, ie, no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patients with > 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 (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)
  • 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 (eg, 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: NCT00117676

  Show 113 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Anuj Gaggar, MD Gilead Sciences
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: 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: August 21, 2015
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 B, Chronic
Hepatitis, Chronic
DNA Virus Infections
Digestive System Diseases
Enterovirus Infections
Hepadnaviridae Infections
Hepatitis, Viral, Human
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases
Adefovir
Adefovir dipivoxil
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on September 03, 2015