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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00117676
First Posted: July 8, 2005
Last Update Posted: March 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Gilead Sciences
June 30, 2005
July 8, 2005
February 11, 2010
May 19, 2010
March 7, 2017
February 2005
April 2007   (Final data collection date for primary outcome measure)
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 ]

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.

Not Provided
Complete list of historical versions of study NCT00117676 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48 [ Time Frame: Week 48 ]
  • Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96 [ Time Frame: Week 96 ]
  • 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 ]
  • Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480 [ Time Frame: Weeks 432 and 480 ]
  • Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  • Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  • Percentage of Participants With Histological Response at Week 48 [ Time Frame: Baseline; Week 48 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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.
  • Percentage of Participants With ALT Normalization at Weeks 432 and 480 [ Time Frame: Baseline; Weeks 432 and 480 ]
    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, 384, 432, and 480 [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  • Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  • 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 ]
    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 ]
    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, 384, 432, and 480 [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480 ]
    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 ]
    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 96 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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.
  • Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 385 to 432 ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 432 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 384 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 384 and had HBV DNA ≥ 400 copies/mL at the time of the addition.
  • Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance) [ Time Frame: Baseline; Weeks 433 to 480 ]
    Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 480 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 432 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 432 and had HBV DNA ≥ 400 copies/mL at the time of the addition.
Not Provided
Not Provided
Not Provided
 
A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of Presumed Pre-Core Mutant Chronic Hepatitis B
This primary objectives of this study are to compare the efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) for the treatment of pre-core mutant chronic hepatitis B. Participants will receive TDF or ADV for 48 weeks (double-blind). After 48 weeks, eligible participants switched to open-label TDF for up to 480 weeks.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Chronic Hepatitis B
  • Drug: TDF
    300 mg tablet administered orally once daily
    Other Name: Viread®
  • Drug: ADV
    10 mg tablet administered orally once daily
    Other Name: Hepsera®
  • Drug: TDF placebo
    Tablet administered orally once daily
  • Drug: ADV placebo
    Tablet administered orally once daily
  • Drug: FTC/TDF
    200/300 mg fixed-dose combination (FDC) tablet administered orally once daily
    Other Name: Truvada®
  • Experimental: TDF-TDF
    TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.
    Interventions:
    • Drug: TDF
    • Drug: ADV placebo
    • Drug: FTC/TDF
  • Active Comparator: ADV-TDF
    ADV plus TDF placebo (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.
    Interventions:
    • Drug: TDF
    • Drug: ADV
    • Drug: TDF placebo
    • Drug: FTC/TDF

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
382
January 2016
April 2007   (Final data collection date for primary outcome measure)

Key Inclusion Criteria:

  • 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

Key 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

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Sexes Eligible for Study: All
18 Years to 69 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Bulgaria,   Canada,   Czech Republic,   France,   Germany,   Greece,   Italy,   Netherlands,   New Zealand,   Poland,   Spain,   Turkey,   United Kingdom,   United States
 
 
NCT00117676
GS-US-174-0102
2004-005119-27 ( EudraCT Number )
Yes
Not Provided
Not Provided
Gilead Sciences
Gilead Sciences
Not Provided
Study Director: Gilead Study Director Gilead Sciences
Gilead Sciences
January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP