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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00116805
First received: June 30, 2005
Last updated: August 21, 2015
Last verified: August 2015

June 30, 2005
August 21, 2015
June 2005
May 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 ] [ 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.

Not Provided
Complete list of historical versions of study NCT00116805 on ClinicalTrials.gov Archive Site
  • 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 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 Alanine Aminotransferase (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 Week 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 e Antigen (HBeAg) Loss/Seroconversion at Week 48 [ Time Frame: Baseline; Week 48 ] [ Designated as safety issue: No ]
    HBeAg loss was defined as HBeAg positive at baseline and HBeAg negative at Week 48. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative at baseline to positive at Week 48.
  • Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    HBeAg loss was defined as HBeAg positive at baseline and HBeAg negative at Week 96. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative at baseline to positive 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 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 or Seroconversion to Anti-HBs at Week 96 [ Time Frame: Baseline; Weeks 96, 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.
  • Percentage of Participants With HBsAg Loss 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, 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.
Not Provided
Not Provided
Not Provided
 
A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Positive Chronic Hepatitis B
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Chronic Hepatitis B
  • Drug: TDF
    TDF 300 mg tablet administered orally once daily
    Other Name: Viread®
  • Drug: ADV
    ADV 10 mg tablet administered orally once daily
    Other Name: Hepsera®
  • Drug: TDF placebo
    Placebo to match TDF administered orally once daily
  • 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®
  • 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.
    Interventions:
    • Drug: TDF
    • Drug: ADV placebo
    • Drug: FTC/TDF
  • 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.
    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.
 
Active, not recruiting
266
February 2016
May 2007   (final data collection date for primary outcome measure)

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
Both
18 Years to 69 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Bulgaria,   Canada,   Czech Republic,   France,   Germany,   Greece,   Italy,   Netherlands,   New Zealand,   Poland,   Spain,   Turkey,   United Kingdom
 
NCT00116805
GS-US-174-0103
Yes
Gilead Sciences
Gilead Sciences
Not Provided
Study Director: Anuj Gaggar, MD Gilead Sciences
Gilead Sciences
August 2015

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