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

Gilead Sciences382 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

382

Conditions

Chronic Hepatitis B

Interventions

TDFDRUG

300 mg tablet administered orally once daily

ADVDRUG

10 mg tablet administered orally once daily

TDF placeboDRUG

Tablet administered orally once daily

ADV placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 69 Years

Medical Language ↔ Plain English

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.

Locations (80)

Outcomes

Primary Outcomes

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

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.

Time frame: Baseline; Week 48

Secondary Outcomes

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

Data from ClinicalTrials.gov

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Tablet administered orally once daily

FTC/TDFDRUG

200/300 mg fixed-dose combination (FDC) tablet administered orally once daily

Unnamed facility

La Jolla, California, United States

Unnamed facility

Pasadena, California, United States

Unnamed facility

San Diego, California, United States

Unnamed facility

San Diego, California, United States

Unnamed facility

San Francisco, California, United States

Unnamed facility

San Jose, California, United States

Unnamed facility

Atlanta, Georgia, United States

Unnamed facility

Honolulu, Hawaii, United States

Unnamed facility

Boston, Massachusetts, United States

Unnamed facility

Ann Arbor, Michigan, United States

...and 70 more locations

Time frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

Percentage of Participants With Histological Response at 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.

Time frame: Baseline; Week 48

Percentage of Participants With Histological Response at Week 240

Time frame: Baseline; Week 240

Change From Baseline in Knodell and Ishak Necroinflammatory Scores at 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).

Time frame: Baseline; Week 48

Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240

Time frame: Baseline; Week 240

Ranked Assessment of Necroinflammation and Fibrosis at 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.

Time frame: Baseline; Week 48

Ranked Assessment of Necroinflammation and Fibrosis at Week 240

Time frame: Baseline; Week 240

Percentage of Participants With ALT Normalization at 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.

Time frame: Baseline; Week 48

Percentage of Participants With ALT Normalization at Weeks 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.

Time frame: Baseline; Week 96

Percentage of Participants With ALT Normalization at 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.

Time frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384

Percentage of Participants With ALT Normalization at Weeks 432 and 480

Time frame: Baseline; Weeks 432 and 480

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

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.

Time frame: Baseline; Week 48

Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at 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.

Time frame: Baseline; 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

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.

Time frame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480

Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)

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.

Time frame: Baseline; Week 48

Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 49 to 96

Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 97 to 144

Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 145 to 192

Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 193 to 240

Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 241 to 288

Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 289 to 336

Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 337 to 384

Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 385 to 432

Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)

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.

Time frame: Baseline; Weeks 433 to 480