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

Gilead Sciences

Status and phase: Completed; Phase 3

Conditions: Chronic Hepatitis B

Treatments: Drug: FTC/TDF; Drug: TDF placebo; Drug: ADV; Drug: TDF; Drug: ADV placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT00117676

2004-005119-27 (EudraCT Number)

GS-US-174-0102

Details and patient eligibility

About

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.

Enrollment: 382 patients

Sex: All

Ages: 18 to 69 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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382 participants in 2 patient groups

TDF-TDF

Experimental group

Description:

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.

Treatment:

Drug: TDF

Drug: FTC/TDF

Drug: ADV placebo

ADV-TDF

Active Comparator group

Description:

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.

Treatment:

Drug: TDF

Drug: ADV

Drug: FTC/TDF

Drug: TDF placebo