Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00737568
First received: August 15, 2008
Last updated: March 25, 2014
Last verified: March 2014
  Purpose

The aim of therapy for the treatment of chronic hepatitis B virus (HBV) is to maintain suppression of viral replication to prevent the emergence of complications, which requires long-term therapy. Durable suppression of viral replication is achieved in the treatment of chronic viral diseases by preventing of the emergence of drug-resistant mutations. The clinical guidelines for the management of lamivudine resistant patients are variable. Some recommend switching to another agent without cross-resistance, while others recommend adding on another agent without cross-resistance. Limited clinical data exists to demonstrate whether tenofovir disoproxil fumarate (tenofovir DF; TDF) is an effective monotherapy for lamivudine resistant patients or if it should be used as part of a combination therapy regimen.

This study was designed to evaluate the effectiveness, safety, and tolerability of tenofovir DF monotherapy versus emtricitabine (FTC)/tenofovir DF combination therapy in participants with chronic HBV with lamivudine resistance (presence of the rtM204I/V mutation with or without the rtL180M mutation) over a 240-week period. Participants in this study must have been receiving lamivudine treatment at the time of enrollment.


Condition Intervention Phase
Hepatitis B
Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF)
Drug: Emtricitabine (FTC)/TDF
Drug: TDF Placebo
Drug: FTC/TDF Placebo
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 Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects With Chronic Hepatitis B Who Are Resistant to Lamivudine

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 at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with HBV DNA < 400 copies/mL at Week 96 was summarized.


Secondary Outcome Measures:
  • Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with HBV DNA < 169 copies/mL at Week 96 was summarized.

  • HBV DNA Level at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    Participant HBV DNA level at Week 96 was summarized.

  • Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with normal ALT at Week 96 was summarized. Normal ALT was defined as having a value less than or equal to the upper limit of normal range (ULN).

  • Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBeAg Loss at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at Week 96 was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.

  • Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had Seroconversion to Antibody Against HBeAg (Anti-HBe) at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at Week 96 was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.

  • Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with HBsAg Loss at Week 96 was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.

  • Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with seroconversion to anti-HBs at the Week 96 time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.

  • Percentage of Participants With Virologic Breakthrough at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with virologic breakthrough at Week 96 was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log_10 or greater increases in serum HBV DNA from on-treatment nadir, or two consecutive HBV DNA values ≥ 400 copies/mL after being < 400 copies/mL.

  • Percent Change From Baseline in Mean Bone Mineral Density (BMD) of the Spine at Week 24 [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the spine at Week 24 was summarized. BMD was measured as grams divided by square centimeter (g/cm^2).

  • Percent Change From Baseline in Mean BMD of the Spine at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the spine at Week 48 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean BMD of the Spine at Week 72 [ Time Frame: Baseline to Week 72 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the spine at Week 72 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean BMD of the Spine at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the spine at Week 96 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean BMD of the Hip at Week 24 [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the hip at Week 24 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean MD of the Hip at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the hip at Week 48 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean BMD of the Hip at Week 72 [ Time Frame: Baseline to Week 72 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the hip at Week 72 was summarized. BMD was measured as g/cm^2.

  • Percent Change From Baseline in Mean BMD of the Hip at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: Yes ]
    The percent change from baseline in mean BMD of the hip at Week 96 was summarized. BMD was measured as g/cm^2.

  • Development of Drug-resistant Mutations (DRMs) [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.


Enrollment: 280
Study Start Date: September 2008
Estimated Study Completion Date: August 2014
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tenofovir DF Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF)
TDF 300 mg once daily (QD) plus placebo to match emtricitabine (FTC)/TDF fixed-dose combination tablet QD
Other Name: Viread
Drug: FTC/TDF Placebo
Placebo to match FTC/TDF QD
Experimental: FTC/TDF Drug: Emtricitabine (FTC)/TDF
FTC 200 mg/TDF 300 mg fixed-dose combination tablet QD plus placebo to match TDF QD
Other Name: Truvada
Drug: TDF Placebo
Placebo to match TDF QD

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Chronic HBV infection, defined as positive serum HBsAg for at least 6 months
  • 18 through 75 years of age, inclusive
  • HBV DNA ≥ 10^3 IU/mL
  • Receiving treatment with lamivudine with confirmation of HBV reverse transcriptase mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without rtL180M) by central laboratory assessment prior to randomization; adefovir dipivoxil treatment of ≤ 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) was allowed
  • Willing and able to provide written informed consent
  • Negative serum pregnancy test (for females of childbearing potential only)
  • Calculated creatinine clearance ≥ 50 mL/min
  • Hemoglobin ≥ 10 g/dL
  • Neutrophils ≥ 1000 /mm^3
  • No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other investigational agents for HBV infection other than lamivudine or adefovir dipivoxil

Exclusion Criteria

  • Pregnant women, women who were breast feeding or who believed they may have wished to become pregnant during the course of the study
  • Males and females of reproductive potential who were not willing to use an effective method of contraception during the study
  • Alanine aminotransferase (ALT) ≥ 10 × the upper limit of the normal range (ULN)
  • Decompensated liver disease
  • Received interferon or pegylated interferon therapy within 6 months of the screening visit
  • Alpha fetoprotein > 50 ng/mL
  • Evidence of hepatocellular carcinoma (HCC)
  • Coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV)
  • Significant renal, cardiovascular, pulmonary, or neurological disease
  • Received solid organ or bone marrow transplantation
  • Was receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
  • Had proximal tubulopathy
  • Known hypersensitivity to the study drugs, the metabolites or formulation excipients
  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: NCT00737568

  Show 71 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: John Flaherty, PharmD Gilead Sciences
  More Information

No publications provided by Gilead Sciences

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00737568     History of Changes
Other Study ID Numbers: GS-US-174-0121
Study First Received: August 15, 2008
Results First Received: November 15, 2012
Last Updated: March 25, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
Tenofovir DF
Emtricitabine
Chronic hepatitis B
Combination therapy

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Hepatitis, Chronic
Emtricitabine
Tenofovir disoproxil
Tenofovir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on September 30, 2014