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

February 9, 2016 updated by: Gilead Sciences

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

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 is 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 be receiving lamivudine treatment at the time of enrollment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

280

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Innsbruck, Austria, A-6020
      • Wien, Austria, A-1090
      • Wien, Austria, A-1130
  • Bulgaria
      • Sofia, Bulgaria, 1606
      • Sofia, Bulgaria, 1527
      • Sofia, Bulgaria, 1407
      • Varna, Bulgaria, 9010
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6Z 2K5
      • Vancouver, British Columbia, Canada, V5Z
      • Vancouver, British Columbia, Canada, V6AB46
    • Manitoba
      • Winnepeg, Manitoba, Canada, R3E 3P4
    • Ontario
      • Toronto, Ontario, Canada, M5T 2S8
      • Toronto, Ontario, Canada, M5G 2C4
      • Toronto, Ontario, Canada, M5G 1X5
      • Toronto, Ontario, Canada, M6H 3M1
  • Czech Republic
      • Brno, Czech Republic, 625 00
      • Plzen, Czech Republic, 304 60
      • Prague, Czech Republic, 160 00
      • Praha 4, Czech Republic, 14021
      • Usti Nad Labem, Czech Republic, 40001
  • Germany
      • Berlin, Germany, 13353
      • Duesseldorf, Germany, 40225
      • Essen, Germany, 45122
      • Frankfurt, Germany, 60590
      • Hamburg, Germany, 20099
      • Hannover, Germany, 30625
      • Stuttgart, Germany
    • Baden-Wuerttemberg
      • Ulm, Baden-Wuerttemberg, Germany, 89081
  • Greece
      • Larissa, Greece, 41110
      • Patras, Greece, 25404
      • Thessaloniki, Greece, 54642
  • Hungary
      • Budapest, Hungary, 1126
      • Debrecen, Hungary, 4032
      • Gyula, Hungary, H5700
      • Kasposvar, Hungary, H7400
  • New Zealand
      • Auckland, New Zealand
      • Hamilton, New Zealand
      • Wellington, New Zealand, 6035
  • Poland
      • Bialystok, Poland, 15-540
      • Bydgoszcz, Poland, 85-030
      • Chorzow, Poland, 41-500
      • Krakow, Poland, 31-351
      • Lodz, Poland, 91-347
      • Szczecin, Poland, 71-455
      • Warszawa, Poland, 01-201
      • Warszawa, Poland, 02-507
      • Wroclaw, Poland, 50-220
  • Romania
      • Bucharest, Romania, 021105
      • Bucharest, Romania, 022328
      • Bucharest, Romania, 030303
      • Bucuresti, Romania, 020125
      • Bucuresti, Romania, 022328
      • Bucuresti, Romania, 021105
      • Cluj-Napoca, Romania, 400158
      • Constanta, Romania, 900708
    • Judetul Timis
      • Timisoara, Judetul Timis, Romania, 300736
    • Judetul lasi
      • Lasi, Judetul lasi, Romania, 700111
  • Serbia
      • Belgrade, Serbia, 11000
      • Kragujevac, Serbia, 34000
      • Nis, Serbia, 18000
      • Novi Sad, Serbia, 21000
  • Spain
      • Sevilla, Spain, 4103
  • Turkey
      • Ankara, Turkey, 06100
      • Bursa, Turkey, 16059
      • Izmir, Turkey, 35100
      • Samsun, Turkey, 55139
      • Trabzon, Turkey, 61080
      • Uskudar, Turkey, 34668
  • United States
    • Florida
      • Bradenton, Florida, United States, 34205
    • New York
      • Flushing, New York, United States, 11355
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 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 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
  • Interferon or pegylated interferon therapy within 6 months of the screening visit
  • Alpha fetoprotein > 50 ng/mL
  • Evidence of hepatocellular carcinoma
  • Coinfection with hepatitis C virus, HIV, or hepatitis D virus
  • Significant renal, cardiovascular, pulmonary, or neurological disease
  • Received solid organ or bone marrow transplantation
  • Receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
  • Proximal tubulopathy
  • Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Tenofovir DF
TDF plus placebo to match FTC/TDF
Drug: TDF
Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily
Other Names:
  • Viread®
Drug: FTC/TDF Placebo
FTC/TDF placebo tablet administered orally once daily
EXPERIMENTAL: FTC/TDF
FTC/TDF plus placebo to match TDF
Drug: TDF Placebo
TDF placebo tablet administered orally once daily
Drug: FTC/TDF
Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily
Other Names:
  • Truvada®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96
Time Frame: Week 96
Week 96

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240
Time Frame: Weeks 48, 144, 192, and 240
Weeks 48, 144, 192, and 240
Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240
Time Frame: Weeks 48, 96, 144, 192, and 240
Weeks 48, 96, 144, 192, and 240
HBV DNA Level at Weeks 48, 96, 144, 192, and 240
Time Frame: Weeks 48, 96, 144, 192, and 240
Weeks 48, 96, 144, 192, and 240
Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240
Time Frame: Weeks 48, 96, 144, 192, and 240
Normal ALT was defined as having a value less than or equal to the ULN. 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.
Weeks 48, 96, 144, 192, and 240
Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 48, 96, 144, 192, and 240
The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.
Baseline; Weeks 48, 96, 144, 192, and 240
Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 48, 96, 144, 192, and 240
The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at the given time point was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.
Baseline; Weeks 48, 96, 144, 192, and 240
Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 48, 96, 144, 192, and 240
The percentage of participants with HBsAg Loss at the given time point was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.
Baseline; Weeks 48, 96, 144, 192, and 240
Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 48, 96, 144, 192, and 240
The percentage of participants with seroconversion to anti-HBs at the given time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.
Baseline; Weeks 48, 96, 144, 192, and 240
Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 48, 96, 144, 192, and 240
The percentage of participants with virologic breakthrough at the given time point was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log10 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.
Baseline; Weeks 48, 96, 144, 192, and 240
Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at Weeks 24, 48, 72, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
BMD is calculated as grams per cubic centimeter (g/cm^2); the mean (SD) percentage change is presented.
Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
Percent Change From Baseline in BMD of the Hip at Weeks 24, 48, 72, 96, 144, 192, and 240
Time Frame: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
BMD is calculated as g/cm^2; the mean (SD) percentage change is presented.
Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
Development of Drug-resistant Mutations (DRMs)
Time Frame: Baseline to Week 240
The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.
Baseline to Week 240

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gilead Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2008

Primary Completion (ACTUAL)

November 1, 2011

Study Completion (ACTUAL)

February 1, 2015

Study Registration Dates

First Submitted

August 15, 2008

First Submitted That Met QC Criteria

August 15, 2008

First Posted (ESTIMATE)

August 19, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

March 11, 2016

Last Update Submitted That Met QC Criteria

February 9, 2016

Last Verified

February 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GS-US-174-0121

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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