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

Information source: Gilead Sciences
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hepatitis B

Intervention: TDF (Drug); FTC/TDF (Drug); Placebo to match TDF (Drug); Placebo to match FTC/TDF (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Gilead Sciences

Official(s) and/or principal investigator(s):
John Flaherty, PharmD, Study Director, Affiliation: Gilead Sciences

Summary

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Secondary outcome:

Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96

HBV DNA Level at Week 96

Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 96

Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBeAg Loss at Week 96

Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had Seroconversion to Antibody Against HBeAg (Anti-HBe) at Week 96

Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Week 96

Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Week 96

Percentage of Participants With Virologic Breakthrough at Week 96

Percent Change From Baseline in Mean Bone Mineral Density (BMD) of the Spine at Week 24

Percent Change From Baseline in Mean BMD of the Spine at Week 48

Percent Change From Baseline in Mean BMD of the Spine at Week 72

Percent Change From Baseline in Mean BMD of the Spine at Week 96

Percent Change From Baseline in Mean BMD of the Hip at Week 24

Percent Change From Baseline in Mean MD of the Hip at Week 48

Percent Change From Baseline in Mean BMD of the Hip at Week 72

Percent Change From Baseline in Mean BMD of the Hip at Week 96

Development of Drug-resistant Mutations (DRMs)

Eligibility

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

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

Locations and Contacts

Innsbruck A-6020, Austria

Wien A-1090, Austria

Wien A-1130, Austria

Sofia 1527, Bulgaria

Sofia 1606, Bulgaria

Sofia 1407, Bulgaria

Varna 9010, Bulgaria

Brno 625 00, Czech Republic

Plzen 304 60, Czech Republic

Prague 160 00, Czech Republic

Praha 4 14021, Czech Republic

Usti Nad Labem 40001, Czech Republic

Berlin 13353, Germany

Duesseldorf 40225, Germany

Essen 45122, Germany

Frankfurt 60590, Germany

Hamburg 20099, Germany

Hannover 30625, Germany

Stuttgart, Germany

Larissa 41110, Greece

Patras 25404, Greece

Thessaloniki 54642, Greece

Budapest 1126, Hungary

Debrecen 4032, Hungary

Gyula H5700, Hungary

Kasposvar H7400, Hungary

Auckland, New Zealand

Hamilton, New Zealand

Wellington 6035, New Zealand

Bialystok 15-540, Poland

Bydgoszcz 85-030, Poland

Chorzow 41-500, Poland

Krakow 31-351, Poland

Lodz 91-347, Poland

Szczecin 71-455, Poland

Warszawa 01-201, Poland

Warszawa 02-507, Poland

Wroclaw 50-220, Poland

Bucharest 021105, Romania

Bucharest 030303, Romania

Bucharest 022328, Romania

Bucuresti 020125, Romania

Bucuresti 021105, Romania

Bucuresti 022328, Romania

Cluj-Napoca 400158, Romania

Constanta 900708, Romania

Belgrade 11000, Serbia

Kragujevac 34000, Serbia

Nis 18000, Serbia

Novi Sad 21000, Serbia

Sevilla 4103, Spain

Ankara 06100, Turkey

Bursa 16059, Turkey

Izmir 35100, Turkey

Samsun 55139, Turkey

Trabzon 61080, Turkey

Uskudar 34668, Turkey

Ulm, Baden-Wuerttemberg 89081, Germany

Vancouver, British Columbia V6Z 2K5, Canada

Vancouver, British Columbia V6AB46, Canada

Vancouver, British Columbia V5Z, Canada

Bradenton, Florida 34205, United States

Timisoara, Judetul Timis 300736, Romania

Lasi, Judetul lasi 700111, Romania

Winnepeg, Manitoba R3E 3P4, Canada

Flushing, New York 11355, United States

Toronto, Ontario M5G 1X5, Canada

Toronto, Ontario M5G 2C4, Canada

Toronto, Ontario M6H 3M1, Canada

Toronto, Ontario M5T 2S8, Canada

Philadelphia, Pennsylvania 19107, United States

Additional Information

Starting date: September 2008
Last updated: February 19, 2015

Page last updated: August 23, 2015

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