Clinical trial NCT00737568: Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B
Keywords: Tenofovir DF
Emtricitabine
Chronic hepatitis B
Combination therapy
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-08-19
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 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.


Eligibility 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 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

Primary outcomes:
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96
timeFrame: Week 96
Secondary outcomes:
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240
timeFrame: Weeks 48, 144, 192, and 240
measure: Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240
timeFrame: Weeks 48, 96, 144, 192, and 240
measure: HBV DNA Level at Weeks 48, 96, 144, 192, and 240
timeFrame: Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240
timeFrame: Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 48, 96, 144, 192, and 240
measure: Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 48, 96, 144, 192, and 240
measure: Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at Weeks 24, 48, 72, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
measure: Percent Change From Baseline in BMD of the Hip at Weeks 24, 48, 72, 96, 144, 192, and 240
timeFrame: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
measure: Development of Drug-resistant Mutations (DRMs)
timeFrame: Baseline to Week 240
Other outcomes:
Locations:
city: Bradenton
country: United States
state: Florida
city: Flushing
country: United States
state: New York
city: Philadelphia
country: United States
state: Pennsylvania
city: Innsbruck
country: Austria
city: Wien
country: Austria
city: Wien
country: Austria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Vancouver
country: Canada
state: British Columbia
city: Vancouver
country: Canada
state: British Columbia
city: Vancouver
country: Canada
state: British Columbia
city: Winnepeg
country: Canada
state: Manitoba
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Brno
country: Czech Republic
city: Plzen
country: Czech Republic
city: Prague
country: Czech Republic
city: Praha 4
country: Czech Republic
city: Usti Nad Labem
country: Czech Republic
city: Ulm
country: Germany
state: Baden-Wuerttemberg
city: Berlin
country: Germany
city: Duesseldorf
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Stuttgart
country: Germany
city: Larissa
country: Greece
city: Patras
country: Greece
city: Thessaloniki
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Gyula
country: Hungary
city: Kasposvar
country: Hungary
city: Auckland
country: New Zealand
city: Hamilton
country: New Zealand
city: Wellington
country: New Zealand
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Szczecin
country: Poland
city: Warszawa
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Lasi
country: Romania
state: Judetul lasi
city: Timisoara
country: Romania
state: Judetul Timis
city: Bucharest
country: Romania
city: Bucharest
country: Romania
city: Bucharest
country: Romania
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Cluj-Napoca
country: Romania
city: Constanta
country: Romania
city: Belgrade
country: Serbia
city: Kragujevac
country: Serbia
city: Nis
country: Serbia
city: Novi Sad
country: Serbia
city: Sevilla
country: Spain
city: Ankara
country: Turkey
city: Bursa
country: Turkey
city: Izmir
country: Turkey
city: Samsun
country: Turkey
city: Trabzon
country: Turkey
city: Uskudar
country: Turkey
Study officials:
affiliation: Gilead Sciences
name: John Flaherty, PharmD
role: STUDY_DIRECTOR
References:
citation: Corsa AC, Liu Y, Flaherty JF, Mitchell B, Fung SK, Gane E, Miller MD, Kitrinos KM. No resistance to tenofovir disoproxil fumarate through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Clin Gastroenterol Hepatol. 2014 Dec;12(12):2106-12.e1. doi: 10.1016/j.cgh.2014.05.024. Epub 2014 Jun 11.
citation: Liu Y, Fung S, Gane EJ, Dinh P, Flaherty JF, Svarovskaia ES, Miller MD, Kitrinos KM. Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF. J Med Virol. 2014 Sep;86(9):1473-81. doi: 10.1002/jmv.23982. Epub 2014 May 23.
citation: Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Dinh P, Corsa A, Subramanian GM, McHutchison JG, Husa P, Gane E. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014 Apr;146(4):980-8. doi: 10.1053/j.gastro.2013.12.028. Epub 2013 Dec 22.
citation: Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Kim K, Kitrinos KM, Subramanian GM, McHutchison JG, Yee LJ, Elkhashab M, Berg T, Sporea I, Yurdaydin C, Husa P, Jablkowski MS, Gane E. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study. J Hepatol. 2017 Jan;66(1):11-18. doi: 10.1016/j.jhep.2016.08.008. Epub 2016 Aug 18.