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

Condition(s) targeted: Hepatitis B

Intervention: Tenofovir DF (Drug); Emtricitabine/tenofovir DF (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Gilead Sciences

Official(s) and/or principal investigator(s):
David Frederick, PhD, Study Director, Affiliation: Gilead Sciences

Overall contact:
Jane Anderson, PhD, Phone: 919-294-7160, Email: jane.anderson@gilead.com

This study will evaluate the effectiveness, safety, and tolerability of tenofovir DF versus emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance.

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: Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: To compare the antiviral efficacy against HBV of once-daily tenofovir DF versus once-daily emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance

Secondary outcome: To evaluate the safety and tolerability of tenofovir DF versus emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance

Detailed description: The aim of therapy for the treatment of chronic hepatitis B is to maintain suppression of the viral replication to prevent the emergence of complications. Achieving this goal requires long-term therapy. Chronically administered treatments for any disease should have the following properties to be suitable: long-term tolerability, practicality (linked with adherence), potency, and durability of effect. Durable suppression of viral replication is achieved in the treatment of chronic viral diseases through the prevention of emergence of drug-resistance mutations; to this end, monotherapies have been found to be insufficient in most chronic viral diseases. In the setting of chronic hepatitis B, the use of combination therapy (when the combined drugs have different resistance profiles) is likely to reduce the rate of development of drug resistance mutations. Therefore, the use of combination therapy for the treatment of chronic hepatitis B represents a potential advance in the treatment of this disease where monotherapies may have limitations.

Accordingly, the present study will compare the efficacy and safety of tenofovir DF to emtricitabine plus tenofovir DF in chronic hepatitis B subjects currently receiving lamivudine monotherapy with lamivudine associated resistance mutations (rtM204V/I with or with the rtL180M). In addition, the study will help to further elucidate the PK profiles of tenofovir DF in patients with mild (CLcr 50-80 mL/min) renal impairment to provide better guidance for the use of this drug in this patient population.

This is a randomized, double-blind, double-dummy, 240-week study comparing the antiviral efficacy, safety, and tolerability of tenofovir DF versus the fixed-dose combination of emtricitabine/tenofovir DF for the treatment of chronic HBV infection. Enrolled subjects must be currently receiving lamivudine and must be deemed lamivudine resistant (confirmed lamivudine resistance-associated mutation[s] in the HBV polymerase gene and an HBV deoxyribonucleic acid [DNA] level of >/= 4 log10 copies/mL at screening). Adefovir dipivoxil treatment of Treatment Arm A: tenofovir DF 300 mg once daily plus emtricitabine/tenofovir DF placebo once daily

Treatment Arm B: emtricitabine 200 mg/tenofovir DF 300 mg once daily plus tenofovir DF placebo once daily

Randomization will be stratified by hepatitis e antigen (HBeAg) status (negative or positive) and alanine aminotransferase (ALT) level (>/= 2 × upper limit of normal [ULN] or < 2 × ULN) at screening.

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 >/= 10,000 copies/mL

- Currently receiving 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 - 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 >/= 1,500 /mm3

- 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.

- ALT > 10 × ULN

- Decompensated liver disease

- Received interferon (pegylated or not) therapy within 6 months of the screening visit

- alpha fetoprotein > 50 ng/mL

- Evidence of hepatocellular carcinoma (HCC)

- Co infection with HCV (by serology), HIV, or HDV

- Significant renal, cardiovascular, pulmonary, or neurological disease.

- Received solid organ or bone marrow transplantation

- Is currently receiving therapy with immunomodulators (e. g., corticosteroids, etc.),

investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion

- Has proximal tubulopathy

- Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Jane Anderson, PhD, Phone: 919-294-7160, Email: jane.anderson@gilead.com

Wien A-1130, Austria; Recruiting

Wien A-1090, Austria; Recruiting

Innsbruck A-6020, Austria; Recruiting

Prague 160 00, Czech Republic; Recruiting

Hradec Kralove 500 1, Czech Republic; Recruiting

Brno 625 00, Czech Republic; Recruiting

Praha 4 14021, Czech Republic; Recruiting

Gyula H5700, Hungary; Recruiting

Hamilton, New Zealand; Recruiting

Auckland, New Zealand; Recruiting

Bydgoszcz 85-030, Poland; Recruiting

Wroclaw 50-220, Poland; Recruiting

Lodz 91-347, Poland; Recruiting

Warszawa 01-201, Poland; Recruiting

Chorzow 41-500, Poland; Recruiting

Krakow 31-351, Poland; Recruiting

Bialystok 15-540, Poland; Recruiting

Bucuresti 021105, Romania; Recruiting

Bucuresti 022328, Romania; Recruiting

Bucuresti 020125, Romania; Recruiting

Sevilla 4103, Spain; Recruiting

Uskudar 34668, Turkey; Recruiting

Trabzon 61080, Turkey; Recruiting

Izmir 35100, Turkey; Recruiting

Samsun 55139, Turkey; Recruiting

Bursa 16059, Turkey; Recruiting

Ankara 06100, Turkey; Recruiting

Ulm, Baden-Wuerttemberg 89081, Germany; Recruiting

Vancouver, British Columbia V5Z, Canada; Recruiting

Vancouver, British Columbia V6Z 2K5, Canada; Recruiting

Vancouver, British Columbia V6AB46, Canada; Recruiting

Bradenton, Florida 34205, United States; Recruiting

Jacksonville, Florida 32256, United States; Recruiting

Indianapolis, Indiana 46202, United States; Recruiting

Timisoara, Judetul Timis 300736, Romania; Recruiting

lasi, Judetul lasi 700111, Romania; Recruiting

Winnepeg, Manitoba R3E 3P4, Canada; Recruiting

Detroit, Michigan 48201, United States; Recruiting

Flushing, New York 11355, United States; Recruiting

Toronto, Ontario M6H 3M1, Canada; Recruiting

Toronto, Ontario M5G 2C4, Canada; Recruiting

Toronto, Ontario M5T 2S8, Canada; Recruiting

Toronto, Ontario M5G 1X5, Canada; Recruiting

Cranston, Rhode Island 02920, United States; Recruiting

Houston, Texas 77030, United States; Recruiting

Starting date: October 2008
Ending date: August 2014
Last updated: August 21, 2009