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

Sponsor:	Gilead Sciences
Information provided by:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00737568

Purpose

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

Condition	Intervention	Phase
Hepatitis B	Drug: Tenofovir DF Drug: Emtricitabine/tenofovir DF	Phase IV

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) 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:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis B

Drug Information available for: Lamivudine Tenofovir Tenofovir disoproxil Tenofovir Disoproxil Fumarate Truvada

U.S. FDA Resources

Further study details as provided by Gilead Sciences:

Primary Outcome Measures:

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 [ Time Frame: After last subjects completes 48 weeks of blinded treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To evaluate the safety and tolerability of tenofovir DF versus emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance [ Time Frame: Throughout the 240 week study duration ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	250
Study Start Date:	October 2008
Estimated Study Completion Date:	August 2014
Estimated Primary Completion Date:	November 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: A Tenofovir DF 300 mg once daily plus emtricitabine/tenofovir DF placebo	Drug: Tenofovir DF 300 mg tablet once daily Other Name: Viread
Experimental: B Emtricitabine 200 mg/tenofovir DF 300 mg once daily plus tenofovir DF placebo	Drug: Emtricitabine/tenofovir DF Emtricitabine 200 mg/tenofovir DF 300 mg fixed-dose tablet once daily Other Name: Truvada

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 </= 48 weeks inclusive of combination adefovir dipivoxil + lamivudine treatment at entry is allowed. Approximately 250 subjects will be randomized in a 1:1 ratio to treatment arm A or B.

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.

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 >/= 10,000 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 </= 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) is 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 >/= 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00737568

Show 71 Study Locations

Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:

Y. Sunila Reddy, PharmD

Gilead Sciences

More Information

No publications provided

Responsible Party:	Y. Sunila Reddy, Pharm.D./ Sr. Manager, Liver Disease Therapeutics, Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00737568 History of Changes
Other Study ID Numbers:	GS-US-174-0121
Study First Received:	August 15, 2008
Last Updated:	January 5, 2011
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, Chronic
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

Lamivudine
Tenofovir disoproxil
Tenofovir
Emtricitabine
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on February 09, 2012