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

Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00737568
• Other study ID #: GS-US-174-0121
• Status: Completed
• Phase: Phase 3
• First received: August 15, 2008
• Last updated: February 9, 2016
• Start date: September 2008
• Est. completion date: February 2015

Study information

• Verified date: February 2016
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 280
• Est. completion date: February 2015
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis B

Intervention

Drug:
• TDF
Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily
• FTC/TDF
Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily
• TDF Placebo
TDF placebo tablet administered orally once daily
• FTC/TDF Placebo
FTC/TDF placebo tablet administered orally once daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Canada,  Czech Republic,  Germany,  Greece,  Hungary,  New Zealand,  Poland,  Romania,  Serbia,  Spain,  Turkey, 

References & Publications (3)

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 — View 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 dis — View 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 th — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96		Week 96	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240		Weeks 48, 144, 192, and 240	No
Secondary	Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240		Weeks 48, 96, 144, 192, and 240	No
Secondary	HBV DNA Level at Weeks 48, 96, 144, 192, and 240		Weeks 48, 96, 144, 192, and 240	No
Secondary	Percentage of Participants With Normal ALT at 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	No
Secondary	Percentage of Participants With HBeAg Loss at 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	No
Secondary	Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at 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	No
Secondary	Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at 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	No
Secondary	Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at 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	No
Secondary	Percentage of Participants With Virologic Breakthrough at 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	No
Secondary	Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at 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	Yes
Secondary	Percent Change From Baseline in BMD of the Hip at 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	Yes
Secondary	Development of Drug-resistant Mutations (DRMs)	The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.	Baseline to Week 240	No