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

NCT00737568 | Completed Phase 3 Results DMC

• 1 other identifier: GS-US-174-0121
• Study Type: interventional
• Target: 280
• Locations: 14 countries
• Sites: 69

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.

Conditions

Hepatitis B

Keywords

Tenofovir DF; Emtricitabine; Chronic hepatitis B; Combination therapy

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

  Week 96

Secondary Outcomes (12)

• Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

  Weeks 48, 144, 192, and 240

• Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

  Weeks 48, 96, 144, 192, and 240

• HBV DNA Level at Weeks 48, 96, 144, 192, and 240

  Weeks 48, 96, 144, 192, and 240

• Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240

  Weeks 48, 96, 144, 192, and 240

• Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240

  Baseline; Weeks 48, 96, 144, 192, and 240

Study Arms (2)

Tenofovir DF

EXPERIMENTAL

TDF plus placebo to match FTC/TDF

Drug: TDF; Drug: FTC/TDF Placebo

FTC/TDF

EXPERIMENTAL

FTC/TDF plus placebo to match TDF

Drug: FTC/TDF; Drug: TDF Placebo

Interventions

TDF DRUG

Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily

Also known as: Viread®

Tenofovir DF

FTC/TDF DRUG

Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily

Also known as: Truvada®

FTC/TDF

TDF Placebo DRUG

TDF placebo tablet administered orally once daily

FTC/TDF

FTC/TDF Placebo DRUG

FTC/TDF placebo tablet administered orally once daily

Tenofovir DF

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic HBV infection, defined as positive serum HBsAg for at least 6 months
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (69)

Unknown Facility

Bradenton, Florida, 34205, United States

Location

Unknown Facility

Flushing, New York, 11355, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, 19107, United States

Location

Unknown Facility

Innsbruck, A-6020, Austria

Location

Unknown Facility

Vienna, A-1090, Austria

Location

Unknown Facility

Vienna, A-1130, Austria

Location

Unknown Facility

Sofia, 1407, Bulgaria

Location

Unknown Facility

Sofia, 1527, Bulgaria

Location

Unknown Facility

Sofia, 1606, Bulgaria

Location

Unknown Facility

Varna, 9010, Bulgaria

Location

Unknown Facility

Vancouver, British Columbia, V5Z, Canada

Location

Unknown Facility

Vancouver, British Columbia, V6AB46, Canada

Location

Unknown Facility

Vancouver, British Columbia, V6Z 2K5, Canada

Location

Unknown Facility

Winnepeg, Manitoba, R3E 3P4, Canada

Location

Unknown Facility

Toronto, Ontario, M5G 1X5, Canada

Location

Unknown Facility

Toronto, Ontario, M5G 2C4, Canada

Location

Unknown Facility

Toronto, Ontario, M5T 2S8, Canada

Location

Unknown Facility

Toronto, Ontario, M6H 3M1, Canada

Location

Unknown Facility

Brno, 625 00, Czechia

Location

Unknown Facility

Pilsen, 304 60, Czechia

Location

Unknown Facility

Prague, 14021, Czechia

Location

Unknown Facility

Prague, 160 00, Czechia

Location

Unknown Facility

Ústí nad Labem, 40001, Czechia

Location

Unknown Facility

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Unknown Facility

Berlin, 13353, Germany

Location

Unknown Facility

Düsseldorf, 40225, Germany

Location

Unknown Facility

Essen, 45122, Germany

Location

Unknown Facility

Frankfurt, 60590, Germany

Location

Unknown Facility

Hamburg, 20099, Germany

Location

Unknown Facility

Hanover, 30625, Germany

Location

Unknown Facility

Stuttgart, Germany

Location

Unknown Facility

Larissa, 41110, Greece

Location

Unknown Facility

Pátrai, 25404, Greece

Location

Unknown Facility

Thessaloniki, 54642, Greece

Location

Unknown Facility

Budapest, 1126, Hungary

Location

Unknown Facility

Debrecen, 4032, Hungary

Location

Unknown Facility

Gyula, H5700, Hungary

Location

Unknown Facility

Kasposvar, H7400, Hungary

Location

Unknown Facility

Auckland, New Zealand

Location

Unknown Facility

Hamilton, New Zealand

Location

Unknown Facility

Wellington, 6035, New Zealand

Location

Unknown Facility

Bialystok, 15-540, Poland

Location

Unknown Facility

Bydgoszcz, 85-030, Poland

Location

Unknown Facility

Chorzów, 41-500, Poland

Location

Unknown Facility

Krakow, 31-351, Poland

Location

Unknown Facility

Lodz, 91-347, Poland

Location

Unknown Facility

Szczecin, 71-455, Poland

Location

Unknown Facility

Warsaw, 01-201, Poland

Location

Unknown Facility

Warsaw, 02-507, Poland

Location

Unknown Facility

Wroclaw, 50-220, Poland

Location

Unknown Facility

Lasi, Judetul Lasi, 700111, Romania

Location

Unknown Facility

Timișoara, Timiș County, 300736, Romania

Location

Unknown Facility

Bucharest, 020125, Romania

Location

Unknown Facility

Bucharest, 021105, Romania

Location

Unknown Facility

Bucharest, 022328, Romania

Location

Unknown Facility

Bucharest, 030303, Romania

Location

Unknown Facility

Cluj-Napoca, 400158, Romania

Location

Unknown Facility

Constanța, 900708, Romania

Location

Unknown Facility

Belgrade, 11000, Serbia

Location

Unknown Facility

Kragujevac, 34000, Serbia

Location

Unknown Facility

Niš, 18000, Serbia

Location

Unknown Facility

Novi Sad, 21000, Serbia

Location

Unknown Facility

Seville, 4103, Spain

Location

Unknown Facility

Ankara, 06100, Turkey (Türkiye)

Location

Unknown Facility

Bursa, 16059, Turkey (Türkiye)

Location

Unknown Facility

Izmir, 35100, Turkey (Türkiye)

Location

Unknown Facility

Samsun, 55139, Turkey (Türkiye)

Location

Unknown Facility

Trabzon, 61080, Turkey (Türkiye)

Location

Unknown Facility

Üsküdar, 34668, Turkey (Türkiye)

Location

Related Publications (4)

• 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.

  PMID: 24929235 RESULT

• 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.

  PMID: 24861361 RESULT

• 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.

  PMID: 24368224 RESULT

• 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.

  PMID: 27545497 DERIVED

MeSH Terms

Conditions

Hepatitis B; Hepatitis B, Chronic

Interventions

Tenofovir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

There were no limitations affecting the analysis or results.

Results Point of Contact

• Title: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.

ClinicalTrialDisclosures@gilead.com

Study Officials

• John Flaherty, PharmD

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 15, 2008
• First Posted: August 19, 2008
• Study Start: September 1, 2008
• Primary Completion: November 1, 2011
• Study Completion: February 1, 2015
• Last Updated: March 11, 2016
• Results First Posted: April 11, 2013

Record last verified: 2016-02

Locations

TU (6); US (3); BU (4); GR (3); NZ (3); AU (3); CA (8); CZ (5); RO (8); DE (8); SE (4); ES (1); HU (4); PL (9)