Treatment of Persistent Viremia (Virus in Blood) in Chronic Hepatitis B Subjects Already Receiving Adefovir Dipivoxil

A Phase 2, Randomized, Double-Blind Study Exploring the Efficacy, Safety and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects Currently Being Treated With Adefovir Dipivoxil for Chronic Hepatitis B and Having Persistent Viral Replication

This study explores the efficacy, safety and tolerability of tenofovir DF (TDF) 300 mg once daily monotherapy versus the combination of emtricitabine 200 mg plus tenofovir DF 300 mg (FTC/TDF) once daily in subjects currently being treated with adefovir dipivoxil (Hepsera) for chronic hepatitis B who have persistent viral replication (detectable hepatitis B virus deoxyribonucleic acid [HBV DNA]).

Subjects with confirmed (within 4 weeks) plasma HBV DNA ≥ 400 copies/mL during double blind treatment at Week 24 or any time thereafter have the option of receiving 12 weeks of open-label FTC/TDF which may be continued through the end of the 168-week treatment period if there is a virologic response (HBV DNA < 400 copies/mL). Alternatively, subjects with confirmed HBV DNA < 400 copies/mL at or any time after Week 24 of double-blind treatment may continue blinded therapy up to Week 168 at the discretion of the investigator. If, in the investigator's opinion, it is felt that continued blinded treatment beyond 24 weeks in subjects with confirmed HBV DNA ≥ 400 copies/mL is not beneficial, the subject may discontinue the study and begin commercially available HBV therapy rather than initiate open-label FTC/TDF.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: tenofovir DF; Drug: emtricitabine /tenofovir DF

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
  • Clichy, France, 92110
  • Lille, France, 59037
  • Lyon, France, 69288
  • Marseille, France, 13285
  • Rouen, France, 76031
  • Strasbourg, France, 67091
• Germany
  • Berlin, Germany, 13353
  • Berlin, Germany, 10969
  • Bonn, Germany, 53105
  • Erlangen, Germany, 91054
  • Essen, Germany, 45122
  • Frankfurt, Germany, 60590
  • Hamburg, Germany, 20999
  • Hannover, Germany, 30623
  • Herne, Germany, 44623
  • Munchen, Germany, 81377
• Spain
  • Sevilla, Spain, 41014
• United States
  • California
    • San Francisco, California, United States, 94115
    • San Jose, California, United States, 95128
  • New York
    • Flushing, New York, United States, 11355
    • New York, New York, United States, 10016
    • New York, New York, United States, 10021
    • New York, New York, United States, 10013
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
  • Virginia
    • Fairfax, Virginia, United States, 22031
    • Norfolk, Virginia, United States, 23502
    • Richmond, Virginia, United States, 23249

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 through 69 years of age, inclusive
• Chronic HBV infection, defined as positive serum HBsAg for at least 6 months

• Active chronic HBV infection with all the following:

  1. Currently treated with adefovir dipivoxil 10 mg QD (for at least 24 weeks but not more than 96 weeks)
  2. HBeAg positive or negative at screening
  3. Plasma HBV DNA >/= 1000 copies/mL at screening (irrespective of HBeAg status)
  4. Serum ALT less than 10 times the upper limit of normal (ULN)
  5. Calculated creatinine clearance of at least 70 mL/min using the Cockcroft-Gault formula
  6. Hemoglobin at least 8 g/dL
  7. Neutrophils at least 1,000 /mm3
• Nucleoside naive except for lamivudine (>/= 12 weeks of therapy)
• Negative serum beta human chorionic gonadotropin
• Compliant with adefovir dipivoxil
• Willing and able to provide written informed consent

Exclusion Criteria:

• Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study
• Male or females of reproductive potential who are unwilling to use an effective method of contraceptive while enrolled in the study. For males, condoms should be used and for females, a barrier contraception method should be used
• Decompensated liver disease defined as conjugated bilirubin greater than 1.5 times ULN, prothrombin time (PT) greater than 1.5 times ULN, platelets less than 75,000/mm3, serum albumin less than 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage)
• Prior use of tenofovir DF or entecavir
• Received treatment with interferon or pegylated interferon within 6 months of the screening visit
• Evidence of hepatocellular carcinoma (HCC); for example, alpha-fetoprotein greater than 50 ng/mL or by any other standard of care measure.
• Co-infection with HCV (based on serology), human immunodeficiency virus (HIV), or hepatitis delta virus (HDV)
• Significant renal, cardiovascular, pulmonary, or neurological disease.
• Received solid organ or bone marrow transplantation.
• Is currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion
• Has proximal tubulopathy
• Known hypersensitivity to the study drugs (tenofovir DF or emtricitabine/tenofovir DF), the metabolites (tenofovir or emtricitabine) or formulation excipients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; TDF	Drug: tenofovir DF; 300 mg tablet, once daily (QD)
Experimental: 2; FTC/TDF	Drug: emtricitabine /tenofovir DF; emtricitabine 200 mg/tenofovir DF 300 mg once daily (combination tablet)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48	48 weeks
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48	48 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in log10 Plasma HBV DNA Levels at Week 48		48 Weeks
Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48		48 Weeks
Percentage of Participants With Normal ALT at Week 48	ULN for males = 43 U/L; 34 U/L for females	48 Weeks
Percentage of Participants With Normalized ALT at Week 48	Subjects with elevated ALT at baseline that return to normal by Week 48.	48 Weeks
Hepatitis B Early Antigen (HBeAg) Loss at Week 48	Defined as having negative serum HBeAg for subjects with positive HBeAg at baseline.	48 Weeks
HBeAg Seroconversion at Week 48	Defined as having negative serum HBeAg and positive serum antibody to HBeAg [anti-HBe] for subjects with positive serum HBeAg at baseline.	48 Weeks
HBsAg Loss at Week 48	Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.	48 Weeks
Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48	Defined as having negative serum HBsAg and positive serum antibody to HBsAg [anti-HBs] for subject with positive serum HBsAg at baseline.	48 Weeks
Change From Baseline in log10 Plasma HBV DNA Levels at Week 168		168 weeks
Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168		168 weeks
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168		168 weeks
Percentage of Participants With Normal ALT at Week 168	ULN for males = 43 U/L; ULN for females = 34 U/L	168 weeks
Percentage of Participants With Normalized ALT at Week 168	Subjects with elevated ALT at baseline that return to normal by Week 48.	168 weeks
Hepatitis B Early Antigen (HBeAg) Loss at Week 168	Defined as having negative serum HBeAg for subjecst with positive HBeAg at baseline.	168 weeks
Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168	Defined as having negative serum BHsAg and positive serum antibody to HBsAg (anti-HBs) for subject with positive serum BHsAg at baseline.	168 weeks
HBsAg Loss at Week 168	Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.	168 weeks
Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168	P-values were from a Cochran-Mantel-Haenszel test, controlling for baseline HBeAg status and prior lamivudine use.	168 weeks

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Stephen J Rossi, PharmD, Gilead Sciences

Publications and helpful links

General Publications

• Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55. doi: 10.1056/NEJMoa0802878.
• van Bommel F, Zollner B, Sarrazin C, Spengler U, Huppe D, Moller B, Feucht HH, Wiedenmann B, Berg T. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology. 2006 Aug;44(2):318-25. doi: 10.1002/hep.21253.
• Reijnders JG, Janssen HL. Potency of tenofovir in chronic hepatitis B: mono or combination therapy? J Hepatol. 2008 Mar;48(3):383-6. doi: 10.1016/j.jhep.2007.12.006. Epub 2007 Dec 31. No abstract available.
• Tan J, Degertekin B, Wong SN, Husain M, Oberhelman K, Lok AS. Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J Hepatol. 2008 Mar;48(3):391-8. doi: 10.1016/j.jhep.2007.09.020. Epub 2008 Jan 3.
• van Bommel F, de Man RA, Wedemeyer H, Deterding K, Petersen J, Buggisch P, Erhardt A, Huppe D, Stein K, Trojan J, Sarrazin C, Bocher WO, Spengler U, Wasmuth HE, Reinders JG, Moller B, Rhode P, Feucht HH, Wiedenmann B, Berg T. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology. 2010 Jan;51(1):73-80. doi: 10.1002/hep.23246.
• Berg T, Marcellin P, Zoulim F, Moller B, Trinh H, Chan S, Suarez E, Lavocat F, Snow-Lampart A, Frederick D, Sorbel J, Borroto-Esoda K, Oldach D, Rousseau F. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology. 2010 Oct;139(4):1207-17. doi: 10.1053/j.gastro.2010.06.053. Epub 2010 Jun 20.

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: March 24, 2006
• First Submitted That Met QC Criteria: March 24, 2006
• First Posted (Estimate): March 28, 2006

Study Record Updates

• Last Update Posted (Estimate): November 1, 2011
• Last Update Submitted That Met QC Criteria: October 4, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Emtricitabine
• Other Study ID Numbers: GS-US-174-0106