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

• ClinicalTrials.gov Identifier: NCT00307489
• Recruitment Status: Completed
• First Posted: March 28, 2006
• Results First Posted: July 7, 2009
• Last Update Posted: November 1, 2011
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Hepatitis B	Drug: tenofovir DF; Drug: emtricitabine /tenofovir DF	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2006
• Actual Primary Completion Date: January 2008
• Actual Study Completion Date: October 2010

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48 [ Time Frame: 48 weeks ]
2. Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 [ Time Frame: 48 Weeks ]

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

San Francisco, California, United States, 94115

San Jose, California, United States, 95128

United States, New York

Flushing, New York, United States, 11355

New York, New York, United States, 10013

New York, New York, United States, 10016

New York, New York, United States, 10021

United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19107

United States, Virginia

Fairfax, Virginia, United States, 22031

Norfolk, Virginia, United States, 23502

Richmond, Virginia, United States, 23249

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, 10969

Berlin, Germany, 13353

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

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Stephen J Rossi, PharmD; Gilead Sciences

More Information

Publications of Results:

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.

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.

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.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00307489
• Other Study ID Numbers: GS-US-174-0106
• First Posted: March 28, 2006
• Results First Posted: July 7, 2009
• Last Update Posted: November 1, 2011
• Last Verified: October 2011

Additional relevant MeSH terms:

Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Hepadnaviridae Infections; DNA Virus Infections; Chronic Disease; Disease Attributes; Pathologic Processes; Tenofovir; Emtricitabine; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents