Clinical trial NCT00307489: Treatment of Persistent Viremia (Virus in Blood) in Chronic Hepatitis B Subjects Already Receiving Adefovir Dipivoxil
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis B
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2006-03-28
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48
timeFrame: 48 weeks
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48
timeFrame: 48 Weeks
Secondary outcomes:
measure: Change From Baseline in log10 Plasma HBV DNA Levels at Week 48
timeFrame: 48 Weeks
measure: Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48
timeFrame: 48 Weeks
measure: Percentage of Participants With Normal ALT at Week 48
timeFrame: 48 Weeks
measure: Percentage of Participants With Normalized ALT at Week 48
timeFrame: 48 Weeks
measure: Hepatitis B Early Antigen (HBeAg) Loss at Week 48
timeFrame: 48 Weeks
measure: HBeAg Seroconversion at Week 48
timeFrame: 48 Weeks
measure: HBsAg Loss at Week 48
timeFrame: 48 Weeks
measure: Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48
timeFrame: 48 Weeks
measure: Change From Baseline in log10 Plasma HBV DNA Levels at Week 168
timeFrame: 168 weeks
measure: Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168
timeFrame: 168 weeks
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168
timeFrame: 168 weeks
measure: Percentage of Participants With Normal ALT at Week 168
timeFrame: 168 weeks
measure: Percentage of Participants With Normalized ALT at Week 168
timeFrame: 168 weeks
measure: Hepatitis B Early Antigen (HBeAg) Loss at Week 168
timeFrame: 168 weeks
measure: Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168
timeFrame: 168 weeks
measure: HBsAg Loss at Week 168
timeFrame: 168 weeks
measure: Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168
timeFrame: 168 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
state: California
city: San Jose
country: United States
state: California
city: Flushing
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Philadelphia
country: United States
state: Pennsylvania
city: Fairfax
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Angers
country: France
city: Clichy
country: France
city: Lille
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Rouen
country: France
city: Strasbourg
country: France
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Bonn
country: Germany
city: Erlangen
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Herne
country: Germany
city: Munchen
country: Germany
city: Sevilla
country: Spain
Study officials:
affiliation: Gilead Sciences
name: Stephen J Rossi, PharmD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.