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

Chronic Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00307489
• Other study ID #: GS-US-174-0106
• Status: Completed
• Phase: Phase 2
• First received: March 24, 2006
• Last updated: October 4, 2011
• Start date: March 2006
• Est. completion date: October 2010

Study information

• Verified date: October 2011
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: October 2010
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 69 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• tenofovir DF
300 mg tablet, once daily (QD)
• emtricitabine /tenofovir DF
emtricitabine 200 mg/tenofovir DF 300 mg once daily (combination tablet)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain, 

References & Publications (6)

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-hepat — View 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 — View 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. — View 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. — View Citation

van Bömmel F, de Man RA, Wedemeyer H, Deterding K, Petersen J, Buggisch P, Erhardt A, Hüppe D, Stein K, Trojan J, Sarrazin C, Böcher WO, Spengler U, Wasmuth HE, Reinders JG, Möller B, Rhode P, Feucht HH, Wiedenmann B, Berg T. Long-term efficacy of tenofov — View Citation

van Bömmel F, Zöllner B, Sarrazin C, Spengler U, Hüppe D, Möller 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48		48 weeks	No
Primary	Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48		48 Weeks	No
Secondary	Change From Baseline in log10 Plasma HBV DNA Levels at Week 48		48 Weeks	No
Secondary	Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48		48 Weeks	No
Secondary	Percentage of Participants With Normal ALT at Week 48	ULN for males = 43 U/L; 34 U/L for females	48 Weeks	No
Secondary	Percentage of Participants With Normalized ALT at Week 48	Subjects with elevated ALT at baseline that return to normal by Week 48.	48 Weeks	No
Secondary	Hepatitis B Early Antigen (HBeAg) Loss at Week 48	Defined as having negative serum HBeAg for subjects with positive HBeAg at baseline.	48 Weeks	No
Secondary	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	No
Secondary	HBsAg Loss at Week 48	Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.	48 Weeks	No
Secondary	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	No
Secondary	Change From Baseline in log10 Plasma HBV DNA Levels at Week 168		168 weeks	No
Secondary	Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168		168 weeks	No
Secondary	Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168		168 weeks	No
Secondary	Percentage of Participants With Normal ALT at Week 168	ULN for males = 43 U/L; ULN for females = 34 U/L	168 weeks	No
Secondary	Percentage of Participants With Normalized ALT at Week 168	Subjects with elevated ALT at baseline that return to normal by Week 48.	168 weeks	No
Secondary	Hepatitis B Early Antigen (HBeAg) Loss at Week 168	Defined as having negative serum HBeAg for subjecst with positive HBeAg at baseline.	168 weeks	No
Secondary	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	No
Secondary	HBsAg Loss at Week 168	Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.	168 weeks	No
Secondary	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	No