A Study to Evaluate Tenofovir Disoproxil Fumarate (DF) in Asian-American Adults With Chronic Hepatitis B Infection

Phase 4

Completed

• Conditions: Chronic Hepatitis B
• Interventions: Drug: Tenofovir disoproxil fumarate

• Registration Number: NCT00736190
• Lead Sponsor: Gilead Sciences

Brief Summary

The purpose of this study is to evaluate the antiviral activity and safety of tenofovir disoproxil fumarate (TDF) in Asian-American adults (self-reported Asian descent, living in the United States) with chronic hepatitis B infection. All participants will receive active treatment with TDF for 48 weeks.

Detailed Description

Efficacy of TDF will be evaluated for reductions in serum HBV DNA, changes in liver enzymes, and the generation of antibody to the virus. Safety will be assessed by evaluating adverse events, laboratory abnormalities, and the development of drug resistance mutations.

Study Timeline

• Study Start: 2008-08
• Study First Submitted: 2008-08-13
• Study First Submitted QC: 2008-08-14
• Study First Posted: 2008-08-15
• Primary Completion: 2010-07
• Study Completion: 2010-07
• Results First Submitted: 2011-07-07
• Results First Submitted QC: 2011-07-07
• Results First Posted: 2011-08-03
• Status Verified: 2011-11
• Last Update Submitted: 2011-11-30
• Last Update Posted: 2011-12-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• Male or female
• Asian-American, defined as a person of self-reported Asian ancestry who is residing in the United States (US)
• 18 through 75 years of age, inclusive
• Documented chronic HBV infection, defined as positive serum HBsAg =/> 6 months
• HBV DNA =/> 10,000 copies/mL (PCR method)
• ALT > ULN and </= 10 × ULN at screening or within the past 12 months prior to screening
• Willing and able to provide written informed consent
• Negative serum beta-human chorionic gonadotropin (HCG) pregnancy test (females of child-bearing potential)
• Estimated glomerular filtration rate (creatinine clearance) =/> 60 mL/min/1.73m^2 by the Cockcroft-Gault equation
• Adequate hematologic function (absolute neutrophil count =/> 1,500/mm^3; hemoglobin =/> 10.0 g/dL)
• No prior TDF therapy; participants may have taken < 12 weeks of oral anti-HBV therapy, with the last dose =/> 16 weeks prior to screening; participants may have received prior interferon, but must have discontinued interferon therapy =/> 6 months prior to screening

Exclusion Criteria

Participants who meet any of the following exclusion criteria are not to be enrolled in this study.

• 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. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception.
• Decompensated liver disease defined as direct (conjugated) bilirubin > 1.2 X ULN, prothrombin time (PT) > 1.2 X ULN, platelets < 150,000/mm3, or serum albumin < 3.5 g/dL
• Prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy) or variceal hemorrhage
• Receipt of prior TDF treatment
• Receipt of =/> 12 weeks of oral anti-HBV nucleoside/nucleotide therapy, or receipt of ANY oral anti-HBV treatment < 16 weeks prior to screening
• Receipt of interferon (pegylated or not) therapy within 6 months of the Screening Visit
• alpha-fetoprotein > 50 ng/mL
• Evidence of hepatocellular carcinoma (HCC)
• Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV)
• History of significant renal disease (eg, nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)
• History of significant bone disease (eg, osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses, multiple bone fractures)
• Significant cardiovascular, pulmonary or neurological disease
• Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
• History of solid organ or bone marrow transplantation
• Ongoing therapy with any of the following: nephrotoxic agents, competitors of renal excretion (eg, probenecid), systemic chemotherapeutic agents, systemic corticosteroids, Interleukin-2 (IL-2) and other immunomodulating agents, investigational agents (except with the expressed approval of the Sponsor); administration of any of the above medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period
• Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
• Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TDF	Tenofovir disoproxil fumarate	300-mg tablet (marketed formulation) taken orally once daily

Primary Outcome Measures

Name	Time	Method
Number of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <400 Copies/mL (<69 IU/mL)	Week 48	Blood samples were collected from study participants for measuring HBV DNA via polymerase chain reaction (PCR) method.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Alanine Aminotransferase (ALT) Normal at Week 48	Week 48	Number of participants with normal ALT (at or below the upper limit of normal \[ULN\] for the central laboratory \[34 U/L\])at Week 48
Number of Participants With ALT Normalized (Baseline Values > ULN [34 U/L] and <= ULN at a Subsequent Visit) at Week 48	Week 48	A normal value at Week 48 after having elevated ALT at baseline; normal ALT is defined as being at or below the ULN for the central laboratory (34 U/L)
Number of Participants With Composite Endpoint of Hepatitis B Virus (HBV) DNA <400 Copies/mL (<69 IU/mL) and Normal ALT at Week 48	Week 48	Blood samples were collected for evaluating serum chemistry, including determination of ALT, and for measuring HBV DNA via PCR method. Composite endpoints proposed in the protocol included the percentage of participants with HBV DNA \< 400 copies/mL (\<69 IU/mL) and normal ALT (ALT \<= ULN \[34 U/L\]); and with HBV DNA \< 400 copies/mL, normal ALT, and HBeAg loss/seroconversion. Because so few participants lost hepatitis B e antigen (HBeAg) or developed antibody to hepatitis B e antigen (anti-HBe), only the composite endpoint of HBV DNA \< 400 copies/mL and normal ALT was analyzed.
Change From Baseline in FibroTest Value	Baseline and Week 48	The FibroTest score is used to assess liver fibrosis and is calculated based on a formula including the participant's age and sex and 5 laboratory parameters: alpha 2 macroglobulin, haptoglobin, gamma-glutamyl transferase (GGT), bilirubin, and apolipoprotein A1. Scores can range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis.
Number of Participants With HBeAg/Hepatitis B Surface Antigen (HBsAg) Loss and Seroconversion	Week 48	HBeAg/HBsAg loss is defined for an individual participant as HBeAg+/HBsAg+ at baseline and HBeAg-/HBsAg- at Week 48. HBeAg/HBsAg serocoversion is defined for an individual participant as HBeAg+/HBsAg+ at baseline and HBeAg-/HBsAg- and anti-HBe+/antibody to hepatitis B surface antigen+ (anti-HBs+) at Week 48.
Number of Participants With HBV DNA < 169 Copies/mL (<29 IU/mL) at Week 48	Week 48	Blood samples from study participants were collected for measuring HBV DNA via PCR method.
Number of Participants With Composite Endpoint of HBV DNA <400 Copies/mL (<69 IU/mL), Normal ALT, and HBeAg Loss	Week 48	Composite endpoints proposed in the protocol included the percentage of participants with HBV DNA \< 400 copies/mL (\<69 IU/mL) and normal ALT (ALT \<= ULN \[34 U/L\]); and with HBV DNA \< 400 copies/mL, normal ALT, and HBeAg loss/seroconversion. Because so few participants lost HBeAg or seroconverted to anti-HBe, only the composite endpoint of HBV DNA \< 400 copies/mL and normal ALT was analyzed.
Number of Participants With Composite Endpoint of HBV DNA <400 Copies/mL (<69 IU/mL), Normal ALT, and Seroconversion to Anti-HBe	Week 48	Composite endpoints proposed in the protocol included the percentage of participants with HBV DNA \< 400 copies/mL (\<69 IU/mL) and normal ALT (ALT \<= ULN); and with HBV DNA \< 400 copies/mL, normal ALT, and HBeAg loss/seroconversion. Because so few participants lost HBeAg or seroconverted to anti-HBe, only the composite endpoint of HBV DNA \< 400 copies/mL and normal ALT was analyzed.
Summary of Resistance Surveillance for Participants Without Virologic Breakthrough	Week 48	Serum was collected for HBV resistance surveillance, and sequence analysis of the HBV polymerase was assessed through di-deoxy sequencing of baseline and postbaseline samples.
Summary of Resistance Surveillance for Participants With Virologic Breakthrough	Week 48	Serum was collected for HBV resistance surveillance, and sequence analysis of the HBV polymerase was assessed through di-deoxy sequencing of baseline and postbaseline samples.
Summary of Resistance Surveillance for Participants Who Discontinued the Study Early	Week 48	Serum was collected for HBV resistance surveillance, and sequence analysis of the HBV polymerase was assessed through di-deoxy sequencing of baseline and postbaseline samples.