A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of Hepatitis Be Antigen (HBeAg) Positive Chronic Hepatitis B - Full Text View

Sponsor:	Gilead Sciences
Information provided by (Responsible Party):	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00116805

Purpose

This study is designed to evaluate the safety and antiviral activity of tenofovir disoproxil fumarate (TDF, tenofovir DF) compared to adefovir dipivoxil (ADV, Hepsera) for the treatment of HBeAg-positive chronic hepatitis B. Participants will receive either TDF or the approved hepatitis B therapy ADV. After 48 weeks all participants will be switched to open-label (OL) TDF.

Condition	Intervention	Phase
Chronic Hepatitis B	Drug: tenofovir disoproxil fumarate Drug: adefovir dipivoxil	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis B

Drug Information available for: Adefovir Adefovir dipivoxil Tenofovir Tenofovir disoproxil Tenofovir Disoproxil Fumarate Recombinant hepatitis B vaccine Hepatitis B Vaccines Hepatitis A Vaccines

U.S. FDA Resources

Further study details as provided by Gilead Sciences:

Primary Outcome Measures:

Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Complete response was a composite endpoint defined as histological response and HBV DNA below 400 copies/mL. Histological response was defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).

Secondary Outcome Measures:

Percentage of Participants With Histological Response at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Histological response was defined as Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).
Percentage of Participants With HBV DNA <400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Percentage of Participants With HBV DNA <400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at the end of blinded treatment.
Percentage of Participants With ALT Normalization at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.
Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Hepatitis B e-antigen (HBeAg) loss was defined as negative HBeAg result for those subjects with HBeAg-positive result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.
Percentage of Participants With HBeAg Loss or Seroconversion at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
HBeAg loss was defined as a negative HBeAg result for those participants with a positive HBeAg result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.
Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Hepatitis B s-antigen (HBsAg) loss was defined as negative HBsAg result for those participants with positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.
Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
HBsAg loss was defined as a negative HBsAg result for those participants with a positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.
Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
Participants evaluated for resistance included those with HBV DNA >/= 400 copies/mL at Week 96 in TDF monotherapy, those who discontinued after Week 48 with HBV DNA >/= 400 copies/mL, and those who added emtricitabine to their open-label TDF regimen and had HBV DNA >/= 400 copies/mL at the time of the addition.

Enrollment:	266
Study Start Date:	June 2005
Estimated Study Completion Date:	June 2014
Primary Completion Date:	June 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: A Double-blind tenofovir disoproxil fumarate (TDF) 300 mg once daily and then switch to open-label (OL) TDF 300 mg once daily for an additional 336 weeks (TDF-TDF)	Drug: tenofovir disoproxil fumarate TDF 300 mg once daily for 48 weeks and then open-label TDF 300 mg once daily for an additional 336 weeks Other Name: Viread
Active Comparator: B Double-blind adefovir dipivoxil (ADV) 10 mg once daily and then switch to OL TDF 300 mg once daily for an additional 336 weeks (ADV-TDF)	Drug: adefovir dipivoxil ADV 10 mg once daily for 48 weeks and then open-label TDF 300 mg once daily for an additional 336 weeks Other Name: Hepsera (first 48 weeks) and then switch to Viread (additional 336 weeks)

Detailed Description:

Efficacy of TDF versus ADV will be evaluated for histologic improvement, 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-resistant mutations. After 48 weeks, all participants will receive OL TDF, and the efficacy and safety of TDF will be monitored for an additional 336 weeks.

Eligibility

Ages Eligible for Study:	18 Years to 69 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

A patient must meet all of the following inclusion criteria to be eligible for participation in this study.

Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for more than 6 months.
18 through 69 years of age, inclusive.
Active hepatitis B e-antigen (HBeAg) positive chronic HBV infection, with all of the following:
- HBeAg positive at screening;
- Alanine aminotransferase (ALT) levels > 2 × ULN and </= 10 × ULN;
- Serum HBV DNA > 1 million copies/mL at screening;
- creatinine clearance >/= 70 mL/min;
- hemoglobin >/= 8 g/dL;
- neutrophils >/= 1,000 /mL
Knodell necroinflammatory score >/= 3 and a Knodell fibrosis score < 4. However, up to 96 patients with cirrhosis, i.e., a Knodell fibrosis score equal to 4, will be eligible for enrollment.
Negative serum β-HCG
Nucleotide naïve, i.e., no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks.
Nucleoside naïve, i.e., no prior nucleoside (any nucleoside) therapy for greater than 12 weeks.
Willing and able to provide written informed consent.
Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline.

Exclusion Criteria:

A patient who meets any of the following exclusion criteria is 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 unwilling 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.
Decompensated liver disease defined as conjugated bilirubin >1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, platelets < 75,000/mL, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage).
Received any nucleoside, nucleotide (TDF or ADV) or interferon (pegylated or not) therapy within 6 months prior to the pre-treatment biopsy.
Evidence of hepatocellular carcinoma (HCC), i.e., α-fetoprotein >50 ng/mL.
Coinfection with hepatitis C virus (HCV), 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 (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion.
Has proximal tubulopathy.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00116805

Show 114 Study Locations

Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:

Jeffrey D Bornstein, MD

Gilead Sciences

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

No publications provided by Gilead Sciences

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Heathcote EJ, Marcellin P, 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, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011 Jan;140(1):132-43. Epub 2010 Oct 16.

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.

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00116805 History of Changes
Other Study ID Numbers:	GS-US-174-0103
Study First Received:	June 30, 2005
Results First Received:	February 11, 2010
Last Updated:	October 31, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Gilead Sciences:

tenofovir
adefovir
hepatitis B
HBeAg Positive

Additional relevant MeSH terms:

Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections

Adefovir dipivoxil
Adefovir
Tenofovir disoproxil
Tenofovir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on February 09, 2012