A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B

Chronic Hepatitis B Clinical Trial

Official title:

A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of Presumed Pre-Core Mutant Chronic Hepatitis B

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00117676
• Other study ID #: GS-US-174-0102
• Status: Completed
• Phase: Phase 3
• First received: June 30, 2005
• Last updated: February 4, 2016
• Start date: February 2005
• Est. completion date: January 2016

Study information

• Verified date: February 2016
• 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 is designed to evaluate the safety and antiviral activity of tenofovir disoproxil fumarate (TDF) compared to adefovir dipivoxil (ADV) for 48 weeks for the treatment of HBeAg-negative chronic hepatitis B. Subjects will either receive TDF or the approved hepatitis B therapy ADV. After 48 weeks all subjects will be switched to open-label TDF.

Description:

The efficacy of TDF versus ADV will be evaluated for histologic improvement, reductions in serum hepatitis B virus deoxyribonucleic acid (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 subjects will receive open-label TDF, and the efficacy and safety of TDF will continue to be monitored for the remainder of the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 375
• Est. completion date: January 2016
• Est. primary completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 69 Years

Eligibility

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 at least 6 months.

• 18 through 69 years of age, inclusive.

• Active hepatitis B e-antigen (HBeAg) negative chronic HBV infection, with all of the following:

• HBeAg negative and HBeAb positive at screening

• Alanine aminotransferase (ALT) levels > the upper limit of the normal range (ULN) and = 10 x ULN

• Serum HBV DNA > 100,000 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 120 patients with cirrhosis, ie, a Knodell fibrosis score equal to 4, will be eligible for enrollment

• Negative serum ß-human chorionic gonadotropin (hCG)

• Nucleotide naive, ie, no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks

• Nucleoside naive, ie, no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patients with > 12 weeks prior lamivudine experience will be eligible

• 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:

• Pregnant women, women who are breast feeding, or women 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.

• 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 (eg, 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)

• Coinfection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D 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 susceptible of modifying renal excretion

• Has proximal tubulopathy

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, 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:
• TDF
Tenofovir disoproxil fumarate (TDF) 300 mg tablet administered orally once daily
• ADV
Adefovir dipivoxil (ADV) 10 mg tablet administered orally once daily
• TDF placebo
Placebo to match TDF administered orally once daily
• ADV placebo
Placebo to match ADV administered orally once daily
• FTC/TDF
Emtricitabine (FTC) 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet administered orally once daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Canada,  Czech Republic,  France,  Germany,  Greece,  Italy,  Netherlands,  New Zealand,  Poland,  Spain,  Turkey,  United Kingdom, 

References & Publications (5)

Fung S, Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Gane E, Jacobson IM, Yee LJ, Dinh P, Martins EB, Flaherty JF, Kitrinos KM, Dusheiko G, Trinh H, Flisiak R, Rustgi VK, Buti M, Marcellin P. Tenofovir disoproxil fumarate in Asian or Pacific Islan — View Citation

Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Dinh P, Martins EB, Yee LJ, Flaherty JF, Kitrinos KM, Rustgi VK, Marcellin P. Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. H — View Citation

Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, Borroto-Esoda K, Miller MD. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2014 Feb;59(2):434-42. — View Citation

Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Aguilar Schall R, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir dis — View Citation

Tsai NC, Marcellin P, Buti M, Washington MK, Lee SS, Chan S, Trinh H, Flaherty JF, Kitrinos KM, Dinh P, Charuworn P, Subramanian GM, Gane E. Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48	Complete response was a composite endpoint defined as histological response and HBV DNA < 400 copies/mL. Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.; A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40.	Baseline; Week 48	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48		Week 48	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96		Week 96	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384		Weeks 144, 192, 240, 288, 336, and 384	No
Secondary	Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, and 384		Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384	No
Secondary	Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, and 384		Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384	No
Secondary	Percentage of Participants With Histological Response at Week 48	Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.	Baseline; Week 48	No
Secondary	Percentage of Participants With Histological Response at Week 240	Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.	Baseline; Week 240	No
Secondary	Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48	The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).	Baseline; Week 48	No
Secondary	Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240	The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).	Baseline; Week 240	No
Secondary	Ranked Assessment of Necroinflammation and Fibrosis at Week 48	Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.	Baseline; Week 48	No
Secondary	Ranked Assessment of Necroinflammation and Fibrosis at Week 240	Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.	Baseline; Week 240	No
Secondary	Percentage of Participants With ALT Normalization at Week 48	ALT normalization was defined as ALT > upper limit of normal (ULN) at baseline and within the normal range at the end of blinded treatment. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged = 69.	Baseline; Week 48	No
Secondary	Percentage of Participants With ALT Normalization at Weeks 96	ALT normalization was defined as ALT > ULN at baseline and within the normal range at Week 96. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged = 69.	Baseline; Week 96	No
Secondary	Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384	ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged = 69.	Baseline; Weeks 144, 192, 240, 288, 336, and 384	No
Secondary	Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, and 384		Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384	No
Secondary	Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, and 384		Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384	No
Secondary	Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 48. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 48.	Baseline; Week 48	No
Secondary	Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 96. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 96.	Baseline; Week 96	No
Secondary	Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, and 384	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at the subsequent time point. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at the subsequent time point.	Baseline; Weeks 144, 192, 240, 288, 336, and 384	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 48, those with viral breakthrough, and those who discontinued after Week 24 with HBV DNA = 400 copies/mL.	Baseline; Week 48	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 96 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 48 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 49 to 95	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 144 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 96 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 96 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 97 to 144	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 192 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 144 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 144 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 145 to 192	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 240 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 192 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 192 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 193 to 240	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 288 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 240 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 240 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 241 to 288	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 336 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 288 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 288 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 289 to 336	No
Secondary	Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA = 400 copies/mL at Week 384 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 336 with HBV DNA = 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 336 and had HBV DNA = 400 copies/mL at the time of the addition.	Baseline; Weeks 337 to 384	No