Clinical trial NCT00117676: A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Hepatitis B
Keywords: tenofovir
adefovir
hepatitis B virus
HBeAg Negative
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2005-07-08
Enrollment: 382
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 primary objectives of this study are to compare the efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) for the treatment of pre-core mutant chronic hepatitis B. Participants will receive TDF or ADV for 48 weeks (double-blind). After 48 weeks, eligible participants switched to open-label TDF for up to 480 weeks.


Eligibility criteria: Key Inclusion Criteria:

* 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 β-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

Key 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

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: 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
timeFrame: Baseline; Week 48
Secondary outcomes:
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
timeFrame: Week 96
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384
timeFrame: Weeks 144, 192, 240, 288, 336, and 384
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480
timeFrame: Weeks 432 and 480
measure: Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
timeFrame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
measure: Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
timeFrame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
measure: Percentage of Participants With Histological Response at Week 48
timeFrame: Baseline; Week 48
measure: Percentage of Participants With Histological Response at Week 240
timeFrame: Baseline; Week 240
measure: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48
timeFrame: Baseline; Week 48
measure: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240
timeFrame: Baseline; Week 240
measure: Ranked Assessment of Necroinflammation and Fibrosis at Week 48
timeFrame: Baseline; Week 48
measure: Ranked Assessment of Necroinflammation and Fibrosis at Week 240
timeFrame: Baseline; Week 240
measure: Percentage of Participants With ALT Normalization at Week 48
timeFrame: Baseline; Week 48
measure: Percentage of Participants With ALT Normalization at Weeks 96
timeFrame: Baseline; Week 96
measure: Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384
timeFrame: Baseline; Weeks 144, 192, 240, 288, 336, and 384
measure: Percentage of Participants With ALT Normalization at Weeks 432 and 480
timeFrame: Baseline; Weeks 432 and 480
measure: Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
timeFrame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
measure: Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
timeFrame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
measure: Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48
timeFrame: Baseline; Week 48
measure: Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96
timeFrame: Baseline; Week 96
measure: Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480
timeFrame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)
timeFrame: Baseline; Week 48
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)
timeFrame: Baseline; Weeks 49 to 96
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)
timeFrame: Baseline; Weeks 97 to 144
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)
timeFrame: Baseline; Weeks 145 to 192
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)
timeFrame: Baseline; Weeks 193 to 240
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)
timeFrame: Baseline; Weeks 241 to 288
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)
timeFrame: Baseline; Weeks 289 to 336
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)
timeFrame: Baseline; Weeks 337 to 384
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)
timeFrame: Baseline; Weeks 385 to 432
measure: Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)
timeFrame: Baseline; Weeks 433 to 480
Other outcomes:
Locations:
city: La Jolla
country: United States
state: California
city: Pasadena
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: San Jose
country: United States
state: California
city: Atlanta
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: St. Louis
country: United States
state: Missouri
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: Falls Church
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Camperdown
country: Australia
state: New South Wales
city: Concord
country: Australia
state: New South Wales
city: Westmead
country: Australia
state: New South Wales
city: Woolloongabba
country: Australia
state: Queensland
city: Clayton
country: Australia
state: Victoria
city: Fitzroy
country: Australia
state: Victoria
city: Heidelberg
country: Australia
state: Victoria
city: Prahan
country: Australia
state: Victoria
city: Sofia
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Winnipeg
country: Canada
state: Manitoba
city: Toronto
country: Canada
state: Ontario
city: Brno
country: Czech Republic
city: Hradec Kralove
country: Czech Republic
city: Praha 4
country: Czech Republic
city: Praha 6 - Stresovice
country: Czech Republic
city: Clichy
country: France
city: Creteil
country: France
city: Lille
country: France
city: Lyon
country: France
city: Nancy
country: France
city: Paris
country: France
city: Strasbourg
country: France
city: Toulouse
country: France
city: Duesseldorf
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Herne
country: Germany
city: Homburg/Saar
country: Germany
city: Mainz
country: Germany
city: Munchen
country: Germany
city: Tubingen
country: Germany
city: Athens
country: Greece
city: Larissa
country: Greece
city: Leipzig
country: Greece
city: Thessaloniki
country: Greece
city: Thessaloniki
country: Greece
city: Thessaloniki
country: Greece
city: Bologna
country: Italy
city: Torino
country: Italy
city: Rotterdam
country: Netherlands
city: Auckland
country: New Zealand
city: Hamilton
country: New Zealand
city: Whakatane
country: New Zealand
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Krakow
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Majadahonda
country: Spain
state: Madrid
city: Barcelona
country: Spain
city: Valencia
country: Spain
city: Bursa
country: Turkey
city: Istanbul
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: London
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
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. doi: 10.1002/hep.26686.
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 disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013 Feb 9;381(9865):468-75. doi: 10.1016/S0140-6736(12)61425-1. Epub 2012 Dec 10.
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. Hepatology. 2013 Aug;58(2):505-13. doi: 10.1002/hep.26277. Epub 2013 May 3.
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. Dig Dis Sci. 2015 Jan;60(1):260-8. doi: 10.1007/s10620-014-3336-7. Epub 2014 Sep 2.
citation: 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 Islander chronic hepatitis B patients with high viral load (>/= 9 log10 copies/ml). Liver Int. 2015 Feb;35(2):422-8. doi: 10.1111/liv.12694. Epub 2014 Oct 28.
citation: Buti M, Fung S, Gane E, Afdhal NH, Flisiak R, Gurel S, Flaherty JF, Martins EB, Yee LJ, Dinh P, Bornstein JD, Mani Subramanian G, Janssen HL, George J, Marcellin P. Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years. Hepatol Int. 2015 Apr;9(2):243-50. doi: 10.1007/s12072-015-9614-4. Epub 2015 Mar 13.
citation: Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, Aguilar Schall R, Flaherty JF, Martins EB, Charuworn P, Kitrinos KM, Subramanian GM, Gane E, Marcellin P. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci. 2015 May;60(5):1457-64. doi: 10.1007/s10620-014-3486-7. Epub 2014 Dec 23.
citation: Corsa A, Liu Y, Flaherty JF, Marcellin P, Miller M, Kitrinos KM. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) in HBeAg+ and HBeAg- Patients With Chronic Hepatitis B (CHB) After Eight Years of Treatment [Abstract 1707]. The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 08-10 November; Boston MA.
citation: Marcellin P, Gane EJ, Flisiak R, Trinh HN, Petersen J, Gurel S, et al. Long Term Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Infection is Safe and Well Tolerated and Associated with Durable Virologic Response with no Detectable Resistance: 8 Year Results from Two Phase 3 Trials [Abstract]. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2014 November 7-11; Boston, MA.
citation: Gane EJ, Marcellin P, Sievert W, Trinh HN, Shiffman ML, Washington MK, et al. Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection in Asian Patients is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis [Poster Number 1429]. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 2011 November 4-8; San Francisco, California.
citation: Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, Kitrinos KM, Marcellin P, Gane EJ. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat. 2017 Jan;24(1):68-74. doi: 10.1111/jvh.12613. Epub 2016 Sep 23.
citation: Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, Manns M, Kaita K, Krastev Z, Lee SS, Cathcart AL, Crans G, Op den Brouw M, Jump B, Gaggar A, Flaherty J, Buti M. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 2019 Oct;39(10):1868-1875. doi: 10.1111/liv.14155. Epub 2019 Jul 10.
citation: Buti M, Wong DK, Gane E, Flisiak R, Manns M, Kaita K, Janssen HLA, Op den Brouw M, Jump B, Kitrinos K, Crans G, Flaherty J, Gaggar A, Marcellin P. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials. Lancet Gastroenterol Hepatol. 2019 Apr;4(4):296-304. doi: 10.1016/S2468-1253(19)30015-9. Epub 2019 Feb 20.
citation: Jacobson IM, Washington MK, Buti M, Thompson A, Afdhal N, Flisiak R, Akarca US, Tchernev KG, Flaherty JF, Aguilar Schall R, Myers RP, Subramanian GM, McHutchison JG, Younossi Z, Marcellin P, Patel K. Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1087-1094.e2. doi: 10.1016/j.cgh.2017.01.032. Epub 2017 Feb 12.
citation: Pan CQ, Chan S, Trinh H, Yao A, Bae H, Lou L. Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B. World J Gastroenterol. 2015 May 14;21(18):5524-31. doi: 10.3748/wjg.v21.i18.5524.
citation: 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. doi: 10.1053/j.gastro.2010.10.011. Epub 2010 Oct 16.
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.