A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
NCT ID: NCT00117676
Last Updated: 2017-03-07
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
382 participants
INTERVENTIONAL
2005-02-28
2016-01-31
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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TDF-TDF
TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.
TDF
300 mg tablet administered orally once daily
ADV placebo
Tablet administered orally once daily
FTC/TDF
200/300 mg fixed-dose combination (FDC) tablet administered orally once daily
ADV-TDF
ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
TDF
300 mg tablet administered orally once daily
ADV
10 mg tablet administered orally once daily
TDF placebo
Tablet administered orally once daily
FTC/TDF
200/300 mg fixed-dose combination (FDC) tablet administered orally once daily
Interventions
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TDF
300 mg tablet administered orally once daily
ADV
10 mg tablet administered orally once daily
TDF placebo
Tablet administered orally once daily
ADV placebo
Tablet administered orally once daily
FTC/TDF
200/300 mg fixed-dose combination (FDC) tablet administered orally once daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
18 Years
69 Years
ALL
No
Sponsors
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Gilead Sciences
INDUSTRY
Responsible Party
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Principal Investigators
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Gilead Study Director
Role: STUDY_DIRECTOR
Gilead Sciences
Locations
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La Jolla, California, United States
Pasadena, California, United States
San Diego, California, United States
San Diego, California, United States
San Francisco, California, United States
San Jose, California, United States
Atlanta, Georgia, United States
Honolulu, Hawaii, United States
Boston, Massachusetts, United States
Ann Arbor, Michigan, United States
Detroit, Michigan, United States
St Louis, Missouri, United States
Flushing, New York, United States
New York, New York, United States
New York, New York, United States
Falls Church, Virginia, United States
Richmond, Virginia, United States
Camperdown, New South Wales, Australia
Concord, New South Wales, Australia
Westmead, New South Wales, Australia
Woolloongabba, Queensland, Australia
Clayton, Victoria, Australia
Fitzroy, Victoria, Australia
Heidelberg, Victoria, Australia
Prahan, Victoria, Australia
Sofia, , Bulgaria
Sofia, , Bulgaria
Varna, , Bulgaria
Calgary, Alberta, Canada
Vancouver, British Columbia, Canada
Winnipeg, Manitoba, Canada
Toronto, Ontario, Canada
Brno, , Czechia
Hradec Králové, , Czechia
Prague, , Czechia
Praha 6 - Stresovice, , Czechia
Clichy, , France
Créteil, , France
Lille, , France
Lyon, , France
Nancy, , France
Paris, , France
Strasbourg, , France
Toulouse, , France
Düsseldorf, , Germany
Frankfurt, , Germany
Hamburg, , Germany
Hanover, , Germany
Herne, , Germany
Homburg/Saar, , Germany
Mainz, , Germany
München, , Germany
Tübingen, , Germany
Athens, , Greece
Larissa, , Greece
Leipzig, , Greece
Thessaloniki, , Greece
Thessaloniki, , Greece
Thessaloniki, , Greece
Bologna, , Italy
Torino, , Italy
Rotterdam, , Netherlands
Auckland, , New Zealand
Hamilton, , New Zealand
Whakatane, , New Zealand
Bialystok, , Poland
Bydgoszcz, , Poland
Chorzów, , Poland
Krakow, , Poland
Warsaw, , Poland
Wroclaw, , Poland
Majadahonda, Madrid, Spain
Barcelona, , Spain
Valencia, , Spain
Bursa, , Turkey (Türkiye)
Istanbul, , Turkey (Türkiye)
Istanbul, , Turkey (Türkiye)
Izmir, , Turkey (Türkiye)
London, , United Kingdom
London, , United Kingdom
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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2004-005119-27
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
GS-US-174-0102
Identifier Type: -
Identifier Source: org_study_id
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