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

NCT00117676 | Completed Phase 3 Results DMC

• 2 other identifiers: GS-US-174-01022004-005119-27
• Study Type: interventional
• Target: 382
• Locations: 15 countries
• Sites: 80

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.

Conditions

Chronic Hepatitis B

Keywords

tenofovir; adefovir; hepatitis B virus; HBeAg Negative

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (31)

• Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

  Week 48

• Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96

  Week 96

• 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

• Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

  Weeks 432 and 480

• Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

  Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

Study Arms (2)

TDF-TDF

EXPERIMENTAL

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.

Drug: TDF; Drug: ADV placebo; Drug: FTC/TDF

ADV-TDF

ACTIVE COMPARATOR

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.

Drug: TDF; Drug: ADV; Drug: TDF placebo; Drug: FTC/TDF

Interventions

TDF DRUG

300 mg tablet administered orally once daily

Also known as: Viread®

ADV-TDF; TDF-TDF

ADV DRUG

10 mg tablet administered orally once daily

Also known as: Hepsera®

ADV-TDF

TDF placebo DRUG

Tablet administered orally once daily

ADV-TDF

ADV placebo DRUG

Tablet administered orally once daily

TDF-TDF

FTC/TDF DRUG

200/300 mg fixed-dose combination (FDC) tablet administered orally once daily

Also known as: Truvada®

ADV-TDF; TDF-TDF

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for at least 6 months.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (80)

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La Jolla, California, 92037, United States

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Pasadena, California, 91105, United States

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San Diego, California, 92105, United States

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San Diego, California, 92123, United States

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San Francisco, California, 94115, United States

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San Jose, California, 95116, United States

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Atlanta, Georgia, 30308, United States

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Honolulu, Hawaii, 96817, United States

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Boston, Massachusetts, 02215, United States

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Ann Arbor, Michigan, 48109, United States

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Detroit, Michigan, 48202, United States

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St Louis, Missouri, 63104, United States

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Flushing, New York, 11355, United States

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New York, New York, 10003, United States

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New York, New York, 10029, United States

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Falls Church, Virginia, 22042, United States

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Richmond, Virginia, 23298, United States

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Camperdown, New South Wales, 2050, Australia

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Concord, New South Wales, 2139, Australia

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Westmead, New South Wales, 2145, Australia

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Woolloongabba, Queensland, 40102, Australia

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Clayton, Victoria, 3168, Australia

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Fitzroy, Victoria, 3065, Australia

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Heidelberg, Victoria, 3084, Australia

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Prahan, Victoria, 3004, Australia

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Sofia, 1407, Bulgaria

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Sofia, 1431, Bulgaria

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Varna, 9010, Bulgaria

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Calgary, Alberta, T2N 4Z6, Canada

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Vancouver, British Columbia, V5Z1H2, Canada

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Winnipeg, Manitoba, R3E3P4, Canada

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Toronto, Ontario, M5T 2S8, Canada

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Brno, 62500, Czechia

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Hradec Králové, Czechia

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Prague, 14021, Czechia

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Praha 6 - Stresovice, 169 02, Czechia

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Clichy, 92110, France

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Créteil, 94010, France

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Lille, 59037, France

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Lyon, 69317, France

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Nancy, 54500, France

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Paris, 75651, France

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Strasbourg, 67901, France

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Toulouse, 31059, France

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Düsseldorf, 40237, Germany

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Frankfurt, 60590, Germany

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Hamburg, 20099, Germany

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Hanover, 30623, Germany

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Herne, 44623, Germany

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Homburg/Saar, 66421, Germany

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Mainz, 55131, Germany

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München, 81377, Germany

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Tübingen, 72076, Germany

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Athens, 11526, Greece

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Larissa, 41110, Greece

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Leipzig, 04103, Greece

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Thessaloniki, 54636, Greece

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Thessaloniki, 56429, Greece

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Thessaloniki, 57010, Greece

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Bologna, 40138, Italy

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Torino, 10134, Italy

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Rotterdam, 3015, Netherlands

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Auckland, New Zealand

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Hamilton, New Zealand

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Whakatane, New Zealand

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Bialystok, 15-540, Poland

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Bydgoszcz, 85-030, Poland

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Chorzów, 41-500, Poland

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Krakow, 31-501, Poland

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Warsaw, 01-201, Poland

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Wroclaw, 50-136, Poland

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Majadahonda, Madrid, 28222, Spain

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Barcelona, 08035, Spain

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Valencia, 46009, Spain

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Bursa, Turkey (Türkiye)

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Istanbul, 34098, Turkey (Türkiye)

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Istanbul, 34899, Turkey (Türkiye)

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Izmir, Turkey (Türkiye)

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London, NW1 2BU, United Kingdom

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London, WC1E 6HX, United Kingdom

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Related Publications (17)

• 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.

  PMID: 23939953 RESULT

• 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.

  PMID: 23234725 RESULT

• 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.

  PMID: 23364953 RESULT

• 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.

  PMID: 25179493 RESULT

• 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.

  PMID: 25277773 RESULT

• 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.

  PMID: 25788199 RESULT

• 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.

  PMID: 25532501 RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  PMID: 27658343 RESULT

• 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.

  PMID: 31136052 DERIVED

• 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.

  PMID: 30795958 DERIVED

• 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.

  PMID: 28215615 DERIVED

• 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.

  PMID: 25987775 DERIVED

• 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.

  PMID: 20955704 DERIVED

• 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.

  PMID: 19052126 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic; Hepatitis B

Interventions

Tenofovir; adefovir dipivoxil; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.

ClinicalTrialDisclosures@gilead.com

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2005
• First Posted: July 8, 2005
• Study Start: February 1, 2005
• Primary Completion: April 1, 2007
• Study Completion: January 1, 2016
• Last Updated: March 7, 2017
• Results First Posted: May 19, 2010

Record last verified: 2017-01

Locations

NL (1); DE (9); CA (4); FR (8); AU (8); GR (6); ES (3); CZ (4); GB (2); PL (6); BU (3); NZ (3); IT (2); US (17); TU (4)