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出境医 / 临床实验 / Tenofovir Alafenamide Versus Entecavir for the Treatment of Chronic Hepatitis B

Tenofovir Alafenamide Versus Entecavir for the Treatment of Chronic Hepatitis B

Study Description
Brief Summary:
To compare the efficacy and renal safety of tenofovir alafenamide (TAF) versus entecavir (ETV) in the chronic hepatitis B patients.

Condition or disease Intervention/treatment Phase
Hepatitis B Viral Hepatitis Drug: Tenofovir alafenamide Drug: Entecavir Phase 4

Detailed Description:
With high antiviral potency and low drug resistance rate, both ETV and tenofovir disoproxil fumarate (TDF) have been recommended as the first-line antiviral therapy for chronic hepatitis B (CHB). However, risk of renal dysfunction remains an issue in TDF long-term therapy. Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir and is formulated to deliver the active metabolite to target cells more efficiently than TDF at lower doses, thereby reducing systemic exposure to tenofovir. Importantly, TAF had improved renal safety as compared to TDF. TAF has been approved for treating CHB since 2017; however, it is still unknown whether the efficacy and renal safety of TAF is compatible to those of ETV. The investigators aim to conduct an open label, randomized controlled trial comparing TAF with ETV for assessing their efficacy and renal safety in CHB patients. The eligible CHB patients are randomly assigned (1:1) to receive TAF or ETV. After allocation to TAF group or ETV group, study subjects will receive therapy for 3 years (144 weeks).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 420 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The eligible chronic hepatitis B patients are randomly assigned (1:1) to receive once-daily oral doses of tenofovir alafenamide 25 mg or entecavir 0.5mg.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Tenofovir Alafenamide Versus Entecavir for the Treatment of Chronic Hepatitis B: An Open Label, Randomized Controlled Trial
Actual Study Start Date : August 19, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2025
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Tenofovir alafenamide group
Study subjects will receive tenofovir alafenamide 25 mg/tab once daily for 3 years (144 weeks).
 Drug: Tenofovir alafenamide
Tenofovir alafenamide 25mg/tab once daily
Other Name: Vemlidy
Active Comparator: Entecavir group
Study subjects will receive entecavir 0.5 mg/tab once daily for 3 years (144 weeks).
 Drug: Entecavir
Entecavir 0.5mg/tab once daily
Other Name: Baraclude
Outcome Measures
Primary Outcome Measures :
  1. HBV viral suppression [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with hepatitis B virus(HBV) -DNA suppression

  2. Renal safety: Change of estimated glomerular filtration rate [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    Change of estimated glomerular filtration rate


Secondary Outcome Measures :
  1. Normalization alanine aminotransferase (ALT) [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with ALT normalization

  2. HBsAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBsAg loss

  3. HBeAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBeAg loss

  4. Bone mineral density [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    change of bone mineral density


Eligibility Criteria
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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients more than 20 years old
  2. Chronic hepatitis B patients
  3. Patients who were indicated for hepatitis B virus antiviral therapy

Exclusion Criteria:

  1. Decompensated liver disease (Child-Pugh B &C)
  2. End stage renal disease (eGRF < 15 ml/min/1.73m2)
  3. Prior use of nucleot(s)ide analogues for chronic hepatitis B
  4. Prior use of interferon for chronic hepatitis B within six months
  5. Known history of human immunodeficiency virus or hepatitis C virus co-infection
  6. Concurrent other uncontrolled malignancy
  7. Women in pregnancy or lactation
  8. Cannot conform to the study protocol of this study
Contacts and Locations

Contacts
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Contact: Teng-Yu Lee, MD, PhD 886-4-23592525 ext 3301 tylee@vghtc.gov.tw
Contact: Hsin-Ju Tsai, MD 886-4-23592525 ext 3301 a9194024@hotmail.com

Locations
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Taiwan
Taichung Veterans General Hospital Recruiting
Taichung, Taiwan
Contact: Teng-Yu Lee, MD, PhD    886-4-23592525 ext 3301    tylee@vghtc.gov.tw   
Sponsors and Collaborators
Taichung Veterans General Hospital
Investigators
Layout table for investigator information
Study Chair: Teng-Yu Lee, MD, PhD Taichung Veterans General Hospital
Tracking Information
First Submitted Date  ICMJE April 28, 2019
First Posted Date  ICMJE May 1, 2019
Last Update Posted Date October 8, 2020
Actual Study Start Date  ICMJE August 19, 2019
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • HBV viral suppression [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with hepatitis B virus(HBV) -DNA suppression
  • Renal safety: Change of estimated glomerular filtration rate [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    Change of estimated glomerular filtration rate
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 6, 2020)
  • Normalization alanine aminotransferase (ALT) [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with ALT normalization
  • HBsAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBsAg loss
  • HBeAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBeAg loss
  • Bone mineral density [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    change of bone mineral density
Original Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • Normalization alanine aminotransferase (ALT) [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with ALT normalization
  • HBsAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBsAg loss
  • HBeAg loss [ Time Frame: After 48-week therapy of Tenofovir alafenamide or entecavir ]
    proportion of patients with HBeAg loss
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tenofovir Alafenamide Versus Entecavir for the Treatment of Chronic Hepatitis B
Official Title  ICMJE Tenofovir Alafenamide Versus Entecavir for the Treatment of Chronic Hepatitis B: An Open Label, Randomized Controlled Trial
Brief Summary To compare the efficacy and renal safety of tenofovir alafenamide (TAF) versus entecavir (ETV) in the chronic hepatitis B patients.
Detailed Description With high antiviral potency and low drug resistance rate, both ETV and tenofovir disoproxil fumarate (TDF) have been recommended as the first-line antiviral therapy for chronic hepatitis B (CHB). However, risk of renal dysfunction remains an issue in TDF long-term therapy. Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir and is formulated to deliver the active metabolite to target cells more efficiently than TDF at lower doses, thereby reducing systemic exposure to tenofovir. Importantly, TAF had improved renal safety as compared to TDF. TAF has been approved for treating CHB since 2017; however, it is still unknown whether the efficacy and renal safety of TAF is compatible to those of ETV. The investigators aim to conduct an open label, randomized controlled trial comparing TAF with ETV for assessing their efficacy and renal safety in CHB patients. The eligible CHB patients are randomly assigned (1:1) to receive TAF or ETV. After allocation to TAF group or ETV group, study subjects will receive therapy for 3 years (144 weeks).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The eligible chronic hepatitis B patients are randomly assigned (1:1) to receive once-daily oral doses of tenofovir alafenamide 25 mg or entecavir 0.5mg.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatitis B
  • Viral Hepatitis
Intervention  ICMJE
  • Drug: Tenofovir alafenamide
    Tenofovir alafenamide 25mg/tab once daily
    Other Name: Vemlidy
  • Drug: Entecavir
    Entecavir 0.5mg/tab once daily
    Other Name: Baraclude
Study Arms  ICMJE
  • Active Comparator: Tenofovir alafenamide group
    Study subjects will receive tenofovir alafenamide 25 mg/tab once daily for 3 years (144 weeks).
    Intervention: Drug: Tenofovir alafenamide
  • Active Comparator: Entecavir group
    Study subjects will receive entecavir 0.5 mg/tab once daily for 3 years (144 weeks).
    Intervention: Drug: Entecavir
Publications *
  • Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006 Oct;45(4):529-38. Epub 2006 Jun 23.
  • Chen DS, Sung JL. Hepatitis B virus infection on Taiwan. N Engl J Med. 1977 Sep 22;297(12):668-9.
  • Ni YH, Chang MH, Wu JF, Hsu HY, Chen HL, Chen DS. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol. 2012 Oct;57(4):730-5. doi: 10.1016/j.jhep.2012.05.021. Epub 2012 Jun 2.
  • Chiang CJ, Yang YW, Chen JD, You SL, Yang HI, Lee MH, Lai MS, Chen CJ. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology. 2015 Apr;61(4):1154-62. doi: 10.1002/hep.27630. Epub 2015 Feb 10.
  • Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800.
  • European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.
  • Kang L, Pan J, Wu J, Hu J, Sun Q, Tang J. Anti-HBV Drugs: Progress, Unmet Needs, and New Hope. Viruses. 2015 Sep 15;7(9):4960-77. doi: 10.3390/v7092854. Review.
  • Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1011-20. Erratum in: N Engl J Med. 2006 Apr 27;354(17):1863.
  • 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.
  • van Bömmel F, Wünsche T, Mauss S, Reinke P, Bergk A, Schürmann D, Wiedenmann B, Berg T. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004 Dec;40(6):1421-5.
  • Tsai HJ, Chuang YW, Lee SW, Wu CY, Yeh HZ, Lee TY. Using the chronic kidney disease guidelines to evaluate the renal safety of tenofovir disoproxil fumarate in hepatitis B patients. Aliment Pharmacol Ther. 2018 Jun;47(12):1673-1681. doi: 10.1111/apt.14682. Epub 2018 Apr 25.
  • Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013 Jun 4;158(11):825-30. doi: 10.7326/0003-4819-158-11-201306040-00007.
  • Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22. Erratum in: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
  • Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. doi: 10.1016/S2468-1253(16)30107-8. Epub 2016 Sep 22. Erratum in: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 30, 2019) 		420
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2025
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients more than 20 years old
  2. Chronic hepatitis B patients
  3. Patients who were indicated for hepatitis B virus antiviral therapy

Exclusion Criteria:

  1. Decompensated liver disease (Child-Pugh B &C)
  2. End stage renal disease (eGRF < 15 ml/min/1.73m2)
  3. Prior use of nucleot(s)ide analogues for chronic hepatitis B
  4. Prior use of interferon for chronic hepatitis B within six months
  5. Known history of human immunodeficiency virus or hepatitis C virus co-infection
  6. Concurrent other uncontrolled malignancy
  7. Women in pregnancy or lactation
  8. Cannot conform to the study protocol of this study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Teng-Yu Lee, MD, PhD 886-4-23592525 ext 3301 tylee@vghtc.gov.tw
Contact: Hsin-Ju Tsai, MD 886-4-23592525 ext 3301 a9194024@hotmail.com
Listed Location Countries  ICMJE Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03933384
Other Study ID Numbers  ICMJE CF18341A
106DHA0500150 ( Other Grant/Funding Number: Taichung Veterans General Hospital, Taiwan )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Teng-Yu Lee, Taichung Veterans General Hospital
Study Sponsor  ICMJE Taichung Veterans General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Teng-Yu Lee, MD, PhD Taichung Veterans General Hospital
PRS Account Taichung Veterans General Hospital
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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