search
Back to results

Antiviral Efficacy of Switching to ETV Plus TDF

Primary Purpose

Chronic Hepatitis B

Status
Unknown status
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Group A (Zeffix, Sebivo, Hepsera)
Group B (Baraclude, Viread)
Sponsored by
Yonsei University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Hepatitis B focused on measuring Chronic hepatitis B, Partial virologic response, YMDD mutation

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. ≥ 20 years of age
  2. History of HBsAg positive for more than 6 months
  3. History of genotypic resistance to LAM or LdT (YMDDm)
  4. Partial responder (HBV DNA ≥ 60 IU/mL) currently receiving antiviral combination rescue therapy for at least 24 weeks of treatment with LAM+ADV or LdT+ADV
  5. Hepatitis B e Antigen(HBeAg)-positive and -negative
  6. Compensated liver disease (Child-Pugh A)
  7. Signed written informed consent after being instructed about the objective and procedure of the clinical study

Exclusion Criteria:

  1. History of genotypic resistance to ADV
  2. Most previous treatment of other than LAM+ADV and LdT+ADV
  3. Subjects with Alanine Aminotransferase(ALT) > 10xUpper Limit of normal(ULN)
  4. Co-infected with hepatitis C virus(HCV) or HIV
  5. Pregnant or lactating woman
  6. Subject who needs long-term administration of drugs including immunosuppressive agents, agents related to high risk in the hepatic/renal toxicity, agents influencing renal excretion
  7. History of liver transplantation or planned for liver transplantation
  8. Subject who was diagnosed malignant tumor and has been receiving chemotherapy
  9. Subject who has HCC history or who shows potential hepatocellular carcinoma (HCC) finding such as suspicious region in the radiologic exam(abdominal US or CT) or serum Alpha Feto Protein(AFP) elevation
  10. Renal Insufficiency (CLcr < 50ml/min based on Cockcroft-Gault equation considering weight, ages and serum creatinine)
  11. Subject who has a liver disease other than chronic hepatitis B (e.g. hemochromatosis, Wilson's disease, alcoholic liver disease, nonalcoholic fatty liver disease, alpha 1-antitrypsin deficiency etc.)
  12. Subject who has a history of hypersensitivity to study drug or its ingredients
  13. Subject who is involved in other clinical trial within 60 days prior to study entry
  14. Subject who the investigator deems inappropriate to participate in this study

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Group A:

    Group B

    Arm Description

    Maintaining LAM/LdT+ADV combination Lamivudine 100mg / Telbivudine 600mg +Adefovir 10mg

    Switching to ETV plus TDF combination Entecavir 1.0mg + Tenofovir 300mg

    Outcomes

    Primary Outcome Measures

    The proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time PCR at Week 48
    To compare the proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) in switching group(Entecavir plus Tenofovir) with that in maintaining group(Lamivudine/Telbivudine plus Adefovir) by real-time Polymerase chain reaction(PCR) at Week 48

    Secondary Outcome Measures

    Virologic efficacy
    To compare virologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    serologic efficacy
    To compare serologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    biochemical efficacy
    To compare biochemical response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    Safety issue
    To compare safety issue in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48 - severity of adverse event

    Full Information

    First Posted
    May 8, 2012
    Last Updated
    January 30, 2014
    Sponsor
    Yonsei University
    Collaborators
    Bristol-Myers Squibb, Seoul St. Mary's Hospital, The Catholic University of Korea, Soonchunhyang University Hospital, Pusan National University Hospital, Kyungpook National University Hospital, Hallym University Medical Center, Chonbuk National University Hospital
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT01597934
    Brief Title
    Antiviral Efficacy of Switching to ETV Plus TDF
    Official Title
    A Randomized, Multicenter, Prospective Study to Compare Antiviral Efficacy and Safety of Switching to ETV Plus TDF Versus Maintaining LAM/LDT Plus ADF Combination in CHC With PVR to LAM/LDF Plus ADF Combination Rescue Therapy for YMDD Mutation
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2014
    Overall Recruitment Status
    Unknown status
    Study Start Date
    August 2012 (undefined)
    Primary Completion Date
    May 2014 (Anticipated)
    Study Completion Date
    May 2014 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Yonsei University
    Collaborators
    Bristol-Myers Squibb, Seoul St. Mary's Hospital, The Catholic University of Korea, Soonchunhyang University Hospital, Pusan National University Hospital, Kyungpook National University Hospital, Hallym University Medical Center, Chonbuk National University Hospital

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Switching to Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will result in faster and greater antiviral activity and lower rates of resistance emergence over maintaining Lamivudine(LAM)/Telbivudine(LdT)+Adefovir(ADV) combination in partial responders to LAM/LdT+ADV rescue therapy. Earlier switching to combination with the most potent regimen will be more effective to achieve virologic response(VR) and prevent further resistance emergence. All subjects will orally take assigned drugs once daily for 48 weeks. All subjects will be assessed at baseline and every three months thereafter. Evaluations at each visit will include vital signs, physical examinations, laboratory tests, HBV DNA levels and adverse events. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.
    Detailed Description
    As TDF has not been approved yet in Korea, current KASL practice guideline generally recommends to add ADV in LAM-resistant or LdT-resistant patients. However, several local literatures reported a substantial proportion of patients treated with LAM plus ADV combination therapy showed a persistently inadequate or partial virologic response('VR') and YMDDm still maintained in spite of under rescue combination therapy. Due to the unavailability of TDF in Korea, ETV plus ADV combination has being considered a better salvage therapy with non-overlapping cross-resistance profiles in pts who fail to LAM plus ADV rescue therapy and local report demonstrated that the rate of VR was significantly higher with ETV+ADV switching group than LAM+ADV continuation group in partial responder to LAM plus ADV combination rescue therapy for LAM resistance. Hence, more earlier combination therapy with the most potent Nucleoside and Nucleotide analogue would be a promising salvage treatment for previous NA treatment failures but comparative prospective trials are limited. Therefore, this study will investigate the greater effectiveness and safety of switching to the most potent combination versus maintaining LAM(or LdT) plus ADV and also compare the rate of VR based on the HBV DNA cut-off level at switching - more than and less than 20,000 IU/mL. All subjects will orally take assigned drugs once daily for 48 weeks. All subjects will be assessed at baseline and every three months thereafter. Evaluations at each visit will include vital signs, physical examinations, laboratory tests, HBV DNA levels and adverse events. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Chronic Hepatitis B
    Keywords
    Chronic hepatitis B, Partial virologic response, YMDD mutation

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    104 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Group A:
    Arm Type
    Active Comparator
    Arm Description
    Maintaining LAM/LdT+ADV combination Lamivudine 100mg / Telbivudine 600mg +Adefovir 10mg
    Arm Title
    Group B
    Arm Type
    Experimental
    Arm Description
    Switching to ETV plus TDF combination Entecavir 1.0mg + Tenofovir 300mg
    Intervention Type
    Drug
    Intervention Name(s)
    Group A (Zeffix, Sebivo, Hepsera)
    Other Intervention Name(s)
    Zeffix, Sebivo, Hepsera
    Intervention Description
    Maintaining LAM/LdT+ADV combination Lamivudine 100mg / Telbivudine 600mg +Adefovir 10mg
    Intervention Type
    Drug
    Intervention Name(s)
    Group B (Baraclude, Viread)
    Other Intervention Name(s)
    Baraclude, Viread
    Intervention Description
    Switching to ETV plus TDF combination Entecavir 1.0mg + Tenofovir 300mg
    Primary Outcome Measure Information:
    Title
    The proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time PCR at Week 48
    Description
    To compare the proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) in switching group(Entecavir plus Tenofovir) with that in maintaining group(Lamivudine/Telbivudine plus Adefovir) by real-time Polymerase chain reaction(PCR) at Week 48
    Time Frame
    at Week 48
    Secondary Outcome Measure Information:
    Title
    Virologic efficacy
    Description
    To compare virologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    Time Frame
    Week 12, 24, 36, and 48
    Title
    serologic efficacy
    Description
    To compare serologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    Time Frame
    Week 12, 24, 36, and 48
    Title
    biochemical efficacy
    Description
    To compare biochemical response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48
    Time Frame
    Week 12, 24, 36, and 48
    Title
    Safety issue
    Description
    To compare safety issue in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48 - severity of adverse event
    Time Frame
    Week 12, 24, 36, and 48

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    20 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: ≥ 20 years of age History of HBsAg positive for more than 6 months History of genotypic resistance to LAM or LdT (YMDDm) Partial responder (HBV DNA ≥ 60 IU/mL) currently receiving antiviral combination rescue therapy for at least 24 weeks of treatment with LAM+ADV or LdT+ADV Hepatitis B e Antigen(HBeAg)-positive and -negative Compensated liver disease (Child-Pugh A) Signed written informed consent after being instructed about the objective and procedure of the clinical study Exclusion Criteria: History of genotypic resistance to ADV Most previous treatment of other than LAM+ADV and LdT+ADV Subjects with Alanine Aminotransferase(ALT) > 10xUpper Limit of normal(ULN) Co-infected with hepatitis C virus(HCV) or HIV Pregnant or lactating woman Subject who needs long-term administration of drugs including immunosuppressive agents, agents related to high risk in the hepatic/renal toxicity, agents influencing renal excretion History of liver transplantation or planned for liver transplantation Subject who was diagnosed malignant tumor and has been receiving chemotherapy Subject who has HCC history or who shows potential hepatocellular carcinoma (HCC) finding such as suspicious region in the radiologic exam(abdominal US or CT) or serum Alpha Feto Protein(AFP) elevation Renal Insufficiency (CLcr < 50ml/min based on Cockcroft-Gault equation considering weight, ages and serum creatinine) Subject who has a liver disease other than chronic hepatitis B (e.g. hemochromatosis, Wilson's disease, alcoholic liver disease, nonalcoholic fatty liver disease, alpha 1-antitrypsin deficiency etc.) Subject who has a history of hypersensitivity to study drug or its ingredients Subject who is involved in other clinical trial within 60 days prior to study entry Subject who the investigator deems inappropriate to participate in this study
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Sang Hoon Ahn, MD, PhD
    Organizational Affiliation
    Yonsei University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    32460460
    Citation
    Woo HY, Park JY, Bae SH, Kim CW, Jang JY, Tak WY, Kim DJ, Kim IH, Heo J, Ahn SH. Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response. Clin Mol Hepatol. 2020 Jul;26(3):352-363. doi: 10.3350/cmh.2019.0044n. Epub 2020 May 28.
    Results Reference
    derived

    Learn more about this trial

    Antiviral Efficacy of Switching to ETV Plus TDF

    We'll reach out to this number within 24 hrs