Antiviral Efficacy of Switching to ETV Plus TDF

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Bristol-Myers Squibb
Seoul St. Mary's Hospital
The Catholic University of Korea
Soonchunhyang University Hospital
Pusan National University Hospital
Kyungpook National University
Hallym University Medical Center
Chonbuk National University Hospital
Information provided by (Responsible Party):
Sang Hoon Ahn, Yonsei University
ClinicalTrials.gov Identifier:
NCT01597934
First received: May 8, 2012
Last updated: January 30, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Chronic Hepatitis B
Drug: Group A (Zeffix, Sebivo, Hepsera)
Drug: Group B (Baraclude, Viread)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Yonsei University:

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 [ Time Frame: at Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    To compare virologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48

  • serologic efficacy [ Time Frame: Week 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    To compare serologic response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48

  • biochemical efficacy [ Time Frame: Week 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    To compare biochemical response in switching group(Entecavir plus Tenofovir) with those in maintaining group (Lamivudine/Telbivudine plus Adefovir) at Week 48

  • Safety issue [ Time Frame: Week 12, 24, 36, and 48 ] [ Designated as safety issue: Yes ]
    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


Estimated Enrollment: 104
Study Start Date: August 2012
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A:
Maintaining LAM/LdT+ADV combination Lamivudine 100mg / Telbivudine 600mg +Adefovir 10mg
Drug: Group A (Zeffix, Sebivo, Hepsera)
Maintaining LAM/LdT+ADV combination Lamivudine 100mg / Telbivudine 600mg +Adefovir 10mg
Other Names:
  • Zeffix
  • Sebivo
  • Hepsera
Experimental: Group B
Switching to ETV plus TDF combination Entecavir 1.0mg + Tenofovir 300mg
Drug: Group B (Baraclude, Viread)
Switching to ETV plus TDF combination Entecavir 1.0mg + Tenofovir 300mg
Other Names:
  • Baraclude
  • Viread

Detailed Description:
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

  Eligibility

Ages Eligible for Study:   20 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01597934

Sponsors and Collaborators
Yonsei University
Bristol-Myers Squibb
Seoul St. Mary's Hospital
The Catholic University of Korea
Soonchunhyang University Hospital
Pusan National University Hospital
Kyungpook National University
Hallym University Medical Center
Chonbuk National University Hospital
Investigators
Principal Investigator: Sang Hoon Ahn, MD, PhD Yonsei University
  More Information

No publications provided

Responsible Party: Sang Hoon Ahn, Associate Professor, Yonsei University
ClinicalTrials.gov Identifier: NCT01597934     History of Changes
Other Study ID Numbers: AI463-274
Study First Received: May 8, 2012
Last Updated: January 30, 2014
Health Authority: Korea: Institutional Review Board

Keywords provided by Yonsei University:
Chronic hepatitis B
Partial virologic response
YMDD mutation

Additional relevant MeSH terms:
Hepatitis
Hepatitis, Chronic
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepadnaviridae Infections
DNA Virus Infections
Virus Diseases
Hepatitis, Viral, Human
Entecavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 16, 2014