Entecavir Plus Tenofovir Combination in Subjects With Multi-drug Resistant Chronic Hepatitis B Virus Infection

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Bristol-Myers Squibb
Seoul St. Mary's Hospital
The Catholic University of Korea
Information provided by (Responsible Party):
Sang Hoon Ahn, Yonsei University
ClinicalTrials.gov Identifier:
NCT01594905
First received: May 7, 2012
Last updated: January 30, 2014
Last verified: January 2014
  Purpose

Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will show effective antiviral activity and prevent further development of antiviral resistance in hepatitis B e antigen(HBeAg)-positive or -negative Chronic Hepatitis B(CHB) patients who experienced multidrug resistance

All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. 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: Entecavir + Tenofovir (MDR group)
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Open-label, Prospective Study to Evaluate Antiviral Efficacy and Safety of Entecavir Plus Tenofovir Combination in Subjects With Multi-drug Resistant Chronic Hepatitis B Virus Infection

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 evaluate the proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time Polymerase chain reaction(PCR) at Week 48 after Entecavir plus Tenofovir combination therapy


Secondary Outcome Measures:
  • Virologic, serologic, biochemical efficacy and safety profile, as measured by the incidence of clinical adverse events and laboratory abnormalities including renal marker [ Time Frame: Week 4, 12, 24, 36, and 48 ] [ Designated as safety issue: Yes ]
    To evaluate virologic, serologic and biochemical response and safety of Entecavir plus Tenofovir combination therapy for 48 weeks


Estimated Enrollment: 90
Study Start Date: August 2012
Estimated Study Completion Date: April 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Entecavir 1.0mg + Tenofovir 300mg
All subjects will orally take investigational drugs once daily for 48 weeks.
Drug: Entecavir + Tenofovir (MDR group)
Entecavir 1.0mg + Tenofovir 300mg
Other Names:
  • Entecavir 1.0mg - Braclude
  • Tenofovir 300mg - Viread

Detailed Description:
  1. It has been one of unsolved issues and unmet needs in CHB management to develop an optimal combination regimen to manage multidrug resistant HBV characterized by selection of variants with two or more classes A of signature genotypic resistant mutations1-3
  2. Currently adding on Adefovir(ADV) has been generally recommended in Lamivudine(LAM)- or Telbivudine(LdT)-resistant patients but little is known about the optimal management of CHB patients who developed multidrug resistance4
  3. Recent report has shown that the combination of LAM plus ADV did not suppress HBV DNA effectively in CHB patients with resistance mutations to both drugs. Only 12.2% of these pts achieved virologic response(VR; HBV DNA <60 IU/mL) at 12 months and multivariable analysis showed that LAM+ADV group and the presence of the rtA181V/T mutation were independently associated with a decreased rate of virologic response (HBV DNA <2,000 IU/ml) at 12 months4
  4. ETV has been demonstrated to be effective in patients with ADV resistance but not in patients with proven YMDD mutation. In contrast, TDF has been shown to be effective in patients with YMDD mutation but not necessarily in all patients with ADV resistance.1-3
  5. Thus theoretically, the combination of the most potent nucleoside analogue and nucleotide analogue with non-overlapping resistance profiles, such as ETV plus TDF, is expected to be a promising salvage treatment for multidrug resistant HBV but clinical evidence is limited
  6. Therefore, this study will explore that adequate management of multidrug resistant patients using ETV plus TDF combination may lead to faster and greater viral suppression and prevent further emergence of antiviral resistance

All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. 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. Subject who has a history of genotypic resistance to NAs from two different classes A
  4. Detectable HBV DNA (≥ 60 IU/mL) while on any rescue treatment regimen for at least 24 weeks
  5. 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. Subjects with Alanine Aminotransferase(ALT) > 10xUpper Limit of normal(ULN)
  2. Co-infected with hepatitis C virus(HCV) or HIV
  3. Pregnant or lactating woman
  4. 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
  5. History of liver transplantation or planned for liver transplantation
  6. Subject who was diagnosed malignant tumor and has been receiving chemotherapy
  7. Subject who has hepatocellular carcinoma(HCC) history or who shows potential HCC finding such as suspicious region in the radiologic exam(abdominal US or CT) or serum Alpha Feto Protein(AFP) elevation
  8. Renal Insufficiency (CLcr < 50ml/min based on Cockcroft-Gault equation considering weight, ages and serum creatinine)
  9. Patient 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.)
  10. Subject who has a history of hypersensitivity to study drug or its ingredients
  11. Subject who is involved in other clinical trial within 60 days prior to study entry
  12. 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: NCT01594905

Sponsors and Collaborators
Yonsei University
Bristol-Myers Squibb
Seoul St. Mary's Hospital
The Catholic University of Korea
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: NCT01594905     History of Changes
Other Study ID Numbers: AI463-273
Study First Received: May 7, 2012
Last Updated: January 30, 2014
Health Authority: Korea: Institutional Review Board

Keywords provided by Yonsei University:
To explore
adequate management
CHB
Multidrug resistance

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Encephalitis, Herpes Simplex
Virus Diseases
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Encephalitis, Viral
Encephalitis
Central Nervous System Viral Diseases
Herpesviridae Infections
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Tenofovir
Tenofovir disoproxil
Entecavir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 29, 2014