search
Back to results

Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B (IN-US-0202)

Primary Purpose

Chronic Viral Hepatitis B Without Delta-agent

Status
Completed
Phase
Phase 4
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Tenofovir
Tenofovir
Entecavir
Sponsored by
Asan Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Viral Hepatitis B Without Delta-agent focused on measuring Resistance of Entecavir

Eligibility Criteria

20 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: All of below

  • Compensated liver disease (Child-Pugh class A)
  • HBsAg positive at least 6 months or more
  • HBeAg positive or negative
  • Confirmation of resistance mutations to Lamivudine (rtM204V/I and/or rtL180M) and ETV (rtT184 or rtS202 or rtM250) at any time before screening
  • Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
  • Patient is ambulatory.
  • Patient is willing and able to comply with the study drug regimen and all other study requirements.
  • The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria: Any of below

  • Patient previously received TDF for more than 1 week
  • Patient had documented resistance mutations to ADV at any time before or at screening
  • Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
  • Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study.
  • Patient has concomitant other chronic viral infection (HCV or HIV)
  • Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
  • Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
  • Patient is currently abusing alcohol (more than 40 g/day) or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years.
  • Patient is pregnant or breastfeeding or willing to be pregnant
  • Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
  • A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
  • Clinical signs of decompensated liver disease as indicated by any one of the following:

    1. serum bilirubin > 3 mg/dL
    2. prothrombin time > 6 seconds prolonged or INR >1.5
    3. serum albumin < 2.8 g/dL
    4. History of ascites, variceal hemorrhage, or hepatic encephalopathy
    5. Child-Pugh score ≥7

Sites / Locations

  • Asan Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tenofovir monotherapy

Tenofovir plus Entecavir combination

Arm Description

Tenofovir 300 mg/day orally

Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally

Outcomes

Primary Outcome Measures

Proportion of patients with complete virologic response
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)

Secondary Outcome Measures

Changes in serum HBV DNA levels
Changes in serum HBV DNA levels during 48 weeks of treatment
Proportion of patients with normal ALT
Proportion of patients with HBe-Ag loss or seroconversion
Proportion of patients with resistance mutations to Entecavir or Tenofovir
The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
Proportion of patients with virologic breakthrough
Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment
Proportion of patients with complete virologic response
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)

Full Information

First Posted
July 10, 2012
Last Updated
May 8, 2018
Sponsor
Asan Medical Center
Collaborators
Samsung Medical Center, Konkuk University Medical Center, Korea University Guro Hospital, Seoul National University Hospital
search

1. Study Identification

Unique Protocol Identification Number
NCT01639092
Brief Title
Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B
Acronym
IN-US-0202
Official Title
A Multicenter Randomized Controlled Open-label Trial of Tenofovir vs. Tenofovir Plus Entecavir in Chronic Hepatitis B Patients With Genotypic Resistance to Entecavir and Partial Virologic Response to Ongoing Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
September 28, 2012 (Actual)
Primary Completion Date
March 29, 2018 (Actual)
Study Completion Date
March 29, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Asan Medical Center
Collaborators
Samsung Medical Center, Konkuk University Medical Center, Korea University Guro Hospital, Seoul National University Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Until recently, however, many patients commenced antiviral treatment with inferior NAs prior to the availability of TDF or ETV, such as lamivudine (LAM) which has a low genetic barrier to resistance. ETV resistance increase up to 51% of patients after 5 years of ETV treatment in lamivudine-refractory patients. Resistance to ETV appears to occur through a two-hit mechanism with initial selection of M204V/I mutation followed by amino acid substitutions at rtT184, rtS202, or rtM250. In vitro studies showed that ETV-resistant mutations are susceptible to TDF, but there are little clinical data on the efficacy of TDF monotherapy in patients with ETV-resistance. On the other hand, there was a retrospective cohort study reporting that, with the combination of TDF and ETV, most of patients became HBV DNA undetectable after median 6 months of treatment. Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV-resistance. Thus, there is no consistent treatment recommendation for patients with ETV-resistance. In this clinical trial, the investigators will clarify whether tenofovir monotherapy is as effective as tenofovir plus entecavir in inducing complete virologic response in CHB patients with genotypic resistance to ETV and partial virologic response to ongoing treatment.
Detailed Description
A multi-center randomized active-controlled open-label trial Patients will be randomly assigned 1:1 to receive tenofovir (300 mg/day) or tenofovir (300 mg/day) plus entecavir (1 mg/day) for 48 weeks. Because over 98% of Korean patients with CHB have HBV genotype C, HBV genotype will not determined or be regarded as a stratification factor. Patients' treatment information before randomization will be retrospectively collected.(DNA change, HBeAg status, HBsAg titre, ALT, and treatment duration. etc) Patients will be screened within 4 weeks before randomization to determine study eligibility.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Viral Hepatitis B Without Delta-agent
Keywords
Resistance of Entecavir

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Tenofovir monotherapy
Arm Type
Experimental
Arm Description
Tenofovir 300 mg/day orally
Arm Title
Tenofovir plus Entecavir combination
Arm Type
Active Comparator
Arm Description
Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally
Intervention Type
Drug
Intervention Name(s)
Tenofovir
Other Intervention Name(s)
Viread
Intervention Description
Tenofovir 300mg Daily Oral
Intervention Type
Drug
Intervention Name(s)
Tenofovir
Other Intervention Name(s)
Viread
Intervention Description
Tenofovir 300mg Daily Oral
Intervention Type
Drug
Intervention Name(s)
Entecavir
Other Intervention Name(s)
Baraclude
Intervention Description
Entecavir 1 mg daily Oral
Primary Outcome Measure Information:
Title
Proportion of patients with complete virologic response
Description
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Time Frame
at week 48 of treatment
Secondary Outcome Measure Information:
Title
Changes in serum HBV DNA levels
Description
Changes in serum HBV DNA levels during 48 weeks of treatment
Time Frame
at week 48, 96, 144, and 240 of treatment
Title
Proportion of patients with normal ALT
Time Frame
at week 48, 96, 144, and 240 of treatment
Title
Proportion of patients with HBe-Ag loss or seroconversion
Time Frame
at week 48, 96, 144, and 240 of treatment
Title
Proportion of patients with resistance mutations to Entecavir or Tenofovir
Description
The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
Time Frame
at week 48, 96, 144, and 240 of treatment
Title
Proportion of patients with virologic breakthrough
Description
Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment
Time Frame
at week 48, 96, 144, and 240 of treatment
Title
Proportion of patients with complete virologic response
Description
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Time Frame
at week 48, 96, 144, and 240 of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: All of below Compensated liver disease (Child-Pugh class A) HBsAg positive at least 6 months or more HBeAg positive or negative Confirmation of resistance mutations to Lamivudine (rtM204V/I and/or rtL180M) and ETV (rtT184 or rtS202 or rtM250) at any time before screening Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study) Patient is ambulatory. Patient is willing and able to comply with the study drug regimen and all other study requirements. The patient is willing and able to provide written informed consent to participate in the study. Exclusion Criteria: Any of below Patient previously received TDF for more than 1 week Patient had documented resistance mutations to ADV at any time before or at screening Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study. Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study. Patient has concomitant other chronic viral infection (HCV or HIV) Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent) Patient is currently abusing alcohol (more than 40 g/day) or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years. Patient is pregnant or breastfeeding or willing to be pregnant Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.). A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years. Clinical signs of decompensated liver disease as indicated by any one of the following: serum bilirubin > 3 mg/dL prothrombin time > 6 seconds prolonged or INR >1.5 serum albumin < 2.8 g/dL History of ascites, variceal hemorrhage, or hepatic encephalopathy Child-Pugh score ≥7
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Young-Suk Lim, M.D.,Ph.D.
Organizational Affiliation
Asan Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Asan Medical Center
City
Seoul
ZIP/Postal Code
138-736
Country
Korea, Republic of

12. IPD Sharing Statement

Citations:
PubMed Identifier
25596179
Citation
Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016 May;65(5):852-60. doi: 10.1136/gutjnl-2014-308353. Epub 2015 Jan 16.
Results Reference
result
PubMed Identifier
30876946
Citation
Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol. 2019 Jul;71(1):35-44. doi: 10.1016/j.jhep.2019.02.021. Epub 2019 Mar 13.
Results Reference
derived
Available IPD and Supporting Information:
Available IPD/Information Type
Pubmed
Available IPD/Information URL
http://www.ncbi.nlm.nih.gov/pubmed/25596179
Available IPD/Information Identifier
25596179
Available IPD/Information Comments
Publication for the primary study results

Learn more about this trial

Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B

We'll reach out to this number within 24 hrs