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

May 8, 2018 updated by: Young-Suk Lim, Asan Medical Center

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

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.

Study Overview

Status

Completed

Conditions

Intervention / 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.

Study Type

Interventional

Enrollment (Actual)

88

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Tenofovir monotherapy
Tenofovir 300 mg/day orally
Drug: Tenofovir
Tenofovir 300mg Daily Oral
Other Names:
  • Viread
ACTIVE_COMPARATOR: Tenofovir plus Entecavir combination
Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally
Drug: Entecavir
Entecavir 1 mg daily Oral
Other Names:
  • Baraclude
Drug: Tenofovir
Tenofovir 300mg Daily Oral
Other Names:
  • Viread

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with complete virologic response
Time Frame: at week 48 of treatment
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
at week 48 of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in serum HBV DNA levels
Time Frame: at week 48, 96, 144, and 240 of treatment
Changes in serum HBV DNA levels during 48 weeks of treatment
at week 48, 96, 144, and 240 of treatment
Proportion of patients with normal ALT
Time Frame: at week 48, 96, 144, and 240 of treatment
at week 48, 96, 144, and 240 of treatment
Proportion of patients with HBe-Ag loss or seroconversion
Time Frame: at week 48, 96, 144, and 240 of treatment
at week 48, 96, 144, and 240 of treatment
Proportion of patients with virologic breakthrough
Time Frame: at week 48, 96, 144, and 240 of treatment
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
at week 48, 96, 144, and 240 of treatment
Proportion of patients with complete virologic response
Time Frame: at week 48, 96, 144, and 240 of treatment
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
at week 48, 96, 144, and 240 of treatment
Proportion of patients with resistance mutations to Entecavir or Tenofovir
Time Frame: at week 48, 96, 144, and 240 of treatment
The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
at week 48, 96, 144, and 240 of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Asan Medical Center

Collaborators

Samsung Medical Center
Seoul National University Hospital
Korea University Guro Hospital
Konkuk University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 28, 2012

Primary Completion (ACTUAL)

March 29, 2018

Study Completion (ACTUAL)

March 29, 2018

Study Registration Dates

First Submitted

July 10, 2012

First Submitted That Met QC Criteria

July 10, 2012

First Posted (ESTIMATE)

July 12, 2012

Study Record Updates

Last Update Posted (ACTUAL)

May 9, 2018

Last Update Submitted That Met QC Criteria

May 8, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AMC2012-1215

Plan for Individual participant data (IPD)

Study Data/Documents

  1. Pubmed
    Information identifier: 25596179
    Information comments: Publication for the primary study results

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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