We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01639092
Recruitment Status : Active, not recruiting
First Posted : July 12, 2012
Last Update Posted : July 26, 2016
Information provided by (Responsible Party):

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.

Condition or disease Intervention/treatment Phase
Chronic Viral Hepatitis B Without Delta-agent Drug: Tenofovir Drug: Entecavir Phase 4

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : September 2012
Primary Completion Date : June 2014
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Tenofovir monotherapy
Tenofovir 300 mg/day orally
Drug: Tenofovir
Tenofovir 300mg Daily Oral
Other Name: Viread
Active Comparator: Tenofovir plus Entecavir combination
Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally
Drug: Tenofovir
Tenofovir 300mg Daily Oral
Other Name: Viread
Drug: Entecavir
Entecavir 1 mg daily Oral
Other Name: Baraclude

Outcome Measures

Primary Outcome Measures :
  1. 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)

Secondary Outcome Measures :
  1. 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

  2. Proportion of patients with normal ALT [ Time Frame: at week 48, 96, 144, and 240 of treatment ]
  3. Proportion of patients with HBe-Ag loss or seroconversion [ Time Frame: at week 48, 96, 144, and 240 of treatment ]
  4. 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

  5. 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

  6. 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)

Eligibility Criteria

Information from the National Library of Medicine

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, Learn About Clinical Studies.

Ages Eligible for Study:   20 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01639092

Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Sponsors and Collaborators
Asan Medical Center
Samsung Medical Center
Konkuk University Medical Center
Korea University Guro Hospital
Seoul National University Hospital
Principal Investigator: Young-Suk Lim, M.D.,Ph.D. Asan Medical Center
More Information

Study Data/Documents: Pubmed  This link exits the ClinicalTrials.gov site
Identifier: 25596179
Publication for the primary study results

Responsible Party: Young-Suk Lim, Associate Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01639092     History of Changes
Other Study ID Numbers: AMC2012-1215
First Posted: July 12, 2012    Key Record Dates
Last Update Posted: July 26, 2016
Last Verified: July 2016

Keywords provided by Young-Suk Lim, Asan Medical Center:
Resistance of Entecavir

Additional relevant MeSH terms:
Hepatitis A
Hepatitis, Chronic
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents