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

NCT01639092 | Completed Phase 4 DMC

• 1 other identifier: AMC2012-1215
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Viral Hepatitis B Without Delta-agent

Keywords

Resistance of Entecavir

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with complete virologic response

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

  at week 48 of treatment

Secondary Outcomes (6)

• Changes in serum HBV DNA levels

  at week 48, 96, 144, and 240 of treatment

• Proportion of patients with normal ALT

  at week 48, 96, 144, and 240 of treatment

• Proportion of patients with HBe-Ag loss or seroconversion

  at week 48, 96, 144, and 240 of treatment

• Proportion of patients with resistance mutations to Entecavir or Tenofovir

  at week 48, 96, 144, and 240 of treatment

• Proportion of patients with virologic breakthrough

  at week 48, 96, 144, and 240 of treatment

Study Arms (2)

Tenofovir monotherapy

EXPERIMENTAL

Tenofovir 300 mg/day orally

Drug: Tenofovir

Tenofovir plus Entecavir combination

ACTIVE COMPARATOR

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

Drug: Tenofovir; Drug: Entecavir

Interventions

Tenofovir DRUG

Tenofovir 300mg Daily Oral

Also known as: Viread

Tenofovir monotherapy

Entecavir DRUG

Entecavir 1 mg daily Oral

Also known as: Baraclude

Tenofovir plus Entecavir combination

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Asan Medical Center: lead
• Samsung Medical Center: collaborator
• Konkuk University Medical Center: collaborator
• Korea University Guro Hospital: collaborator
• Seoul National University Hospital: collaborator

Study Sites (1)

Asan Medical Center

Seoul, 138-736, South Korea

Location

Related Publications (2)

• 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.

  PMID: 25596179 RESULT

• 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.

  PMID: 30876946 DERIVED

MeSH Terms

Interventions

Tenofovir; entecavir

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Young-Suk Lim, M.D.,Ph.D.

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 10, 2012
• First Posted: July 12, 2012
• Study Start: September 28, 2012
• Primary Completion: March 29, 2018
• Study Completion: March 29, 2018
• Last Updated: May 9, 2018

Record last verified: 2018-05

Locations

KR (1)