Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

October 18, 2012 updated by: Hyung Joon Yim, Korea University

Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. However, combination of lamivudine and adefovir decreased the adefovir resistance rate as low as 0% in the recent studies. By overcoming the antiviral resistance, the efficacy of therapy will be maximized. This study is intended to compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Recently, published data showed combination of lamivudine and adefovir lead to PCR negativity (<1000 copies/mL) up to 80% in the treatment of lamivudine-resistant chronic hepatitis B at year 2 [Rapti et al. Hepatology 2007 Feb;45(2):307-13.]. Other studies also showed 76% and 69% PCR negativity in mostly HBeAg negative subjects [Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:556A-557A, Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:693A-694A].

In the study for the treatment of lamivudine-resistant chronic hepatitis B patients which included HBeAg positive subjects more predominantly, entecavir monotherapy showed 34% of PCR negativity (<300 copies/mL) at year 2 [Tenney DJ, et al. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11].

Although it is assumed that combination of lamivudine and adefovir would be more effective than entecavir monotherapy for lamivudine resistant patients, we cannot verify the assumption, because there is no data directly comparing these two strategies until now.

The aim of this study is to determine the most effective therapy for the patients with lamivudine resistant chronic hepatitis B. We will compare the PCR negativity (<60 IU/ml) of HBV DNA at year 2 in patients receiving 'the combination of lamivudine and adefovir' and 'entecavir monotherapy'.

Since we are planning to include lamivudine-resistant chronic hepatitis B patients regardless of HBeAg status, we assumed the PCR negativity (<300 copies/mL or <60 IU/mL) in adefovir-lamivudine combination and entecavir monotherapy group as 55% and 34%, respectively, considering HBeAg status and lower detection limit of PCR.

The result of this study will be able to clearly demonstrate the superiority of combination therapy with lamivudine and adefovir to entecavir monotherapy, which provide us the guide to rescue therapy for patients with lamivudine resistant HBV.

Study Type

Interventional

Enrollment (Actual)

219

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

  • Korea, Republic of
      • Seoul, Korea, Republic of
        • Korea University Anam Hospital
    • Gyeonggi-do
      • Ansan, Gyeonggi-do, Korea, Republic of
        • Korea University Ansan Hospital

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

16 years to 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Chronic hepatitis B patients (positive HBsAg > 6 months)
  2. Age > 16 year old
  3. Serum alanine aminotransferase (ALT) >1.5 x ULN
  4. History of treatment with lamivudine more than 6 months
  5. Proven lamivudine resistant mutation
  6. HBV DNA level> 20000 IU/mL
  7. Compensated liver disease (Child-Pugh-Turcotte score over 7; prothrombin time prolonged more than 3 sec above ULN or INR over 1.5; serum albumin >3 g/dL; total bilirubin <2.5 mg/dL; No history of variceal bleeding, ascites, or hepatic encephalopathy)
  8. Patients willing to give informed consent

Exclusion Criteria:

  1. Out of inclusion criteria

  2. Any one of following

    • Serum phosphorus level under 2.4 mg/dL
    • Serum creatinine level over 1.5 mg/dL or creatinine clearance <50 mL/min
    • Absolute neutrophil count lower than 1000 cell/mL
    • Hb level under 10 g/dL (male), under 9 g/dL (female)
    • Serum AFP >100 ng/mL
  3. History of treatment with interferon-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening
  4. Recipient of organ transplantation
  5. Positive antibody test to HIV, HCV or HDV
  6. Pregnant or breast feeding women
  7. Patients with hepatocellular carcinoma or uncontrolled malignant disease
  8. Habitual alcohol drinker (>140 g/week for men, >70 g/week for women)

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 Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
combination therapy
Drug: combination of lamivudine+adefovir vs entecavir
Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day
Other Names:
  • Zeffix, Hepsera, Baraclude
Active Comparator: B
entecavir
Drug: combination of lamivudine+adefovir vs entecavir
Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day
Other Names:
  • Zeffix, Hepsera, Baraclude

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
PCR negativity (<60 IU/ml) of HBV DNA
Time Frame: At the end of year 2 (since starting rescue therapy for lamivudine resistance)
At the end of year 2 (since starting rescue therapy for lamivudine resistance)

Secondary Outcome Measures

Outcome Measure
Time Frame
1. PCR negativity (<60 IU/ml) of HBV DNA at year 1 (interim analysis) 2. Degrees of HBV DNA reduction 3. ALT normalization 4. HBeAg seroconversion 5. Development of resistant mutation 6. Virologic breakthrough 7. Biochemical breakthrough
Time Frame: At the end of year 2 except interim analysis
At the end of year 2 except interim analysis

Collaborators and Investigators

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

Sponsor

Korea University

Collaborators

GlaxoSmithKline

Investigators

  • Principal Investigator: Hyung Joon Yim, M.D., Korea University
  • Study Director: Eileen Yoon, Korea University
  • Study Director: Yeon Seok Seo, M.D, Korea University
  • Study Director: Soon Ho Um, M.D, Korea University
  • Study Director: Chang Wook Kim, M.D, The Catholic University of Korea
  • Study Director: Chang Don Lee, The Catholic University of Korea
  • Study Director: Sang Hoon Park, M.D, Hallym University
  • Study Director: Myung Seok Lee, M.D, Hallym University
  • Study Director: Choong Kee Park, M.D, Hallym University
  • Study Director: Hee Bok Chae, M.D, Chungbuk National University
  • Study Director: Moon young Kim, M.D, Yonsei University
  • Study Director: Soon Koo Baik, M.D, Yonsei University
  • Study Director: Ju Hyun Kim, M.D, Gachon University Gil Medical Center
  • Study Director: Yun Soo Kim, M.D, Gachon University Gil Medical Center
  • Study Director: Jung Il Lee, M.D, Inha University
  • Study Director: Jin Woo Lee, M.D, Inha University
  • Study Director: Sun Pyo Hong, PhD, Genematrix Inc.

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

April 1, 2007

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

October 1, 2012

Study Registration Dates

First Submitted

September 17, 2007

First Submitted That Met QC Criteria

September 17, 2007

First Posted (Estimate)

September 18, 2007

Study Record Updates

Last Update Posted (Estimate)

October 22, 2012

Last Update Submitted That Met QC Criteria

October 18, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CRT 111098

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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