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

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ClinicalTrials.gov Identifier: NCT00531167
Recruitment Status : Completed
First Posted : September 18, 2007
Last Update Posted : October 22, 2012
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis B Drug: combination of lamivudine+adefovir vs entecavir Phase 4

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 219 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B
Study Start Date : April 2007
Primary Completion Date : April 2011
Study Completion Date : October 2012

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

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 Name: 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 Name: Zeffix, Hepsera, Baraclude


Outcome Measures

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

Secondary Outcome Measures :
  1. 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 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 75 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
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): NCT00531167


Locations
Korea, Republic of
Korea University Ansan Hospital
Ansan, Gyeonggi-do, Korea, Republic of
Korea University Anam Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Korea University
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.
More Information

Publications:
Responsible Party: Hyung Joon Yim, associate professor, Korea University
ClinicalTrials.gov Identifier: NCT00531167     History of Changes
Other Study ID Numbers: CRT 111098
First Posted: September 18, 2007    Key Record Dates
Last Update Posted: October 22, 2012
Last Verified: October 2012

Keywords provided by Hyung Joon Yim, Korea University:
lamivudine resistant mutations
rescue therapy

Additional relevant MeSH terms:
Hepatitis
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
Lamivudine
Adefovir
Adefovir dipivoxil
Entecavir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents