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

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Hyung Joon Yim, Korea University
ClinicalTrials.gov Identifier:
NCT00531167
First received: September 17, 2007
Last updated: October 18, 2012
Last verified: October 2012

September 17, 2007
October 18, 2012
April 2007
April 2011   (final data collection date for primary outcome measure)
PCR negativity (<60 IU/ml) of HBV DNA [ Time Frame: At the end of year 2 (since starting rescue therapy for lamivudine resistance) ] [ Designated as safety issue: Yes ]
PCR negativity (<60 IU/ml) of HBV DNA [ Time Frame: At the end of year 2 (since starting rescue therapy for lamivudine resistance) ]
Complete list of historical versions of study NCT00531167 on ClinicalTrials.gov Archive Site
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 ] [ Designated as safety issue: Yes ]
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 ]
Not Provided
Not Provided
 
Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B
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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Chronic Hepatitis B
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
  • Experimental: A
    combination therapy
    Intervention: Drug: combination of lamivudine+adefovir vs entecavir
  • Active Comparator: B
    entecavir
    Intervention: Drug: combination of lamivudine+adefovir vs entecavir

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
219
October 2012
April 2011   (final data collection date for primary outcome measure)

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)
Both
16 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
Korea, Republic of
 
NCT00531167
CRT 111098
Yes
Hyung Joon Yim, Korea University
Korea University
GlaxoSmithKline
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.
Korea University
October 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP