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

NCT00531167 | Completed Phase 4 DMC

• 1 other identifier: CRT 111098
• Study Type: interventional
• Target: 219
• Locations: 1 country
• Sites: 2

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.

Conditions

Chronic Hepatitis B

Keywords

lamivudine resistant mutations; rescue therapy

Outcome Measures

Primary Outcomes (1)

• PCR negativity (<60 IU/ml) of HBV DNA

  At the end of year 2 (since starting rescue therapy for lamivudine resistance)

Secondary Outcomes (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

  At the end of year 2 except interim analysis

Study Arms (2)

A

EXPERIMENTAL

combination therapy

Drug: combination of lamivudine+adefovir vs entecavir

B

ACTIVE COMPARATOR

entecavir

Drug: combination of lamivudine+adefovir vs entecavir

Interventions

combination of lamivudine+adefovir vs entecavir DRUG

Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day

Also known as: Zeffix, Hepsera, Baraclude

A; B

Eligibility Criteria

• Age: 16 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic hepatitis B patients (positive HBsAg \> 6 months)
• Age \> 16 year old
• Serum alanine aminotransferase (ALT) \>1.5 x ULN
• History of treatment with lamivudine more than 6 months
• Proven lamivudine resistant mutation
• HBV DNA level\> 20000 IU/mL
• 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)
• Patients willing to give informed consent

You may not qualify if:

• 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
• History of treatment with interferon-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening
• Recipient of organ transplantation
• Positive antibody test to HIV, HCV or HDV
• Pregnant or breast feeding women
• Patients with hepatocellular carcinoma or uncontrolled malignant disease
• Habitual alcohol drinker (\>140 g/week for men, \>70 g/week for women)

Sponsors & Collaborators

• Korea University: lead
• GlaxoSmithKline: collaborator

Study Sites (2)

Korea University Ansan Hospital

Ansan, Gyeonggi-do, South Korea

Location

Korea University Anam Hospital

Seoul, South Korea

Location

Related Publications (4)

• Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. doi: 10.1002/hep.21513. No abstract available.

  PMID: 17256718 BACKGROUND

• Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007 Feb;45(2):307-13. doi: 10.1002/hep.21534.

  PMID: 17256746 BACKGROUND

• Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11. doi: 10.1128/AAC.00833-06. Epub 2006 Dec 18.

  PMID: 17178796 BACKGROUND

• Peters MG, Hann Hw Hw, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df Df, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004 Jan;126(1):91-101. doi: 10.1053/j.gastro.2003.10.051.

  PMID: 14699491 BACKGROUND

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

Lamivudine; adefovir dipivoxil; entecavir

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Study Officials

• Hyung Joon Yim, M.D.

  Korea University

  PRINCIPAL INVESTIGATOR

• 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.

  STUDY DIRECTOR

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: September 17, 2007
• First Posted: September 18, 2007
• Study Start: April 1, 2007
• Primary Completion: April 1, 2011
• Study Completion: October 1, 2012
• Last Updated: October 22, 2012

Record last verified: 2012-10

Locations

KR (2)