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

NCT ID: NCT00531167

Last Updated: 2012-10-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

219 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-04-30

Study Completion Date

2012-10-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Chronic Hepatitis B

Keywords

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lamivudine resistant mutations rescue therapy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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A

combination therapy

Group Type EXPERIMENTAL

combination of lamivudine+adefovir vs entecavir

Intervention Type DRUG

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

B

entecavir

Group Type ACTIVE_COMPARATOR

combination of lamivudine+adefovir vs entecavir

Intervention Type DRUG

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

Interventions

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combination of lamivudine+adefovir vs entecavir

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

Intervention Type DRUG

Other Intervention Names

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Zeffix, Hepsera, Baraclude

Eligibility Criteria

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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

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)
Minimum Eligible Age

16 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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GlaxoSmithKline

INDUSTRY

Sponsor Role collaborator

Korea University

OTHER

Sponsor Role lead

Responsible Party

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Hyung Joon Yim

associate professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Hyung Joon Yim, M.D.

Role: PRINCIPAL_INVESTIGATOR

Korea University

Eileen Yoon

Role: STUDY_DIRECTOR

Korea University

Yeon Seok Seo, M.D

Role: STUDY_DIRECTOR

Korea University

Soon Ho Um, M.D

Role: STUDY_DIRECTOR

Korea University

Chang Wook Kim, M.D

Role: STUDY_DIRECTOR

The Catholic University of Korea

Chang Don Lee

Role: STUDY_DIRECTOR

The Catholic University of Korea

Sang Hoon Park, M.D

Role: STUDY_DIRECTOR

Hallym University

Myung Seok Lee, M.D

Role: STUDY_DIRECTOR

Hallym University

Choong Kee Park, M.D

Role: STUDY_DIRECTOR

Hallym University

Hee Bok Chae, M.D

Role: STUDY_DIRECTOR

Chungbuk National University

Moon young Kim, M.D

Role: STUDY_DIRECTOR

Yonsei University

Soon Koo Baik, M.D

Role: STUDY_DIRECTOR

Yonsei University

Ju Hyun Kim, M.D

Role: STUDY_DIRECTOR

Gachon University Gil Medical Center

Yun Soo Kim, M.D

Role: STUDY_DIRECTOR

Gachon University Gil Medical Center

Jung Il Lee, M.D

Role: STUDY_DIRECTOR

Inha University

Jin Woo Lee, M.D

Role: STUDY_DIRECTOR

Inha University

Sun Pyo Hong, PhD

Role: STUDY_DIRECTOR

Genematrix Inc.

Locations

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Korea University Ansan Hospital

Ansan, Gyeonggi-do, South Korea

Site Status

Korea University Anam Hospital

Seoul, , South Korea

Site Status

Countries

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South Korea

References

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

Reference Type BACKGROUND
PMID: 17256718 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17256746 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17178796 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 14699491 (View on PubMed)

Other Identifiers

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CRT 111098

Identifier Type: -

Identifier Source: org_study_id