Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

NCT ID: NCT01546116

Last Updated: 2014-02-17

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

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-02-28

Study Completion Date

2014-02-28

Brief Summary

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* Entecavir has been one of the option for treatment of lamivudine resistant chronic hepatitis B (CHB).
* In case of entecavir resistance, adefovir could be used. However, sequential monotherapy may result in multidrug resistance.
* It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued therapy will lead to suppression of hepatitis B virus (HBV) DNA to be undetectable in patients with entecavir resistance.
* This study aim to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Detailed Description

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Entecavir is a potent antiviral agent for the treatment of chronic hepatitis B (CHB). However, the incidence of entecavir resistance increases over 50% at 5th year in lamivudine-refractory CHB patients. Considering cross resistance profile, adefovir is a good option for managing entecavir resistance. However adefovir monotherapy may lead to adefovir resistance, because entecavir resistant hepatitis B virus (HBV) retain lamivudine resistance. Previously, combination of adefovir and lamivudine was reported to be effective in a patient with entecavir resistance, but only as a case report form. No further data are available on this combination therapy in a sufficient number of patients. It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued combination treatment will result in suppression of HBV DNA to be undetectable in patients with entecavir resistance.

The aim of this study is to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Conditions

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Chronic Hepatitis B

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Adefovir and lamivudine combination

Group Type EXPERIMENTAL

ADEFOVIR, LAMIVUDINE

Intervention Type DRUG

Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week

Interventions

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ADEFOVIR, LAMIVUDINE

Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week

Intervention Type DRUG

Other Intervention Names

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Adefovir (Hepasera) Lamivudine (Zeffix)

Eligibility Criteria

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Inclusion Criteria

1. Chronic hepatitis B patients (positive HBsAg \> 6 months)
2. Age \> 18 year old
3. History of treatment with entecavir more than 6 months
4. Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V)
5. HBV DNA level\> 2000 IU/mL
6. 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)
7. 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-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening
4. History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past)
5. Recipient of organ transplantation
6. Positive antibody test to HIV, HCV or HDV
7. Pregnant or breast feeding women
8. Patients with hepatocellular carcinoma or uncontrolled malignant disease
9. Habitual alcohol drinker (\>140 g/week for men, \>70 g/week for women) -
Minimum Eligible Age

18 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., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Korea University Ansan Hospital

Locations

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Chungbuk National University Hospital

Cheongju-si, Chngcheongbuk-do, South Korea

Site Status

Yonsei University Wonju Christian Hospital

Wŏnju, Gangwon-do, South Korea

Site Status

Korea University Ansan Hospital

Ansan, Gyeonggi-do, South Korea

Site Status

Hallym University, Sacred Heart Hospital

Anyang-si, Gyeonggi-do, South Korea

Site Status

The Catholic University of Korea, Euijeongbu Saint Mary's Hospital

Euijeongbu, Gyeonggi-do, South Korea

Site Status

Gachon University Gil Medical Center

Incheon, , South Korea

Site Status

Inha University Hospital

Incheon, , South Korea

Site Status

Hallym University, Gangnam Sacred Heart Hospital

Seoul, , 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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Lee WM. Hepatitis B virus infection. N Engl J Med. 1997 Dec 11;337(24):1733-45. doi: 10.1056/NEJM199712113372406. No abstract available.

Reference Type BACKGROUND
PMID: 9392700 (View on PubMed)

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190. No abstract available.

Reference Type BACKGROUND
PMID: 19714720 (View on PubMed)

Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.

Reference Type BACKGROUND
PMID: 19280622 (View on PubMed)

Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006 Sep;44(3):703-12. doi: 10.1002/hep.21290.

Reference Type BACKGROUND
PMID: 16941700 (View on PubMed)

Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007 Nov;133(5):1445-51. doi: 10.1053/j.gastro.2007.08.079. Epub 2007 Sep 2.

Reference Type BACKGROUND
PMID: 17983801 (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)

Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo C, Zoulim F. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007 Mar;46(3):531-8. doi: 10.1016/j.jhep.2006.11.016. Epub 2006 Dec 18.

Reference Type RESULT
PMID: 17239478 (View on PubMed)

Yatsuji H, Hiraga N, Mori N, Hatakeyama T, Tsuge M, Imamura M, Takahashi S, Fujimoto Y, Ochi H, Abe H, Maekawa T, Suzuki F, Kumada H, Chayama K. Successful treatment of an entecavir-resistant hepatitis B virus variant. J Med Virol. 2007 Dec;79(12):1811-7. doi: 10.1002/jmv.20981.

Reference Type RESULT
PMID: 17935165 (View on PubMed)

Other Identifiers

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ALTER_114093

Identifier Type: -

Identifier Source: org_study_id

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