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Adefovir and Lamivudine for Entecavir Resistance (ALTER Study) (ALTER)

Primary Purpose

Chronic Hepatitis B

Status
Completed
Phase
Phase 4
Locations
Korea, Republic of
Study Type
Interventional
Intervention
ADEFOVIR, LAMIVUDINE
Sponsored by
Korea University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Hepatitis B focused on measuring adefovir, lamivudine, entecavir resistance

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

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-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) -

Sites / Locations

  • Chungbuk National University Hospital
  • Yonsei University Wonju Christian Hospital
  • Hallym University, Sacred Heart Hospital
  • The Catholic University of Korea, Euijeongbu Saint Mary's Hospital
  • Korea University Ansan Hospital
  • Gachon University Gil Medical Center
  • Inha University Hospital
  • Hallym University, Gangnam Sacred Heart Hospital
  • Korea University Anam Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Adefovir and lamivudine combination

Arm Description

Outcomes

Primary Outcome Measures

Degree of HBV DNA reduction from baseline
Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.

Secondary Outcome Measures

HBV DNA undetectability by PCR (<60 IU/mL)
ALT normalization
HBeAg loss
HBeAg to anti- HBe seroconversion
Development of adefovir resistance
Virologic breakthrough
virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

Full Information

First Posted
December 22, 2011
Last Updated
February 14, 2014
Sponsor
Korea University
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT01546116
Brief Title
Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)
Acronym
ALTER
Official Title
Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance
Study Type
Interventional

2. Study Status

Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
February 2010 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Korea University
Collaborators
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis B
Keywords
adefovir, lamivudine, entecavir resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Adefovir and lamivudine combination
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
ADEFOVIR, LAMIVUDINE
Other Intervention Name(s)
Adefovir (Hepasera), Lamivudine (Zeffix)
Intervention Description
Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week
Primary Outcome Measure Information:
Title
Degree of HBV DNA reduction from baseline
Description
Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.
Time Frame
at week 52
Secondary Outcome Measure Information:
Title
HBV DNA undetectability by PCR (<60 IU/mL)
Time Frame
at week 52
Title
ALT normalization
Time Frame
at week 52
Title
HBeAg loss
Time Frame
at week 52
Title
HBeAg to anti- HBe seroconversion
Time Frame
at week 52
Title
Development of adefovir resistance
Time Frame
at week 52
Title
Virologic breakthrough
Description
virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).
Time Frame
at week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic hepatitis B patients (positive HBsAg > 6 months) Age > 18 year old History of treatment with entecavir more than 6 months Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V) HBV DNA level> 2000 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 Exclusion Criteria: Out of inclusion criteria 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-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past) 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) -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
HYUNG JOON YIM, M.D., Ph.D.
Organizational Affiliation
Korea University Ansan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chungbuk National University Hospital
City
Cheongju
State/Province
Chngcheongbuk-do
Country
Korea, Republic of
Facility Name
Yonsei University Wonju Christian Hospital
City
Wonju
State/Province
Gangwon-do
Country
Korea, Republic of
Facility Name
Hallym University, Sacred Heart Hospital
City
Anyang
State/Province
Gyeonggi-do
Country
Korea, Republic of
Facility Name
The Catholic University of Korea, Euijeongbu Saint Mary's Hospital
City
Euijeongbu
State/Province
Gyeonggi-do
Country
Korea, Republic of
Facility Name
Korea University Ansan Hospital
City
Ansan
State/Province
Gyeonggi
Country
Korea, Republic of
Facility Name
Gachon University Gil Medical Center
City
Incheon
Country
Korea, Republic of
Facility Name
Inha University Hospital
City
Incheon
Country
Korea, Republic of
Facility Name
Hallym University, Gangnam Sacred Heart Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Korea University Anam Hospital
City
Seoul
Country
Korea, Republic of

12. IPD Sharing Statement

Citations:
PubMed Identifier
9392700
Citation
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Results Reference
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PubMed Identifier
19714720
Citation
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190. No abstract available.
Results Reference
background
PubMed Identifier
19280622
Citation
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.
Results Reference
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PubMed Identifier
16941700
Citation
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.
Results Reference
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PubMed Identifier
17983801
Citation
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.
Results Reference
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PubMed Identifier
17256746
Citation
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.
Results Reference
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PubMed Identifier
17239478
Citation
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.
Results Reference
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PubMed Identifier
17935165
Citation
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.
Results Reference
result

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Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

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