Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Hyung Joon Yim, Korea University
ClinicalTrials.gov Identifier:
NCT01546116
First received: December 22, 2011
Last updated: February 14, 2014
Last verified: February 2014
  Purpose
  • 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.

Condition Intervention Phase
Chronic Hepatitis B
Drug: ADEFOVIR, LAMIVUDINE
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance

Resource links provided by NLM:


Further study details as provided by Korea University:

Primary Outcome Measures:
  • Degree of HBV DNA reduction from baseline [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
    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) [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
  • ALT normalization [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
  • HBeAg loss [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
  • HBeAg to anti- HBe seroconversion [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
  • Development of adefovir resistance [ Time Frame: at week 52 ] [ Designated as safety issue: Yes ]
  • Virologic breakthrough [ Time Frame: at week 52 ] [ Designated as safety issue: Yes ]
    virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).


Enrollment: 20
Study Start Date: February 2010
Study Completion Date: February 2014
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Adefovir and lamivudine combination Drug: ADEFOVIR, LAMIVUDINE
Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week
Other Names:
  • Adefovir (Hepasera)
  • Lamivudine (Zeffix)

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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) -
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01546116

Locations
Korea, Republic of
Chungbuk National University Hospital
Cheongju, Chngcheongbuk-do, Korea, Republic of
Yonsei University Wonju Christian Hospital
Wonju, Gangwon-do, Korea, Republic of
Hallym University, Sacred Heart Hospital
Anyang, Gyeonggi-do, Korea, Republic of
The Catholic University of Korea, Euijeongbu Saint Mary's Hospital
Euijeongbu, Gyeonggi-do, Korea, Republic of
Korea University Ansan Hospital
Ansan, Gyeonggi, Korea, Republic of
Gachon University Gil Medical Center
Incheon, Korea, Republic of
Inha University Hospital
Incheon, Korea, Republic of
Korea University Anam Hospital
Seoul, Korea, Republic of
Hallym University, Gangnam Sacred Heart Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Korea University
GlaxoSmithKline
Investigators
Principal Investigator: HYUNG JOON YIM, M.D., Ph.D. Korea University
  More Information

Publications:

Responsible Party: Hyung Joon Yim, Associate Professor, Korea University
ClinicalTrials.gov Identifier: NCT01546116     History of Changes
Other Study ID Numbers: ALTER_114093
Study First Received: December 22, 2011
Last Updated: February 14, 2014
Health Authority: Korea: Food and Drug Administration

Keywords provided by Korea University:
adefovir
lamivudine
entecavir resistance

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Adefovir
Adefovir dipivoxil
Lamivudine
Entecavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on April 16, 2014