Entecavir Plus Adefovir in Lamivudine-Resistant Chronic Hepatitis B Patients Who Fail Lamivudine Plus Adefovir (CAESAR)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Young-Suk Lim, Asan Medical Center
ClinicalTrials.gov Identifier:
NCT01023217
First received: December 1, 2009
Last updated: January 15, 2014
Last verified: January 2014
  Purpose

The presence of persistent inadequate or suboptimal virologic response is a strong risk factor for viral resistance and breakthrough and also for disease progression of chronic hepatitis B, and thus, a change in therapy is required. The combination of entecavir (ETV) and adefovir (ADV) is a promising treatment for patients with lamivudine (LAM)-resistance who show suboptimal response to the combination of LAM and ADV.

In this randomized, open labeled trial,the investigators will compare the efficacy of continuation of ADV plus LAM versus switch to ADV plus ETV in adults with LAM-resistant chronic hepatitis B who shows suboptimal response to the combination treatment of ADV and LAM.


Condition Intervention Phase
Hepatitis B, Chronic
Drug: Adefovir
Drug: Entecavir
Drug: Lamivudine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Continuation of Lamivudine Plus Adefovir Versus Switching to Entecavir Plus Adefovir in Adults With Chronic Hepatitis B Who Have Resistant Mutants to Lamivudine and Show Suboptimal Response to Combination of Lamivudine Plus Adefovir

Resource links provided by NLM:


Further study details as provided by Asan Medical Center:

Primary Outcome Measures:
  • Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL) [ Time Frame: at week 52 from randomization ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Reduction in Serum HBV DNA Levels [ Time Frame: at week 52 and at week 104 from randomization ] [ Designated as safety issue: Yes ]
  • Genotypic Resistance to ADV or ETV [ Time Frame: at week 52 and at week 104 from randomization ] [ Designated as safety issue: Yes ]
  • Normalization of ALT Level [ Time Frame: at week 52 and at week 104 from randomization ] [ Designated as safety issue: Yes ]
  • Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL) [ Time Frame: at week 104 from randomization ] [ Designated as safety issue: No ]

Enrollment: 90
Study Start Date: November 2009
Study Completion Date: September 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Adefovir plus Entecavir
Adefovir + Entecavir for 104 weeks
Drug: Adefovir
Adefovir dipivoxil (Hepsera) 10 mg/day orally for 104 weeks
Other Name: Adefovir dipivoxil (Hepsera)
Drug: Entecavir
Entecavir 1 mg/day orally
Other Name: Entecavir (Baraclude)
Active Comparator: Adefovir plus Lamivudine
Adefovir + Lamivudine for 52 weeks, and thereafter, Adefovir + Entecavir for 52 more weeks
Drug: Adefovir
Adefovir dipivoxil (Hepsera) 10 mg/day orally for 104 weeks
Other Name: Adefovir dipivoxil (Hepsera)
Drug: Entecavir
Entecavir 1 mg/day orally
Other Name: Entecavir (Baraclude)
Drug: Lamivudine
Lamivudine (Zeffix) 100 mg/day orally
Other Name: Lamivudine (Zeffix)

Detailed Description:

In this randomized, open label, two-arm, single center phase IV trial, the investigators will assess and compare the efficacy and safety of continuation of ADV plus LAM versus switching to ADV plus ETV up to 52-weeks in Korean adults with chronic hepatitis B who have resistant mutants to LAM and show suboptimal response to combination of ADV plus LAM.

All study subjects who complete the initial treatments of 52-weeks will be thereafter treated with the combination of ADV plus ETV for 52 more weeks.

Study period: Nov 2009 - October 2012 Patient enrollment period: November 2009 - December 2010

Study protocol

  1. Group A (ADV+LAM group): Adefovir (10 mg/day) + Lamivudine (100 mg/day) for 52 weeks, and thereafter, Adefovir (10 mg/day) + Entecavir (1 mg/day) for 52 more weeks
  2. Group B (ADV+ETV group): Adefovir (10 mg/day) + Entecavir (1 mg/day) for 104 weeks
  Eligibility

Ages Eligible for Study:   16 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, 16 to 75 years of age
  2. Compensated liver disease(Child-Pugh class A)
  3. HBsAg positive at least 6 months or more
  4. HBeAg positive or negative
  5. Confirmation of Lamivudine-resistance HBV mutation anytime before the study
  6. Patients with suboptimal response (HBV DNA > 2000 IU/mL despite combination of Adefovir [10 mg/day] plus Lamivudine [100 mg/day] for 6 months or more). Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study
  7. Patient is ambulatory.
  8. Patient is willing and able to comply with the study drug regimen and all other study requirements.
  9. The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria:

  1. Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies or elevated serum alpha fetoprotein (AFP) levels. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
  2. Patient previously received oral antiviral agent other than Lamivudine or Adefovir
  3. Patient has received interferon or other immunomodulatory treatment for HBV infection within 12 months before screening for this study.
  4. Patient has concomitant other chronic viral infection (HCV or HIV)
  5. Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
  6. Patient has medical condition that requires use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
  7. Patient is currently abusing alcohol or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years.
  8. Patient is pregnant or breastfeeding or willing to be pregnant
  9. Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
  10. A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
  11. Clinical signs of decompensated liver disease as indicated by any one of the following:

    • serum bilirubin > 3 mg/dL
    • prothrombin time > 6 seconds prolonged or INR >1.6
    • serum albumin < 2.8 g/dL
    • History of ascites, variceal hemorrhage, or hepatic encephalopathy
    • Child-Pugh score ≥7
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01023217

Locations
Korea, Republic of
Asan Medical Center
Seoul, the Meteropolis of Seoul, Korea, Republic of, 138-736
Sponsors and Collaborators
Asan Medical Center
Investigators
Principal Investigator: Young-suk Lim, M.D.,Ph.D. Asan Medical Center
  More Information

No publications provided by Asan Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Young-Suk Lim, Associate Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01023217     History of Changes
Other Study ID Numbers: AMC-2009-0536
Study First Received: December 1, 2009
Results First Received: November 23, 2013
Last Updated: January 15, 2014
Health Authority: South Korea: Institutional Review Board

Keywords provided by Asan Medical Center:
Chronic hepatitis B
lamivudine
adefovir
entecavir

Additional relevant MeSH terms:
Hepatitis B, Chronic
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, 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 August 21, 2014