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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Adefovir; Drug: Entecavir; Drug: Lamivudine

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

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • the Meteropolis of Seoul
    • Seoul, the Meteropolis of Seoul, Korea, Republic of, 138-736
      • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adefovir plus Entecavir; Adefovir + Entecavir for 104 weeks	Drug: Adefovir; Adefovir dipivoxil (Hepsera) 10 mg/day orally for 104 weeks; Other Names: Adefovir dipivoxil (Hepsera); Drug: Entecavir; Entecavir 1 mg/day orally; Other Names: 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 Names: Adefovir dipivoxil (Hepsera); Drug: Entecavir; Entecavir 1 mg/day orally; Other Names: Entecavir (Baraclude); Drug: Lamivudine; Lamivudine (Zeffix) 100 mg/day orally; Other Names: Lamivudine (Zeffix)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL)	at week 52 from randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
Reduction in Serum HBV DNA Levels	at week 52 and at week 104 from randomization
Genotypic Resistance to ADV or ETV	at week 52 and at week 104 from randomization
Normalization of ALT Level	at week 52 and at week 104 from randomization
Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL)	at week 104 from randomization

Collaborators and Investigators

• Sponsor: Asan Medical Center

Publications and helpful links

General Publications

• Lim YS, Lee JY, Lee D, Shim JH, Lee HC, Lee YS, Suh DJ. Randomized trial of the virologic response during up to two years of entecavir-adefovir combination therapy in multiple-drug-refractory chronic hepatitis B virus patients. Antimicrob Agents Chemother. 2013 Jul;57(7):3369-74. doi: 10.1128/AAC.00587-13. Epub 2013 May 6.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: December 1, 2009
• First Submitted That Met QC Criteria: December 1, 2009
• First Posted (Estimate): December 2, 2009

Study Record Updates

• Last Update Posted (Estimate): February 10, 2014
• Last Update Submitted That Met QC Criteria: January 15, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: entecavir; Chronic hepatitis B; lamivudine; adefovir
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Entecavir; Lamivudine; Adefovir; Adefovir dipivoxil
• Other Study ID Numbers: AMC-2009-0536