Hepatitis B, Chronic
Conditions
Keywords
Chronic hepatitis B, lamivudine, adefovir, entecavir
Brief summary
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.
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
Interventions
DRUGAdefovir
Adefovir dipivoxil (Hepsera) 10 mg/day orally for 104 weeks
DRUGEntecavir
Entecavir 1 mg/day orally
DRUGLamivudine
Lamivudine (Zeffix) 100 mg/day orally
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| 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 |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Adefovir Plus Entecavir Adefovir (10 mg/day) + Entecavir (1 mg/day) for 104 weeks
Adefovir plus Entecavir: Adefovir (10 mg/day) + Entecavir (1 mg/day) for 104 weeks | 45 |
| Adefovir Plus Lamivudine 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
Adefovir plus Lamivudine: 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 | 45 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Adefovir Plus Lamivudine | Total | Adefovir Plus Entecavir |
|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 11 | 47 years STANDARD_DEVIATION 11 | 45 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 45 Participants | 90 Participants | 45 Participants |
| Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients | 45 participants | 90 participants | 45 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 45 Participants | 90 Participants | 45 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Korea, Republic of | 45 participants | 90 participants | 45 participants |
| Sex: Female, Male Female | 11 Participants | 23 Participants | 12 Participants |
| Sex: Female, Male Male | 34 Participants | 67 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 45 | 5 / 45 |
| serious Total, serious adverse events | 2 / 45 | 2 / 45 |
Outcome results
Primary
Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL)
Time frame: at week 52 from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adefovir Plus Entecavir | Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL) | 13 participants |
| Adefovir Plus Lamivudine | Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL) | 2 participants |
Secondary
Complete Virologic Response (CVR, Serum HBV DNA Undetectable by PCR or Less Than 60 IU/mL)
Time frame: at week 104 from randomization
Secondary
Genotypic Resistance to ADV or ETV
Time frame: at week 52 and at week 104 from randomization
Secondary
Normalization of ALT Level
Time frame: at week 52 and at week 104 from randomization
Secondary
Reduction in Serum HBV DNA Levels
Time frame: at week 52 and at week 104 from randomization