Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B
Overview
- Phase
- Phase 3
- Intervention
- Entecavir and peginterferon
- Conditions
- Hepatitis B
- Sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Enrollment
- 28
- Locations
- 21
- Primary Endpoint
- Incidence of Serious Adverse Events (SAEs) Per Person-Year
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
The investigators evaluated the safety and efficacy of a short lead-in course (8 weeks) of entecavir followed by combination of entecavir plus peginterferon alfa-2a for 40 weeks.
Detailed Description
To determine the efficacy of treatment with 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon in the treatment of chronic hepatitis B in hepatitis B "e" antigen (HBeAg) positive adults who are in the immune tolerant phase. To evaluate safety and sustained responses after treatment with entecavir and peginterferon alfa-2a in the treatment of chronic hepatitis B in HBeAg positive adults who are in the immune tolerant phase. A single arm treatment study of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon alfa-2a in adults with HBeAg-positive chronic hepatitis B with normal or near normal alanine aminotransferase (ALT) levels and high serum levels of hepatitis B virus (HBV) DNA ("immune tolerant" HBeAg-positive chronic hepatitis B). All participants followed for 48 weeks after treatment discontinuation (week 96 for those who completed treatment).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Enrolled in \& completed the baseline evaluation for NCT01263587 or completed the necessary components of NCT01263587 by the end of baseline visit.
- •\>18 years of age at the baseline visit (day 0). Patients \>50 years of age at baseline will need to have a liver biopsy as standard of care with hepatic activity index (HAI) ≤3 \& Ishak fibrosis score ≤1 within 96 weeks prior to baseline visit.
- •Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥24 weeks prior to baseline visit OR at least one positive HBsAg \& negative anti-hepatitis B core (HBc) immunoglobulin (IgM) within 24 weeks prior to baseline visit OR at least one positive HBsAg \& two positive HBV DNA over a period of ≥24 weeks prior to baseline visit.
- •Presence of HBeAg in serum at last screening visit within 6 weeks of baseline visit.
- •Serum HBV DNA level \>10˄7 IU/mL on at least two occasions at least 12 weeks apart during the 52 weeks before baseline visit. One of the two HBV DNA levels must be within 6 weeks of baseline visit.
- •ALT levels persistently ≤45 U/L in males, ≤30 U/L in females (approx. 1.5 times the upper limit of normal (ULN) range) as documented by at least three values: one taken 28-52 weeks before baseline visit, one taken 6 to 24 weeks before the baseline visit, \& the final value within 6 weeks prior to baseline visit.
- •No evidence of hepatocellular carcinoma (HCC) based upon alpha-fetoprotein (AFP) ≤20 ng/mL at screening visit (up to 6 weeks prior to baseline visit). a. Participants who meet American Association for the Study of Liver Diseases (AASLD) criteria for HCC surveillance must have negative liver imaging as shown by ultrasound, computerized tomography (CT) or magnetic resonance imaging (MRI) within 28 weeks prior to baseline visit. b. Participants with AFP \>20 ng/mL must be evaluated clinically with additional imaging \& shown not to have HCC on CT or MRI before they can be enrolled.
Exclusion Criteria
- •History of hepatic decompensation
- •Evidence of decompensated liver disease prior to or during screening, including direct bilirubin \>0.5 mg/dL, international normalization ratio (INR) \>1.5, or serum albumin \<3.5 g/dL.
- •Platelet count \<120,000/mm3, hemoglobin \<13 g/dL (males) or \<12 g/dL (females), absolute neutrophil count \< 1500 /mm3 (\<1000/mm3 for African-Americans) at last screening visit.
- •Previous treatment with medications that have established activity against HBV including interferon \& nucleos(t)ide analogs ≥24 weeks. Patients with \<24 weeks of prior HBV treatment \& a wash-out period \>24 weeks are not excluded.
- •Known allergy or intolerance to study medications.
- •Females who are pregnant or breastfeeding. Females of childbearing potential unable or unwilling to use a reliable method of contraception during the treatment period.
- •Renal insufficiency with calculated creatinine clearance \<50 mL/min at screening.
- •History of alcohol or drug abuse within 48 weeks of baseline visit.
- •Previous liver or other organ transplantation (including engrafted bone marrow).
- •Any other concomitant liver disease, including hepatitis C or D. Non-alcoholic fatty liver disease (NAFLD) with steatosis \&/or mild to moderate steatohepatitis is acceptable but NAFLD with severe steatohepatitis is exclusionary.
Arms & Interventions
Peginterferon and entecavir
A combination of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon.
Intervention: Entecavir and peginterferon
Outcomes
Primary Outcomes
Incidence of Serious Adverse Events (SAEs) Per Person-Year
Time Frame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
The incidence is calculated as the number of SAEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL
Time Frame: End of follow-up (up to 96 weeks)
Lack of data was considered to be treatment failure.
Incidence of Adverse Events (AEs) Per Person-Year of Observation
Time Frame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
The number of AEs includes both AEs and Serious Adverse Events (SAEs). The incidence is calculated as the number of AEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Secondary Outcomes
- Proportion of Participants With HBsAg Seroconversion(End of follow-up (up to 96 weeks))
- Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women(End of follow-up (up to 96 weeks))
- Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women(End of treatment (up to 48 weeks))
- Proportion of Participants With HBeAg Seroconversion(End of follow-up (up to 96 weeks))
- Proportion of Participants With HBeAg Loss(End of follow-up (up to 96 weeks))
- Proportion of Participants With HBsAg Loss(End of follow-up (up to 96 weeks))
- Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)(End of follow-up (up to 96 weeks))
- Proportion of Participants With HBV DNA <20 IU/mL(End of follow-up (up to 96 weeks))
- Proportion of Participants With HBV DNA ≤1000 IU/mL(End of follow-up (up to 96 weeks))
- Absence of Detectable Antiviral Drug-resistance HBV Mutations(End of treatment (up to 48 weeks))