Clinical trial NCT01369199: Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B
Official title: Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hepatitis B
Keywords: Hepatitis B
Immune-tolerant hepatitis B
HBV
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: University of Pittsburgh
name: National Center for Research Resources (NCRR)
First posted: 2011-06-08
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.
* Presence of anti-hepatitis D virus (HDV) or anti-hepatitis C virus (HCV) (unless HCV RNA negative) in serum on any occasion in the 144 weeks prior to baseline visit. Presence of anti-HIV (test completed within 6 weeks prior to baseline visit).
* Pre-existing psychiatric condition(s), including, but not limited to: current moderate or severe depression, history of depression requiring hospitalization within the past 10 years, history of suicidal or homicidal attempt within the past 10 years, history of severe psychiatric disorders as determined by a study physician.
* History of immune-mediated or cerebrovascular disease, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease, poorly controlled diabetes or uncontrolled seizure disorder, as determined by a study physician.
* Any medical condition that would, in the opinion of a study physician, be predicted to be exacerbated by therapy or that would limit study participation.
* Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study.
* Evidence of active or suspected malignancy, or a history of malignancy within the 144 weeks prior to baseline visit (except adequately treated carcinoma in situ or basal cell carcinoma of the skin).
* Expected need for ongoing use of any antivirals with activity against HBV during the course of the study.
* Concomitant use of complementary or alternative medications purported to have antiviral activity.
* Participation in any other clinical trial involving investigational drugs within 30 days of the baseline visit or intention to participate in another clinical trial involving investigational drugs during participation in this study.

Primary outcomes:
measure: Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL
timeFrame: End of follow-up (up to 96 weeks)
measure: Incidence of Adverse Events (AEs) Per Person-Year of Observation
timeFrame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
measure: Incidence of Serious Adverse Events (SAEs) Per Person-Year
timeFrame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
Secondary outcomes:
measure: Proportion of Participants With HBeAg Loss
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBeAg Loss
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBeAg Seroconversion
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBeAg Seroconversion
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBsAg Loss
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBsAg Loss
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBsAg Seroconversion
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBsAg Seroconversion
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBV DNA ≤1000 IU/mL
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBV DNA ≤1000 IU/mL
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBV DNA <20 IU/mL
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBV DNA <20 IU/mL
timeFrame: End of follow-up (up to 96 weeks)
measure: Absence of Detectable Antiviral Drug-resistance HBV Mutations
timeFrame: End of treatment (up to 48 weeks)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Bethesda
country: United States
facility: NIH Clinical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Averell Sherker, MD
role: STUDY_CHAIR
affiliation: University of Michigan
name: Anna Lok, MD
role: PRINCIPAL_INVESTIGATOR
References: