Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B (HBRN)

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

28

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Ontario
      • Toronto, Ontario, Canada, M5T 2S8
        • University of Toronto
    • California
      • Los Angeles, California, United States, 90095
        • University of California Los Angeles
      • Los Angeles, California, United States, 90048
        • Cedars Sinai Medical Center
      • San Francisco, California, United States, 94143
        • University of California San Francisco
      • San Francisco, California, United States, 94115
        • California Pacific Medical Center
    • Hawaii
      • Honolulu, Hawaii, United States, 96813
        • Queen's Medical Center
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • NIH Clinical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Medical Center
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Health System
    • Minnesota
      • Minneapolis, Minnesota, United States, 55446
        • University of Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University
      • Saint Louis, Missouri, United States, 63104
        • Saint Louis University
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern
      • Dallas, Texas, United States, 75246
        • Baylor University Medical Center
    • Virginia
      • Richmond, Virginia, United States, 23498
        • Virginia Commonwealth University
    • Washington
      • Seattle, Washington, United States, 98101
        • Virginia Mason Medical Center
      • Seattle, Washington, United States, 98105
        • University of Washington Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Peginterferon and entecavir
A combination of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon.
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon 180 µg sq weekly during weeks 9-48 of treatment.
Other Names:
  • PEGASYS, peginterferon alfa 2a, Baraclude

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
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.
End of follow-up (up to 96 weeks)
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.
From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Participants With HBeAg Seroconversion
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBeAg Seroconversion
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With HBsAg Seroconversion
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBsAg Seroconversion
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With HBV DNA ≤1000 IU/mL
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBV DNA ≤1000 IU/mL
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With HBeAg Loss
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBeAg Loss
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With HBsAg Loss
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBsAg Loss
Time Frame: End of follow-up (up to 96 weeks)
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
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Proportion of Participants With HBV DNA <20 IU/mL
Time Frame: End of treatment (up to 48 weeks)
End of treatment (up to 48 weeks)
Proportion of Participants With HBV DNA <20 IU/mL
Time Frame: End of follow-up (up to 96 weeks)
End of follow-up (up to 96 weeks)
Absence of Detectable Antiviral Drug-resistance HBV Mutations
Time Frame: End of treatment (up to 48 weeks)
HBV drug resistance variant testing was performed at the CDC laboratory. The sequences of the HBV polymerase spanning nucleotide positions 311-1021 were determined by Sanger sequencing. Drug resistance mutations that were tested in this study included L80VI, L82M, T128N, W153Q, F166L, I169T, V173L, L180M, A181TV, T184ACFGILMS, V191T, A194T, A200V, S202ETV, M204IV, V207I, N236T, M250ILV, and G145R.
End of treatment (up to 48 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Principal Investigator: Anna Lok, MD, University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2012

Primary Completion (Actual)

February 14, 2017

Study Completion (Actual)

February 14, 2017

Study Registration Dates

First Submitted

June 6, 2011

First Submitted That Met QC Criteria

June 7, 2011

First Posted (Estimate)

June 8, 2011

Study Record Updates

Last Update Posted (Actual)

May 26, 2022

Last Update Submitted That Met QC Criteria

May 24, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Other Study ID Numbers

  • DK082864 HBRN IT Adult Trial
  • UL1RR024986 (U.S. NIH Grant/Contract)
  • UL1TR001111 (U.S. NIH Grant/Contract)
  • U01DK082916 (U.S. NIH Grant/Contract)
  • U01DK082864 (U.S. NIH Grant/Contract)
  • U01DK082874 (U.S. NIH Grant/Contract)
  • U01DK082944 (U.S. NIH Grant/Contract)
  • U01DK082843 (U.S. NIH Grant/Contract)
  • U01DK082871 (U.S. NIH Grant/Contract)
  • UL1TR000004 (U.S. NIH Grant/Contract)
  • A-DK-3002-001 (Other Grant/Funding Number: Interagency agreement with NIDDK)
  • U01DK082863 (U.S. NIH Grant/Contract)
  • U01DK082866 (U.S. NIH Grant/Contract)
  • U01DK082867 (U.S. NIH Grant/Contract)
  • U01DK082872 (U.S. NIH Grant/Contract)
  • U01DK082919 (U.S. NIH Grant/Contract)
  • U01DK082923 (U.S. NIH Grant/Contract)
  • U01DK082927 (U.S. NIH Grant/Contract)
  • U01DK082943 (U.S. NIH Grant/Contract)
  • UL1TR000058 (U.S. NIH Grant/Contract)
  • P30DK050306 (U.S. NIH Grant/Contract)
  • M01RR000040 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All data collected will be sent to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported data repository.

IPD Sharing Time Frame

At completion of HBRN project. Length of availability determined by NIDDK data repository.

IPD Sharing Access Criteria

Per NIDDK-supported data repository

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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