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

This study is currently recruiting participants.
Verified October 2013 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor:
Collaborator:
University of Pittsburgh
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT01369199
First received: June 6, 2011
Last updated: October 23, 2013
Last verified: October 2013
  Purpose

The investigators propose to evaluate 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. The investigators hypothesize that using a potent nucleos(t)ide analogue will provide a higher rate of loss of HBeAg loss and suppression of HBV DNA.


Condition Intervention Phase
Hepatitis B
Drug: Entecavir and peginterferon
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Safety: Number, type and rate of adverse events/serious adverse events through treatment and end of follow-up 48 weeks after stopping treatment. Efficacy: HBeAg loss (lack of detectable HBeAg) AND HBV DNA ≤1,000 IU/mL 48 weeks after stopping treatment. [ Time Frame: at 96 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • HBeAg loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • HBeAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • HBeAg seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • HBeAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Time to HBsAg loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Time to HBsAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • ALT <45 IU/L for men, <30 IU/L for women (approximately 1.5 ULN) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • ALT <45 IU/L for men, <30 IU/L for women (approximately 1.5 ULN) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • ALT normalization (men <30 IU/L, women <20 IU/L) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • ALT normalization (men <30 IU/L, women <20 IU/L) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • HBV DNA ≤1000 IU/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • HBV DNA ≤1000 IU/mL [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • HBV DNA <20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • HBV DNA <20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 96 ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: May 2012
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Peginterferon and entecavir
A combination of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon.
Drug: 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 Name: PEGASYS, peginterferon alfa 2a, Baraclude

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 "off treatment" 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 ALT levels and high serum levels of HBV DNA ("immune tolerant" HBeAg-positive chronic hepatitis B). All participants will be followed until week 96 (48 weeks after discontinuation of therapy in the treatment group) at which time the primary outcome will be measured.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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-HBc 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 IU/L in males, ≤30 IU/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 HCC based upon alpha-fetoprotein (AFP) ≤20 ng/mL at screening visit (up to 6 weeks prior to baseline visit). a. Participants who meet 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, 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 NALFD with severe steatohepatitis is exclusionary.
  • Presence of anti-HDV or anti-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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01369199

Contacts
Contact: Michelle E Danielson, PhD 412-624-5555 danielsonm@edc.pitt.edu
Contact: Joan MacGregor, MS 412-624-4300 macgreg@edc.pitt.edu

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Steven Han, MD    310-206-0645    steven.han@ucla.edu   
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Tram T. Tran, MD    310-423-1971    tram.tran@cshs.org   
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Norah Terrault, MD    415-476-2227    norah.terrault@ucsf.edu   
Principal Investigator: Mandana Khalili, MD, MAS         
California Pacific Medical Center Recruiting
San Francisco, California, United States, 94115
Contact: Stewart Cooper, MD    415-600-1548    coopersl@sutterhealth.org   
United States, Hawaii
Queen's Medical Center Recruiting
Honolulu, Hawaii, United States, 96813
Contact: Naoky Tsai, MD    808-691-7609    tsain@queens.org   
United States, Maryland
NIH Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: Marc Ghany, MD    301-402-5115    marcg@intra.niddk.nih.gov   
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Daryl Lau, MD, MPH    617-632-1098    dlau@bidmc.harvard.edu   
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Raymond T. Chung, MD    617-724-7562    rtchung@partners.org   
United States, Michigan
University of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Anna Lok, MD    734-936-7511    aslok@med.umich.edu   
United States, Minnesota
University of Minnesota Recruiting
Plymouth, Minnesota, United States, 55446
Contact: Coleman Smith, MD    612-871-1145 ext 2908    smith146@umn.edu   
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: W. Ray Kim, MD    507-538-0254    kim.woong@mayo.edu   
United States, Missouri
Saint Louis University Recruiting
St. Louis, Missouri, United States, 63104
Contact: Adrian M. Di Bisceglie, MD    314-577-8551    dibiscam@slu.edu   
Washington University Recruiting
St. Louis, Missouri, United States, 63110
Contact: Mauricio Lisker-Melman, MD    314-747-3969    mlisker@dom.wustl.edu   
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Michael W. Fried, MD    919-966-2516    mfried@med.unc.edu   
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Keyur Patel, MD    919-681-4044    keyur.patel@duke.edu   
United States, Texas
Baylor University Medical Center Recruiting
Dallas, Texas, United States, 75246
Contact: Robert Perrillo, MD    214-820-2956    roberper@baylorhealth.edu   
University of Texas Southwestern Recruiting
Dallas, Texas, United States, 75390
Contact: William M. Lee, MD    214-645-6110    william.lee@utsouthwestern.edu   
United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23498
Contact: Richard Sterling, MD, MSc    804-828-4060    rksterli@vcu.edu   
United States, Washington
University of Washington Medical Center Recruiting
Seattle, Washington, United States, 98105
Contact: Robert Carithers, MD    206-598-4956    robertc@medicine.washington.edu   
Virginia Mason Medical Center Recruiting
Seattle, Washington, United States, 98101
Contact: Kris Kowdley, MD    206-223-2319    kris.kowdley@vmmc.org   
Canada, Ontario
University of Toronto Recruiting
Toronto, Ontario, Canada, M5T 2S8
Contact: Harry Janssen, MD, PhD    416-603-5800 ext 2776    harry.janssen@uhn.ca   
Principal Investigator: Jordan Feld, MD, MPH         
Principal Investigator: David K. Wong, MD, FRCP (C)         
Sponsors and Collaborators
University of Pittsburgh
Investigators
Study Chair: Averell Sherker, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01369199     History of Changes
Obsolete Identifiers: NCT01534611
Other Study ID Numbers: DK082864 HBRN IT Adult Trial
Study First Received: June 6, 2011
Last Updated: October 23, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Hepatitis B
immune-tolerant hepatitis b
HBV

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Peginterferon alfa-2a
Entecavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014