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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 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: May 7, 2014
Last verified: May 2014

June 6, 2011
May 7, 2014
May 2012
May 2015   (final data collection date for primary outcome measure)
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 ]
To compare the efficacy of combination therapy of entecavir and peginterferon versus no treatment [ Time Frame: at 48 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01369199 on ClinicalTrials.gov Archive Site
  • 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 ]
  • Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Proportion with hepatitis B DNA [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
    ≤1000 IU/mL
  • Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
  • Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
  • Proportion with hepatitis B DNA [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
    ≤1000 IU/mL
  • Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B
Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B

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.

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.

Interventional
Phase 3
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Hepatitis B
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
Experimental: Peginterferon and entecavir
A combination of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon.
Intervention: Drug: Entecavir and peginterferon
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
40
May 2016
May 2015   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact: Michelle E Danielson, PhD 412-624-5555 danielsonm@edc.pitt.edu
Contact: Joan MacGregor, MS 412-624-4300 macgreg@edc.pitt.edu
United States,   Canada
 
NCT01369199
DK082864 HBRN IT Adult Trial
Yes
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pittsburgh
Study Chair: Averell Sherker, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP