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

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ClinicalTrials.gov Identifier: NCT01369199
Recruitment Status : Terminated
First Posted : June 8, 2011
Results First Posted : July 3, 2018
Last Update Posted : July 3, 2018
Sponsor:
Collaborators:
University of Pittsburgh
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

June 6, 2011
June 8, 2011
March 7, 2018
July 3, 2018
July 3, 2018
May 2012
February 14, 2017   (Final data collection date for primary outcome measure)
  • 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.
  • 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.
To compare the efficacy of combination therapy of entecavir and peginterferon versus no treatment [ Time Frame: at 48 weeks ]
Complete list of historical versions of study NCT01369199 on ClinicalTrials.gov Archive Site
  • Proportion of Participants With HBeAg Loss [ Time Frame: End of treatment (up to 48 weeks) ]
  • Proportion of Participants With HBeAg Loss [ Time Frame: End of follow-up (up to 96 weeks) ]
  • Proportion of Participants With HBeAg Seroconversion [ Time Frame: End of treatment (up to 48 weeks) ]
  • Proportion of Participants With HBeAg Seroconversion [ Time Frame: End of follow-up (up to 96 weeks) ]
  • Proportion of Participants With HBsAg Loss [ Time Frame: End of treatment (up to 48 weeks) ]
  • Proportion of Participants With HBsAg Loss [ Time Frame: End of follow-up (up to 96 weeks) ]
  • Proportion of Participants With HBsAg Seroconversion [ Time Frame: End of treatment (up to 48 weeks) ]
  • Proportion of Participants With HBsAg Seroconversion [ Time Frame: 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) ]
  • 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) ]
  • Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L) [ Time Frame: 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) ]
  • Proportion of Participants With HBV DNA ≤1000 IU/mL [ Time Frame: 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) ]
  • Proportion of Participants With HBV DNA <20 IU/mL [ Time Frame: 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) ]
  • Absence of Detectable Antiviral Drug-resistance HBV Mutations [ Time Frame: End of treatment (up to 48 weeks) ]
  • Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ]
  • Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 48 ]
  • Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ]
  • Hepatitis B e antigen (HBeAg) seroconversion [ Time Frame: at week 48 ]
  • Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ]
  • Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 48 ]
  • Proportion with hepatitis B DNA [ Time Frame: at week 48 ]
    ≤1000 IU/mL
  • Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 48 ]
  • Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ]
  • Hepatitis B surface antigen (HBeAg) seroconversion [ Time Frame: at week 96 ]
  • Time to hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 96 ]
  • Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 96 ]
  • Normalization of Alanine Transaminase (ALT) levels [ Time Frame: at week 96 ]
  • Proportion with hepatitis B DNA [ Time Frame: at week 96 ]
    ≤1000 IU/mL
  • Proportion with hepatitis B DNA <20 IU/mL [ Time Frame: at week 96 ]
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 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.

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).

Interventional
Phase 3
Intervention Model: Single Group Assignment
Masking: None (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.
 
Terminated
28
250
February 14, 2017
February 14, 2017   (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 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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United States
 
 
NCT01369199
DK082864 HBRN IT Adult Trial
U01DK082916 ( U.S. NIH Grant/Contract )
U01DK082843 ( U.S. NIH Grant/Contract )
U01DK082863 ( U.S. NIH Grant/Contract )
U01DK082864 ( U.S. NIH Grant/Contract )
U01DK082866 ( U.S. NIH Grant/Contract )
U01DK082867 ( U.S. NIH Grant/Contract )
U01DK082871 ( U.S. NIH Grant/Contract )
U01DK082872 ( U.S. NIH Grant/Contract )
U01DK082874 ( 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 )
U01DK082944 ( U.S. NIH Grant/Contract )
P30DK050306 ( U.S. NIH Grant/Contract )
A-DK-3002-001 ( Other Grant/Funding Number: Interagency agreement with NIDDK )
M01RR000040 ( U.S. NIH Grant/Contract )
UL1TR000058 ( U.S. NIH Grant/Contract )
UL1TR000004 ( U.S. NIH Grant/Contract )
UL1TR001111 ( U.S. NIH Grant/Contract )
UL1RR024986 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Yes
Plan Description: All data collected will be sent to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported data repository.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: At completion of HBRN project. Length of availability determined by NIDDK data repository.
Access Criteria: Per NIDDK-supported data repository
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • University of Pittsburgh
  • National Center for Research Resources (NCRR)
Study Chair: Averell Sherker, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Anna Lok, MD University of Michigan
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
June 2018

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