Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01368497
Recruitment Status : Completed
First Posted : June 8, 2011
Last Update Posted : February 26, 2018
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary:
The purpose of this study is to determine the safety and efficacy of treatment using a combination of drugs (entecavir and pegylated interferon) in children ages 3-<18 years old with immunotolerant chronic hepatitis B.

Condition or disease Intervention/treatment Phase
Hepatitis B Drug: Entecavir and peginterferon Phase 3

Detailed Description:

This multicenter, randomized, controlled study will be conducted by the pediatric centers within the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK)-sponsored Hepatitis B Research Network (HBRN). Children age 3-<18 years with immunotolerant chronic hepatitis B (CHB) infection who fulfill the entry criteria will receive entecavir as monotherapy for 8 weeks and then combination therapy with entecavir and pegylated interferon by weekly subcutaneous injection until week 48. Children will be followed for 96 weeks which is 48 weeks after discontinuation of therapy.

Assessment will be undertaken at baseline, weeks 4, 8, 10, 12, 14, & 16, then every 4 weeks until week 48, and then at week 52, 56, 60, 72, 84 and 96. Data collected will describe baseline demographics, symptoms of liver disease, intercurrent illnesses, and findings on physical examination. Blood work will be drawn to measure markers of viral and liver disease status, assessment of drug adverse effects, and for research biospecimen banking.

Participants will continue on therapy until week 48 and complete the full study follow-up protocol thereafter, including those who undergo seroconversion to anti-HBe or anti-HBs before reaching week 48. Participants who experience a sustained elevation of ALT will be eligible to receive treatment as recommended by their hepatologist and will continue to complete the study follow-up protocol. Participants who exhibit adverse effects of therapy will undergo dose adjustment or discontinuation of therapy as detailed in the protocol, and will continue to complete the study follow-up protocol.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Trial of Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic HBV Infection (HBRN)
Study Start Date : September 2012
Actual Primary Completion Date : December 23, 2016
Actual Study Completion Date : December 23, 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Entecavir and peginterferon
Entecavir for 8 weeks and then combination therapy with entecavir and peginterferon 180 mcg/1.73m2 by weekly subcutaneous injection until week 48
Drug: Entecavir and peginterferon
Entecavir 0.015 mg/kg/day (up to 0.5 mg maximum daily dose) once daily for 48 weeks and Peginterferon alfa-2a 180 µg/1.73m2 subcutaneously once weekly for 40 weeks beginning 8 weeks after entecavir monotherapy).
Other Name: PEGASYS, peginterferon alfa 2a, Baraclude

Primary Outcome Measures :
  1. HBeAg loss (lack of detectable HBeAg) & HBV DNA levels ≤1,000 IU/mL [ Time Frame: at weeks 48 & 96 ]
  2. Number, type & rate of adverse events/serious adverse events through end of treatment [ Time Frame: at weeks 48 & 96 ]

Secondary Outcome Measures :
  1. Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ]
  2. HBsAg loss [ Time Frame: at week 96 ]
  3. Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ]
  4. HBeAg loss [ Time Frame: at week 96 ]
  5. HBeAg seroconversion [ Time Frame: at week 48 ]
  6. HBeAg seroconversion [ Time Frame: at week 96 ]
  7. HBsAg seroconversion [ Time Frame: at week 48 ]
  8. HBsAg seroconversion [ Time Frame: at week 96 ]
  9. Alanine aminotransferase (ALT) ≤ 40 U/L for males, ≤ 35 U/L for females [ Time Frame: at week 48 ]
  10. ALT ≤ 40 U/L for males, ≤ 35 U/L for females [ Time Frame: at week 96 ]
  11. HBV DNA ≤1000 IU/mL [ Time Frame: at week 48 ]
  12. HBV DNA ≤1000 IU/mL [ Time Frame: at week 96 ]
  13. HBV DNA < 20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 48 ]
  14. HBV DNA < 20 IU/mL (LLOQ of COBAS Ampliprep/COBAS TaqMan HBV v2.0 test) [ Time Frame: at week 96 ]
  15. Absence of detectable antiviral drug-resistance HBV mutations [ Time Frame: at week 48 ]
  16. Growth parameters [ Time Frame: at week 48 ]
    weight, height, Body Mass Index, Tanner scores

  17. Growth parameters [ Time Frame: at week 96 ]
    weight, height, Body Mass Index, Tanner scores

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   3 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Enrolled in & completed the baseline evaluation in NCT01263600 OR completed necessary components of NCT01263600 baseline evaluation by the end of the baseline visit.
  • 3 to <18 years at time of randomization (day 0).
  • Documented chronic Hepatitis B virus (HBV) infection as evidenced by detection of HBsAg in serum for ≥ 24 weeks prior to baseline OR positive HBsAg and negative anti-HBc IgM within 24 weeks of baseline visit.
  • Presence of HBeAg in serum at the last screening visit within 6 weeks of baseline visit.
  • Serum HBV DNA level >10^7 IU/mL on at least 2 occasions at least 12 weeks apart during the 52 weeks before baseline visit. The HBV DNA levels must be within 6 weeks of baseline visit.
  • ALT ≤60 U/l in males or ≤40 U/l in females, measured on at least 2 occasions, at screening (within 6 weeks prior to baseline visit) & at least 12 weeks prior to the screening visit & within the 52 weeks prior to baseline visit.
  • Compensated liver disease, with normal total bilirubin (except if Gilbert's syndrome), direct bilirubin ≤0.5 mg/dL, INR ≤1.5, and serum albumin ≥3.5 g/dL.
  • Creatinine clearance 90 ml/min.
  • Absence of hepatocellular carcinoma on liver ultrasound in the past 48 weeks.

Exclusion criteria:

  • Presence of infection with Hepatitis C virus (HCV)-RNA or anti-HCV, anti-Hepatitis D virus (HDV), or HIV at screening.
  • Presence of another cause of liver disease or hepatocellular cancer (HCC) (serum alpha-fetoprotein >50ng /ml).
  • Evidence of decompensated liver disease (Childs B-C).
  • History or other evidence of a medical condition associated with chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures).
  • Females who are pregnant or breastfeeding.
  • Adolescent females unwilling or unable to use an acceptable method of contraception if sexually active during the treatment period.
  • Children currently breastfeeding while their mother is taking lamivudine, or those who were exposed to lamivudine for ≥24 weeks via maternal lamivudine treatment during pregnancy and/or while breastfeeding.
  • Previous liver or other organ transplantation including engrafted bone marrow transplant.
  • Hematological abnormalities during the screening period that contraindicate full dosing with study drugs, e.g absolute neutrophil count < 1.5 x 10^9 cells/L or platelet count < 120 x 10^9 cells/L.
  • Known allergy to study drugs; peginterferon alfa-2a or entecavir.
  • Treatment with systemic acyclovir or famciclovir within the previous 6 months.
  • Need for ongoing use of any antivirals with activity against HBV during the course of the study or history of receiving treatment for HBV.
  • Any use of illegal drugs OR use of alcoholic beverages which in the opinion of a study physician is sufficient to prevent adequate compliance with study procedures or increase the risk of pancreatitis or hepatotoxicity.
  • History of immunologically mediated disease (e.g. inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis).
  • History or other evidence of bleeding from esophageal varices or consistent with decompensated liver disease.
  • History or other evidence of chronic pulmonary disease associated with functional limitation.
  • History of significant cardiovascular diseases.
  • History of a severe seizure disorder or current anticonvulsant use.
  • History or other evidence of severe retinopathy.
  • History of thyroid disease poorly controlled on prescribed medications. Participants with elevated thyroid stimulating hormone concentrations with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease are excluded.
  • Concomitant use or use during ≤ 6 months prior to the first dose of study drug of anti-neoplastic, immunosuppressive, nephrotoxic or hepatotoxic medication, methadone, theophylline or medications that may affect renal excretion or hepatic metabolism are not permitted.
  • Concomitant use of complementary or alternative medications purported to have antiviral activity.
  • A participant may not be co-enrolled in another clinical trial where an investigational drug is administered.
  • Any other condition or situation that in the opinion of a study physician would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01368497

United States, California
University of California San Francisco Medical Center
San Francisco, California, United States, 94143
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Saint Louis Children's Medical Center
Saint Louis, Missouri, United States, 63104
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States, 75235
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98015
Canada, Ontario
Hospital of Sick Children
Toronto, Ontario, Canada, m5g1x8
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Chair: Averell Sherker, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Chair: Ed Doo, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Kathleen Schwarz, MD Johns Hopkins University

Additional Information:
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Identifier: NCT01368497     History of Changes
Other Study ID Numbers: DK082864 HBRN IT Peds Trial
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 )
UL1TR000423 ( U.S. NIH Grant/Contract )
UL1TR000004 ( U.S. NIH Grant/Contract )
A-DK-3002-001 ( Other Identifier: Interagency agreement with NIDDK )
First Posted: June 8, 2011    Key Record Dates
Last Update Posted: February 26, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Hepatitis B
Liver Diseases
Digestive System Diseases
Hepadnaviridae Infections
DNA Virus Infections
Virus Diseases
Hepatitis, Viral, Human
Peginterferon alfa-2a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs