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

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ClinicalTrials.gov Identifier: NCT01368497
Recruitment Status : Completed
First Posted : June 8, 2011
Results First Posted : July 3, 2018
Last Update Posted : September 21, 2018
Sponsor:
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 single arm treatment study was 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 fulfilled the entry criteria received entecavir as monotherapy for 8 weeks and then combination therapy with entecavir and pegylated interferon by weekly subcutaneous injection until week 48. Children were to be followed for 48 weeks after discontinuation of therapy (week 96 for those who completed 48 weeks of treatment).

Assessment was undertaken at baseline, weeks 4, 8, 10, 12, 14, & 16, then every 4 weeks until week 48, and then 4, 8, 12, 24,36, and 48 weeks following treatment discontinuation corresponding to weeks 52, 56, 60, 72, 84 and 96 for those who received treatment for 48 weeks. Blood work was drawn to measure markers of viral and liver disease status and for research biospecimen banking.

Participants were to receive therapy until week 48 and enter 48 weeks of follow-up thereafter. Participants who experienced a sustained elevation of alanine aminotransferase (ALT) were eligible to receive treatment as recommended by their hepatologist and continued to complete the study 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 followed by 40 weeks of both entecavir and peginterferon
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. Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss & Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels ≤1,000 International Units (IU) Per Milliliter (mL) [ Time Frame: End of follow-up (up to 96 weeks) ]
  2. Incidence of Adverse Events (AEs) 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 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.

  3. 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.


Secondary Outcome Measures :
  1. Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss [ Time Frame: End of treatment (up to 48 weeks) ]
  2. Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss [ Time Frame: End of follow-up (up to 96 weeks) ]
  3. Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss [ Time Frame: End of treatment (up to 48 weeks) ]
  4. Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss [ Time Frame: End of follow-up (up to 96 weeks) ]
  5. Proportion of Participants With HBeAg Seroconversion [ Time Frame: End of treatment (up to 48 weeks) ]
  6. Proportion of Participants With HBeAg Seroconversion [ Time Frame: End of follow-up (up to 96 weeks) ]
  7. Proportion of Participants With HBsAg Seroconversion [ Time Frame: End of treatment (up to 48 weeks) ]
  8. Proportion of Participants With HBsAg Seroconversion [ Time Frame: End of follow-up (up to 96 weeks) ]
  9. Proportion of Participants With Alanine Aminotransferase (ALT) ≤ 40 Units (U) Per Liter (L) for Males, ≤ 35 U/L for Females [ Time Frame: End of treatment (up to 48 weeks) ]
  10. Proportion of Participants With ALT ≤ 40 U/L for Males, ≤ 35 U/L for Females [ Time Frame: End of follow-up (up to 96 weeks) ]
  11. Proportion of Participants With HBV DNA ≤1000 IU/mL [ Time Frame: End of treatment (up to 48 weeks) ]
  12. Proportion of Participants With HBV DNA ≤1000 IU/mL [ Time Frame: End of follow-up (up to 96 weeks) ]
  13. Proportion of Participants With HBV DNA < 20 IU/mL [ Time Frame: End of treatment (up to 48 weeks) ]
  14. Proportion of Participants With HBV DNA < 20 IU/mL [ Time Frame: End of follow-up (up to 96 weeks) ]
  15. Absence of Detectable Antiviral Drug-resistance HBV Mutations [ Time Frame: End of treatment (up to 48 weeks) ]
  16. Growth Measures: Z-scores Weight, Height, and Body Mass Index [ Time Frame: End of treatment (up to 48 weeks) ]
    A child's Z-score is the number of standard deviations that the child is from the average of children of the same sex and age from a reference population. The reference population is provided in the 2000 Centers for Disease Control and Prevention (CDC) growth charts. Positive Z scores mean the growth measure (weight, height, or body mass index) is above the average, negative Z scores mean the growth measure is below the average.

  17. Growth Measures: Z-scores Weight, Height, and Body Mass Index [ Time Frame: End of follow-up (up to 96 weeks) ]
    A child's Z-score is the number of standard deviations that the child is from the average of children of the same sex and age from a reference population. The reference population is provided in the 2000 Centers for Disease Control and Prevention (CDC) growth charts. Positive Z scores mean the growth measure (weight, height, or body mass index) is above the average, negative Z scores mean the growth measure is below the average.

  18. Tanner Stages of Physical Growth [ Time Frame: End of treatment (up to 48 weeks) ]

    The Tanner Stage questionnaire is only completed by participants 8 years of age and older. The copyrighted form includes pictures and descriptions. Girls selected the picture closest to their self-perceived breast growth from among 5 stages of breast growth and boys did the same for testes, scrotum, and penis growth.

    Boys: I-prepubertal; II-enlargement of scrotum and testes; III-enlargement of the penis and further growth of testes; IV- increased size of penis with growth in breadth and development of glans, testes, and scrotum larger, scrotum skin darker; V- adult genitalia.

    Girls: I-prepubertal; II-breast bud stage with the elevation of breast and papilla and enlargement of the areola; III-further enlargement of breast and areola, no separation of their contour; IV-areola and papilla form a secondary mound above the level of the breast; V: mature adult stage.

    There is no "better" or "worse" outcome. They are self-assessed descriptive measures of physical growth.


  19. Tanner Stages of Physical Growth [ Time Frame: End of follow-up (up to 96 weeks) ]

    The Tanner Stage questionnaire is only completed by participants 8 years of age and older. The copyrighted form includes pictures and descriptions. Girls selected the picture closest to their self-perceived breast growth from among 5 stages of breast growth and boys did the same for testes, scrotum, and penis growth.

    Boys: I-prepubertal; II-enlargement of scrotum and testes; III-enlargement of the penis and further growth of testes; IV- increased size of penis with growth in breadth and development of glans, testes, and scrotum larger, scrotum skin darker; V- adult genitalia.

    Girls: I-prepubertal; II-breast bud stage with the elevation of breast and papilla and enlargement of the areola; III-further enlargement of breast and areola, no separation of their contour; IV-areola and papilla form a secondary mound above the level of the breast; V: mature adult stage.

    There is no "better" or "worse" outcome. They are self-assessed descriptive measures of physical growth.


  20. Tanner Stages of Pubic Hair Growth [ Time Frame: End of treatment (up to 48 weeks) ]

    The Tanner Stage questionnaire is only completed by participants 8 years of age and older. The copyrighted form includes pictures and descriptions. Participants selected the picture closest to their self-perceived pubic hair growth.

    Boys and girls: I-prepubertal (no pubic hair at all); II-sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia; III: darker, coarser and more curled hair, spreading sparsely over junction of pubes; IV- hair adult in type, but covering smaller area than in adult; V-adult in type and quantity.

    There is no "better" or "worse" outcome. They are self-assessed descriptive measures of physical growth.


  21. Tanner Stages of Pubic Hair Growth [ Time Frame: End of follow-up (up to 96 weeks) ]

    The Tanner Stage questionnaire is only completed by participants 8 years of age and older. The copyrighted form includes pictures and descriptions. Participants selected the picture closest to their self-perceived pubic hair growth.

    Boys and girls: I-prepubertal (no pubic hair at all); II-sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia; III: darker, coarser and more curled hair, spreading sparsely over junction of pubes; IV- hair adult in type, but covering smaller area than in adult; V-adult in type and quantity.

    There is no "better" or "worse" outcome. They are self-assessed descriptive measures of physical growth.




Information from the National Library of Medicine

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

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 hepatitis B surface antigen (HBsAg) in serum for ≥ 24 weeks prior to baseline OR positive HBsAg and negative anti-Hepatitis B core (HBc) immunoglobulin (IgM) within 24 weeks of baseline visit.
  • Presence of hepatitis B e-antigen (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, International Normalized Ratio (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 ClinicalTrials.gov identifier (NCT number): NCT01368497


Locations
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)
Investigators
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
  Study Documents (Full-Text)

Documents provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Additional Information:
Publications:
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov 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
Results First Posted: July 3, 2018
Last Update Posted: September 21, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All data will be sent to the NIDDK-supported data repository.
Supporting Materials: Study Protocol
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.

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

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Hepatitis B
HBV

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