Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection
This study is currently recruiting participants.
Verified April 2013 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT01368497
First received: June 6, 2011
Last updated: April 30, 2013
Last verified: April 2013
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Purpose
The purpose of this study is to determine the effectiveness of treatment using a combination of drugs (entecavir and pegylated interferon) vs. no treatment in children ages 3-<18 years old with immunotolerant chronic hepatitis B.
| Condition | Intervention | Phase |
|---|---|---|
|
Hepatitis B |
Drug: Entecavir and peginterferon |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Clinical Trial of Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic HBV Infection (HBRN) |
Resource links provided by NLM:
Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Primary Outcome Measures:
- HBeAg loss (lack of detectable HBeAg) and HBV DNA levels ≤1,000 IU/mL at the time of last follow up 48 weeks after end-of-treatment [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Hepatitis B surface antigen (HBsAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
- HBsAg loss [ Time Frame: at week 84 ] [ Designated as safety issue: No ]
- HBsAg loss [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
- Hepatitis B e antigen (HBeAg) loss [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
- HBeAg loss [ Time Frame: at week 84 ] [ 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 84 ] [ Designated as safety issue: No ]
- HBeAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
- HBsAg seroconversion [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
- HBsAg seroconversion [ Time Frame: at week 84 ] [ Designated as safety issue: No ]
- HBsAg seroconversion [ Time Frame: at week 96 ] [ Designated as safety issue: No ]
- Alanine aminotransferase (ALT) ≤ 40 IU/L for males, ≤ 35 IU/L for females [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
- ALT ≤ 40 IU/L for males, ≤ 35 IU/L for females [ Time Frame: at week 84 ] [ Designated as safety issue: No ]
- ALT ≤ 40 IU/L for males, ≤ 35 IU/L for females [ 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 84 ] [ 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 84 ] [ 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 ]
- Absence of detectable antiviral drug-resistance HBV mutations [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
- Growth parameters [ Time Frame: at week 48 ] [ Designated as safety issue: No ]weight, height, Body Mass Index, Tanner scores
- Growth parameters [ Time Frame: at week 84 ] [ Designated as safety issue: No ]weight, height, Body Mass Index, Tanner scores
- Growth parameters [ Time Frame: at week 96 ] [ Designated as safety issue: No ]weight, height, Body Mass Index, Tanner scores
- Serious Adverse Events [ Time Frame: up to 48 weeks ] [ Designated as safety issue: Yes ]
- Adverse events [ Time Frame: up to 48 weeks ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 136 |
| Study Start Date: | May 2012 |
| Estimated Study Completion Date: | May 2015 |
| Estimated Primary Completion Date: | May 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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
|
|
No Intervention: Control
Participants will receive the current standard of care treatment for immune tolerant hepatitis B, which is no treatment.
|
Detailed Description:
This multicenter, randomized, controlled study will be conducted by the pediatric centers within the 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 be randomized in a 1:1 ratio to one of two groups. The treated group 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 in the control group will receive standard of care which is no active treatment. All children will be followed for 96 weeks which is 48 weeks after discontinuation of therapy in the treatment group. Those children initially randomized to the control group will be offered compassionate combination therapy once all data for the primary outcome are analyzed if combination therapy is shown to be efficacious for the primary outcome.
Assessment in the treatment group 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. Assessments in the control group will be undertaken at baseline, weeks 8, 12, 20, 32, 48, 72, 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 storage.
Participants in the treatment group 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 in either group 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.
Eligibility| Ages Eligible for Study: | 3 Years to 18 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Enrolled in and completed the baseline evaluation in NCT01263600
- 3 to <18 years at time of randomization (day 0).
- Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥ 24 weeks prior to randomization or positive HBsAg and negative anti-HBc IgM within 24 weeks of randomization.
- Presence of HBeAg in serum at the last screening visit within 6 weeks of randomization AND ≥24 weeks prior to randomization.
- Serum HBV DNA level >107 IU/mL on at least two occasions at least 12 weeks apart during the 52 weeks before randomization. The HBV DNA level from the last of the screening visits (within 6 weeks of randomization) must be used to meet this criterion.
- ALT ≤60 IU/l in males or ≤40 IU/l in females, measured on at least 2 occasions, at screening and at another time that is at least 12 weeks prior to the screening visit in the 52 weeks before randomization with no ALT values >60IU/l in males or >40 IU/l in females within the 48 weeks.
- 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 at screening with HCV-RNA or anti-HCV, anti-HDV, or HIV.
- Presence of another cause of liver disease or 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 109 cells/L or platelet count < 120 x 109 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.
- During the treatment phase of the study, 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.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01368497
Contacts
| Contact: Michelle E Danielson, PhD | 412-624-5555 | danielsonm@edc.pit.edu |
| Contact: Ethan Obstarczyk, BA | 412-383-9584 | obstarczyke@edc.pitt.edu |
Locations
| United States, California | |
| University of California San Francisco Medical Center | Recruiting |
| San Francisco, California, United States, 94143 | |
| Contact: Phillip Rosenthal, MD 415-476-7114 prosenth@peds.ucsf.edu | |
| United States, Maryland | |
| Johns Hopkins University | Recruiting |
| Baltimore, Maryland, United States, 21287 | |
| Contact: Kathleen Schwarz, MD 410-955-8769 kschwarz@jhmi.edu | |
| United States, Minnesota | |
| University of Minnesota | Recruiting |
| Minneapolis, Minnesota, United States, 55455 | |
| Contact: Sarah Jane Schwarzenberg, MD 612-624-1113 schwa005@umn.edu | |
| United States, Missouri | |
| Saint Louis Children's Medical Center | Recruiting |
| Saint Louis, Missouri, United States, 63104 | |
| Contact: Jeffery Teckman, MD 314-577-5647 teckmanj@slu.edu | |
| United States, Texas | |
| University of Texas Southwestern | Recruiting |
| Dallas, Texas, United States, 75235 | |
| Contact: Norberto Rodriguez-Baez, MD 214-456-8000 norberto.rodriguez-baez@childrens.com | |
| United States, Washington | |
| Seattle Children's Hospital | Recruiting |
| Seattle, Washington, United States, 98015 | |
| Contact: Karen Murray, MD 206-987-1036 karen.murray@seattlechildrens.org | |
| Canada, Ontario | |
| Hospital of Sick Children | Recruiting |
| Toronto, Ontario, Canada, m5g1x8 | |
| Contact: Simon Ling, MD 416-813-7734 simon.ling@sickkids.ca | |
Sponsors and Collaborators
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 |
More Information
Additional Information:
No publications provided
| 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 |
| Study First Received: | June 6, 2011 |
| Last Updated: | April 30, 2013 |
| Health Authority: | United States: Institutional Review Board United States: Federal Government United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Hepatitis Hepatitis A Hepatitis B Hepatitis, Chronic Hepatitis B, Chronic Hepatitis, Viral, Human Liver Diseases Digestive System Diseases Virus Diseases Enterovirus Infections Picornaviridae Infections RNA Virus Infections Hepadnaviridae Infections |
DNA Virus Infections Interferons Peginterferon alfa-2a Interferon-alpha Entecavir Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Antiviral Agents Anti-Infective Agents Immunologic Factors Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 22, 2013