Clinical trial NCT01368497: Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection
Official title: Clinical Trial of Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic HBV Infection (HBRN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B
Keywords: Hepatitis B
HBV
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2011-06-08
Enrollment: 60
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: 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)
timeFrame: End of follow-up (up to 96 weeks)
measure: Incidence of Adverse Events (AEs) Per Person-Year
timeFrame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
measure: Incidence of Serious Adverse Events (SAEs) Per Person-Year
timeFrame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
Secondary outcomes:
measure: Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBeAg Seroconversion
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBeAg Seroconversion
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBsAg Seroconversion
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBsAg Seroconversion
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With Alanine Aminotransferase (ALT) ≤ 40 Units (U) Per Liter (L) for Males, ≤ 35 U/L for Females
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With ALT ≤ 40 U/L for Males, ≤ 35 U/L for Females
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBV DNA ≤1000 IU/mL
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBV DNA ≤1000 IU/mL
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion of Participants With HBV DNA < 20 IU/mL
timeFrame: End of treatment (up to 48 weeks)
measure: Proportion of Participants With HBV DNA < 20 IU/mL
timeFrame: End of follow-up (up to 96 weeks)
measure: Proportion Without Detectable Antiviral Drug-resistance HBV Mutations
timeFrame: End of treatment (up to 48 weeks)
measure: Growth Measures: Z-scores Weight, Height, and Body Mass Index
timeFrame: End of treatment (up to 48 weeks)
measure: Growth Measures: Z-scores Weight, Height, and Body Mass Index
timeFrame: End of follow-up (up to 96 weeks)
measure: Tanner Stages of Physical Growth
timeFrame: End of treatment (up to 48 weeks)
measure: Tanner Stages of Physical Growth
timeFrame: End of follow-up (up to 96 weeks)
measure: Tanner Stages of Pubic Hair Growth
timeFrame: End of treatment (up to 48 weeks)
measure: Tanner Stages of Pubic Hair Growth
timeFrame: End of follow-up (up to 96 weeks)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis Children's Medical Center
state: Missouri
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: Hospital of Sick Children
state: Ontario
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Averell Sherker, MD
role: STUDY_CHAIR
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Ed Doo, MD
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Kathleen Schwarz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of adolescent development. J Youth Adolesc. 1980 Jun;9(3):271-80. doi: 10.1007/BF02088471.