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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Clinical Trial of Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic HBV Infection (HBRN)

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Entecavir and peginterferon


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entecavir and peginterferon<br>Entecavir for 8 weeks followed by 40 weeks of both entecavir and peginterferon | Drug: Entecavir and peginterferon<br>* 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).<br>* Other names: PEGASYS, peginterferon alfa 2a, Baraclude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | End of follow-up (up to 96 weeks) | 
| Incidence of Adverse Events (AEs) Per Person-Year | 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. | From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks) | 
| Incidence of Serious Adverse Events (SAEs) Per Person-Year | 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. | From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With Hepatitis B Surface Antigen (HBsAg) Loss |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With HBeAg Seroconversion |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With HBeAg Seroconversion |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With HBsAg Seroconversion |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With HBsAg Seroconversion |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With Alanine Aminotransferase (ALT) ≤ 40 Units (U) Per Liter (L) for Males, ≤ 35 U/L for Females |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With ALT ≤ 40 U/L for Males, ≤ 35 U/L for Females |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With HBV DNA ≤1000 IU/mL |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With HBV DNA ≤1000 IU/mL |  | End of follow-up (up to 96 weeks) | 
| Proportion of Participants With HBV DNA < 20 IU/mL |  | End of treatment (up to 48 weeks) | 
| Proportion of Participants With HBV DNA < 20 IU/mL |  | End of follow-up (up to 96 weeks) | 
| Proportion Without Detectable Antiviral Drug-resistance HBV Mutations | HBV drug resistance variant testing was performed at the CDC laboratory. The sequences of the HBV polymerase spanning nucleotide positions 311-1021 were determined by Sanger sequencing. Drug resistance mutations that were tested in this study included L80VI, L82M, T128N, W153Q, F166L, I169T, V173L, L180M, A181TV, T184ACFGILMS, V191T, A194T, A200V, S202ETV, M204IV, V207I, N236T, M250ILV, and G145R. | End of treatment (up to 48 weeks) | 
| Growth Measures: Z-scores Weight, Height, and Body Mass Index | 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. | End of treatment (up to 48 weeks) | 
| Growth Measures: Z-scores Weight, Height, and Body Mass Index | 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. | End of follow-up (up to 96 weeks) | 
| Tanner Stages of Physical Growth | 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. | End of treatment (up to 48 weeks) | 
| Tanner Stages of Physical Growth | 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. | End of follow-up (up to 96 weeks) | 
| Tanner Stages of Pubic Hair Growth | 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. | End of treatment (up to 48 weeks) | 
| Tanner Stages of Pubic Hair Growth | 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. | End of follow-up (up to 96 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B, HBV