A Phase III Study of the Safety and Efficacy of Entecavir in Pediatric Patients With Chronic Hepatitis B Virus Infection

A Comparative Study of the Antiviral Efficacy and Safety of Entecavir (ETV) Versus Placebo in Pediatric Subjects With Chronic Hepatitis B Virus (HBV) Infection Who Are HBeAg-Positive

The purpose of this study was to evaluate the safety and efficacy of entecavir in pediatric patients with chronic hepatitis B virus infection

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B Virus, Pediatric
• Intervention / Treatment: Drug: Entecavir; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Bunos Aires, Buenos Aires, Argentina, 1425
      • Local Institution
• Belgium
  • Bruxelles, Belgium, 1200
    • Local Institution
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Local Institution
• Germany
  • Starnberg, Germany, 82319
    • Local Institution
  • Wuppertal, Germany, 42283
    • Local Institution
  • Rheinland Pfalz
    • Mainz, Rheinland Pfalz, Germany, 55131
      • Local Institution
• Greece
  • Thesaloniki, Greece, 54635
    • Local Institution
• India
  • Guwahati, India, 781006
    • Local Institution
  • Hyderabad, India, 500029
    • Local Institution
• Israel
  • Beer-sheva, Israel, 84101
    • Local Institution
  • Petach Tikva, Israel
    • Local Institution
  • Zefat, Israel, 13110
    • Local Institution
• Korea, Republic of
  • Daegu, Korea, Republic of, 700-721
    • Local Institution
  • Seoul, Korea, Republic of, 135-710
    • Local Institution
  • Seoul, Korea, Republic of, 138-736
    • Local Institution
• Poland
  • Bydgoszcz, Poland, 85-030
    • Local Institution
  • Krakow, Poland, 31-202
    • Local Institution
  • Wroclaw, Poland, 50-345
    • Local Institution
• Romania
  • Bucharest, Romania, 011743
    • Local Institution
  • Iasi, Romania, 700309
    • Local Institution
  • Timisoara, Romania, 300011
    • Local Institution
• Russian Federation
  • Moscow, Russian Federation, 111123
    • Local Institution
  • Moscow, Russian Federation, 117198
    • Local Institution
  • Novokuznetsk, Russian Federation, 654063
    • Local Institution
  • St. Petersburg, Russian Federation, 197022
    • Local Institution
• Taiwan
  • Tainan, Taiwan, 704
    • Local Institution
  • Taipei, Taiwan, 100
    • Local Institution
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • Local Institution
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B4 6NH
      • Local Institution
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Romero, Rene
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School Of Medicine / Riley Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital
    • Boston, Massachusetts, United States, 02114
      • Shah, Uzma
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital at Carolinas Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Fairfax Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria

• Males and females, aged 2 to <18 years
• Hepatitis B surface antigen-positive
• Detectable hepatitis B e (HBe) antigen, and no detectable anti-HBe antibodies
• Alanine aminotransferase (ALT) 1.5 to <10 times the upper limit of normal at screening and within 8 to 24 weeks prior to screening
• Evidence of the presence of hepatitis B virus DNA at least 4 weeks before screening and >100,000 copies/mL at screening

Key Exclusion Criteria

• Any prior therapy with entecavir
• At least 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent
• Therapy with interferon alpha, thymosin alpha, or nucleototide antiviral agents within 24 weeks of screening
• Coinfection with HIV, hepatitis C virus, or hepatitis D virus
• Decompensated liver disease
• Liver transplant recipients
• Other forms of acute and chronic conditions which may cause increased ALT levels
• Children who were breastfed while their mothers received lamivudine or whose mothers received lamivudine during pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Entecavir; Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response	Drug: Entecavir; Tablets/oral solution, 0.015 mg/kg up to 0.5 mg, administered orally, once daily, for 96 to144 weeks, depending on response; Other Names: Baraclude; BMS-200475
Placebo Comparator: Placebo; Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response	Drug: Placebo; Tablets/oral solution, 0 mg, administered orally, once daily, for 48 to 96 weeks, depending on response

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48	Suppression=HBV DNA<50 IU/mL (approximately 300 copies/mL) using the Roche COBAS TaqMan HBV Test for use with the High Pure System assay; seroconversion=undetectable HBeAg and detectable anti-hepatitis B e antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.	At Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48	While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.	At Week 48
Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48	While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.	At Week 48
Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48	LOQ=29 IU/mL. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.	At Week 48
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb)	Percentage of participants in the primary cohort with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBe antibodies) at week 48	At Week 48
Percentage of Participants Who Achieved Sustained HBeAg Seroconversion During Off-treatment Follow up Among Participants Who Achieved HBeAg Seroconversion at End of Dosing (EOD).	Participants who demonstrated HBeAg seroconversion at EOD were followed and assessed for presence of sustained HBeAg seroconversion during entire study. The study reached the end of dosing (EOD) on 22 Feb-2016.	Week 48, EOD (2 years)
Number of Participants With Adverse Events (Including Palatability Issues), SAEs, Discontinuous Due to Adverse Events, and HBV Disease Progression Through Week 48	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.	Day 1 through Week 48 on blinded therapy
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4)	Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. INR=international normalization ratio of prothrombin time; ULN=upper limit of normal. Hemoglobin (g/dL): Grade 1=10-10.9; Grade 2=9-9.9; Grade 3=7-8.9; Grade 4= <7. Platelets (/mm^3): Grade 1=100,000-124,999; Grade 2=50,000-99,999; Grade 3=25,000-49,999; Grade 4= <25,000. INR (*ULN): Grade 1=1.1-1.5; Grade 2=1.6-2; Grade 3=2.1-3; Grade 4= >3. WBC (/mm^3): Grade 1=2000-2500; Grade 2=1500-1999; Grade 3=1000-1499; Grade 4= <1000. Neutrophils (/mm^3): Grade 1=1000-1300; Grade 2=750-999; Grade 3=500-749; Grade 4= <500.	Day 1 through Week 48 on blinded therapy
Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued)	Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ULN=upper limit of normal; LLN=lower limit of normal. ALT, AST (*ULN): Grade 1=1.25-2; Grade 2=2.6-5; Grade 3=5.1-10; Grade 4 => 10. Bilirubin (*ULN): Grade 1 = 1.1-1.5; Grade 2=1.6-2.5; Grade 3 = 2.6-5; Grade 4= >5. Albumin (g/dL): Grade 1=3- <LLN; Grade 2=2-2.9; Grade 3= <2. Lipase (*ULN): Grade 1=1.1-1.5; Grade 2=1.6-3; Grade 3=3.1-5; Grade 4= >5. BUN/urea (*ULN): Grade 1=1.25-<2.6; Grade 2=2.6-<5.1; Grade 3=5.1-10; Grade 4= >10. Chloride, high (mEq/L): Grade 1=113-<117; Grade 2=117-<121; Grade 3=121-125; Grade 4= >125. Potassium, low (mEq/L): Grade 1=3-3.4; Grade 2=2.5-<3; Grade 3=2-<2.5; Grade 4=<2. Potassium, high (mEq/L): : Grade 1= 5.6-<6.1; Grade 2=6.1-<6.6; Grade 3=6.6-7; Grade 4= >7. Sodium, high (mEq/L): Grade 1=146<151; Grade 2=151-<155; Grade 3=155-<160; Grade 4= >=160.	Day 1 through Week 48 on blinded therapy
Percentage of Participants With HBeAg Seroconversion on ETV Over-time at Week 96 (All ETV Cohort)	HBe seroconversion=undetectable HBe antigen and detectable anti-HBe antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.	At Week 96
Percentage of Participants Who Maintained HBeAg Seroconversion at Week 96 (End of Blinded Therapy) Among Participants With HBeAg Seroconversion at Week 48	Participants who achieved HBeAg seroconversion by Week 48 and maintained seroconversion to week 96	At Week 96
Percentage of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression Through Week 96	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.	Day 1 through Week 96
Percentage of Participants With HBeAg Seroconversion (Undetectable HBeAg and Presence of Anti-HBeAb) up to Week 96	On Treatment through week 96 - 2 year cohort NC = F: (The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures.)	up to week 96
Histological Analysis (Percentage) Among Participants With Available Liver Biopsy Data	Liver function test elevations and abnormalities on blinded and open-label ETV (the All ETV Safety Cohort). Participants who experienced elevation of alanine aminotransferase (ALT) greater than three times ETV (entecavir) baseline measure (Participants who displayed liver biopsy with ALT value greater than three times baseline.)	Between weeks 48 and 96
Percentage of Participants With HbeAg Loss at Weeks 48 and 96	HBeAg Loss (NC = F and NC = M) - On Treatment through Week 96 - Year 2 Efficacy Cohort Non-Completer - Failure (NC=F): The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures. Non-Completer - Missing (NC=M): The numerator was based on participants meeting the response criteria. The denominator was based on participants with data at the analysis week. Participants who had missing data at the analysis week were excluded.	At 48 and 96 weeks

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Jonas MM, Chang MH, Sokal E, Schwarz KB, Kelly D, Kim KM, Ling SC, Rosenthal P, Oraseanu D, Reynolds L, Thiry A, Ackerman P. Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen-positive chronic hepatitis B. Hepatology. 2016 Feb;63(2):377-87. doi: 10.1002/hep.28015. Epub 2015 Oct 16. Erratum In: Hepatology. 2017 Apr;65(4):1427.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2010
• Primary Completion (Actual): March 31, 2013
• Study Completion (Actual): March 31, 2018

Study Registration Dates

• First Submitted: March 2, 2010
• First Submitted That Met QC Criteria: March 2, 2010
• First Posted (Estimate): March 3, 2010

Study Record Updates

• Last Update Posted (Actual): May 9, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Anti-Infective Agents; Antiviral Agents; Entecavir
• Other Study ID Numbers: AI463-189 ST

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No