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

Bristol-Myers Squibb180 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

180

Conditions

Chronic Hepatitis B Virus, Pediatric

Interventions

EntecavirDRUG

Tablets/oral solution, 0.015 mg/kg up to 0.5 mg, administered orally, once daily, for 96 to144 weeks, depending on response

PlaceboDRUG

Tablets/oral solution, 0 mg, administered orally, once daily, for 48 to 96 weeks, depending on response

Eligibility

Sex: ALLMin age: 2 YearsMax age: 17 Years

Medical Language ↔ Plain English

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

Locations (44)

Outcomes

Primary Outcomes

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.

Time frame: At Week 48

Secondary Outcomes

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.

Time frame: At Week 48

Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48

Time frame: 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.

Time frame: At Week 48

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (Undetectable HBeAg and Presence of Anti-HBeAb)

Data from ClinicalTrials.gov

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University Of California, San Francisco

San Francisco, California, United States

Connecticut Children'S Medical Center

Hartford, Connecticut, United States

Children'S National Medical Center

Washington D.C., District of Columbia, United States

University Of Florida

Gainesville, Florida, United States

Romero, Rene

Atlanta, Georgia, United States

Indiana University School Of Medicine / Riley Hospital

Indianapolis, Indiana, United States

Johns Hopkins School Of Medicine

Baltimore, Maryland, United States

Shah, Uzma

Boston, Massachusetts, United States

Boston Childrens Hospital

Boston, Massachusetts, United States

Mount Sinai Medical Center

New York, New York, United States

...and 34 more locations

Percentage of participants in the primary cohort with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBe antibodies) at week 48

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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.)

Time frame: 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.)

Time frame: 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.

Time frame: At 48 and 96 weeks