The purpose of this clinical study is to determine the appropriate doses of entecavir to use in children and adolescents. Safety, tolerability and efficacy will also be studied
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
64
Tablets / Oral Solution, Oral, Naïve: 0.015 mg/kg up to 0.5 mg; Experienced: 0.030 mg/kg up to 1 mg, once daily, 48 - 120 weeks depending on response
University of California, San Francisco
San Francisco, California, United States
Connecticut Children'S Medical Center
Hartford, Connecticut, United States
Number of Participants With Serious Adverse Events (SAE) and Discontinuations Due to Adverse Events (AEs) - On Treatment
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. Medical Dictionary for Regulatory Activities (MedDRA) version 16.0 was used.
Time frame: Day 1 to Week 120
Mean Maximum Observed Plasma Concentration (Cmax) and Mean Trough Observed Plasma Concentration (Cmin) of Entecavir in LVD-naive and LVD-experienced Participants, by Age Cohort
Cmax and Cmin were derived from plasma concentration of ETV versus time and measured in nanograms per milliliters (ng/mL). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. Note: PK parameters were summarized for only Groups A and B. PK assessment was optional for Group C participants (NA-experienced participants who were included with the September 2011 country-specific protocol amendment). No Group C participants chose to participate in the PK assessment.
Time frame: Day 14
Median Time of Maximum Observed Plasma Concentration (Tmax) in LVD-naive and LVD-experienced Participants, by Age Cohort
Tmax was derived from plasma concentration of ETV versus time and measured in hours (h). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. Age categories presented below: participants age as of first day of dosing. PK assessment was optional for Group C participants (NA-experienced participants who were included with the September 2011 country-specific protocol amendment). No Group C participants chose to participate in the PK assessment.
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University Of Florida
Gainesville, Florida, United States
Johns Hopkins School Of Medicine
Baltimore, Maryland, United States
Boston Childrens Hospital
Boston, Massachusetts, United States
Mount Sinai School Of Medicine
New York, New York, United States
Children'S Hospital Of Philadelphia
Philadelphia, Pennsylvania, United States
Rhode Island Hospital
Providence, Rhode Island, United States
University Of Texas Southwestern Medical Center
Dallas, Texas, United States
Local Institution
Buenos Aires, Argentina
...and 9 more locations
Time frame: Day 14
Mean Area Under the Concentration-Time Curve in One Dosing Interval [AUC(TAU)] of Entecavir in LVD-naive and LVD-experienced Participants, by Age Cohort
Area under the Curve (AUC) was derived from plasma concentration of ETV versus time. AUC(TAU) was calculated by log- and linear trapezoidal summations, TAU = 24 hours, and was measured in nanograms\*hours per milliliter (ng\*h/mL). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. PK assessment was optional for Group C participants (NA-experienced participants who were included with the September 2011 country-specific protocol amendment). No Group C participants chose to participate in the PK assessment.
Time frame: Day 14
Mean Apparent Total Body Clearance (CLT/F) of Entecavir in LVD-naive and LVD-experienced Participants, by Age Cohort
CLT/F was calculated by dividing the dose of ETV by AUC(TAU) of ETV and was measured in liters per hour (L/h). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. PK assessment was optional for Group C participants (NA-experienced participants who were included with the September 2011 country-specific protocol amendment). No Group C participants chose to participate in the PK assessment.
Time frame: At 2 weeks
Number of Participants With HBV DNA Less Than 50 IU/mL Through Week 96 in Treated Participants
Hepatitis B virus DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS TaqMan - high pure system (HPS) assay and was reported in international units per milliliter (IU/mL). Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Number of Participants With Hepatitis B e Antigen (HBeAg) Loss Through Week 96 in Treated Participants
HBeAg loss: HBeAg negative. The method used for the detection of HBe Ag was the DiaSorin - Anti HBe enzyme immunoassay kit. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Number of Participants With Hepatitis B s Antigen (HBsAg) Loss Through Week 96 in Treated Participants
HBsAg loss: HBsAg negative. The method used for detection of HBsAg was the ADVIA Centaur iImmunoassay system. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Number of Participants With Hepatitis B e Antigen Seroconversion Through Week 96 in Treated Participants
HBe seroconversion: loss of HBeAg (HBeAg negative) with positive HB e antibodies (HBeAb), ie both the presence of HBeAb and the absence of HBeAg. The method used for the detection HBeAg seroconversion was the DiaSorin - Anti HBe enzyme immunoassay kit. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline through Week 96
Number of Participants With HBV DNA Less Than Lower Limit of Detection (LLD) for the Roche COBAS TaqMan - HPS Assay at Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLD = 6 IU/mL). Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Number of Participants With HBV DNA Less Than Lower Limit of Quantification (LLQ) for the Roche COBAS TaqMan - HPS Assay Through Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLQ = 29 IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline through Week 96
Number of Participants With HB s Antigen (HBsAg) Seroconversion Through Week 96 in Treated Participants
HB s Ag seroconversion: loss of HBsAg (HBsAg negative) and presence of HB s antibodies (HBsAb). The method used for the detection of HBsAg seroconversion was the ADVIA Centaur iImmunoassay system. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline through Week 96
Number of Participants Who Had a Protocol Defined Response (PDR) Through Week 96 in Treated Participants
PDR was defined as confirmed HBV DNA \< 50 IU/mL plus confirmed HBeAg seroconversion on 2 sequential measurements at least 14 days apart. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Mean Log10 Change From Baseline in HBV DNA Using Roche COBAS TaqMan - HPS Through Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. HBV DNA log10 changes from baseline were summarized over time.
Time frame: Baseline to Week 96
Alanine Aminotransferase (ALT) Normalization From Baseline Through Week 96 in Treated Participants
Normalization in ALT= ALT ≤ 1.0\*upper limit of normal (ULN). Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline to Week 96
Number of Participants With HBV DNA by PCR Categories at Weeks 48 and 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLQ = 29 IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy.
Time frame: Baseline, Week 48, Week 96
Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL Through Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0\*ULN.
Time frame: Baseline to Week 96
Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL, Plus HBeAg Seroconversion Through Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0\*ULN. HBe seroconversion was determination of presence of HBeAb and loss of HBeAg. The method used for the detection of HBeAg seroconversion was the DiaSorin - Anti HBe enzyme immunoassay kit.
Time frame: Baseline to Week 96
Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL, Without HBeAg Seroconversion, Through Week 96 in Treated Participants
Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0\*ULN. HBe seroconversion: loss of HBeAg (HBeAg negative) with positive HBeAb. The method used for the detection of HBeAg/Ab serologies was the DiaSorin enzyme immunoassay kit.
Time frame: Baseline to Week 96
Number of Participants With Hematology Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants
Toxicity Scale: Division of AIDs (DAIDS) grades Version 1.0. Upper limit of normal (ULN); lower limit of normal (LLN); Cells per Liter (c/L); cells per microliter (c/µL); grams per deciliter (g/dL); milliequivalents per liter (mEq/L); cells per microliter (c/µL): Grade (Gr). Hemoglobin g/dL: Gr1:10.0-10.9;Gr2: 9.0-9.9; Gr3:7.0-8.9; Gr4: \<7.0. International normalization ratio (INR): Gr1:1.1-\<1.5\*ULN; Gr2: 1.6-\<2.0\*ULN; Gr3: 2.1-3.0\*ULN;Gr4: \>3.0\*ULN. Neutrophils/bands c/µL: Gr1;1.0-1.3\*10\^3; Gr2: 0.75-0.99\*10\^3; Gr 3: 0.50-0.749\*10\^3; Gr4: \<0.5\*10\^3.
Time frame: Day 1 to Week 120
Number of Participants With Chemistry Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants
Toxicity Scale: DAIDS Version 1.0 and modified World Health Organization (WHO). Grade (Gr). ALT: Gr1:1.25-\<2.5\*ULN; Gr2: 2.6-\<5.0 \*ULN; Gr3: 5.1-10.0\*ULN; Gr4:\>10.0\*ULN. Aspartate aminotransferase (AST): Gr1: 1.25-\<2.5\*ULN; Gr2:2.6-\<5.0\*ULN; Gr 3: 5.1-10.0\*ULN; Gr4\>10.0\*ULN. Alkaline phosphatase: Gr1:1.25-\<2.5\*ULN; Gr2: 2.6-\<5.0\*ULN; Gr3: 5.1-10.0\*ULN; Gr4: \>10.0\*ULN. Lipase: Gr1:1.1-\<1.5\*ULN;Gr2:1.6-\<3.0\*ULN; Gr3: 3.1-5.0\*ULN; Gr4: \>5.0\*ULN. Creatinine: Gr1: 1.1-1.3\*ULN; Gr2: 1.4-\<1.8\*ULN; Gr3: 1.9 - \<3.4\*ULN; Gr4: \>=3.5\*ULN. Glucose mg/dL (high): Gr1:110-\<125 (Fasting)/116-\<160;Gr2:126-\<250 (F)/161-\<250; Gr3: 251-500; Gr4: \>500.Glucose (low): Gr1: 55-64; Gr2: 40 - \<54; Gr3: 30-39; Gr4: \<30 mg/dL.
Time frame: Day 1 to Week 120
Number of Participants With Electrolyte Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants
Toxicity Scale: DAIDS Version 1.0 and modified World Health Organization (WHO) for chloride. Milliequivalents per liter (mEq/L); Grade (Gr). Chloride high (mEq/L): Gr1: 113-\<117; Gr2: 117-\<121; Gr3: 121-125; Gr4: \>125. Potassium low (mEq/L): Gr1: 3.0-3.4; Gr2: 2.5-2.9; Gr3:2.0-\<2.4; Gr4: \<2.0. Potassium high: Gr1; 5.6- \<6.0; Gr2: 6.1-\<6.5; Gr3: 6.6-7.0; Gr4: \>7.0. Sodium high (mEq/L): Gr1; 146-\<150; Gr2: 151-\<154; Gr3: 155-\<159; Gr4: \>=160.
Time frame: Day 1 Week 120