A Study of Entecavir in Pediatric Patients With Chronic Hepatitis B Virus (HBV)-Infection

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

Population: All participants who received at least one dose of study drug. On-treatment period began on the first day of study therapy and ended 5 days after the last dose of study therapy.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: Participants in Groups A and B who received study drug and had PK assessment.

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

Population: Participants in Groups A and B who received study drug and had PK assessment.

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

Population: Participants who received at least one dose of study drug, and had a measurement at baseline and at the specific analysis week.

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

Population: Participants in Groups A and B who received study drug and had PK assessment.

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.

Time frame: Day 14

Population: Participants in Groups A and B who received study drug and had PK assessment.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: Participants who received at least one dose of study drug, and had a measurement during the on-treatment period (i.e., after the first day of study therapy through 5 days after the last dose of study therapy).

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

Population: Participants who received at least one dose of study drug, and had a measurement during the on-treatment period (i.e., after the first day of study therapy through 5 days after the last dose of study therapy).

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: Participants who received at least 1 dose of study therapy, and had a measurement during the on-treatment period (i.e., after the first day of study therapy through 5 days after the last dose of study therapy).

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.

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

Population: The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated participants were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which participants with missing data at the analysis week were excluded.