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

Hepatitis B, Chronic Clinical Trial

Official title:

Evaluation of the Pharmacokinetics, Safety, Tolerability and Efficacy of Entecavir (ETV) in Pediatric Subjects With Chronic Hepatitis B Virus (HBV) Infection Who Are HBeAg-Positive

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00423891
• Other study ID #: AI463-028
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 30, 2007
• Est. completion date: September 4, 2017

Study information

• Verified date: March 2018
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: September 4, 2017
• Est. primary completion date: August 31, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

Inclusion Criteria:

• 2-18 years of age

• Group A: Lamivudine naive (<1 week of Lamivudine) and not within 24 weeks of screening; Group B: Lamivudine experienced (> 12 weeks of Lamivudine); Group C: nucleoside/nucleotide experienced (> 12 weeks of nucleoside/tide therapy) added as a country-specific protocol amendment (not all sites had Group C).

• HBV Deoxyribonucleic acid (DNA) = 100000 copies/mL; = 10000 copies for nucleoside/nucleotide experienced (Group C)

• Detectable Hepatitis B surface antigen (HBsAg) for 24 weeks prior to screening

• Hepatitis B e antigen (HBeAg) positive

• Compensated liver and renal function

• Elevated alanine aminotransferase (ALT) at screening and during the 24 weeks prior to screening (for Groups A and B)

Exclusion Criteria:

• Coinfection with Human immunodeficiency virus (HIV), Hepatitis C virus (HCV), Hepatitis D Virus (HDV)

• Children who were breastfed while their mother received Lamivudine, or children whose mothers received Lamivudine during pregnancy

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Entecavir
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

Locations

Country	Name	City	State
Argentina	Local Institution	Buenos Aires
Belgium	Local Institution	Bruxelles
Brazil	Local Institution	Porto Alegre	Rio Grande Do Sul
Brazil	Local Institution	Sco Paulo	Sao Paulo
Canada	Local Institution	Toronto	Ontario
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Taiwan	Local Institution	Taipei
United Kingdom	Local Institution	Birmingham	West Midlands
United Kingdom	Local Institution	London	Greater London
United States	Johns Hopkins School Of Medicine	Baltimore	Maryland
United States	Boston Childrens Hospital	Boston	Massachusetts
United States	University Of Texas Southwestern Medical Center	Dallas	Texas
United States	University Of Florida	Gainesville	Florida
United States	Connecticut Children'S Medical Center	Hartford	Connecticut
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 California, San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  Korea, Republic of,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 1 to Week 120
Secondary	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.	Day 14
Secondary	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.	Day 14
Secondary	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.	Day 14
Secondary	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.	At 2 weeks
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline through Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline through Week 96
Secondary	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.	Baseline through Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline, Week 48, Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Baseline to Week 96
Secondary	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.	Day 1 to Week 120
Secondary	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.	Day 1 to Week 120
Secondary	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.	Day 1 Week 120

External Links

•   BMS clinical trial educational resource
•   BMS Clinical Trial Information
•   FDA Safety Alerts and Recalls
•   Investigator Inquiry form