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Hepatitis B, ChronicPhase 1/2NCT00423891

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

A Phase 1/2 study testing Entecavir in people with Hepatitis B, Chronic, run by Bristol-Myers Squibb at 19 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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 Read more about this study

Who is it for?
Ages 2 to 18 years
Conditions the study is for
Hepatitis B, Chronic
What is being tested?
Entecavir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
64 participants
Where
19 sitesin 8 countries
Study dates
30 Jun 2007to 4 Sep 2017
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)

Who cannot join

  • 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

Trial locations and contacts

19 sites in 8 countries.

19 sites in 8 countries

United States9 sites
  • Johns Hopkins School Of Medicine

    Baltimore, Maryland, 21287

  • Boston Childrens Hospital

    Boston, Massachusetts, 02115

  • University Of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • University Of Florida

    Gainesville, Florida, 32610

  • Connecticut Children'S Medical Center

    Hartford, Connecticut, 06106

  • Mount Sinai School Of Medicine

    New York, New York, 10029

  • Children'S Hospital Of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Rhode Island Hospital

    Providence, Rhode Island, 02903

  • University of California, San Francisco

    San Francisco, California, 94143

Other trials in United States

Brazil2 sites
  • Local Institution

    Porto Alegre, Rio Grande do Sul, 90035

  • Local Institution

    Sco Paulo, São Paulo, 05403

Other trials in Brazil

South Korea2 sites
  • Local Institution

    Seoul, 135-710

  • Local Institution

    Seoul, 138-736

Other trials in South Korea

United Kingdom2 sites
  • Local Institution

    Birmingham, West Midlands, B4 6NH

  • Local Institution

    London, Greater London, SE5 9RS

Other trials in United Kingdom

Argentina1 site
  • Local Institution

    Buenos Aires, 1425

Other trials in Argentina

Belgium1 site
  • Local Institution

    Brussels, 1200

Other trials in Belgium

Canada1 site
  • Local Institution

    Toronto, Ontario, M5G 1X8

Other trials in Canada

Taiwan1 site
  • Local Institution

    Taipei, 100

Other trials in Taiwan

About this study

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

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

Being tested
Entecavir
Medical subject headings
Hepatitis B, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EntecavirDrug

    Also called Baraclude, BMS-200475

    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

Study groups in NCT00423891
Study groupRoleWhat they receive
Arm 1: EntecavirExperimentalNot described
Receives: Drug: Entecavir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Day 1 to Week 120

Secondary outcomes (21)
  1. 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.

    Measured: Day 14

  2. 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.

    Measured: Day 14

  3. 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.

    Measured: Day 14

  4. 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.

    Measured: At 2 weeks

  5. 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.

    Measured: Baseline to Week 96

  6. 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.

    Measured: Baseline to Week 96

  7. 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.

    Measured: Baseline to Week 96

  8. 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.

    Measured: Baseline through Week 96

  9. 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.

    Measured: Baseline to Week 96

  10. 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.

    Measured: Baseline through Week 96

  11. 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.

    Measured: Baseline through Week 96

  12. 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.

    Measured: Baseline to Week 96

  13. 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.

    Measured: Baseline to Week 96

  14. 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.

    Measured: Baseline to Week 96

  15. 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.

    Measured: Baseline, Week 48, Week 96

  16. 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.

    Measured: Baseline to Week 96

  17. 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.

    Measured: Baseline to Week 96

  18. 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.

    Measured: Baseline to Week 96

  19. 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.

    Measured: Day 1 to Week 120

  20. 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.

    Measured: Day 1 to Week 120

  21. 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.

    Measured: Day 1 Week 120

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2007 (estimated)
  2. Study start30 Jun 2007
  3. Primary completion31 Aug 2013
  4. Study completion4 Sep 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
64 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00423891
Sponsor's protocol ID
AI463-028
Status last verified
Mar 2018
First submitted
16 Jan 2007
Last updated
2 May 2018
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Entecavir in people with Hepatitis B, Chronic, run by Bristol-Myers Squibb at 19 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 19 sites in United States, Brazil, South Korea, United Kingdom, Argentina and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Serious Adverse Events (SAE) and Discontinuations Due to Adverse Events (AEs) - On Treatment (time frame: Day 1 to Week 120). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2018.

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