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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00423891
First received: January 16, 2007
Last updated: August 19, 2014
Last verified: August 2014
Results First Received: July 15, 2014  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Hepatitis B, Chronic
Intervention: Drug: Entecavir

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study started June 2007, currently ongoing. Cohort 1: age ≥ 2 to ≤ 6 years; Cohort 2: >6 to ≤ 12 years; Cohort 3: age >12 to ≤18 years. Groups A and B: lamivudine-naive and experienced participants, respectively. Nucleoside/tide analog - treatment-experienced participants (Group C) added September 2011 via country-specific amendment to protocol.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
64 enrolled. 48 treated. Participants received a minimum of 48 weeks study drug but depending on response to drug, could remain on treatment for up to a total of 120 weeks. Participants were to receive post dosing follow up after last dose, for a total of 5 years on-study (on and off study drug).

Reporting Groups
  Description
Lamivudine (LVD)-Naive (Group A) Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
Lamivudine (LVD)-Experienced (Group B) Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
Nucleoside/Tide Analog (NA) - Experienced (Group C) Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.

Participant Flow for 3 periods

Period 1:   Enrolled
    Lamivudine (LVD)-Naive (Group A)     Lamivudine (LVD)-Experienced (Group B)     Nucleoside/Tide Analog (NA) - Experienced (Group C)  
STARTED     35     21     8  
COMPLETED     24     19     5  
NOT COMPLETED     11     2     3  
Withdrawal by Subject                 0                 0                 1  
Lost to Follow-up                 0                 0                 1  
No longer met criteria                 11                 2                 1  

Period 2:   Treatment
    Lamivudine (LVD)-Naive (Group A)     Lamivudine (LVD)-Experienced (Group B)     Nucleoside/Tide Analog (NA) - Experienced (Group C)  
STARTED     24     19     5  
COMPLETED     22     19     1  
NOT COMPLETED     2     0     4  
Withdrawal by Subject                 1                 0                 0  
Lost to Follow-up                 1                 0                 0  
continuing treatment                 0                 0                 4  

Period 3:   Post-Dosing Follow Up
    Lamivudine (LVD)-Naive (Group A)     Lamivudine (LVD)-Experienced (Group B)     Nucleoside/Tide Analog (NA) - Experienced (Group C)  
STARTED     22     18 [1]   1  
COMPLETED     20     1     0  
NOT COMPLETED     2     17     1  
Withdrawal by Subject                 0                 2                 0  
Lost to Follow-up                 2                 0                 0  
Continuing Post Dosing Follow up                 0                 15                 1  
[1] 1 participant completed treatment but did not enter post dosing follow up period: Withdrew Consent.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received at least one dose of study drug.

Reporting Groups
  Description
Lamivudine (LVD)-Naive (Group A) Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
Lamivudine (LVD)-Experienced (Group B) Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
Nucleoside/Tide Analog (NA) - Experienced (Group C) Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
Total Total of all reporting groups

Baseline Measures
    Lamivudine (LVD)-Naive (Group A)     Lamivudine (LVD)-Experienced (Group B)     Nucleoside/Tide Analog (NA) - Experienced (Group C)     Total  
Number of Participants  
[units: participants]
  24     19     5     48  
Age  
[units: years]
Mean ± Standard Deviation
  9.2  ± 5.41     11.0  ± 4.42     8.8  ± 5.02     9.9  ± 4.98  
Age, Customized  
[units: participants]
       
≥ 2 years to ≤ 6 years     7     3     2     12  
>6 years to ≤ 12 years     9     7     2     18  
>12 years to ≤18 years     8     9     1     18  
Gender  
[units: participants]
       
Female     14     7     2     23  
Male     10     12     3     25  
Race (NIH/OMB)  
[units: participants]
       
American Indian or Alaska Native     0     0     0     0  
Asian     17     10     5     32  
Native Hawaiian or Other Pacific Islander     0     1     0     1  
Black or African American     0     2     0     2  
White     5     6     0     11  
More than one race     1     0     0     1  
Unknown or Not Reported     1     0     0     1  
Region of Enrollment  
[units: participants]
       
United States     10     5     1     16  
Taiwan     3     0     0     3  
Canada     1     0     0     1  
Argentina     3     0     0     3  
Belgium     1     1     0     2  
Brazil     1     3     0     4  
United Kingdom     2     1     0     3  
Korea, Republic of     3     9     4     16  
Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) [1]
[units: log10┬áIU/mL]
Mean ± Standard Deviation
  7.92  ± 0.864     7.74  ± 0.856     7.96  ± 0.238     7.85  ± 0.812  
Hepatitis B E Antigen (HBeAg) Positive [2]
[units: participants]
  24     19     5     48  
Hepatitis B E Antibody Negative [3]
[units: participants]
  24     19     5     48  
Alanine Aminotransferase (ALT) [4]
[units: U/L]
Mean ± Standard Deviation
  142.8  ± 85.18     125.7  ± 67.96     44.6  ± 22.96     125.8  ± 78.83  
[1] 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).
[2] The method used for the detection of HBeAg was the DiaSorin - Anti HBe enzyme immunoassay kit.
[3] The method used for the detection of Hepatitis Be Antibodies (HBeAb) was the DiaSorin - Anti HBe enzyme immunoassay kit.
[4] The normal range for serum ALT as established by the study's central laboratory was 5 - 45 units per liter (U/L). Group A and Group B participants were to demonstrate persistent ALT elevation during screening but this inclusion criterion was waived for those enrolling in Group C.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   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   [ Time Frame: Day 14 ]

2.  Primary:   Median Time of Maximum Observed Plasma Concentration (Tmax) in LVD-naive and LVD-experienced Participants, by Age Cohort   [ Time Frame: Day 14 ]

3.  Primary:   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   [ Time Frame: Day 14 ]

4.  Primary:   Mean Apparent Total Body Clearance (CLT/F) of Entecavir in LVD-naive and LVD-experienced Participants, by Age Cohort   [ Time Frame: At 2 weeks ]

5.  Primary:   Number of Participants With Serious Adverse Events (SAE) and Discontinuations Due to Adverse Events (AEs) - On Treatment   [ Time Frame: Day 1 to Week 120 ]

6.  Secondary:   Number of Participants With HBV DNA Less Than 50 IU/mL Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

7.  Secondary:   Number of Participants With Hepatitis B e Antigen (HBeAg) Loss Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

8.  Secondary:   Number of Participants With Hepatitis B s Antigen (HBsAg) Loss Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

9.  Secondary:   Number of Participants With Hepatitis B e Antigen Seroconversion Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline through Week 48 ]

10.  Secondary:   Number of Participants With HBV DNA Less Than Lower Limit of Detection (LLD) for the Roche COBAS TaqMan - HPS Assay (Non-Completer=Failure) at Week 48 in Treated Participants   [ Time Frame: Baseline to Week 48 ]

11.  Secondary:   Number of Participants With HBV DNA Less Than Lower Limit of Quantification (LLQ) for the Roche COBAS TaqMan - HPS Assay (Non-Completer=Failure) Through Week 48 in Treated Participants   [ Time Frame: Baseline through Week 48 ]

12.  Secondary:   Number of Participants With HB s Antigen (HBsAg) Seroconversion Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline through Week 48 ]

13.  Secondary:   Number of Participants Who Had a Protocol Defined Response (PDR) Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

14.  Secondary:   Mean Log10 Change From Baseline in HBV DNA Using Roche COBAS TaqMan - HPS Through Week 48 in Treated Participants   [ Time Frame: Baseline to Week 48 ]

15.  Secondary:   Alanine Aminotransferase (ALT) Normalization From Baseline Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

16.  Secondary:   Number of Participants With HBV DNA by PCR Categories (Non-Completer=Failure) at Week 48 in Treated Participants   [ Time Frame: Baseline, Week 48 ]

17.  Secondary:   Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

18.  Secondary:   Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL, Plus HBeAg Seroconversion Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

19.  Secondary:   Number of Participants With a Combination of ALT Normalization and HBV DNA Less Than 50 IU/mL, Without HBeAg Seroconversion, Through Week 48 (Non-Completer=Failure) in Treated Participants   [ Time Frame: Baseline to Week 48 ]

20.  Secondary:   Number of Participants With Hematology Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants   [ Time Frame: Day 1 to Week 120 ]

21.  Secondary:   Number of Participants With Chemistry Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants   [ Time Frame: Day 1 to Week 120 ]

22.  Secondary:   Number of Participants With Electrolyte Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Participants   [ Time Frame: Day 1 Week 120 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00423891     History of Changes
Other Study ID Numbers: AI463-028
Study First Received: January 16, 2007
Results First Received: July 15, 2014
Last Updated: August 19, 2014
Health Authority: United States: Food and Drug Administration