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    Clinical Trial Results:
    A Comparative Study of the Antiviral Efficacy and Safety of Entecavir (ETV) versus Placebo in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are HBeAg-Positive

    Summary
    EudraCT number
    		 2009-016357-17
    Trial protocol
    		 DE   GB   GR   BE   Outside EU/EEA  
    Global end of trial date
    03 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2018
    First version publication date
    20 Oct 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI463-189 ST
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01079806
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb International, EU Study Start-Up Unit, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000339-PIP02-03
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective was to compare the proportion of subjects in each treatment group who demonstrated the combination of HBV deoxyribonucleic acid (DNA) viral suppression (< 50 IU/mL) and HBeAg seroconversion (undetectable HBeAg and detectable anti-HBe antibody [HBeAb]) at Week 48.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    180
    EEA total number of subjects
    56
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    87
    Adolescents (12-17 years)
    93
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 228 patients enrolled, 43 no longer met study criteria, 4 withdrew consent, and 1 withdrew for surgery. While the primary endpoint analysis was based on a randomized sample size of 123 participants, the overall study population was augmented to 180 to meet global regulatory requirements. All 180 randomized patients received study drug.

    Period 1
    Period 1 title
    Day 1 to Week 96
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Entecavir
    Arm description
    		 Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir was dosed at 0.015 mg/kg/day up to a maximum dose of 0.5 mg/day using oral solution or tablets.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo administered using oral solution or tablets

    Number of subjects in period 1
    		Entecavir Placebo
    Started
    120
    60
    Received treatment
    120
    60
    Completed
    113
    53
    Not completed
    7
    7
         Consent withdrawn by subject
    3
    2
         Adverse event, non-fatal
    -
    3
         Subject request to stop study treatment
    1
    -
         Pregnancy
    -
    1
         Poor compliance or noncompliance
    2
    -
         Lost to follow-up
    1
    -
         Removal by Medical Monitor
    -
    1
    Period 2
    Period 2 title
    Long-term Follow-up: Day 1-End of study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Entecavir
    Arm description
    		 Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir was dosed at 0.015 mg/kg/day up to a maximum dose of 0.5 mg/day using oral solution or tablets.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
    Arm type
    		 Placebo

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir was dosed at 0.015 mg/kg/day up to a maximum dose of 0.5 mg/day using oral solution or tablets.

    Number of subjects in period 2
    		Entecavir Placebo
    Started
    111
    58
    Completed
    92
    43
    Not completed
    19
    15
         Investigator Left Institution
    -
    1
         Consent withdrawn by subject
    13
    8
         Lost to follow-up
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Entecavir
    Reporting group description
    		 Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response

    Reporting group values
    		 Entecavir Placebo Total
    Number of subjects
    		 120 60 180
    Age, Customized
    Units: Subjects
        >=2 years to <=6 years|
    		 27 14 41
        >6 years to <=12 years|
    		 31 15 46
        >12 years to <18 years|
    		 62 31 93
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 10.5 ± 4.87 10.8 ± 4.82 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 42 29 71
        Male
    		 78 31 109
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 48 21 69
        Unknown or Not Reported
    		 70 39 109
    Race/Ethnicity, Customized
    Units: Subjects
        Asian|
    		 57 30 87
        Black/African American|
    		 14 2 16
        Native Hawaiian/Other Pacific Islander|
    		 1 0 1
        White|
    		 44 27 71
        Other|
    		 4 1 5

    End points

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    End points reporting groups
    Reporting group title
    Entecavir
    Reporting group description
    		 Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response
    Reporting group title
    Entecavir
    Reporting group description
    		 Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response

    Subject analysis set title
    Blinded and Open-Label (All ETV)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Randomized ETV subjects combined with PBO-randomized subjects who received open-label ETV

    Subject analysis set title
    Blinded and Open-Label (All ETV)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All ETV group during long-term follow-up that show increased ALT (alanine aminotransferase)

    Primary: Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48

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    End point title
    		 Percentage of Participants Who Achieved a Combination of Hepatitis B Virus (HBV) DNA Suppression and Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48
    End point description
    Suppression=HBV DNA<50 IU/mL (approximately 300 copies/mL) using the Roche COBAS TaqMan HBV Test for use with the High Pure System assay; seroconversion=undetectable HBeAg and detectable anti-hepatitis B e antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Primary
    End point timeframe
    At Week 48
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    82
    41
    Units: Percentage of participants
        number (not applicable)
    24.4
    2.4
    Statistical analysis title
    		 Week 48 HBV DNA Suppression + HBeAg Seroconversion
    Comparison groups
    Entecavir v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0049
    Method
    		 Normal approximation
    Parameter type
    		 Difference estimate
    Point estimate
    20.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.1
         upper limit
    		 31.4

    Secondary: Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48

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    End point title
    		 Percentage of Participants With Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48
    End point description
    While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    82
    41
    Units: Percentage of participants
        number (not applicable)
    46.3
    2.4
    Statistical analysis title
    		 Hepatitis B Virus (HBV) DNA <50 IU/mL at Week 48
    Comparison groups
    Entecavir v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation
    Parameter type
    		 Difference estimate
    Point estimate
    41.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.4
         upper limit
    		 54.2

    Secondary: Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48

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    End point title
    		 Percentage of Participants With Serum Alanine Aminotransferase ≤1*Upper Limit of Normal at Week 48
    End point description
    While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    82
    41
    Units: Percentage of participants
        number (not applicable)
    67.1
    22.0
    Statistical analysis title
    		 Serum ALT ≤1*ULN at Week 48
    Comparison groups
    Entecavir v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation
    Parameter type
    		 Difference estimate
    Point estimate
    45.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.2
         upper limit
    		 61.2

    Secondary: Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48

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    End point title
    		 Percentage of Participants With Hepatitis B Virus DNA <Limit of Quantitation (LOQ) at Week 48
    End point description
    LOQ=29 IU/mL. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    82
    41
    Units: Percentage of participants
        number (not applicable)
    42.7
    2.4
    Statistical analysis title
    		 HBV DNA
    Comparison groups
    Entecavir v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation
    Parameter type
    		 Difference estimate
    Point estimate
    38.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.9
         upper limit
    		 50.5

    Secondary: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (undetectable HBeAg and presence of anti-HBeAb)

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    End point title
    		 Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 (undetectable HBeAg and presence of anti-HBeAb)
    End point description
    HBe seroconversion=undetectable HBe antigen and detectable anti-HBe antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    82
    41
    Units: Percentage of participants
        number (not applicable)
    24.4
    12.2
    Statistical analysis title
    		 HBeAg) Seroconversion at Week 48
    Comparison groups
    Entecavir v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Normal approximation
    Parameter type
    		 Difference estimate
    Point estimate
    12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 25.7

    Secondary: Percentage of participants who achieved sustained HBeAg seroconversion during off-treatment follow up among participants who achieved HBeAg seroconversion at end of treatment.

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    End point title
    		 Percentage of participants who achieved sustained HBeAg seroconversion during off-treatment follow up among participants who achieved HBeAg seroconversion at end of treatment.
    End point description
    Participants who demonstrated HBeAg seroconversion at EOD (end-of-dosing) were followed and assessed for presence of sustained HBeAg seroconversion during entire study. The study reached the end of dosing (EOD) on 22 Feb-2016.
    End point type
    Secondary
    End point timeframe
    Off-treatment follow-up
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    39
    22
    Units: Percentage of participants
    number (not applicable)
        EOD (end of dosing)|
    100.0
    100.0
        Week 48|
    74.4
    59.1
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events (including palatability issues), SAEs, discontinuous due to adverse events, and HBV disease progression through Week 48

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    End point title
    		 Number of participants with adverse events (including palatability issues), SAEs, discontinuous due to adverse events, and HBV disease progression through Week 48
    End point description
    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. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 48 on blinded therapy
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60
    Units: participants
    number (not applicable)
        Deaths|
    0
    0
        Serious Adverse Events|
    4
    7
        Discontinuation due to Adverse Event|
    0
    2
        any adverse event|
    78
    46
        Related Adverse Events|
    11
    6
        Related Grade 2 - 4 Adverse Events|
    4
    2
        Grade 3 - 4 Adverse Events|
    4
    3
        ALT Flares|
    2
    5
        HBV disease progression|
    0
    0
        Malignant neoplasms or pre-malignant lesions|
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4)

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    End point title
    		 Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4)
    End point description
    Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. INR=international normalization ratio of prothrombin time; ULN=upper limit of normal. Hemoglobin (g/dL): Grade 1=10-10.9; Grade 2=9-9.9; Grade 3=7-8.9; Grade 4= <7. Platelets (/mm^3): Grade 1=100,000-124,999; Grade 2=50,000-99,999; Grade 3=25,000-49,999; Grade 4= <25,000. INR (*ULN): Grade 1=1.1-1.5; Grade 2=1.6-2; Grade 3=2.1-3; Grade 4= >3. WBC (/mm^3): Grade 1=2000-2500; Grade 2=1500-1999; Grade 3=1000-1499; Grade 4= <1000. Neutrophils (/mm^3): Grade 1=1000-1300; Grade 2=750-999; Grade 3=500-749; Grade 4= <500.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 48 on blinded therapy
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60
    Units: Participants
    number (not applicable)
        Hemoglobin|
    5
    4
        Platelets|
    3
    2
        INR|
    2
    6
        White blood cells (WBC)|
    2
    1
        Neutrophils + bands (absolute)|
    14
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued)

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    End point title
    		 Number of Participants With Laboratory Test Results Meeting the Criteria for Abnormality (Grades 1-4) (Continued)
    End point description
    Toxicities graded per Division of AIDS criteria, Version 1.0, and modified World Health Organization criteria. ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ULN=upper limit of normal; LLN=lower limit of normal. ALT, AST (*ULN): Grade 1=1.25-2; Grade 2=2.6-5; Grade 3=5.1-10; Grade 4 => 10. Bilirubin (*ULN): Grade 1 = 1.1-1.5; Grade 2=1.6-2.5; Grade 3 = 2.6-5; Grade 4= >5. Albumin (g/dL): Grade 1=3- <LLN; Grade 2=2-2.9; Grade 3= <2. Lipase (*ULN): Grade 1=1.1-1.5; Grade 2=1.6-3; Grade 3=3.1-5; Grade 4= >5. BUN/urea (*ULN): Grade 1=1.25-<2.6; Grade 2=2.6-<5.1; Grade 3=5.1-10; Grade 4= >10. Chloride, high (mEq/L): Grade 1=113-<117; Grade 2=117-<121; Grade 3=121-125; Grade 4= >125. Potassium, low (mEq/L): Grade 1=3-3.4; Grade 2=2.5-<3; Grade 3=2-<2.5; Grade 4=<2. Potassium, high (mEq/L): : Grade 1= 5.6-<6.1; Grade 2=6.1-<6.6; Grade 3=6.6-7; Grade 4= >7. Sodium, high (mEq/L): Grade 1=146<151; Grade 2=151-<155; Grade 3=155-<160; Grade 4= >=160.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 48 on blinded therapy
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60
    Units: participants
    number (not applicable)
        ALT|
    113
    59
        AST|
    87
    51
        Total bilirubin|
    5
    6
        Albumin|
    0
    1
        Lipase|
    38
    20
        BUN/Urea|
    10
    2
        Chloride, high|
    2
    1
        Potassium, low|
    1
    1
        Potassium, high|
    1
    0
        Sodium, high|
    8
    4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBeAg Seroconversion on ETV over-time at Week 96 (All ETV cohort)

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    End point title
    		 Percentage of Participants With HBeAg Seroconversion on ETV over-time at Week 96 (All ETV cohort)
    End point description
    HBe seroconversion=undetectable HBe antigen and detectable anti-HBe antibodies. While the analysis of the primary endpoint was based on a randomized sample size of 123 participants (the Primary Cohort), the size of the overall study population was augmented to 180 randomized participants to meet global regulatory requirements.
    End point type
    Secondary
    End point timeframe
    At Week 96
    End point values
    		 Blinded and Open-Label (All ETV)
    Number of subjects analysed
    171
    Units: Percentage of participants
        number (not applicable)
    38.6
    No statistical analyses for this end point

    Secondary: Percentage of participants who maintained HBeAg seroconversion at Week 96 (end of blinded therapy) among participants with HBeAg seroconversion at Week 48

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    End point title
    		 Percentage of participants who maintained HBeAg seroconversion at Week 96 (end of blinded therapy) among participants with HBeAg seroconversion at Week 48
    End point description
    Participants who achieved HBeAg seroconversion by Week 48 and maintained seroconversion to week 96
    End point type
    Secondary
    End point timeframe
    At Week 96
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60
    Units: Percentage of participants
    number (not applicable)
        Week 48|
    24.2
    10.0
        Week 96|
    36.7
    99999
    No statistical analyses for this end point

    Secondary: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression through week 96

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    End point title
    		 Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations due to Adverse Events (AEs), Related AEs, Grade 2-4 Related AEs, Grade 3-4 AEs, Malignancies, ALT Flares, and Hepatic Disease Progression through week 96
    End point description
    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. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death. ALT=alanine aminotransferase.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 96
    End point values
    		 Blinded and Open-Label (All ETV)
    Number of subjects analysed
    171
    Units: Participants
    number (not applicable)
        Deaths|
    0
        SAEs|
    8
        Discontinuations due to AEs|
    1
        Related AEs|
    14
        Grade 2-4 Related AEs|
    4
        Grade 3-4 AEs|
    7
        Malignancies|
    0
        ALT flares|
    3
        Hepatic disease progression|
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBeAb) up to Week 96

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    End point title
    		 Percentage of participants with HBeAg seroconversion (undetectable HBeAg and presence of anti-HBeAb) up to Week 96
    End point description
    On Treatment through week 96 - 2 year cohort NC = F: (The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures.)
    End point type
    Secondary
    End point timeframe
    up to week 96
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60 [1]
    Units: Percentage of participants
        number (not applicable)
    40.8
    99999
    Notes
    [1] - Analysis was not performed
    No statistical analyses for this end point

    Secondary: Histological analysis (percentage) among participants with available liver biopsy data

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    End point title
    		 Histological analysis (percentage) among participants with available liver biopsy data
    End point description
    Liver function test elevations and abnormalities on blinded and open-label ETV (the All ETV Safety Cohort). Participants who experienced elevation of alanine aminotransferase (ALT) greater than three times ETV (entecavir) baseline measure (Participants who displayed liver biopsy with ALT value greater than three times baseline.)
    End point type
    Secondary
    End point timeframe
    Between weeks 48 and 96
    End point values
    		 Blinded and Open-Label (All ETV)
    Number of subjects analysed
    171
    Units: Percentage of participants
        number (not applicable)
    5.9
    No statistical analyses for this end point

    Secondary: Percentage of participants with HbeAg loss at weeks 48 and 96

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    End point title
    		 Percentage of participants with HbeAg loss at weeks 48 and 96
    End point description
    HBeAg Loss (NC = F and NC = M) - On Treatment through Week 96 - Year 2 Efficacy Cohort Non-Completer - Failure (NC=F): The numerator was based on participants meeting the response criteria. The denominator was based on treated participants. Participants who had missing data at the analysis week were considered failures. Non-Completer - Missing (NC=M): The numerator was based on participants meeting the response criteria. The denominator was based on participants with data at the analysis week. Participants who had missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    At 48 and 96 weeks
    End point values
    		 Entecavir Placebo
    Number of subjects analysed
    120
    60 [2]
    Units: Percentage of participants
    number (not applicable)
        48 weeks|
    25.0
    10.0
        96 Weeks|
    40.8
    99999
    Notes
    [2] - Subjects without HBeAg seroconversion were switched to open-label ETV
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment non serious adverse events (NSAEs) and serious adverse events (SAEs) were reported with onset on or after the first dosing date and on or prior to the 96 weeks of study ETV therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Entecavir (ETV)
    Reporting group description
    		 Subjects received 0.015 milligram per kilogram per day (mg/kg/day) (up to a maximum dose of 0.5 mg/day) ETV oral solution or tablets, once daily (QD).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received ETV matched placebo oral solution or tablets, QD.

    Serious adverse events
    		 Entecavir (ETV) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 120 (3.33%)
    9 / 60 (15.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 120 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Juvenile idiopathic arthritis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis b
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Entecavir (ETV) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 120 (79.17%)
    53 / 60 (88.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 120 (15.00%)
    9 / 60 (15.00%)
         occurrences all number
    24
    55
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    18 / 120 (15.00%)
    10 / 60 (16.67%)
         occurrences all number
    29
    18
    Fatigue
         subjects affected / exposed
    3 / 120 (2.50%)
    5 / 60 (8.33%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    5 / 120 (4.17%)
    3 / 60 (5.00%)
         occurrences all number
    10
    13
    Diarrhoea
         subjects affected / exposed
    7 / 120 (5.83%)
    7 / 60 (11.67%)
         occurrences all number
    8
    16
    Abdominal pain
         subjects affected / exposed
    9 / 120 (7.50%)
    9 / 60 (15.00%)
         occurrences all number
    16
    14
    Dyspepsia
         subjects affected / exposed
    0 / 120 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    6
    Nausea
         subjects affected / exposed
    6 / 120 (5.00%)
    5 / 60 (8.33%)
         occurrences all number
    6
    6
    Vomiting
         subjects affected / exposed
    14 / 120 (11.67%)
    10 / 60 (16.67%)
         occurrences all number
    17
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 120 (12.50%)
    12 / 60 (20.00%)
         occurrences all number
    18
    21
    Epistaxis
         subjects affected / exposed
    8 / 120 (6.67%)
    3 / 60 (5.00%)
         occurrences all number
    17
    5
    Oropharyngeal pain
         subjects affected / exposed
    7 / 120 (5.83%)
    5 / 60 (8.33%)
         occurrences all number
    8
    9
    Rhinitis allergic
         subjects affected / exposed
    5 / 120 (4.17%)
    3 / 60 (5.00%)
         occurrences all number
    7
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 120 (0.83%)
    5 / 60 (8.33%)
         occurrences all number
    1
    5
    Acne
         subjects affected / exposed
    3 / 120 (2.50%)
    3 / 60 (5.00%)
         occurrences all number
    4
    3
    Urticaria
         subjects affected / exposed
    2 / 120 (1.67%)
    3 / 60 (5.00%)
         occurrences all number
    2
    4
    Rash
         subjects affected / exposed
    7 / 120 (5.83%)
    2 / 60 (3.33%)
         occurrences all number
    8
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 120 (6.67%)
    6 / 60 (10.00%)
         occurrences all number
    9
    9
    Gastroenteritis
         subjects affected / exposed
    6 / 120 (5.00%)
    4 / 60 (6.67%)
         occurrences all number
    9
    4
    Ear infection
         subjects affected / exposed
    7 / 120 (5.83%)
    1 / 60 (1.67%)
         occurrences all number
    7
    2
    Influenza
         subjects affected / exposed
    6 / 120 (5.00%)
    4 / 60 (6.67%)
         occurrences all number
    6
    4
    Pharyngitis
         subjects affected / exposed
    5 / 120 (4.17%)
    11 / 60 (18.33%)
         occurrences all number
    6
    16
    Pharyngitis streptococcal
         subjects affected / exposed
    4 / 120 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    4
    4
    Nasopharyngitis
         subjects affected / exposed
    18 / 120 (15.00%)
    14 / 60 (23.33%)
         occurrences all number
    28
    26
    Pneumonia
         subjects affected / exposed
    6 / 120 (5.00%)
    0 / 60 (0.00%)
         occurrences all number
    10
    0
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 120 (15.83%)
    12 / 60 (20.00%)
         occurrences all number
    61
    45
    Tonsillitis
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2010
    1) Augment the number of randomized subjects from 123 to 180 and increase the estimated number of participating study centers; 2) Change the entry ALT entry criteria from => 1.3 to => 1.5 x upper limit of normal (ULN), increase the minimum time span between the 2 pre-randomization ALT measurements from 4 to 8 weeks, and exclude other reasons for elevated ALT; 3) Specify the early unblinding and mechanism for doing so if subjects demonstrate significant worsening of HBV clinical symptoms or increases in ALT; 4) Specify additional analyses that will be conducted as key secondary and exploratory endpoints; 5) Modify the blood volume collected at some visits due to minimum fill volume requirements of available specimen collection tubes; 6) Summarize the plan for PK/PD analyses that will integrate Studies AI463028 and AI463189.
    04 Sep 2012
    Address the potential safety issues associated with extreme elevations of ALT (serum ALT > 1,000 U/L or > 20x ULN and clinical or laboratory findings suggestive of liver dysfunction) due to acute exacerbation of CHB by providing emergency access to open-label study ETV (“rescue open-label ETV”) for subjects who cannot access acceptable alternative anti-HBV therapy. 1) Specify that rescue open-label ETV would be provided by the sponsor at the request of a primary investigator and approval of the Central Medical Monitor; 2) Specify that rescue therapy provided by the sponsor would be open-label ETV only, and would be provided for up to 96 consecutive weeks; 3) Specify that the management of extreme elevations of ALT are at the discretion of the primary investigator; 4) Clarify that non-serious adverse events should be documented for all LTFU subjects receiving rescue open-label ETV; 5) Change the duration of study to, “5 years, or until the last study subject treated with rescue open-label ETV for an extreme elevation of ALT completes 48-weeks of off-treatment follow-up; whichever is later”; 6) Specify that on-treatment efficacy endpoints are based on double-blind or open-label ETV therapy, and therefore exclude rescue open-label ETV: 7) Modify Figure 5.3.2.1 to provide guidance to investigators managing significant

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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