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    Clinical Trial Results:
    Randomized, Observational Study of Entecavir to Assess Long-term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection: The REALM Study

    Summary
    EudraCT number
    		 2005-003284-22
    Trial protocol
    		 FR   DE   ES   IT   PT   GR   CZ  
    Global end of trial date
    26 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Feb 2018
    First version publication date
    04 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AI463-080
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00388674
    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 Study Director, EU Study Start-Up Unit, , Bristol-Myers Squibb International, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, EU Study Start-Up Unit, , Bristol-Myers Squibb International, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to prospectively assess the long-term outcomes (benefits and risks) associated with entecavir (ETV) therapy as compared to other antivirals approved for the treatment of chronic HBV infection. For the China substudy, patients randomized to entecavir will have safety and efficacy assessments performed during the first year of the study.
    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
    18 Dec 2006
    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
    Argentina: 49
    Country: Number of subjects enrolled
    Brazil: 529
    Country: Number of subjects enrolled
    Canada: 151
    Country: Number of subjects enrolled
    China: 5333
    Country: Number of subjects enrolled
    Colombia: 10
    Country: Number of subjects enrolled
    Czech Republic: 58
    Country: Number of subjects enrolled
    France: 92
    Country: Number of subjects enrolled
    Germany: 175
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    India: 1016
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 2500
    Country: Number of subjects enrolled
    Mexico: 114
    Country: Number of subjects enrolled
    Philippines: 310
    Country: Number of subjects enrolled
    Poland: 69
    Country: Number of subjects enrolled
    Portugal: 35
    Country: Number of subjects enrolled
    Romania: 300
    Country: Number of subjects enrolled
    Russian Federation: 453
    Country: Number of subjects enrolled
    Singapore: 139
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Taiwan: 416
    Country: Number of subjects enrolled
    Thailand: 309
    Country: Number of subjects enrolled
    Turkey: 59
    Country: Number of subjects enrolled
    United States: 318
    Worldwide total number of subjects
    12522
    EEA total number of subjects
    816
    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)
    0
    Adolescents (12-17 years)
    113
    Adults (18-64 years)
    12111
    From 65 to 84 years
    294
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Overall, 12,522 subjects were enrolled;12,485 subjects were randomized; and 12,378 randomized subjects received treatment. 107 randomized not treated; 100 subjects were never treated with the study medication; 3 subjects were at subject's request; 2 subjects were not reported; 1 subject was administrative reason by sponsor; and 1 was other.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 entecavir (ETV)
    Arm description
    		 Tablets / Oral Solution, Oral, ETV = 0.5 mg - 1 mg, once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    entecavir (ETV)
    Investigational medicinal product code
    Other name
    Baraclude
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets / Oral Solution, Oral, ETV = 0.5 mg - 1 mg, once daily, Investigator/Patient decision

    Arm title
    		 Other anti-HBV medication (Non-ETV)
    Arm description
    		 Standard of care HBV Nucleoside/Nucleotide Monotherapy, specific agent selected at the discretion of the investigator
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Adefovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Standard of Care dependent on Country

    Investigational medicinal product name
    Lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Standard of Care dependent on Country

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Standard of Care dependent on Country

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Standard of Care dependent on Country

    Number of subjects in period 1 [1]
    		entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Started
    6216
    6162
    Completed Treatment
    4388 [2]
    3576 [3]
    Completed
    4482
    3993
    Not completed
    1734
    2169
         Adverse event, serious fatal
    239
    262
         Subject Withdrew Consent
    437
    673
         Not Reported
    -
    1
         Non-Study Related Comorbidities
    3
    4
         Not Defined
    135
    214
         Administrative Reason By Sponsor
    299
    253
         Lost to follow-up
    587
    715
         No Off-Treatment Status Data
    22
    30
         HBV Disease Progression (Non-HCC)
    3
    9
         HCC
    8
    7
         Malignancy (Non-HCC)
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 12,522 subjects were enrolled. Baseline Characteristics are shown for the 12,378 randomized and treated subjects.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 6216 subjects started the study. 4388 subjects completed the treatment period. 4482 subjects completed the overall study.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 6162 subjects started the study. 3576 subjects completed the treatment period. 3993 subjects completed the overall study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 All randomized treated subjects

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 12378 12378
    Age categorical
    All randomized treated subjects
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 112 112
        Adults (18-64 years)
    		 11973 11973
        From 65-84 years
    		 289 289
        85 years and over
    		 4 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.7 ± 12.12 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 2993 2993
        Male
    		 9385 9385
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 2
        Asian
    		 10422 10422
        Native Hawaiian or Other Pacific Islander
    		 4 4
        Black or African American
    		 127 127
        White
    		 1599 1599
        Other
    		 224 224
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 3
        Not Hispanic or Latino
    		 307 307
        Unknown or Not Reported
    		 12068 12068

    End points

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    End points reporting groups
    Reporting group title
    entecavir (ETV)
    Reporting group description
    		 Tablets / Oral Solution, Oral, ETV = 0.5 mg - 1 mg, once daily.

    Reporting group title
    Other anti-HBV medication (Non-ETV)
    Reporting group description
    		 Standard of care HBV Nucleoside/Nucleotide Monotherapy, specific agent selected at the discretion of the investigator

    Primary: Number of subjects with Adjudicated Overall Malignant Neoplasms

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    End point title
    		 Number of subjects with Adjudicated Overall Malignant Neoplasms
    End point description
    The number of subjects with Overall Malignant Neoplasm, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Primary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: Subjects
    331
    337
    Statistical analysis title
    		 Adjudicated Overall Malignant Neoplasms
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3553
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95.03%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.084

    Primary: Number of Adjudicated Deaths

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    End point title
    		 Number of Adjudicated Deaths
    End point description
    The number of deaths, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Primary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: Subjects
    238
    264
    Statistical analysis title
    		 Adjudicated Deaths
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0676
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95.03%
         sides
    2-sided
         lower limit
    		 0.713
         upper limit
    		 1.012

    Primary: Number of subjects with Adjudicated Liver-related HBV disease progression

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    End point title
    		 Number of subjects with Adjudicated Liver-related HBV disease progression
    End point description
    The number of subjects with Liver-related hepatitis B virus (HBV) disease progression, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Primary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: Subjects
    350
    375
    Statistical analysis title
    		 Adjudicated Liver-related HBV disease progression
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1182
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95.03%
         sides
    2-sided
         lower limit
    		 0.769
         upper limit
    		 1.03

    Secondary: Number of subjects with Adjudicated non-HCC malignant neoplasm

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    End point title
    		 Number of subjects with Adjudicated non-HCC malignant neoplasm
    End point description
    The number of subjects with non-hepatocellular carcinoma (non-HCC) malignant neoplasm, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Secondary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: subjects
    95
    81
    Statistical analysis title
    		 Adjudicated Non-HCC malignant neoplasms
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.817
         upper limit
    		 1.478

    Secondary: Number of subjects with Adjudicated HCC malignant neoplasm

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    End point title
    		 Number of subjects with Adjudicated HCC malignant neoplasm
    End point description
    The number of subjects with hepatocellular carcinoma (HCC) malignant neoplasm, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Secondary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: subjects
    240
    263
    Statistical analysis title
    		 Adjudicated HCC malignant neoplasm
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.727
         upper limit
    		 1.032

    Secondary: Number of subjects with Adjudicated Liver-related death

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    End point title
    		 Number of subjects with Adjudicated Liver-related death
    End point description
    The number of subjects with Liver-related death, as adjudicated by Events Adjudication Committee (EAC)
    End point type
    Secondary
    End point timeframe
    10 years
    End point values
    		 entecavir (ETV) Other anti-HBV medication (Non-ETV)
    Number of subjects analysed
    6216
    6162
    Units: Subjects
    46
    48
    Statistical analysis title
    		 Adjudicated Liver-related deaths
    Statistical analysis description
    ETV : Non-ETV Hazard Ratio
    Comparison groups
    entecavir (ETV) v Other anti-HBV medication (Non-ETV)
    Number of subjects included in analysis
    12378
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.608
         upper limit
    		 1.365

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From first dose until end of study (10 years)
    Adverse event reporting additional description
    Mandatory reporting of non-serious AEs was not required. Reporting of serious adverse events (SAEs) which are considered unrelated (i.e. not likely or not related) to study drug was also not required.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Naive ETV
    Reporting group description
    		 Treatment naïve subjects with CHB received ETV either as the 0.5 mg or 1.0 mg tablet or 0.05 mg/mL oral solution (in countries where the oral solution was approved) up to 10 years and continued on study until the study ended or they died, were lost to follow-up, withdrew informed consent, or discontinued treatment for other reasons.

    Reporting group title
    Experienced ETV
    Reporting group description
    		 Subjects with CHB received ETV either as the 0.5 mg or 1.0 mg tablet or 0.05 mg/mL oral solution (in countries where the oral solution was approved) up to 10 years and continued on study until the study ended or they died, were lost to follow-up, withdrew informed consent, or discontinued treatment for other reasons.

    Reporting group title
    Experienced Non-ETV
    Reporting group description
    		 Subjects with CHB received non-ETV standard of care HBV therapies up to 10 years and continued on study until the study ended or they died, were lost to follow-up, withdrew informed consent, or discontinued treatment for other reasons.

    Reporting group title
    Naive Non-ETV
    Reporting group description
    		 Treatment naïve subjects with CHB received non-ETV standard of care HBV therapies up to 10 years and continued on study until the study ended or they died, were lost to follow-up, withdrew informed consent, or discontinued treatment for other reasons.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Mandatory reporting of non-serious AEs was not required. Reporting of serious adverse events (SAEs) which are considered unrelated (i.e. not likely or not related) to study drug was also not required.
    Serious adverse events
    		 Naive ETV Experienced ETV Experienced Non-ETV Naive Non-ETV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 4016 (0.87%)
    21 / 2200 (0.95%)
    15 / 2178 (0.69%)
    35 / 3984 (0.88%)
         number of deaths (all causes)
    156
    84
    90
    174
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    4 / 4016 (0.10%)
    4 / 2200 (0.18%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Electrocution
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 4016 (0.05%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 4016 (0.05%)
    2 / 2200 (0.09%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 4016 (0.05%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    2 / 3984 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Atypical femur fracture
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy multiplex
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    2 / 3984 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    2 / 4016 (0.05%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 4016 (0.10%)
    2 / 2200 (0.09%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 4016 (0.02%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic hepatitis
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    2 / 4016 (0.05%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    2 / 4016 (0.05%)
    2 / 2200 (0.09%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hepatic fibrosis
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 4016 (0.05%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    2 / 3984 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    2 / 3984 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    4 / 3984 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    4 / 2178 (0.18%)
    11 / 3984 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    2 / 3984 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 4016 (0.05%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic hepatitis b
         subjects affected / exposed
    0 / 4016 (0.00%)
    1 / 2200 (0.05%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis b
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    1 / 2178 (0.05%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis b reactivation
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    1 / 4016 (0.02%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    3 / 2178 (0.14%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    1 / 3984 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Naive ETV Experienced ETV Experienced Non-ETV Naive Non-ETV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 4016 (0.00%)
    0 / 2200 (0.00%)
    0 / 2178 (0.00%)
    0 / 3984 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2006
    Global Amendment 02: Pharmacogenetics Buccal Sample Amendment
    25 Jun 2007
    Global Amendment Number 03: ETV dose reduction options, updated exclusion criterion, COE Reporting clarifications

    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.
    1. No baseline or on-treatment HBV-related surrogate markers were collected. 2. BMS supplied only the initial therapy, not any subsequent therapies.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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