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    Clinical Trial Results:
    Phase III study of adefovir dipivoxil in patients with treatment naïve CHB. Comparator is Lamivudine 100mcg film coated tablets-D2012-7213

    Summary
    EudraCT number
    		 2015-004890-34
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    16 Jan 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2017
    First version publication date
    22 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADF105220
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    17 Mar 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    TBD
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jan 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 105
    Worldwide total number of subjects
    105
    EEA total number of subjects
    0
    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)
    0
    Adults (18-64 years)
    105
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In this study, informed consent was obtained from 171 subjects. Of those subjects, 66 were withdrawn for not meeting eligibility criteria at screening, including 2 for consent withdrawn.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adefovir (ADV)
    Arm description
    		 ADV 10 mg orally once daily for 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adefovir dipivoxil (ADV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered one ADV 10 mg tablet and one LAM placebo tablet orally once daily for 52 weeks

    Arm title
    		 Lamivudine (LAM)
    Arm description
    		 LAM 100 mg orally once daily for 52 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lamivudine (LAM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered one LAM 100 mg tablet and one ADV placebo tablet orally once daily for 52 weeks

    Number of subjects in period 1
    		Adefovir (ADV) Lamivudine (LAM)
    Started
    52
    53
    Completed
    50
    47
    Not completed
    2
    6
         Adverse event, non-fatal
    -
    6
         Consent withdrawn
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adefovir (ADV)
    Reporting group description
    		 ADV 10 mg orally once daily for 52 weeks

    Reporting group title
    Lamivudine (LAM)
    Reporting group description
    		 LAM 100 mg orally once daily for 52 weeks

    Reporting group values
    		 Adefovir (ADV) Lamivudine (LAM) Total
    Number of subjects
    		 52 53
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    		 44 ± 9.73 43.9 ± 9.95 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 9 18 27
        Male
    		 43 35 78
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 52 53 105
    Region of Enrollment
    Units: Subjects
        Japan
    		 52 53 105

    End points

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    End points reporting groups
    Reporting group title
    Adefovir (ADV)
    Reporting group description
    		 ADV 10 mg orally once daily for 52 weeks

    Reporting group title
    Lamivudine (LAM)
    Reporting group description
    		 LAM 100 mg orally once daily for 52 weeks

    Primary: Mean Change from Baseline in Hepatitis B Virus (HBV) DNA at Week 52

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    End point title
    		 Mean Change from Baseline in Hepatitis B Virus (HBV) DNA at Week 52
    End point description
    Change from baseline was the difference of the HBV DNA copy numbers (log10) in serum collected by blood draw between baseline and Week 52. Per Protocol Set (PPS): participants in the Full Analysis Set (all subjects who entered the study, received at least one dose of investigational product, and had at least one efficacy assessment after the treatment initiation) population with no major protocol violations.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    50 [1]
    52 [2]
    Units: log10 copies/mL
        arithmetic mean (standard deviation)
    -3.69 ± 1.169
    -3.4 ± 1.896
    Notes
    [1] - PPS
    [2] - PPS
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Lamivudine (LAM) v Adefovir (ADV)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (net)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.309
    Notes
    [3] - This is a Non-inferiority Analysis with the margin of -1.0.

    Secondary: Percentage of participants with HBV DNA Loss (<400 copies/mL) at Week 52

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    End point title
    		 Percentage of participants with HBV DNA Loss (<400 copies/mL) at Week 52
    End point description
    The percentages of participants with an HBV DNA level in serum of less than 400 copies/mL, which is the lower limit of detection (HBV DNA loss) at Week 52
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    50 [4]
    52 [5]
    Units: Percentage of participants
    number (not applicable)
        <400 copies/mL
    46
    50
        >400 copies/mL
    54
    50
    Notes
    [4] - PPS
    [5] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants with Hepatitis B e antigen (HBeAg) loss at Week 52

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    End point title
    		 Percentage of participants with Hepatitis B e antigen (HBeAg) loss at Week 52
    End point description
    Participants with loss of Hepatitis B e antigen (HBeAg) in serum collected by blood draw: Cheminoluminescent Immuno Assay (CLIA) method
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    36 [6]
    37 [7]
    Units: percentage of participants
    number (not applicable)
        With loss of HBeAg
    16.7
    16.2
        Positive for HBeAg
    93.3
    93.8
    Notes
    [6] - PPS
    [7] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants with Hepatitis B e antigen/antibody (HBeAg/Ab) Seroconversion at Week 52

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    End point title
    		 Percentage of participants with Hepatitis B e antigen/antibody (HBeAg/Ab) Seroconversion at Week 52
    End point description
    Participants with loss of Hepatitis B e antigen (HBeAg) and positive for anti-Hepatitis B e antibody (HBeAb) in serum collected by blood draw: CLIA method
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    31 [8]
    34 [9]
    Units: Percentage of participants
    number (not applicable)
        With HBeAg/Ab seroconversion
    9.7
    5.9
        Without HBeAg/Ab seroconversion
    90.3
    94.1
    Notes
    [8] - PPS: participants who were positive for HBeAg and negative for HBeAb at baseline
    [9] - PPS: participants who were positive for HBeAg and negative for HBeAb at baseline
    No statistical analyses for this end point

    Secondary: Percentage of participants with Hepatitis B s antigen (HBsAg) loss at Week 52

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    End point title
    		 Percentage of participants with Hepatitis B s antigen (HBsAg) loss at Week 52
    End point description
    Participants with loss of Hepatitis B s antigen (HBsAg) in serum collected by blood draw: CLIA method
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    50 [10]
    52 [11]
    Units: percentage of participants
    number (not applicable)
        With loss of HBsAg
    0
    0
        Positive for HBsAg
    100
    100
    Notes
    [10] - PPS: participants who were positive for HBeAg at baseline
    [11] - PPS: participants who were positive for HBeAg at baseline
    No statistical analyses for this end point

    Secondary: Percentage of participants with Hepatitis B s antigen/ antibody (HBsAg/Ab) Seroconversion at Week 52

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    End point title
    		 Percentage of participants with Hepatitis B s antigen/ antibody (HBsAg/Ab) Seroconversion at Week 52
    End point description
    Participants with loss of Hepatitis B s antigen (HBsAg) and positive for anti-Hepatitis B s antibody (HBsAb) in serum collected by blood draw: CLIA method
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    46 [12]
    45 [13]
    Units: percentage of participants
    number (not applicable)
        With HBsAg/Ab seroconversion
    0
    0
        Without HBsAg/Ab seroconversion
    100
    100
    Notes
    [12] - PPS: participants who were positive for HBeAg and negative for HBeAb at baseline
    [13] - PPS: participants who were positive for HBeAg and negative for HBeAb at baseline
    No statistical analyses for this end point

    Secondary: Mean alanine aminotransferase (ALT) level at Week 52

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    End point title
    		 Mean alanine aminotransferase (ALT) level at Week 52
    End point description
    Summary statistics were displayed for serum ALT.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    50 [14]
    47 [15]
    Units: Units per Liter
        arithmetic mean (standard deviation)
    32.3 ± 14.72
    33 ± 28.12
    Notes
    [14] - PPS
    [15] - PPS
    No statistical analyses for this end point

    Secondary: Percentage of participants with alanine aminotransferase (ALT) normalization at Week 52

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    End point title
    		 Percentage of participants with alanine aminotransferase (ALT) normalization at Week 52
    End point description
    ALT normalization was defined as an ALT value that was in the normal range (<= 45IU/L; upper limit of normal [ULN]) at Week 52 of the participants whose ALT values were abnormal (>45IU/L) at baseline
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    46 [16]
    51 [17]
    Units: Percentage of participants
    number (not applicable)
        With ALT normalization
    82.6
    78.4
        Without ALT normalization
    17.4
    21.6
    Notes
    [16] - PPS: Participants with abnormal ALT value (>ULN) at baseline
    [17] - PPS: Participants with abnormal ALT value (>ULN) at baseline
    No statistical analyses for this end point

    Secondary: Time to onset of ALT normalization

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    End point title
    		 Time to onset of ALT normalization
    End point description
    Time to onset of ALT normalization was summarized using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    46 [18]
    51 [19]
    Units: Week 52
        median (confidence interval 95%)
    12 (8 to 16)
    12 (12 to 16)
    Notes
    [18] - PPS: Participants with abnormal ALT value (>ULN) at baseline
    [19] - PPS: Participants with abnormal ALT value (>ULN) at baseline
    No statistical analyses for this end point

    Secondary: Rate of Emergence of Resistant Virus at Week 52

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    End point title
    		 Rate of Emergence of Resistant Virus at Week 52
    End point description
    Participants with resistant mutation at Week 52. LAM resistant mutation (enzyme-linked mini-sequencing assay): rtM204I/V; ADV resistant mutation (direct sequencing assay): rtN236T or rtA181T/V in HBV DNA ; rt: reverse transcriptase gene
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Adefovir (ADV) Lamivudine (LAM)
    Number of subjects analysed
    50 [20]
    52 [21]
    Units: Percentage of participants
    number (not applicable)
        With resistant mutation
    0
    28.8
        Without resistant mutation
    100
    71.2
    Notes
    [20] - PPS
    [21] - PPS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to Week 52.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Adefovir (ADV)
    Reporting group description
    		 ADV 10 mg orally once daily for 52 weeks

    Reporting group title
    Lamivudine (LAM)
    Reporting group description
    		 LAM 100 mg orally once daily for 52 weeks

    Serious adverse events
    		 Adefovir (ADV) Lamivudine (LAM)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 53 (7.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 53 (1.89%)
         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
    		 Adefovir (ADV) Lamivudine (LAM)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 52 (75.00%)
    47 / 53 (88.68%)
    Investigations
    Blood creatine phosphokinase increased
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    5 / 52 (9.62%)
    4 / 53 (7.55%)
         occurrences all number
    8
    5
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 53 (7.55%)
         occurrences all number
    1
    9
    General disorders and administration site conditions
    Malaise
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 53 (9.43%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Diarrhea
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    7 / 52 (13.46%)
    6 / 53 (11.32%)
         occurrences all number
    10
    6
    Abdominal pain upper
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Nausea
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 53 (7.55%)
         occurrences all number
    1
    4
    Vomiting
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 53 (9.43%)
         occurrences all number
    2
    5
    Cough
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Hepatobiliary disorders
    Hepatitis
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    0 / 52 (0.00%)
    6 / 53 (11.32%)
         occurrences all number
    0
    6
    Skin and subcutaneous tissue disorders
    Eczema
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 53 (5.66%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    11 / 52 (21.15%)
    19 / 53 (35.85%)
         occurrences all number
    15
    27
    Upper respiratory tract inflammation
    alternative dictionary used: MedDRA 9.0
         subjects affected / exposed
    7 / 52 (13.46%)
    10 / 53 (18.87%)
         occurrences all number
    11
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2006
    Revised the description of contraindication medications in the exclusion criteria: transferred the statement “(except ointment and/or cream etc)” to the first sentence, because this statement relates to not only corticosteroid but also entire contraindication medications.
    17 Mar 2006
    Changed the commencement of the period of contraindication medications from the first day of the screening period to the first dosing day.
    19 Sep 2006
    Modified the study administrative structure
    16 Apr 2007
    Modified the study administrative structure

    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
    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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