Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2 to Less Than 18) With Chronic Hepatitis B

    Summary
    EudraCT number
    		 2004-001346-33
    Trial protocol
    		 ES   Outside EU/EEA  
    Global end of trial date
    09 Apr 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-103-0518
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00095121
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    Flowers Building, Granta Park, Abington, Cambridge, United Kingdom, CB21 6GT
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Apr 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to investigate the efficacy and safety of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B in children and adolescents (age 2 to less than 18 years) following 48 weeks of placebo-controlled, double-blind treatment and following an additional 192 weeks of open-label ADV treatment.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2004
    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
    Germany: 19
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    173
    EEA total number of subjects
    125
    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)
    90
    Adolescents (12-17 years)
    83
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The first participant was screened on 17 May 2004. The last study visit occurred on 09 April 2010.

    Pre-assignment
    Screening details
    		 293 subjects were screened.

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ADV - ADV
    Arm description
    		 Participants were randomized to receive ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adefovir dipivoxil
    Investigational medicinal product code
    Other name
    ADV, Hepsera®
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Children aged 2 to < 7 years received 0.3 mg/kg oral suspension; children aged ≥ 7 to < 12 years received 0.25 mg/kg oral suspension; children aged ≥ 12 to < 18 years received a 10 mg tablet.

    Arm title
    		 PLB - ADV
    Arm description
    		 Participants were randomized to receive placebo (PLB) to match ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to match ADV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Children aged 2 to < 12 years received placebo as an oral suspension; children aged ≥ 12 to < 18 years received placebo as a tablet.

    Investigational medicinal product name
    Adefovir dipivoxil
    Investigational medicinal product code
    Other name
    ADV, Hepsera®
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Children aged 2 to < 7 years received 0.3 mg/kg oral suspension; children aged ≥ 7 to < 12 years received 0.25 mg/kg oral suspension; children aged ≥ 12 to < 18 years received a 10 mg tablet.

    Number of subjects in period 1
    		ADV - ADV PLB - ADV
    Started
    115
    58
    Completed double-blind phase
    112
    58
    Started open-label phase
    108
    54
    Received lamivudine (LAM) after Week 96
    21 [1]
    11 [2]
    Completed
    46
    35
    Not completed
    69
    23
         Adverse event, non-fatal
    2
    -
         Did not enter open-label phase
    4
    4
         Other
    47
    16
         Progressive disease
    2
    1
         Withdrew consent
    6
    -
         Lost to follow-up
    1
    1
         Participant noncompliance
    7
    1
    Notes
    [1] - 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: The milestones presented use the current functionality of the EU-CTR in order to best report the summary results in an informative way.
    [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: The milestones presented use the current functionality of the EU-CTR in order to best report the summary results in an informative way.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    ADV - ADV
    Reporting group description
    		 Participants were randomized to receive ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

    Reporting group title
    PLB - ADV
    Reporting group description
    		 Participants were randomized to receive placebo (PLB) to match ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

    Reporting group values
    		 ADV - ADV PLB - ADV Total
    Number of subjects
    		 115 58 173
    Age Categorical
    Units: participants
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.8 ( 4.33 ) 10.7 ( 3.94 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 41 19 60
        Male
    		 74 39 113
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 114 58 172
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 29 12 41
        Black or African American
    		 11 3 14
        White
    		 70 41 111
        More than one race
    		 4 2 6
    Hepatitis B Surface Antigen (HBsAg)
    Units: Subjects
        Negative
    		 0 0 0
        Positive
    		 115 58 173
    Antibody to HBsAg (HBsAb)
    Units: Subjects
        Negative
    		 0 0 0
        Positive
    		 0 0 0
        Not Done
    		 115 58 173
    Hepatitis B e Antigen (HBeAg)
    Units: Subjects
        Negative
    		 2 1 3
        Positive
    		 113 57 170
    Antibody to HBeAg (HBeAb)
    Units: Subjects
        Negative
    		 0 0 0
        Positive
    		 2 1 3
        Not Done
    		 113 57 170
    Alanine aminotransferase (ALT) Normal
    Units: Subjects
        ≥ upper limit of normal (ULN)
    		 108 56 164
        < ULN
    		 7 2 9
    HBV DNA
    Units: log10 copies/mL
        arithmetic mean (standard deviation)
    		 8.74 ( 0.894 ) 8.67 ( 1.016 ) -
    ALT
    Units: U/L
        arithmetic mean (standard deviation)
    		 111 ( 81.6 ) 99 ( 52.8 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    ADV - ADV
    Reporting group description
    		 Participants were randomized to receive ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

    Reporting group title
    PLB - ADV
    Reporting group description
    		 Participants were randomized to receive placebo (PLB) to match ADV in the double-blind period (up to 48 weeks) followed by ADV in the open-label period (up to an additional 192 weeks). Lamivudine was added to the open-label ADV regimen of subjects between 12 and < 18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Study Week 96.

    Primary: Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 copies/mL (polymerase chain reaction [PCR]-based assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 copies/mL (polymerase chain reaction [PCR]-based assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure)
    End point description
    In the absence of biopsy data from these pediatric participants, this endpoint enables assessments of drug effect on viral replication and the underlying degree of inflammation in the liver. All randomized participants who received >= 1 dose study medication. If either endpoint was missing a Week 48 value, Week 44 value was substituted and used in the combined endpoint. If participant did not have serum HBV DNA value at Weeks 44 and 48 or ALT value at Weeks 44 and 48, then participant was considered a failure for the Week-48 analysis.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    115
    58
    Units: percentage of participants
        Baseline
    0
    0
        Week 24
    5
    0
        Week 48
    19
    2
    Statistical analysis title
    		 P-value analysis
    Statistical analysis description
    After unblinding the results, due to the small number of responders in the placebo group, it was determined that a statistical exact test would be more appropriate in the evaluation of treatment group differences than the originally planned 95% confidence intervals of the difference between the groups. Therefore, the results were analyzed by study visit, and a Fisher exact test was used to evaluate treatment differences between the adefovir dipivoxil and placebo groups.
    Comparison groups
    ADV - ADV v PLB - ADV
    Number of subjects included in analysis
    173
    Analysis specification
    Post-hoc
    Analysis type
    		 other [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - Intergroup comparison
    [2] - End of double-blind treatment

    Secondary: Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline)
    End point description
    The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). The open-label (OL) analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV baseline
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serum HBV DNA < 1000 copies/mL (PCR-based assay) While on Treatment - Missing = Failure) (ADV Week 192)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum HBV DNA < 1000 copies/mL (PCR-based assay) While on Treatment - Missing = Failure) (ADV Week 192)
    End point description
    Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV Week 192
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    15
    15
    No statistical analyses for this end point

    Secondary: Secondary: Percentage of Participants With Serum HBV DNA < 1000 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 240)

    		 Close Top of page
    End point title
    		 Secondary: Percentage of Participants With Serum HBV DNA < 1000 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 240) [3]
    End point description
    The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV Week 240
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    108
    Units: percentage of participants
    6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Baseline)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Baseline)
    End point description
    The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV baseline
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 192)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 192)
    End point description
    Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV Week 192
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    11
    13
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 240)

    		 Close Top of page
    End point title
    		 Percentage of Participants With Serum HBV DNA < 400 copies/mL (PCR-based assay) While on Treatment (Missing = Failure) (ADV Week 240) [4]
    End point description
    The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded.
    End point type
    Secondary
    End point timeframe
    ADV Week 240
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    108
    Units: percentage of participants
    6
    No statistical analyses for this end point

    Secondary: ADV Baseline Serum HBV DNA

    		 Close Top of page
    End point title
    		 ADV Baseline Serum HBV DNA
    End point description
    The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: log10 HBV DNA copies/mL
        arithmetic mean (standard deviation)
    8.76 ( 0.869 )
    8.24 ( 1.248 )
    No statistical analyses for this end point

    Secondary: Change from ADV Baseline to ADV Week 192 for Serum HBV DNA

    		 Close Top of page
    End point title
    		 Change from ADV Baseline to ADV Week 192 for Serum HBV DNA
    End point description
    Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV 192 weeks
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    17
    9
    Units: log10 HBV DNA copies/mL
        arithmetic mean (standard deviation)
    -5.89 ( 1.119 )
    -5.41 ( 1.573 )
    No statistical analyses for this end point

    Secondary: Change from ADV Baseline to ADV Week 240 for Serum HBV DNA

    		 Close Top of page
    End point title
    		 Change from ADV Baseline to ADV Week 240 for Serum HBV DNA [5]
    End point description
    The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV 240 weeks
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    7
    Units: log10 HBV DNA copies/mL
        arithmetic mean (standard deviation)
    -5.87 ( 1.826 )
    No statistical analyses for this end point

    Secondary: ADV Baseline ALT

    		 Close Top of page
    End point title
    		 ADV Baseline ALT
    End point description
    The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: U/L
        arithmetic mean (standard deviation)
    108.69 ( 79.069 )
    99.81 ( 97.583 )
    No statistical analyses for this end point

    Secondary: Change from ADV Baseline to ADV Week 192 for ALT

    		 Close Top of page
    End point title
    		 Change from ADV Baseline to ADV Week 192 for ALT
    End point description
    Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV 192 weeks
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    17
    8
    Units: U/L
        arithmetic mean (standard deviation)
    -66.06 ( 42.655 )
    -38.88 ( 33.566 )
    No statistical analyses for this end point

    Secondary: Change from ADV Baseline to ADV Week 240 for ALT

    		 Close Top of page
    End point title
    		 Change from ADV Baseline to ADV Week 240 for ALT [6]
    End point description
    The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV 240 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    6
    Units: U/L
        arithmetic mean (standard deviation)
    -64.33 ( 44.742 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Normal ALT at Adefovir Baseline (Missing = Failure)

    		 Close Top of page
    End point title
    		 Percentage of Participants with Normal ALT at Adefovir Baseline (Missing = Failure)
    End point description
    The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    Adefovir baseline
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    7
    15
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Normal ALT at ADV Week 192 (Missing = Failure)

    		 Close Top of page
    End point title
    		 Percentage of Participants with Normal ALT at ADV Week 192 (Missing = Failure)
    End point description
    Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV Week 192
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    108
    54
    Units: percentage of participants
    14
    13
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Normal ALT at ADV Week 240 (Missing = Failure)

    		 Close Top of page
    End point title
    		 Percentage of Participants with Normal ALT at ADV Week 240 (Missing = Failure) [7]
    End point description
    Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV Week 240
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    108
    Units: percentage of participants
    5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set)

    		 Close Top of page
    End point title
    		 Percentage of Participants with Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set)
    End point description
    HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg− post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg− and hepatitis B e antibody + (anti-HBe+) post baseline. The randomized and treated analysis set included all participants who were randomized into the study and received at least one dose of study medication. For Week 48 data; if Week 48 was missing, Week 44 was carried forward; if Week 44 was missing, missing = failure.
    End point type
    Secondary
    End point timeframe
    Study Week 0 to Study Week 48 (double-blind period)
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    113
    57
    Units: percentage of participants
        HBeAg Loss
    17
    5
        Seroconversion to Anti-HBe
    16
    5
    Statistical analysis title
    		 Comparison of HBeAg Loss
    Comparison groups
    ADV - ADV v PLB - ADV
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.051 [9]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [8] - Intergroup analysis
    [9] - Comparison of HBeAg Loss
    Statistical analysis title
    		 Comparison of HBeAg Seroconversion
    Comparison groups
    ADV - ADV v PLB - ADV
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.051 [11]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - Intergroup analysis
    [11] - Comparison of HBeAg Seroconversion

    Secondary: Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded)

    		 Close Top of page
    End point title
    		 Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded)
    End point description
    ADV baseline = 1st ADV-dose day = Week 0 for ADV-ADV group and Week 48 for PLB-ADV group. ADV week = windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). HBeAg loss is defined per individual participant as HBeAg+ at ADV baseline and HBeAg− post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg− and anti-HBe+ post baseline. The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were excluded. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV Week 192
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    16
    9
    Units: percentage of participants
        HBeAg Loss
    56
    33
        Seroconversion to Anti-HBe
    44
    11
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded)

    		 Close Top of page
    End point title
    		 Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) [12]
    End point description
    Per protocol, participants could discontinue study medication due to HBeAg seroconversion and remain in the study in order to evaluate the durability of seroconversion. HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg− post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg− and anti-HBe+ post baseline. The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were excluded. Analysis set included only data from participants while on study treatment.
    End point type
    Secondary
    End point timeframe
    ADV baseline to ADV Week 240
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants randomized to the ADV-ADV arm completed 240 weeks of ADV treatment.
    End point values
    		 ADV - ADV
    Number of subjects analysed
    6
    Units: percentage of participants
        HBeAg Loss
    33
        Seroconversion to Anti-HBe
    17
    No statistical analyses for this end point

    Secondary: Cumulative Summary of Participants with HBV Genotypic Changes From Baseline (Resistance Surveillance)

    		 Close Top of page
    End point title
    		 Cumulative Summary of Participants with HBV Genotypic Changes From Baseline (Resistance Surveillance)
    End point description
    Resistance surveillance was conducted annually for all participants who remained on treatment and had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR. The last on-ADV sample for all participants in the study was analyzed in the cumulative Week 240 resistance surveillance analysis. Last on-ADV sample through Week 240 was analyzed, and participant was excluded from the cumulative Week 240 analysis if HBV DNA value was < 169 copies/mL at Week 240/last time point or if participant discontinued study drug but remained in study. One ADV-ADV participant had an ADV-specific, conserved-site mutation and is counted twice in the table.
    End point type
    Secondary
    End point timeframe
    240 weeks
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    74
    37
    Units: participants
        No genotypic changes from baseline
    48
    18
        Polymorphic site changes
    17
    12
        Changes at conserved sites in HBV polymerase
    3
    3
        Developed mutations specific to ADV/lamivudine
    1
    0
        Unable to be genotyped
    6
    4
    No statistical analyses for this end point

    Secondary: Cumulative Summary of Participants with HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy

    		 Close Top of page
    End point title
    		 Cumulative Summary of Participants with HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy
    End point description
    Resistance surveillance was conducted at Week 240/last on-treatment study visit for all participants who had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR while on combination ADV + lamivudine treatment. 32/173 added lamivudine from Weeks 108 - 144. Last on-ADV sample through Week 240 analyzed; participant omitted from cumulative Week 240 analysis if HBV DNA <169 copies/mL at Week 240/last time point or stopped study drug but remained in study. 2 ADV-ADV participants had ADV/lamivudine-specific, conserved-site mutation, and counted 2x in table.
    End point type
    Secondary
    End point timeframe
    240 weeks
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    14
    3
    Units: participants
        No genotypic changes from baseline
    5
    1
        Polymorphic site changes
    3
    1
        Changes at conserved sites in HBV polymerase
    3
    1
        Developed mutations specific to ADV and/or LAM
    2
    0
        Unable to be genotyped
    3
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Durable HBeAg Seroconversion

    		 Close Top of page
    End point title
    		 Percentage of Participants with Durable HBeAg Seroconversion
    End point description
    A participant was defined to have durable HBeAg seroconversion only if she/he remained in a seroconverted state (HBeAg−, hepatitis B e antibody + [anti-HBe+]) from the date that she/he first seroconverted through and including her/his last study visit. This endpoint could only be assessed for participants who (HBeAg−) seroconverted on-treatment and subsequently discontinued open-label dosing. Participants who discontinued treatment because of confirmed HBeAg seroconversion in Weeks 49 to 240 were to remain in the study through Week 240 to monitor the durability of seroconversion. Any participant who formally stopped drug early and restarted, by definition, did not have durable HBeAg seroconversion.
    End point type
    Secondary
    End point timeframe
    240 weeks
    End point values
    		 ADV - ADV PLB - ADV
    Number of subjects analysed
    45
    24
    Units: percentage of participants
    82
    71
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Up to 240 weeks (during the 48 weeks of randomized treatment and subsequent 192 weeks of open-label treatment) plus 30 days.
    Adverse event reporting additional description
    Double-blind phase: up to 48 weeks (plus 4 days for participants who discontinued early, or plus 30 days if participants completed the double-blind phase but did not enter the open label phase). Open-label phase: from Week 48 up to Week 240 plus 30 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    ADV (Double-Blind)
    Reporting group description
    		 Adverse events in this reporting group include those occurring in participants who received ADV in the doubleblind phase.

    Reporting group title
    PLB (Double-Blind)
    Reporting group description
    		 Adverse events in this reporting group include those occurring in participants who received placebo to match ADV in the double-blind phase.

    Reporting group title
    ADV-ADV (open-label, on treatment)
    Reporting group description
    		 Adverse events in this reporting group include those occurring while on treatment in the open-label phase in participants originally randomized to ADV in the double-blind phase, and who then continued ADV treatment in the open-label phase.

    Reporting group title
    PLB-ADV (open-label, on treatment)
    Reporting group description
    		 Adverse events in this reporting group include those occurring while on treatment in the open-label phase in participants originally randomized to placebo to match ADV in the double-blind phase, and who then switched to ADV treatment in the open-label phase.

    Reporting group title
    ADV-ADV (open-label, off treatment)
    Reporting group description
    		 Adverse events in this reporting group include those occurring while off treatment in the open-label phase in participants originally randomized to ADV in the double-blind phase, and who then continued ADV treatment in the open-label phase.

    Reporting group title
    PLB-ADV (open-label, off treatment)
    Reporting group description
    		 Adverse events in this reporting group include those occurring while off treatment in the open-label phase in participants originally randomized to placebo to match ADV in the double-blind phase, and who then switched to ADV treatment in the open-label phase.

    Serious adverse events
    		 ADV (Double-Blind) PLB (Double-Blind) ADV-ADV (open-label, on treatment) PLB-ADV (open-label, on treatment) ADV-ADV (open-label, off treatment) PLB-ADV (open-label, off treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 115 (6.09%)
    5 / 58 (8.62%)
    10 / 108 (9.26%)
    3 / 54 (5.56%)
    30 / 108 (27.78%)
    10 / 54 (18.52%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 58 (1.72%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
    6 / 108 (5.56%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    4 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    2 / 108 (1.85%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    1 / 54 (1.85%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    1 / 54 (1.85%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Excoriation
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 58 (1.72%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular haemorrhage
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 58 (1.72%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    19 / 108 (17.59%)
    5 / 54 (9.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    11 / 19
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    1 / 54 (1.85%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 58 (1.72%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 58 (1.72%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Typhus
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 58 (0.00%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ADV (Double-Blind) PLB (Double-Blind) ADV-ADV (open-label, on treatment) PLB-ADV (open-label, on treatment) ADV-ADV (open-label, off treatment) PLB-ADV (open-label, off treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 115 (66.96%)
    41 / 58 (70.69%)
    58 / 108 (53.70%)
    38 / 54 (70.37%)
    33 / 108 (30.56%)
    19 / 54 (35.19%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 58 (1.72%)
    0 / 108 (0.00%)
    5 / 54 (9.26%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    2
    1
    0
    5
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 115 (13.04%)
    8 / 58 (13.79%)
    11 / 108 (10.19%)
    4 / 54 (7.41%)
    4 / 108 (3.70%)
    2 / 54 (3.70%)
         occurrences all number
    24
    12
    14
    8
    4
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 115 (12.17%)
    5 / 58 (8.62%)
    5 / 108 (4.63%)
    3 / 54 (5.56%)
    6 / 108 (5.56%)
    7 / 54 (12.96%)
         occurrences all number
    22
    9
    5
    5
    8
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 115 (8.70%)
    9 / 58 (15.52%)
    9 / 108 (8.33%)
    10 / 54 (18.52%)
    4 / 108 (3.70%)
    2 / 54 (3.70%)
         occurrences all number
    12
    19
    10
    13
    4
    2
    Diarrhoea
         subjects affected / exposed
    7 / 115 (6.09%)
    4 / 58 (6.90%)
    5 / 108 (4.63%)
    3 / 54 (5.56%)
    4 / 108 (3.70%)
    3 / 54 (5.56%)
         occurrences all number
    10
    5
    5
    5
    4
    6
    Vomiting
         subjects affected / exposed
    4 / 115 (3.48%)
    5 / 58 (8.62%)
    4 / 108 (3.70%)
    2 / 54 (3.70%)
    2 / 108 (1.85%)
    3 / 54 (5.56%)
         occurrences all number
    4
    7
    4
    2
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    4 / 115 (3.48%)
    1 / 58 (1.72%)
    4 / 108 (3.70%)
    3 / 54 (5.56%)
    0 / 108 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    7
    5
    0
    1
    Toothache
         subjects affected / exposed
    1 / 115 (0.87%)
    3 / 58 (5.17%)
    5 / 108 (4.63%)
    1 / 54 (1.85%)
    2 / 108 (1.85%)
    0 / 54 (0.00%)
         occurrences all number
    1
    5
    5
    1
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 115 (14.78%)
    12 / 58 (20.69%)
    6 / 108 (5.56%)
    1 / 54 (1.85%)
    4 / 108 (3.70%)
    1 / 54 (1.85%)
         occurrences all number
    25
    17
    7
    1
    5
    1
    Pharyngolaryngeal pain
         subjects affected / exposed
    7 / 115 (6.09%)
    4 / 58 (6.90%)
    3 / 108 (2.78%)
    1 / 54 (1.85%)
    2 / 108 (1.85%)
    0 / 54 (0.00%)
         occurrences all number
    7
    5
    6
    1
    3
    0
    Epistaxis
         subjects affected / exposed
    2 / 115 (1.74%)
    5 / 58 (8.62%)
    6 / 108 (5.56%)
    1 / 54 (1.85%)
    2 / 108 (1.85%)
    0 / 54 (0.00%)
         occurrences all number
    2
    7
    8
    2
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 115 (2.61%)
    3 / 58 (5.17%)
    7 / 108 (6.48%)
    3 / 54 (5.56%)
    3 / 108 (2.78%)
    1 / 54 (1.85%)
         occurrences all number
    3
    3
    8
    7
    4
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 115 (26.09%)
    14 / 58 (24.14%)
    12 / 108 (11.11%)
    8 / 54 (14.81%)
    3 / 108 (2.78%)
    7 / 54 (12.96%)
         occurrences all number
    37
    15
    15
    9
    3
    11
    Pharyngitis
         subjects affected / exposed
    15 / 115 (13.04%)
    7 / 58 (12.07%)
    14 / 108 (12.96%)
    12 / 54 (22.22%)
    8 / 108 (7.41%)
    6 / 54 (11.11%)
         occurrences all number
    21
    7
    21
    20
    12
    8
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 115 (11.30%)
    8 / 58 (13.79%)
    6 / 108 (5.56%)
    4 / 54 (7.41%)
    4 / 108 (3.70%)
    1 / 54 (1.85%)
         occurrences all number
    21
    12
    9
    6
    9
    2
    Bronchitis
         subjects affected / exposed
    8 / 115 (6.96%)
    4 / 58 (6.90%)
    6 / 108 (5.56%)
    4 / 54 (7.41%)
    2 / 108 (1.85%)
    2 / 54 (3.70%)
         occurrences all number
    8
    5
    6
    4
    2
    2
    Tonsillitis
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 58 (3.45%)
    4 / 108 (3.70%)
    5 / 54 (9.26%)
    1 / 108 (0.93%)
    4 / 54 (7.41%)
         occurrences all number
    2
    2
    4
    8
    1
    4
    Rhinitis
         subjects affected / exposed
    5 / 115 (4.35%)
    9 / 58 (15.52%)
    2 / 108 (1.85%)
    1 / 54 (1.85%)
    0 / 108 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    7
    12
    4
    1
    0
    0
    Influenza
         subjects affected / exposed
    4 / 115 (3.48%)
    3 / 58 (5.17%)
    2 / 108 (1.85%)
    3 / 54 (5.56%)
    2 / 108 (1.85%)
    0 / 54 (0.00%)
         occurrences all number
    6
    3
    2
    3
    3
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 115 (0.87%)
    3 / 58 (5.17%)
    2 / 108 (1.85%)
    1 / 54 (1.85%)
    2 / 108 (1.85%)
    0 / 54 (0.00%)
         occurrences all number
    1
    4
    2
    1
    2
    0
    Otitis media
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 58 (3.45%)
    0 / 108 (0.00%)
    3 / 54 (5.56%)
    1 / 108 (0.93%)
    0 / 54 (0.00%)
         occurrences all number
    3
    2
    0
    3
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2004
    The estimated number of subjects to be enrolled was changed from 135 to 150 subjects to provide an adequate safety database.
    07 Jul 2006
    Changed the management of subjects with a serum HBV DNA concentration ≥ 1000 copies/mL at 2 consecutive study visits at or after Week 96. The amendment required that lamivudine (LAM) be added to the ADV regimen for such subjects.
    06 Feb 2007
    Provided recommended treatment options based upon HBV DNA levels and/or age and prior lamivudine exposure in order to reduce risk of developing resistance.

    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.
    There were no limitations affecting the analysis or results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/18433023
    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.

    European Medicines Agency © 1995-Wed Apr 24 04:28:33 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA