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    Clinical Trial Results:
    FINITE CHB – First investigation in stopping TDF treatment after long term virologic suppression in HBeAg-negative Chronic Hepatitis B

    Summary
    EudraCT number
    		 2010-021925-12
    Trial protocol
    		 DE  
    Global end of trial date
    23 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2017
    First version publication date
    07 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-EU-174-0160
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01320943
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate hepatitis B surface antigen (HBsAg) loss and seroconversion in participants who stop tenofovir disoproxil fumarate (TDF) (Stop TDF arm) compared to participants who continue TDF (Continue TDF arm). Only participants who already are on treatment with TDF monotherapy or TDF in combination with lamivudine or emtricitabine for at least 4 years and who achieved and maintained virologic suppression (< 400 copies/mL) for 3.5 or more years will be included in this study. One treatment arm will stop the TDF therapy while the other treatment arm will continue the TDF therapy. Participants in the Stop TDF arm will be monitored very closely with special focus on biochemical flares (especially alanine aminotransferase (ALT) increases) and virological relapses (Hepatitis B viral load increases). If any participant in the Stop TDF arm exceeds one or more predefined limits for such flares or relapses, TDF treatment will be reinstituted.
    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
    26 Apr 2011
    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: 43
    Worldwide total number of subjects
    43
    EEA total number of subjects
    43
    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)
    43
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 13 study sites in Germany. The first participant was screened on 26 April 2011. The last study visit occurred on 23 August 2016.

    Pre-assignment
    Screening details
    		 65 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Stop TDF
    Arm description
    		 Participants stopped tenofovir disoproxil fumarate monotherapy at baseline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF; Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants stopped TDF monotherapy at baseline.

    Arm title
    		 Continue TDF
    Arm description
    		 Participants continued TDF monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF; Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily

    Number of subjects in period 1 [1]
    		Stop TDF Continue TDF
    Started
    21
    21
    Completed
    20
    20
    Not completed
    1
    1
         Physician decision
    -
    1
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant who was enrolled but not treated is not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stop TDF
    Reporting group description
    		 Participants stopped tenofovir disoproxil fumarate monotherapy at baseline.

    Reporting group title
    Continue TDF
    Reporting group description
    		 Participants continued TDF monotherapy

    Reporting group values
    		 Stop TDF Continue TDF Total
    Number of subjects
    		 21 21 42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ± 10.51 45 ± 7.06 -
    Gender categorical
    Units: Subjects
        Female
    		 3 6 9
        Male
    		 18 15 33
    Race
    Units: Subjects
        Asian
    		 1 1 2
        Black or African American
    		 1 0 1
        White
    		 18 19 37
        Other
    		 1 1 2
    Hepatitis B Virus Surface Antigen
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 4.4 ± 0.71 4.5 ± 0.35 -

    End points

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    End points reporting groups
    Reporting group title
    Stop TDF
    Reporting group description
    		 Participants stopped tenofovir disoproxil fumarate monotherapy at baseline.

    Reporting group title
    Continue TDF
    Reporting group description
    		 Participants continued TDF monotherapy

    Subject analysis set title
    Restart TDF
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Stop TDF participants who restarted TDF therapy

    Primary: Proportion of Participants With HBsAg Loss at Week 144 in Both Study Arms

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    End point title
    		 Proportion of Participants With HBsAg Loss at Week 144 in Both Study Arms
    End point description
    • HBsAg loss is defined as qualitative HBsAg result changing from positive at baseline (BL) to negative at any post-baseline visit. Proportions are based on a Kaplan-Meier estimate. • HBsAg Loss and Seroconversion Full Analysis Set: participants in the Full Analysis Set who had at least 1 post-BL HBsAg value and with HBsAg positive and HBsAb negative or missing at BL. • -999/ 999 = Not applicable (No participants in the Continue TDF group had HBsAg loss.)
    End point type
    Primary
    End point timeframe
    Week 144
    End point values
    		 Stop TDF Continue TDF
    Number of subjects analysed
    21
    21
    Units: Proportion of participants
        number (confidence interval 95%)
    0.236 (0.095 to 0.516)
    0 (-999 to 999)
    Statistical analysis title
    		 HBsAg Loss – Stop TDF vs Continue TDF
    Comparison groups
    Stop TDF v Continue TDF
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.022 [1]
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - Log-rank test statistic was used to compare the time to HBsAg loss between the two treatment arms

    Secondary: Proportion of Participants With Seroconversion in Both Study Arms at Weeks 96 and 144

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    End point title
    		 Proportion of Participants With Seroconversion in Both Study Arms at Weeks 96 and 144
    End point description
    • HBsAg seroconversion is defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit. Proportions are based on the Kaplan-Meier estimate. • HBsAg Loss and Seroconversion Full Analysis Set: participants in the Full Analysis Set who had at least 1 post-baseline HBsAg value and with HBsAg positive and HBsAb negative or missing at baseline • -999/ 999 = Not applicable (No participants in the Continue TDF arm achieved HBsAg seroconversion at Weeks 96 and 144)
    End point type
    Secondary
    End point timeframe
    Weeks 96 and 144
    End point values
    		 Stop TDF Continue TDF
    Number of subjects analysed
    21
    21
    Units: Proportion of participants
    number (confidence interval 95%)
        HBsAg Seroconversion at Week 96
    0.056 (0.008 to 0.334)
    0 (-999 to 999)
        HBsAg Seroconversion at Week 144
    0.203 (0.069 to 0.513)
    0 (-999 to 999)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quantitative HBsAg (IU/mL) in Both Study Arms

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    End point title
    		 Change From Baseline in Quantitative HBsAg (IU/mL) in Both Study Arms
    End point description
    • Participants in the Full Analysis Set (participants who were randomized to Stop TDF arm and had a baseline visit or who were randomized to Continue TDF arm and received at least 1 dose of study drug) with available data were analyzed. • The analyses were summarized by 3 treatment subgroups: Stop TDF (TDF-Free), Restart TDF, and Continue TDF • When participant randomized in the Stop TDF group restarted TDF therapy, that participant was considered part of the Restart TDF group from that point forward. • 999 = Not Applicable ( No participants were in the Restart TDF group at Weeks 2, 4, 6, 8 and 10.) • 9999 = Not Applicable (HBsAg assessment in the Continue TDF arm was not performed at Weeks 2, 6, 8, 10, 16, 20, 28, 32, 40, and 44.)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 144
    End point values
    		 Stop TDF Continue TDF Restart TDF
    Number of subjects analysed
    21
    8
    21
    Units: log10 IU/mL
    arithmetic mean (standard deviation)
        Wk2-StopTDF: N=21;ContinueTDF:N=21;RestartTDF:N=0
    -0.03 ± 0.139
    9999 ± 9999
    999 ± 999
        Wk4-StopTDF: N=20;ContinueTDF:N=20;RestartTDF:N=0
    -0.03 ± 0.17
    -0.01 ± 0.105
    999 ± 999
        Wk6-StopTDF: N=20;ContinueTDF:N=21;RestartTDF:N=0
    -0.02 ± 0.192
    9999 ± 9999
    999 ± 999
        Wk8-StopTDF: N=20;ContinueTDF:N=21;RestartTDF:N=0
    0.04 ± 0.5
    9999 ± 9999
    999 ± 999
        Wk10-StopTDF: N=20;ContinueTDF:N=21;RestartTDF:N=0
    0.01 ± 0.556
    9999 ± 9999
    999 ± 999
        Wk12-StopTDF: N=19;ContinueTDF:N=21;RestartTDF:N=1
    -0.11 ± 0.621
    -0.02 ± 0.137
    -0.03 ± 999
        Wk16-StopTDF: N=19;ContinueTDF:N=21;RestartTDF:N=2
    -0.35 ± 0.741
    9999 ± 9999
    -0.73 ± 0.438
        Wk20-StopTDF: N=18;ContinueTDF:N=21;RestartTDF:N=1
    -0.48 ± 0.949
    9999 ± 9999
    -0.42 ± 999
        Wk24-StopTDF: N=18;ContinueTDF:N=21;RestartTDF:N=2
    -0.56 ± 1.029
    -0.07 ± 0.139
    -1.41 ± 1.211
        Wk28-StopTDF: N=17;ContinueTDF:N=21;RestartTDF:N=3
    -0.6 ± 0.969
    9999 ± 9999
    -0.88 ± 0.916
        Wk32-StopTDF: N=16;ContinueTDF:N=21;RestartTDF:N=3
    -0.77 ± 1.126
    9999 ± 9999
    -0.96 ± 1.211
        Wk36-StopTDF: N=17;ContinueTDF:N=21;RestartTDF:N=2
    -0.67 ± 1.151
    -0.08 ± 0.14
    -0.26 ± 0.461
        Wk40-StopTDF: N=18;ContinueTDF:N=21;RestartTDF:N=3
    -0.78 ± 1.198
    9999 ± 9999
    -0.97 ± 1.275
        Wk44-StopTDF: N=17;ContinueTDF:N=21;RestartTDF:N=1
    -0.87 ± 1.238
    9999 ± 9999
    -0.59 ± 999
        Wk48-StopTDF: N=18;ContinueTDF:N=20;RestartTDF:N=3
    -0.88 ± 1.314
    -0.11 ± 0.101
    -1.01 ± 1.295
        Wk60-StopTDF: N=18;ContinueTDF:N=21;RestartTDF:N=3
    -0.96 ± 1.353
    -0.1 ± 0.133
    -1.03 ± 1.236
        Wk72-StopTDF: N=16;ContinueTDF:N=20;RestartTDF:N=5
    -1.22 ± 1.478
    -0.14 ± 0.142
    -0.64 ± 1.085
        Wk84-StopTDF: N=16;ContinueTDF:N=21;RestartTDF:N=5
    -1.21 ± 1.555
    -0.16 ± 0.164
    -0.69 ± 1.084
        Wk96-StopTDF: N=16;ContinueTDF:N=20;RestartTDF:N=5
    -1.22 ± 1.53
    -0.17 ± 0.159
    -0.69 ± 1.031
        Wk108-StopTDF:N=16;ContinueTDF:N=20;RestartTDF:N=5
    -1.43 ± 1.573
    -0.17 ± 0.145
    -0.69 ± 1.088
        Wk120-StopTDF:N=14;ContinueTDF:N=20;RestartTDF:N=7
    -1.56 ± 1.752
    -0.2 ± 0.136
    -0.58 ± 0.87
        Wk132-StopTDF:N=13;ContinueTDF:N=20;RestartTDF:N=7
    -1.74 ± 1.829
    -0.22 ± 0.172
    -0.52 ± 0.941
        Wk144-StopTDF:N=13;ContinueTDF:N=20;RestartTDF:N=8
    -1.8 ± 1.796
    -0.22 ± 0.16
    -0.51 ± 0.861
    No statistical analyses for this end point

    Secondary: Proportion of Participants Who Restart TDF Therapy in the Stop TDF Arm (TDF-Free and Restart TDF)

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    End point title
    		 Proportion of Participants Who Restart TDF Therapy in the Stop TDF Arm (TDF-Free and Restart TDF) [2]
    End point description
    Full Analysis Set • Proportions are based on the Kaplan-Meier estimate.
    End point type
    Secondary
    End point timeframe
    Weeks 48, 96, and 144
    Notes
    [2] - 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: This endpoint was analyzed for Stop TDF arm (TDF-Free and Re-start TDF subgroups) only.
    End point values
    		 Stop TDF
    Number of subjects analysed
    21
    Units: Proportion of participants
    number (confidence interval 95%)
        TDF Restart at Week 48
    0.143 (0.048 to 0.38)
        TDF Restart at Week 96
    0.238 (0.107 to 0.481)
        TDF Restart at Week 144
    0.381 (0.212 to 0.619)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Viral Suppression in the Stop TDF Arm (TDF-Free and Restart TDF)

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    End point title
    		 Percentage of Participants With Viral Suppression in the Stop TDF Arm (TDF-Free and Restart TDF) [3]
    End point description
    • Viral suppression is defined as 2 consecutive assessments of HBV DNA < 400 copies/mL (69 IU/mL) through Week 144. • Participants in the Full Analysis Set with available data were analyzed. When participant randomized in the Stop TDF group restarted TDF therapy, that participant was considered part of the Restart TDF group from that point forward. • 1 participant restarted TDF during Week 72 and thus was reported in both Stop TDF and Restart TDF arms based on the TDF restart date.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 144
    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: This endpoint was analyzed for Stop TDF arm (TDF-Free and Re-start TDF subgroups) only.
    End point values
    		 Stop TDF Restart TDF
    Number of subjects analysed
    21
    8
    Units: Percentage of participants
    number (not applicable)
        Wk 2 (StopTDF: N=21; RestartTDF:N=0)
    52.4
    0
        Wk 4 (StopTDF: N=19; RestartTDF: N=0)
    5.3
    0
        Wk 6 (StopTDF: N=20; RestartTDF: N=0)
    10
    0
        Wk 8 (StopTDF: N=20; RestartTDF: N=0)
    5
    0
        Wk 10 (StopTDF: N=20; RestartTDF :N=0)
    15
    0
        Wk 12 (StopTDF: N=19; RestartTDF: N=1)
    21.1
    0
        Wk 16 (StopTDF: N=19; RestartTDF: N=2)
    31.6
    0
        Wk 20 (StopTDF: N=18; RestartTDF: N=2)
    27.8
    0
        Wk 24 (StopTDF: N=18; RestartTDF: N=2)
    16.7
    0
        Wk 28 (StopTDF: N=17; RestartTDF: N=3)
    17.6
    0
        Wk 32 (StopTDF: N=16; RestartTDF: N=3)
    12.5
    66.7
        Wk 36 (StopTDF: N=17; RestartTDF: N=2)
    29.4
    100
        Wk 40 (StopTDF: N=18; RestartTDF: N=3)
    22.2
    100
        Wk 44 (StopTDF: N=17; RestartTDF: N=1)
    29.4
    100
        Wk 48 (StopTDF: N=18; RestartTDF: N=3)
    27.8
    100
        Wk 60 (StopTDF: N=18; RestartTDF: N=3)
    33.3
    100
        Wk 72 (StopTDF: N=17; RestartTDF: N=5)
    35.3
    60
        Wk 84 (StopTDF: N=16; RestartTDF: N=5)
    31.3
    100
        Wk 96 (StopTDF: N=16; RestartTDF: N=5)
    37.5
    100
        Wk 108 (StopTDF :N=16; RestartTDF: N=5)
    37.5
    100
        Wk 120 (StopTDF: N=15; RestartTDF: N=7)
    40
    71.4
        Wk 132 (StopTDF: N=13; RestartTDF: N=7)
    38.5
    100
        Wk 144 (StopTDF: N=13; RestartTDF: N=8)
    46.2
    87.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Alanine Aminotransferase (ALT) > Upper Limit of the Normal Range in the Stop TDF Arm (TDF-Free and Restart TDF)

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    End point title
    		 Percentage of Participants With Alanine Aminotransferase (ALT) > Upper Limit of the Normal Range in the Stop TDF Arm (TDF-Free and Restart TDF) [4]
    End point description
    • Participants in the Full Analysis Set with available data were analyzed. • Percentages are based on the number of subjects with non-missing laboratory test results at each visit. • One participant restarted TDF during Weeks 72 and 120 and thus was reported in both the Stop TDF and Re-Start TDF groups based on the date of TDF restart.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 144
    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: This endpoint was analyzed for Stop TDF arm (TDF-Free and Re-start TDF subgroups) only.
    End point values
    		 Stop TDF Restart TDF
    Number of subjects analysed
    21
    8
    Units: Percentage of participants
    number (not applicable)
        Wk 2 (StopTDF: N=21; RestartTDF:N=0)
    4.8
    0
        Wk 4 (StopTDF: N=20; RestartTDF:N=0)
    0
    0
        Wk 6 (StopTDF: N=20; RestartTDF:N=0)
    35
    0
        Wk 8 (StopTDF: N=20; RestartTDF:N=0)
    60
    0
        Wk 10 (StopTDF: N=20; RestartTDF:N=0)
    70
    0
        Wk 12 (StopTDF: N=19; RestartTDF:N=2)
    42.1
    100
        Wk 16 (StopTDF: N=19; RestartTDF:N=2)
    26.3
    100
        Wk 20 (StopTDF: N=17; RestartTDF:N=2)
    11.8
    100
        Wk 24 (StopTDF: N=18; RestartTDF:N=2)
    16.7
    50
        Wk 28 (StopTDF: N=17; RestartTDF:N=3)
    11.8
    33.3
        Wk 32 (StopTDF: N=15; RestartTDF:N=3)
    13.3
    0
        Wk 36 (StopTDF: N=17; RestartTDF:N=2)
    11.8
    0
        Wk 40 (StopTDF: N=17; RestartTDF:N=3)
    23.5
    0
        Wk 44 (StopTDF: N=17; RestartTDF:N=1)
    11.8
    0
        Wk 48 (StopTDF: N=18; RestartTDF:N=3)
    16.7
    0
        Wk 60 (StopTDF: N=18; RestartTDF:N=3)
    22.2
    0
        Wk 72 (StopTDF: N=17; RestartTDF:N=5)
    11.8
    40
        Wk 84 (StopTDF: N=16; RestartTDF:N=5)
    18.8
    0
        Wk 96 (StopTDF: N=16; RestartTDF:N=5)
    12.5
    0
        Wk 108 (StopTDF: N=16; RestartTDF:N=5)
    18.8
    0
        Wk 120 (StopTDF: N=15; RestartTDF:N=7)
    20
    14.3
        Wk 132 (StopTDF: N=12; RestartTDF:N=7)
    0
    28.6
        Wk 144 (StopTDF: N=13; RestartTDF:N=8)
    15.4
    0
    No statistical analyses for this end point

    Secondary: Proportion of Participants with HBsAg Loss at Week 96 in Both Study Arms

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    End point title
    		 Proportion of Participants with HBsAg Loss at Week 96 in Both Study Arms
    End point description
    • HBsAg loss is defined as qualitative HBsAg result changing from positive at baseline (BL) to negative at any postbaseline visit. Proportions are based on a Kaplan-Meier estimate. • HBsAg Loss and Seroconversion Full Analysis Set • 999 = No participants in the Continue TDF group had HBsAg loss
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 Stop TDF Continue TDF
    Number of subjects analysed
    21
    21
    Units: Proportion of participants
        number (confidence interval 95%)
    0.172 (0.058 to 0.446)
    0 (-999 to 999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 144 weeks
    Adverse event reporting additional description
    Safety Analysis Set: participants who were either randomized to Stop TDF and had a BL visit, or who were randomized to Continue TDF and received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Stop TDF (TDF-Free)
    Reporting group description
    		 Participants stopped TDF monotherapy at baseline. Adverse Events (AEs) reported are Termination Emergent. Termination-emergent events began on or after Study Day 1 for the Stop TDF group until last study day for subjects who did not restart TDF and prior to date of restart for subjects who restarted TDF.

    Reporting group title
    Restart TDF
    Reporting group description
    		 Stop TDF participants who restarted TDF therapy. AEs reported are Termination Emergent. TDF-emergent events began on or after date of TDF restart until last dose day for subjects who restarted TDF in the Stop TDF group and on or after Study Day 1 until last dose day for subjects in the Continue TDF group.

    Reporting group title
    Continue TDF
    Reporting group description
    		 AEs reported are Termination Emergent. TDF-emergent events began on or after date of TDF restart until last dose day for subjects who restarted TDF in the Stop TDF group and on or after Study Day 1 until last dose day for subjects in the Continue TDF group.

    Serious adverse events
    		 Stop TDF (TDF-Free) Restart TDF Continue TDF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Surgical failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Stop TDF (TDF-Free) Restart TDF Continue TDF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 21 (80.95%)
    6 / 8 (75.00%)
    16 / 21 (76.19%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Keratoacanthoma
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    2
    0
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 8 (25.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    2
    Influenza like illness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    7
    1
    6
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Dyspepsia
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    Gastritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Renal colic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Back pain
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    Myalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    0
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    11 / 21 (52.38%)
    1 / 8 (12.50%)
    6 / 21 (28.57%)
         occurrences all number
    18
    2
    12
    Sinusitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2011
    The calculation of creatinine clearance was changed from using ideal body weight to actual body weight
    05 Mar 2012
    • The following inclusion criterion was added: HBeAg-negative at TDF therapy start. • The inclusion criterion that defined duration of TDF monotherapy prior to screening was modified from “Receiving continuous TDF monotherapy treatment for at least 4 years prior to screening” to “Received continuous TDF therapy for at least 4 years (ie, TDF monotherapy or combination therapy TDF + lamivudine or TDF + emtricitabine). If TDF had been used in combination with lamivudine or emtricitabine, lamivudine or emtricitabine was must have been stopped at least 12 weeks prior to screening.” • A clinicaltrials.gov identifier was added. • Safety reporting procedures were modified to comply with “Communication from the Commission – Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’)” (2011/C 172/01)

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

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