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    Clinical Trial Results:
    A Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects with Chronic Hepatitis B who are Resistant to Lamivudine

    Summary
    EudraCT number
    		 2008-001464-36
    Trial protocol
    		 GB   DE   CZ   HU   ES   AT   GR   BG  
    Global end of trial date
    09 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Feb 2016
    First version publication date
    25 Feb 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-174-0121
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00737568
    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 Trial Information Desk, Gilead Sciences International Ltd, +44 1223897 496, clinical.trials@gilead.com
    Scientific contact
    Clinical Trial Information Desk, Gilead Sciences International Ltd, +44 1223897 496, clinical.trials@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
    09 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the antiviral efficacy against hepatitis B virus (HBV) of once-daily tenofovir DF versus once-daily emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance
    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
    30 Sep 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Turkey: 28
    Country: Number of subjects enrolled
    Canada: 90
    Country: Number of subjects enrolled
    Serbia: 36
    Country: Number of subjects enrolled
    New Zealand: 17
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    280
    EEA total number of subjects
    105
    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)
    252
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Europe, and New Zealand. The first participant was screened on 30 September 2008. The last study visit occurred on 09 February 2015.

    Pre-assignment
    Screening details
    		 752 participants were screened. Randomization was stratified by hepatitis B e antigen (HBeAg) status (negative or positive) and alanine aminotransferase (ALT) level (≥ 2 × upper limit of normal [ULN] or < 2 × ULN) at screening.

    Period 1
    Period 1 title
    Treatment Period Through Week 240
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tenofovir DF
    Arm description
    		 Tenofovir DF once daily plus FTC/TDF placebo once daily
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    FTC/TDF Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    FTC/TDF placebo once daily

    Arm title
    		 FTC/Tenofovir DF
    Arm description
    		 FTC/TDF once daily plus TDF placebo once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    FTC/TDF
    Investigational medicinal product code
    Other name
    Emtricitabine/tenofovir DF, Truvada®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    FTC/TDF 200/300 mg tablet once daily

    Investigational medicinal product name
    Tenofovir DF placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF placebo once daily

    Number of subjects in period 1
    		Tenofovir DF FTC/Tenofovir DF
    Started
    141
    139
    Completed
    121
    118
    Not completed
    20
    21
         Investigator’s discretion
    6
    5
         Protocol violation
    2
    3
         Safety, tolerability, or efficacy reason
    3
    4
         Withdrew consent
    5
    6
         Lost to follow-up
    3
    3
         Study discontinued by sponsor
    1
    -
    Period 2
    Period 2 title
    Treatment-Free Follow-up (TFFU) Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tenofovir DF
    Arm description
    		 TDF once daily plus FTC/TDF placebo once daily. 1 participant not completing the 240 week treatment period enrolled in the TFFU period.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    FTC/TDF Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    FTC/TDF placebo once daily

    Arm title
    		 FTC/Tenofovir DF
    Arm description
    		 FTC/TDF once daily plus TDF placebo once daily. 4 participants not completing the 240 week treatment period enrolled in the TFFU period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FTC/TDF
    Investigational medicinal product code
    Other name
    Emtricitabine/tenofovir DF, Truvada®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    FTC/TDF 200/300 mg tablet once daily

    Investigational medicinal product name
    Tenofovir DF placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF placebo once daily

    Number of subjects in period 2 [1]
    		Tenofovir DF FTC/Tenofovir DF
    Started
    38
    37
    Completed
    12
    19
    Not completed
    26
    18
         Death
    -
    1
         Withdrew consent
    1
    -
         Started commercial therapy
    25
    17
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 103 participants in the Tenofovir DF group and 102 participants in the FTC/Tenofovir DF group did not enter the treatment-free follow-up (TFFU) period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Tenofovir DF
    Reporting group description
    		 Tenofovir DF once daily plus FTC/TDF placebo once daily

    Reporting group title
    FTC/Tenofovir DF
    Reporting group description
    		 FTC/TDF once daily plus TDF placebo once daily

    Reporting group values
    		 Tenofovir DF FTC/Tenofovir DF Total
    Number of subjects
    		 141 139 280
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.1 ( 13.63 ) 46.3 ( 13.56 ) -
    Gender categorical
    Units: Subjects
        Female
    		 37 32 69
        Male
    		 104 107 211
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 138 137 275
        Unknown or not reported
    		 1 1 2
    Race
    Units: Subjects
        Asian
    		 52 42 94
        Black or African American
    		 3 1 4
        Native Hawaiian or other Pacific Islander
    		 0 3 3
        White
    		 83 89 172
        Other
    		 3 4 7
    ALT Normal at Baseline
    The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.
    Units: Subjects
        Abnormal
    		 79 83 162
        Normal
    		 62 56 118
    HBeAg Status at Baseline
    Units: Subjects
        Negative
    		 76 71 147
        Positive
    		 65 68 133
    Hepatitis B Virus (HBV) DNA Level at Baseline
    Units: log_10 copies/mL
        arithmetic mean (standard deviation)
    		 6.4 ( 1.826 ) 6.53 ( 1.968 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tenofovir DF
    Reporting group description
    		 Tenofovir DF once daily plus FTC/TDF placebo once daily

    Reporting group title
    FTC/Tenofovir DF
    Reporting group description
    		 FTC/TDF once daily plus TDF placebo once daily
    Reporting group title
    Tenofovir DF
    Reporting group description
    		 TDF once daily plus FTC/TDF placebo once daily. 1 participant not completing the 240 week treatment period enrolled in the TFFU period.

    Reporting group title
    FTC/Tenofovir DF
    Reporting group description
    		 FTC/TDF once daily plus TDF placebo once daily. 4 participants not completing the 240 week treatment period enrolled in the TFFU period.

    Primary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

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    End point title
    		 Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96
    End point description
    Full Analysis Set: participants were randomized and received at least 1 dose of study drug. The missing = failure method was used in which participants with missing data were considered to have failed to achieve the endpoint.
    End point type
    Primary
    End point timeframe
    Week 96
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
        number (not applicable)
    89.4
    86.3
    Statistical analysis title
    		 Difference in percentages
    Statistical analysis description
    The null hypothesis is that there is no difference between the FTC/TDF and TDF treatment groups. The alternative hypothesis is that there is a difference between the FTC/TDF and TDF treatment groups. These hypotheses were evaluated using a Cochran-Mantel-Haenszel (CMH) test, controlling for randomization strata, with the missing = failure method in which participants with missing data were considered to have failed to achieve the endpoint.
    Comparison groups
    FTC/Tenofovir DF v Tenofovir DF
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.43 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Comparative analysis
    [2] - The p-value for the two-sided Cochran-Mantel-Haenszel test was controlled for strata (HBeAg status and ALT level).

    Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

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    End point title
    		 Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240
    End point description
    Full Analysis Set, missing = failure method
    End point type
    Secondary
    End point timeframe
    Weeks 48, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48
    81.6
    84.2
        Week 144
    87.2
    84.9
        Week 192
    86.5
    85.6
        Week 240
    83
    82.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240
    End point description
    Full Analysis Set, missing = failure method
    End point type
    Secondary
    End point timeframe
    Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48
    76.6
    77.7
        Week 96
    85.8
    83.5
        Week 144
    86.5
    84.9
        Week 192
    85.1
    84.2
        Week 240
    81.6
    82
    No statistical analyses for this end point

    Secondary: HBV DNA Level at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 HBV DNA Level at Weeks 48, 96, 144, 192, and 240
    End point description
    Full analysis set; participants with HBV DNA measurements at the given time point were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: log10 copies/mL
    arithmetic mean (standard deviation)
        Week 48 (TDF: n=130; FTC/TDF: n=133)
    2.42 ( 0.542 )
    2.48 ( 0.887 )
        Week 96 (TDF: n=132; FTC/TDF: n=127)
    2.29 ( 0.254 )
    2.28 ( 0.241 )
        Week 144 (TDF: n=128; FTC/TDF: n=123)
    2.26 ( 0.173 )
    2.29 ( 1.541 )
        Week 192 (TDF: n=126; FTC/TDF: n=119)
    2.25 ( 0.135 )
    2.23 ( 0.027 )
        Week 240 (TDF: n=118; FTC/TDF: n=116)
    2.23 ( 0.052 )
    2.26 ( 0.376 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240
    End point description
    Full Analysis Set, missing = failure method. Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.
    End point type
    Secondary
    End point timeframe
    Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48
    67.4
    69.8
        Week 96
    70.2
    69.8
        Week 144
    70.2
    75.5
        Week 192
    75.9
    76.3
        Week 240
    71.6
    71.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240
    End point description
    Participants in the Full Analysis Set who were HBeAg positive at baseline were analyzed using the missing = failure method. The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    65
    68
    Units: percentage of participants
    number (not applicable)
        Week 48
    9.2
    5.9
        Week 96
    15.4
    13.2
        Week 144
    23.1
    17.6
        Week 192
    21.5
    14.7
        Week 240
    24.6
    19.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240
    End point description
    Participants in the Full Analysis Set who were HBeAg positive at baseline were analyzed using the missing = failure method. The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at the given time point was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    65
    68
    Units: percentage of participants
    number (not applicable)
        Week 48
    6.2
    4.4
        Week 96
    10.8
    10.3
        Week 144
    12.3
    11.8
        Week 192
    10.8
    10.3
        Week 240
    12.3
    10.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240
    End point description
    Full Analysis Set, missing = failure method. The percentage of participants with HBsAg Loss at the given time point was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0.7
        Week 96
    0
    0.7
        Week 144
    0.7
    1.4
        Week 192
    0.7
    2.9
        Week 240
    1.4
    2.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240
    End point description
    Full Analysis Set, missing = failure method. The percentage of participants with seroconversion to anti-HBs at the given time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0
        Week 96
    0
    0
        Week 144
    0
    0.7
        Week 192
    0
    0.7
        Week 240
    0
    0.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240

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    End point title
    		 Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240
    End point description
    Full Analysis Set; the missing-equals-excluded method was used in which participants with missing data were excluded from the analysis. The percentage of participants with virologic breakthrough at the given time point was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log10 or greater increases in serum HBV DNA from on-treatment nadir, or two consecutive HBV DNA values ≥ 400 copies/mL after being < 400 copies/mL.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage of participants
    number (not applicable)
        Week 48 (TDF: n=130; FTC/TDF: n=133)
    0
    0.8
        Week 96 (TDF: n=132; FTC/TDF: n=127)
    0
    0
        Week 144 (TDF: n=128; FTC/TDF: n=123)
    0.8
    0.8
        Week 192 (TDF: n=126; FTC/TDF: n=119)
    0.8
    0
        Week 240 (TDF: n=118; FTC/TDF: n=116)
    0
    0
    No statistical analyses for this end point

    Secondary: Percent change from baseline in bone mineral density (BMD) of the spine at Weeks 24, 48, 72, 96, 144, 192, and 240

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    End point title
    		 Percent change from baseline in bone mineral density (BMD) of the spine at Weeks 24, 48, 72, 96, 144, 192, and 240
    End point description
    BMD is calculated as grams per cubic centimeter (g/cm^2); the mean (SD) percentage change is presented. Participants in the Safety Analysis Set (randomized and received at least 1 dose of study drug) with spine BMD measurements at the given time point were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24, 48, 72, 96, 144, 192
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage change
    arithmetic mean (standard deviation)
        % Change at Week 24 (TDF: n=132; FTC/TDF: n=127)
    -1.74 ( 2.867 )
    -1.83 ( 2.565 )
        % Change at Week 48 (TDF: n=126; FTC/TDF: n=121)
    -1.68 ( 3.094 )
    -1.73 ( 2.944 )
        % Change at Week 72 (TDF: n=123; FTC/TDF: n=119)
    -1.35 ( 3.337 )
    -1.95 ( 2.977 )
        % Change at Week 96 (TDF: n=126; FTC/TDF: n=114)
    -1.24 ( 3.761 )
    -1.72 ( 3.269 )
        % Change at Week 144 (TDF: n=123; FTC/TDF: n=110)
    -1.36 ( 3.81 )
    -1.63 ( 3.591 )
        % Change at Week 192 (TDF: n=120; FTC/TDF: n=106)
    -1.32 ( 4.237 )
    -1.6 ( 4.628 )
        % Change at Week 240 (TDF: n=115; FTC/TDF: n=102)
    -0.83 ( 4.49 )
    -1.15 ( 5.13 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in BMD of the hip at Weeks 24, 48, 72, 96, 144, 192, and 240

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    End point title
    		 Percent change from baseline in BMD of the hip at Weeks 24, 48, 72, 96, 144, 192, and 240
    End point description
    BMD is calculated as g/cm^2; the mean (SD) percentage change is presented. Participants in the Safety Analysis Set with hip BMD measurements at the given time point were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: percentage change
    arithmetic mean (standard deviation)
        % Change at Week 24 (TDF: n=130; FTC/TDF: n=127)
    -0.71 ( 1.724 )
    -0.59 ( 1.835 )
        % Change at Week 48 (TDF: n=126; FTC/TDF: n=118)
    -1.15 ( 2.12 )
    -1 ( 2.063 )
        % Change at Week 72 (TDF: n=121; FTC/TDF: n=115)
    -1.59 ( 2.507 )
    -1.61 ( 2.525 )
        % Change at Week 96 (TDF: n=125; FTC/TDF: n=112)
    -1.7 ( 2.617 )
    -1.77 ( 2.801 )
        % Change at Week 144 (TDF: n=120; FTC/TDF: n=107)
    -2.02 ( 3.03 )
    -1.91 ( 3.281 )
        % Change at Week 192 (TDF: n=116; FTC/TDF: n=105)
    -2.33 ( 3.19 )
    -2.41 ( 3.783 )
        % Change at Week 240 (TDF: n=111; FTC/TDF: n=100)
    -2.46 ( 3.191 )
    -2.63 ( 3.872 )
    No statistical analyses for this end point

    Secondary: Development of Drug-resistant Mutations (DRMs)

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    End point title
    		 Development of Drug-resistant Mutations (DRMs)
    End point description
    Full Analysis Set. The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 240
    End point values
    		 Tenofovir DF FTC/Tenofovir DF
    Number of subjects analysed
    141
    139
    Units: participants
        New tenofovir DF DRMs
    0
    0
        Enrichment of tenofovir DF DRMs
    0
    0
        New FTC DRMs
    0
    0
        Enrichment of FTC DRMs
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of study drug treatment (average exposure 220 weeks) plus 7 days
    Adverse event reporting additional description
    Safety Analysis Set: participants were randomized and received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Tenofovir DF
    Reporting group description
    		 Tenofovir DF once daily plus FTC/TDF placebo once daily

    Reporting group title
    FTC/Tenofovir DF
    Reporting group description
    		 FTC/TDF once daily plus TDF placebo once daily

    Serious adverse events
    		 Tenofovir DF FTC/Tenofovir DF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 141 (16.31%)
    21 / 139 (15.11%)
         number of deaths (all causes)
    3
    4
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenolymphoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal adenoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal neoplasm
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 141 (0.71%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Middle ear inflammation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acarodermatitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tenofovir DF FTC/Tenofovir DF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    109 / 141 (77.30%)
    105 / 139 (75.54%)
    Investigations
    Creatinine renal clearance decreased
         subjects affected / exposed
    2 / 141 (1.42%)
    7 / 139 (5.04%)
         occurrences all number
    2
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 141 (4.96%)
    9 / 139 (6.47%)
         occurrences all number
    7
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 141 (16.31%)
    20 / 139 (14.39%)
         occurrences all number
    48
    42
    Dizziness
         subjects affected / exposed
    7 / 141 (4.96%)
    8 / 139 (5.76%)
         occurrences all number
    7
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 141 (9.93%)
    15 / 139 (10.79%)
         occurrences all number
    16
    17
    Pyrexia
         subjects affected / exposed
    8 / 141 (5.67%)
    5 / 139 (3.60%)
         occurrences all number
    8
    7
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    8 / 141 (5.67%)
    3 / 139 (2.16%)
         occurrences all number
    9
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 141 (8.51%)
    11 / 139 (7.91%)
         occurrences all number
    13
    17
    Abdominal pain upper
         subjects affected / exposed
    8 / 141 (5.67%)
    12 / 139 (8.63%)
         occurrences all number
    9
    14
    Diarrhoea
         subjects affected / exposed
    13 / 141 (9.22%)
    7 / 139 (5.04%)
         occurrences all number
    16
    7
    Abdominal pain
         subjects affected / exposed
    6 / 141 (4.26%)
    7 / 139 (5.04%)
         occurrences all number
    7
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 141 (8.51%)
    13 / 139 (9.35%)
         occurrences all number
    16
    15
    Oropharyngeal pain
         subjects affected / exposed
    12 / 141 (8.51%)
    3 / 139 (2.16%)
         occurrences all number
    13
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 141 (7.09%)
    18 / 139 (12.95%)
         occurrences all number
    12
    22
    Back pain
         subjects affected / exposed
    10 / 141 (7.09%)
    15 / 139 (10.79%)
         occurrences all number
    12
    17
    Myalgia
         subjects affected / exposed
    7 / 141 (4.96%)
    8 / 139 (5.76%)
         occurrences all number
    8
    9
    Musculoskeletal pain
         subjects affected / exposed
    5 / 141 (3.55%)
    7 / 139 (5.04%)
         occurrences all number
    5
    7
    Pain in extremity
         subjects affected / exposed
    4 / 141 (2.84%)
    8 / 139 (5.76%)
         occurrences all number
    4
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 141 (17.02%)
    20 / 139 (14.39%)
         occurrences all number
    32
    35
    Influenza
         subjects affected / exposed
    14 / 141 (9.93%)
    10 / 139 (7.19%)
         occurrences all number
    14
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 141 (1.42%)
    7 / 139 (5.04%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2008
    The Gilead Sciences, Inc. (GSI) Grading Scale for Severity of Adverse Events and Laboratory Abnormalities was modified to be consistent with the toxicity grading scale used for every other GSI-sponsored chronic hepatitis B study in the adult TDF HBV program.
    30 Jun 2008
    The HBV DNA entry threshold was reduced from 10^5 copies/mL to 10^4 copies/mL to reflect the current standard of treatment for either switching or adding on to therapy in patients with resistance to current anti-HBV therapy. It was clarified that dual-energy x-ray absorptiometry (DXA) scans were only required at sites with such capabilities.
    16 Feb 2009
    The entry criteria for the lower threshold of HBV DNA was changed from ≥ 4 log10 copies/mL to ≥ 3 log10 IU/mL, as current treatment practices were such that this cutoff was used more often in a clinical setting to guide treatment change; exclusion criteria relating to laboratory values used to define hepatic decompensation were made less stringent to permit enrollment of compensated cirrhotics; the lower exclusionary limit for neutrophils was modified from ≥ 1500 IU/mL to ≥ 1000 IU/mL to permit inclusion of subjects with physiologically low counts.
    24 Oct 2011
    Analysis of the primary endpoint was modified to occur at Week 96 and was not to be conducted using group sequential testing annually (ie, every 48 weeks) beginning after the last subject reached Week 48; efficacy and safety analyses conducted after Week 96 were considered secondary analyses.

    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/24929235
    http://www.ncbi.nlm.nih.gov/pubmed/24861361
    http://www.ncbi.nlm.nih.gov/pubmed/24368224
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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