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    Clinical Trial Results:
    SSAT058: A phase IV, open-label, multi centre pilot study to assess changes in cerebral function parameters in patients without perceived Central Nervous System (CNS) symptoms when switched from tenofovir/emtricitabine/efavirenz (Atripla®) to a fixed dose combination of tenofovir/emtricitabine/rilpivirine (Eviplera®).

    Summary
    EudraCT number
    		 2014-002284-15
    Trial protocol
    		 GB  
    Global end of trial date
    10 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2018
    First version publication date
    28 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SSAT058
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02529059
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St Stephen's AIDS Trust
    Sponsor organisation address
    Chelsea Chambers, 262a Fulham Road, London, United Kingdom, SW10 9EL
    Public contact
    Marita Marshall, St Stephen's AIDS Trust, +44 2038280567, marita.marshall@ststcr.com
    Scientific contact
    Prof. Mark Nelson, Chelsea and Westminster Hospital, mark.nelson@chelwest.nhs.uk
    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
    18 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess changes in neuropsychiatric and central nervous system (CNS) parameters in patients without perceived Central Nervous System (CNS) symptoms after 4 weeks of switching from Atripla (TDF/FTC/EFV) to Eviplera (TDF/FTC/RPV).
    Protection of trial subjects
    The protocol was written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice, E6 and the principles of the Declaration of Helsinki. The protocol was approved by the National Regulator and an Independent Ethics Committee as required by national legislation. Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were encouraged to ask questions concerning all portions of the conduct of the study to ensure understanding. The purpose of the study together with the procedures benefits and risks of the study; any discomforts and the precautions taken was described during the consent process; allowing subject to make an informed decision about participation. Subjects were also informed of their right to discontinue from the study at any time without any detriment. The inclusion/exclusion criteria were designed to eliminate subjects who may have been put at risk by participating in the study. Women of childbearing potential were required to have a negative pregnancy test at screening in order to exclude any participants who may have been pregnant, and these participants (along with heterosexually active males) were required to use effective birth control for the duration of the study. Safety and tolerability of medications were assessed by questions, physical examination (as required) and laboratory parameters. Any changes in health status during the study were recorded and followed up by the clinical team.
    Background therapy
    		 Only patients who were taking Atripla for at least 12 weeks, with established viral load suppression to undetectable levels (by local assay), were included in this study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    40
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were competitively recruited from 4 sites in the UK; Elton John Centre (Brighton), Chelsea & Westminster Hospital (London), St Mary's Hospital (London) and Guy's & St. Thomas' Hospital (London). 42 patients were recruited from Dec 2015 to June 2016. One patient was deemed non-evaluable at baseline and is not included in the analysis.

    Pre-assignment
    Screening details
    		 Four patients screened for the study were deemed ineligible: - Due to previous nRTI treatment - Could not comply with contraception requirements - Could not comply with treatment switch requirements - Presented with pre-existing cognitive issues at screening

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Experimental Arm
    Arm description
    		 Single Arm Study - all patients were switched from tenofovir/emtricitabine/efavirenz (Atripla®) to a fixed dose combination of tenofovir/emtricitabine/rilpivirine (Eviplera®).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eviplera
    Investigational medicinal product code
    J05AR08
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single-pill fixed dose combination of tenofovir 245mg, emtricitabine 200mg and rilpivirine 25mg once daily.

    Number of subjects in period 1
    		Experimental Arm
    Started
    42
    Week 4
    40
    Week 12
    39
    week 24
    39
    Completed
    39
    Not completed
    3
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
         Determined ineligible
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 40 40
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 47.3 (31.2 to 68.4) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 39 39
    Ethnicity
    Units: Subjects
        Unknown
    		 2 2
        English/Welsh/Scottish/Northern Irish/British
    		 26 26
        Irish
    		 1 1
        other White
    		 7 7
        White & Black African
    		 1 1
        Mixed/multiple ethnicity)
    		 1 1
        African
    		 2 2
        Caribbean
    		 1 1
        other
    		 1 1
    Duration of prior Atripla treatment
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 1778 (938 to 2656) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 Single Arm Study - all patients were switched from tenofovir/emtricitabine/efavirenz (Atripla®) to a fixed dose combination of tenofovir/emtricitabine/rilpivirine (Eviplera®).

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients attending baseline visit (pre-switch). Note: 1 patient excluded from analysis due to protocol deviation

    Subject analysis set title
    Week 4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients attending Week 4 visit post switch

    Subject analysis set title
    Week 12
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients attending Week 12 visit post switch

    Subject analysis set title
    Week 24
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients attending Week 24 visit (post switch)

    Primary: Proportion of patients with grade 2-4 CNS AE at Baseline, Week 4 and Week 12 , as reported in the CNS questionnaire:

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    End point title
    		 Proportion of patients with grade 2-4 CNS AE at Baseline, Week 4 and Week 12 , as reported in the CNS questionnaire: [1]
    End point description
    AEs were graded using a study questionnaire based on the AIDS Clinical Trials Group (ACTG) grading scale. These were then coded as: 0 - None 1 - Mild 2 - Moderate 3 - Severe The following results represent frequency of patients with at least one moderate (or severe) AE from this questionnaire. McNemars Chi squared value for change in individual toxicities given in attached report.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4 and Week 12 post switch
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A summary listing of the 'proportion of patients affected' is the only measure required by protocol
    End point values
    		 Baseline Week 4 Week 12
    Number of subjects analysed
    41
    40
    39
    Units: Patients
        Any
    14
    7
    9
        Dizziness
    3
    1
    1
        Depression/low mood
    3
    1
    3
        Insomnia/sleeplessness
    5
    4
    5
        Anxiety/nervousness
    3
    1
    0
        Confusion
    1
    1
    0
        Impaired concentration/attention
    3
    1
    1
        Headache
    3
    1
    1
        Somnolence/daytime sleepiness
    2
    5
    2
        Aggressive mood/behaviour
    2
    0
    1
        Abnormal dreams
    9
    1
    1
    Attachments
    		 Untitled (Filename: SSAT058 CNS Questionnaire results.pdf)
    No statistical analyses for this end point

    Primary: Median number of grade 2+ neuropsychiatric and CNS AEs, as reported in the CNS questionnaire at Baseline, Week 4 and Week 12

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    End point title
    		 Median number of grade 2+ neuropsychiatric and CNS AEs, as reported in the CNS questionnaire at Baseline, Week 4 and Week 12
    End point description
    Please note that this was not considered a normalised dataset, and therefore range is given instead of the originally intended 95% CI. Incidence of grade 2+ AEs were transformed into a score out of 100 to facilitate comparison.
    End point type
    Primary
    End point timeframe
    Basseline, Week 4 and Week 12
    End point values
    		 Baseline Week 4 Week 12
    Number of subjects analysed
    41
    40
    39
    Units: Score (/100)
        median (full range (min-max))
    0 (0 to 30)
    0 (0 to 25)
    0 (0 to 25)
    Statistical analysis title
    		 Baseline to week 4
    Statistical analysis description
    % improvement in total CNS score from baseline
    Comparison groups
    Baseline v Week 4
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.064
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 12
    Statistical analysis description
    % improvement in total CNS score from baseline
    Comparison groups
    Baseline v Week 12
    Number of subjects included in analysis
    80
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.022
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Median CNS toxicity score (from CNS questionnaire) from baseline compared to Week 4 and Week 12

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    End point title
    		 Median CNS toxicity score (from CNS questionnaire) from baseline compared to Week 4 and Week 12
    End point description
    All grades of CNS adverse events reported in the questionnaire were summed together. This total was then transformed into a score from 0 to 100, where a score of 0 represents no adverse events, and 100 is all events reported as 'Severe'. Due to this dataset not being normalised, inter-quartile range is given instead of the protocol specified 95% CI.
    End point type
    Primary
    End point timeframe
    Baseline to Week 4 and Week 12
    End point values
    		 Baseline Week 4 Week 12
    Number of subjects analysed
    41
    40
    39
    Units: Score (/100)
        median (inter-quartile range (Q1-Q3))
    10 (3 to 23)
    7 (3 to 13)
    10 (3 to 17)
    Statistical analysis title
    		 Baseline to week 4
    Comparison groups
    Baseline v Week 4
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.028
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 12
    Comparison groups
    Baseline v Week 12
    Number of subjects included in analysis
    80
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.064
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Rate of toxicity as measured by change in sleep score from baseline to Week 4, Week 12 & Week 24

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    End point title
    		 Rate of toxicity as measured by change in sleep score from baseline to Week 4, Week 12 & Week 24
    End point description
    Please note that this was not considered a normalised dataset, and therefore inter-quartile range is given instead of the originally intended 95% CI. All reported sleep adverse effects were transformed into a score out of 100 for ease of comparison. 'Change from baseline' measures the improvement in responses. A positive value indicates a reduction in reported adverse events. Note: Week 24 time-point is considered a secondary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to week 4 / week 12
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39 [2]
    Units: Score (/100)
    median (inter-quartile range (Q1-Q3))
        Sleep score
    22 (20 to 32)
    20 (14 to 29)
    19 (14 to 27)
    20 (14 to 26)
        Change from baseline
    0 (0 to 0)
    2 (-1 to 8)
    4 (-1 to 10)
    3 (-2 to 10)
    Attachments
    		 Untitled (Filename: SSAT058 Sleep questionnaire results.pdf)
    Notes
    [2] - Secondary endpoint
    Statistical analysis title
    		 Baseline to week 4
    Comparison groups
    Baseline v Week 4
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 12
    Comparison groups
    Week 12 v Baseline
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 24
    Comparison groups
    Week 24 v Baseline
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Friedman's test
    Comparison groups
    Baseline v Week 4 v Week 12 v Week 24
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.03
    Method
    		 Friedman's test
    Confidence interval

    Secondary: Proportion of patients with grade 2-4 CNS AE at Week 24 , as reported in the CNS questionnaire:

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    End point title
    		 Proportion of patients with grade 2-4 CNS AE at Week 24 , as reported in the CNS questionnaire:
    End point description
    McNemars Chi squared value for change in individual toxicities given in attached report.
    End point type
    Secondary
    End point timeframe
    Week 24 post treatment switch
    End point values
    		 Week 24
    Number of subjects analysed
    37 [3]
    Units: Patients
        Any
    10
        Dizziness
    0
        Depression/low mood
    2
        Insomnia/sleeplessness
    6
        Anxiety/nervousness
    2
        Confusion
    0
        Impaired concentration/attention
    1
        Headache
    1
        Somnolence/daytime sleepiness
    3
    Notes
    [3] - 2 patients DNA
    No statistical analyses for this end point

    Secondary: Median number of grade 2+ neuropsychiatric and CNS AEs, as reported in the CNS questionnaire at Week 24

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    End point title
    		 Median number of grade 2+ neuropsychiatric and CNS AEs, as reported in the CNS questionnaire at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24 visit only
    End point values
    		 Week 24
    Number of subjects analysed
    37 [4]
    Units: Adverse Events
        median (full range (min-max))
    0 (0 to 5)
    Notes
    [4] - 2 patients DNA
    No statistical analyses for this end point

    Secondary: Median CNS toxicity score (from CNS questionnaire) at Week 24

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    End point title
    		 Median CNS toxicity score (from CNS questionnaire) at Week 24
    End point description
    All grades of CNS adverse events reported in the questionnaire were summed together. This total was then transformed into a score from 0 to 100, where a score of 0 represents no adverse events, and 100 is all events reported as 'Severe'. Due to this dataset not being normalised, inter-quartile range is given instead of the protocol specified 95% CI.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Week 24
    Number of subjects analysed
    37 [5]
    Units: Score (/100)
        median (inter-quartile range (Q1-Q3))
    7 (3 to 17)
    Notes
    [5] - 2 patients DNA
    No statistical analyses for this end point

    Secondary: Rate of change in CNS parameters as measured using the Hospital Anxiety and Depression Scale (HADS) at Week12/24 compared to baseline

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    End point title
    		 Rate of change in CNS parameters as measured using the Hospital Anxiety and Depression Scale (HADS) at Week12/24 compared to baseline
    End point description
    A HAD score was derived based on responses in the HAD scale questionnaire. The responses to each question were given scores that ranged from 0 to 3 where response with a score of 0 gave a positive response while 3 gave negative response. All missing responses were scored 3. The total HAD scores from each patient responses were taken as a fraction of the observed HAD score relative to the expected total HAD score. These have been expressed as that out of 100. So the minimum possible score that could be observed could be 0 and maximum possible score that could be observed is 100 (‘worse’). Please note that this was not considered a normalised dataset, and therefore inter-quartile range is given instead of the originally intended 95% CI.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 / Week 24
    End point values
    		 Baseline Week 12 Week 24
    Number of subjects analysed
    41
    39
    39
    Units: Score (/100)
    median (inter-quartile range (Q1-Q3))
        Absolute value
    14.3 (7.1 to 26.2)
    16.7 (2.4 to 23.8)
    9.5 (0.0 to 26.2)
        Change from Baselnie
    0.0 (0.0 to 0.0)
    2.4 (-2.4 to 7.1)
    2.4 (0.0 to 7.1)
    Attachments
    		 Untitled (Filename: SSAT058 HAD Results.pdf)
    Statistical analysis title
    		 Baseline to week 12
    Comparison groups
    Baseline v Week 12
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.049
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 24
    Comparison groups
    Baseline v Week 24
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.024
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Friedman's test
    Comparison groups
    Baseline v Week 12 v Week 24
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 Friedman's test
    Confidence interval

    Secondary: Proportion of patients with undetectable viral load at weeks 4, 12 and 24

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    End point title
    		 Proportion of patients with undetectable viral load at weeks 4, 12 and 24
    End point description
    Undetectable by local assay
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: Patients
    40
    40
    38
    39
    No statistical analyses for this end point

    Secondary: Proportion of patients with viral load below 400 copies/ml at Weeks 4, 12 and 24

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    End point title
    		 Proportion of patients with viral load below 400 copies/ml at Weeks 4, 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24.
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: Patients
        <400
    41
    40
    39
    39
        >=400
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline CD4+ count at Week 12 and Week 24

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    End point title
    		 Change from baseline CD4+ count at Week 12 and Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 12 and 24
    End point values
    		 Baseline Week 12 Week 24
    Number of subjects analysed
    41
    39
    39
    Units: cells/millilitre
    median (inter-quartile range (Q1-Q3))
        Absolute value
    563 (465 to 679)
    590 (481 to 719)
    600 (488 to 682)
        Change from baseline
    0 (0 to 0)
    16 (-34 to 60)
    -2 (-55 to 75)
    Statistical analysis title
    		 Baseline to week 12
    Comparison groups
    Week 12 v Baseline
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.238
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 24
    Comparison groups
    Baseline v Week 24
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.995
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Proportion of patients with grade 2-4 non-lipid laboratory AEs at Weeks, 4, 12 and 24 compared with Baseline

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    End point title
    		 Proportion of patients with grade 2-4 non-lipid laboratory AEs at Weeks, 4, 12 and 24 compared with Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 4, 12 and 24
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: Patients
        Sodium (high)
    0
    0
    0
    0
        Sodium (low)
    0
    0
    0
    0
        Potassium (high)
    0
    0
    0
    0
        Potassium (low)
    0
    0
    0
    0
        Creatinine
    0
    1
    2
    1
        Albumin
    0
    0
    0
    0
        glucose
    1
    2
    2
    2
        ALT
    0
    0
    0
    0
        ALP
    0
    0
    0
    0
        AST
    0
    0
    0
    0
        Total Bilirubin
    0
    0
    0
    0
        Serum Phosphate
    4
    4
    1
    3
        Haemoglobin
    0
    0
    0
    0
        White Blood Cells
    0
    0
    0
    0
        Platelets
    0
    0
    0
    0
        Neutrophils
    0
    0
    0
    0
    Attachments
    		 Untitled (Filename: SSAT058 Lab reults.pdf)
    No statistical analyses for this end point

    Secondary: Proportion of patients with grade 2-4 non-CNS adverse events at Weeks, 4, 12 and 24 compared with Baseline

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    End point title
    		 Proportion of patients with grade 2-4 non-CNS adverse events at Weeks, 4, 12 and 24 compared with Baseline
    End point description
    Proportion of patients experiencing at least one Grade 2+ (moderate or severe) AE. As assessed by the CNS questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4,12 and 24
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    37
    Units: Patients
        None
    27
    33
    30
    27
        1+ Moderate/Severe
    14
    7
    9
    10
    No statistical analyses for this end point

    Secondary: Change in lipid parameters from Baseline to Weeks 4, 12 and 24

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    End point title
    		 Change in lipid parameters from Baseline to Weeks 4, 12 and 24
    End point description
    p-values from Wilcoxon signed rank tests listed in attached lab data table. Additionally this analysis has been performed both with and without protocol deviating patients, as listed in the table attached to the first laboratory parameters endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 4, 12 and 24.
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: mmol/l
    median (inter-quartile range (Q1-Q3))
        Total cholesterol values
    5.2 (4.6 to 5.7)
    4.7 (4.2 to 5.0)
    4.5 (3.8 to 5.0)
    4.4 (4.0 to 5.2)
        Total cholesterol change from baseline
    0.0 (0.0 to 0.0)
    -0.6 (-0.8 to -0.2)
    -0.7 (-1.0 to -0.5)
    -0.8 (-1.2 to -0.3)
        HDL
    1.4 (1.2 to 1.6)
    1.3 (1.1 to 1.5)
    1.3 (1.1 to 1.5)
    1.3 (1.1 to 1.5)
        HDL change from baseline
    0.0 (0.0 to 0.0)
    -0.11 (-0.23 to 0.02)
    -0.10 (-0.26 to 0.00)
    -0.13 (-0.30 to 0.06)
        LDL
    3.1 (2.4 to 3.5)
    2.8 (2.2 to 3.1)
    2.5 (2.1 to 3.1)
    2.7 (2.1 to 3.3)
        LDL change from baseline
    0.0 (0.0 to 0.0)
    -0.36 (-0.61 to -0.07)
    -0.50 (-0.79 to -0.28)
    -0.40 (-0.80 to -0.08)
        total:HDL ratio
    3.6 (3.2 to 4.2)
    3.4 (2.8 to 4.2)
    3.6 (3.0 to 4.1)
    3.5 (2.8 to 4.3)
        total:HDL ratio change from baseline
    0.0 (0.0 to 0.0)
    -0.12 (-0.49 to -0.10)
    -0.24 (-0.50 to 0.01)
    -0.19 (-0.47 to 0.21)
        Triglycerides
    1.3 (0.8 to 2.4)
    0.9 (0.7 to 1.8)
    1.3 (0.6 to 1.6)
    0.9 (0.7 to 1.6)
        Triglycerides change from baseline
    0.0 (0.0 to 0.0)
    -0.26 (-0.71 to 0.01)
    -0.17 (-0.82 to 0.10)
    -0.28 (-0.72 to 0.08)
    No statistical analyses for this end point

    Secondary: Change in quality of life 4, 12 and 24 weeks post switch, as measured by the EuroQOL questionnaire

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    End point title
    		 Change in quality of life 4, 12 and 24 weeks post switch, as measured by the EuroQOL questionnaire
    End point description
    Scores were converted to (/100) to facilitate comparison Max possible=100 (best imaginable health state) Min possible=0 (worst imaginable health state)
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 4, 12 and 24
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: Score (/100)
    median (inter-quartile range (Q1-Q3))
        Absolute score
    80 (75 to 90)
    90 (73 to 94)
    89 (80 to 90)
    90 (75 to 95)
        Change from baseline
    0 (0 to 0)
    -2 (-10 to 0)
    -5 (-10 to 0)
    -3 (-10 to 0)
    Attachments
    		 Untitled (Filename: SSAT058 EQ5d results.pdf)
    Statistical analysis title
    		 Friedman's test
    Comparison groups
    Week 4 v Baseline v Week 12 v Week 24
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 Friedman's test
    Confidence interval
    Statistical analysis title
    		 Baseline to week 4
    Comparison groups
    Baseline v Week 4
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.003
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 12
    Comparison groups
    Baseline v Week 12
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.007
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Baseline to week 24
    Comparison groups
    Baseline v Week 24
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.005
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in neurocognitive function from baseline to Weeks 4, 12 and 24. As measured by Instrumental Activities of Daily Life questionnaire

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    End point title
    		 Change in neurocognitive function from baseline to Weeks 4, 12 and 24. As measured by Instrumental Activities of Daily Life questionnaire
    End point description
    Scores were converted to (/100) to facilitate comparison Max possible=100 (best imaginable health state) Min possible=0 (worst imaginable health state)
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 4, 12 and 24
    End point values
    		 Baseline Week 4 Week 12 Week 24
    Number of subjects analysed
    41
    40
    39
    39
    Units: Score (/100)
    median (inter-quartile range (Q1-Q3))
        Absolute score
    100 (100 to 100)
    100 (100 to 100)
    100 (100 to 100)
    100 (100 to 100)
        Change from Baseline
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Attachments
    		 Untitled (Filename: SSAT058 IADL Results.pdf)
    No statistical analyses for this end point

    Secondary: Change in medication adherence from Baseline to Weeks 12 and 24. As measured by the adherence questionnaire

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    End point title
    		 Change in medication adherence from Baseline to Weeks 12 and 24. As measured by the adherence questionnaire
    End point description
    Adherence to study medication as measured by the Modified Medication Adherence Self-Report Inventory (M-MASRI) questionnaire
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/24
    End point values
    		 Week 12 Week 24
    Number of subjects analysed
    39
    39
    Units: % improvement
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1)
    0 (0 to 5)
    Attachments
    		 Untitled (Filename: SSAT 058 Analysis v3.3 MMASRI.pdf)
    No statistical analyses for this end point

    Secondary: Change in cerebral MRI modalities from Baseline to Week 24

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    End point title
    		 Change in cerebral MRI modalities from Baseline to Week 24
    End point description
    Imaging modalities given as absolute values, then as change from baseline (difference)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Baseline Week 24
    Number of subjects analysed
    11
    10
    Units: Ratio
    median (inter-quartile range (Q1-Q3))
        ThalbasNAACr
    0.96 (0.70 to 1.08)
    1.07 (0.95 to 1.41)
        Difference ThalbasNAACr
    0 (0 to 0)
    0.19 (-0.11 to 0.44)
        Tha cholCr
    0.23 (0.19 to 0.25)
    0.23 (0.21 to 0.27)
        Difference Tha cholCr
    0 (0 to 0)
    0.01 (-0.04 to 0.04)
        Thal GlxCr
    0.80 (0.73 to 1.16)
    0.98 (0.84 to 1.38)
        Difference Thal GlxCr
    0 (0 to 0)
    0.22 (-0.28 to 0.65)
        FW NAACr
    1.24 (1.07 to 1.33)
    1.12 (1.01 to 1.23)
        Difference FW NAACr
    0 (0 to 0)
    -0.05 (-0.17 to 0.02)
        FW CholCr
    0.31 (0.27 to 0.34)
    0.27 (0.24 to 0.34)
        Difference FW CholCr
    0 (0 to 0)
    -0.04 (-0.08 to 0.01)
        FW GlxCr
    0.88 (0.62 to 1.00)
    0.90 (0.85 to 0.96)
        Difference FW GlxCr
    0 (0 to 0)
    0.10 (-0.02 to 0.40)
        FW InsCr
    0.59 (0.53 to 0.71)
    0.61 (0.58 to 0.85)
        Difference FW InsCr
    0 (0 to 0)
    0.106 (-0.01 to 0.19)
        FG NAACr
    1.09 (1.04 to 1.14)
    1.06 (0.94 to 1.13)
        Difference FG NAACr
    0 (0 to 0)
    -0.02 (-0.15 to 0.05)
        FG choCr
    0.25 (0.23 to 0.26)
    0.22 (0.21 to 0.26)
        Difference FG choCr
    0 (0 to 0)
    -0.01 (-0.05 to 0.02)
        FG InsCr
    0.61 (0.53 to 0.64)
    0.62 (0.57 to 0.68)
        Difference FG InsCr
    0 (0 to 0)
    -0.04 (-0.05 to 0.10)
    Attachments
    		 Untitled (Filename: SSAT058 MR results.pdf)
    No statistical analyses for this end point

    Secondary: Change in neurocognitive function from baseline to Weeks 4 and 24. As measured by computerised cognitive testing

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    End point title
    		 Change in neurocognitive function from baseline to Weeks 4 and 24. As measured by computerised cognitive testing
    End point description
    CogState cognitive tasks use novel visual and verbal stimuli to ensure assessment is culture-neutral and not limited by a subject or participant’s level of education. All Cogstate tasks are designed for repeated administration with minimal practice or learning effects. A Cogstate battery comprises a number of individual tasks – each designed to test a specific area of cognition. When a number of these individual tests are put together to form a test battery, a more complete picture of a person’s cognitive state can be defined. Each participants score was measured against available normative data, and is shown as a summary below. Individual comparisons for each test are given in the attached table.
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 4 and 24.
    End point values
    		 Baseline Week 4 Week 24
    Number of subjects analysed
    40
    40
    39
    Units: Score (/100)
        median (inter-quartile range (Q1-Q3))
    -0.01 (-0.71 to 0.80)
    -0.06 (-0.71 to 0.72)
    -0.15 (-0.62 to 0.78)
    Attachments
    		 Untitled (Filename: SSAT058 Cogstate.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent to follow-up (Week 24+30 days)
    Adverse event reporting additional description
    Adverse event incidence for laboratory and CNS categories, are further detailed in the endpoints section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ACTG Adverse Events
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Experimental Arm
    Reporting group description
    		 Single Arm Study - all patients were switched from tenofovir/emtricitabine/efavirenz (Atripla®) to a fixed dose combination of tenofovir/emtricitabine/rilpivirine (Eviplera®).

    Serious adverse events
    		 Experimental Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 40 (5.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Musculoskeletal and connective tissue disorders
    Trauma (foot)
    Additional description: Hospitalisation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Epiglotitis
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 40 (100.00%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    General disorders and administration site conditions
    Tiredness
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Hayfever
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Toothache
    Additional description: including tooth pain
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    6
    Myalgia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Infections and infestations
    Cold
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Influenza
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5
    Viral infection
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Gonorrhea
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2015
    Principal Investigator change
    08 Feb 2016
    Addition of an interim analysis post after all patients had completed their Week 4 visit
    07 Dec 2016
    Addition of an interim analysis after all participants had completed the Week 12 visit

    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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