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    Clinical Trial Results:
    A randomised controlled trial of a strategy of switching to boosted protease inhibitor monotherapy versus continuing combination antiretroviral therapy for the long-term management of HIV-1 infected patients who have achieved sustained virological suppression on highly-active antiretroviral therapy

    Summary
    EudraCT number
    		 2007-006448-23
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jan 2020
    First version publication date
    15 Jan 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PIVOT
    Additional study identifiers
    ISRCTN number
    		 ISRCTN04857074
    US NCT number
    		 NCT01230580
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical Research Council
    Sponsor organisation address
    90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    Wolfgang Stohr, MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology , 44 02706704800, w.stohr@ucl.ac.uk
    Scientific contact
    Wolfgang Stohr, MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology , 44 02706704800, w.stohr@ucl.ac.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
    16 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether a strategy of switching to PI monotherapy is as good as continuing triple drug therapy (the standard of care) in terms of the proportion of patients who maintain all possible drug treatment options after at least 3 years of follow-up.
    Protection of trial subjects
    Inclusion/exclusion criteria and follow-up examinations were carefully chosen to minimise the risk of trial subjects. For example, to minimise the risk of myocardial infarction in patients exposed to PI treatment, PIVOT included formal assessment of cardiovascular risk as part of the screening criteria, and did not enrol patients with very high level of background risk. Lipid levels were measured periodically, and clinicians were encouraged to manage lipid elevations fastidiously according to current guidelines. The protocol also allowed switching to other PIs with smaller effects on lipids. The PIs used in the trial were all licensed drugs which had been used in many thousands of patients. Therefore risk of adverse events was known to be relatively small. Furthermore, the inclusion/exclusion criteria prevented patients at risk of metabolic problems and more serious side effects to enter the trial. Physicians and patients were allowed to select the PI best suited to that patient, and, if necessary, to switch to an alternative PI if there were tolerability or toxicity problems. Patients were monitored carefully during the intervention for side effects of PIs allowing appropriate management of these effects. Lastly, the protocol allowed switch back to triple-therapy in the event of unmanageable toxicity occurring in the PI monotherapy arm. To minimise the risk of virological failure with development of resistance, patients had to be stable on their current standard-of-care regimen, with a relatively low probability of treatment failure in the long-term. In order to minimise the risk of developing resistance, patients who were known to have resistance to PIs or who had any evidence of failure on a PI-containing regimen were excluded. Furthermore, patients will be monitored closely in the initial three months after treatment switch with regular VL testing, and patients who did not maintain virological suppression were switched back promptly to triple-therapy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 587
    Worldwide total number of subjects
    587
    EEA total number of subjects
    587
    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)
    575
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 695 [1]
    Number of subjects completed
    		 587

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not return after screening: 19
    Reason: Number of subjects
    		 VL >=50 cop/mL at screening or previous 24 weeks: 25
    Reason: Number of subjects
    		 previous ART change due to unsatisfactory VL: 26
    Reason: Number of subjects
    		 not on two NRTIs and one NNRTI or PI regimen: 7
    Reason: Number of subjects
    		 Other reason: 25
    Reason: Number of subjects
    		 Multiple reasons: 6
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 108 patients were screened but were not enrolled due to ineligibility or because they did not return after screening.
    Period 1
    Period 1 title
    Main trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ongoing triple therapy
    Arm description
    		 Patients randomised to the control arm will continue to take their standard-of-care triple-therapy regimen. Changes of therapy can be made for virological failure or drug-related toxicity as clinically indicated, but patients will be expected to remain on the strategy of receiving standard-of-care triple-therapy for the duration of the trial. The choice of drugs for use in the triple-therapy strategy is left to the discretion of the physician and patient.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    245 mg once daily

    Investigational medicinal product name
    emtricitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg once daily

    Investigational medicinal product name
    lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg every 12 hours, alternatively 300 mg once daily

    Investigational medicinal product name
    efavirenz
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg once daily

    Investigational medicinal product name
    abacavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg daily in 1–2 divided doses

    Investigational medicinal product name
    darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg twice daily, alternatively 800 mg once daily

    Investigational medicinal product name
    atazanavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    nevirapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg once daily

    Investigational medicinal product name
    lopinavir with ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400/100 mg twice daily, alternatively 800/200 mg once daily

    Investigational medicinal product name
    saquinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 g every 12 hours

    Investigational medicinal product name
    zidovudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    250–300 mg twice daily

    Investigational medicinal product name
    rilpivirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily

    Investigational medicinal product name
    raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg twice daily

    Investigational medicinal product name
    etravirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg twice daily

    Investigational medicinal product name
    fosamprenavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    700 mg twice daily

    Investigational medicinal product name
    maraviroc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg twice daily

    Investigational medicinal product name
    didanosine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg daily in 1–2 divided doses

    Investigational medicinal product name
    ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100–200 mg 1–2 times a day; Low-dose booster to increase effect of other protease inhibitors

    Arm title
    		 PI monotherapy
    Arm description
    		 Treatment with a single ritonavir-boosted protease inhibitor (PI). PIVOT was a strategic trial and hence the choice of protease inhibitor was left to physician and patient discretion. Any licensed, ritonavir-boosted PI was permitted. Switches to alternative PIs were permitted during the trial to avoid or minimise drug-related toxicity, to minimise the risk of interactions with any necessary concomitant medication, to create a more acceptable treatment schedule, or to take account of changes in current opinion of the relative merits of protease inhibitors in this therapeutic setting.
    Arm type
    		 Experimental

    Investigational medicinal product name
    darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg twice daily, alternatively 800 mg once daily

    Investigational medicinal product name
    atazanavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily

    Investigational medicinal product name
    lopinavir with ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400/100 mg twice daily, alternatively 800/200 mg once daily

    Investigational medicinal product name
    saquinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 g every 12 hours

    Investigational medicinal product name
    ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100–200 mg 1–2 times a day; Low-dose booster to increase effect of other protease inhibitors

    Number of subjects in period 1
    		Ongoing triple therapy PI monotherapy
    Started
    291
    296
    Completed
    279
    285
    Not completed
    12
    11
         Adverse event, serious fatal
    1
    6
         Consent withdrawn by subject
    5
    2
         Lost to follow-up
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ongoing triple therapy
    Reporting group description
    		 Patients randomised to the control arm will continue to take their standard-of-care triple-therapy regimen. Changes of therapy can be made for virological failure or drug-related toxicity as clinically indicated, but patients will be expected to remain on the strategy of receiving standard-of-care triple-therapy for the duration of the trial. The choice of drugs for use in the triple-therapy strategy is left to the discretion of the physician and patient.

    Reporting group title
    PI monotherapy
    Reporting group description
    		 Treatment with a single ritonavir-boosted protease inhibitor (PI). PIVOT was a strategic trial and hence the choice of protease inhibitor was left to physician and patient discretion. Any licensed, ritonavir-boosted PI was permitted. Switches to alternative PIs were permitted during the trial to avoid or minimise drug-related toxicity, to minimise the risk of interactions with any necessary concomitant medication, to create a more acceptable treatment schedule, or to take account of changes in current opinion of the relative merits of protease inhibitors in this therapeutic setting.

    Reporting group values
    		 Ongoing triple therapy PI monotherapy Total
    Number of subjects
    		 291 296 587
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 283 292 575
        From 65-84 years
    		 8 4 12
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 43 (37 to 49) 45 (39 to 50) -
    Gender categorical
    Units: Subjects
        Female
    		 64 73 137
        Male
    		 227 223 450
    Route of infection
    Units: Subjects
        Homosexual
    		 175 176 351
        Heterosexual
    		 108 108 216
        Other
    		 8 12 20
    Ethnic origin
    Units: Subjects
        White
    		 206 195 401
        Black
    		 73 90 163
        Other
    		 12 11 23
    Hepatitis C virus antibody status
    Units: Subjects
        positive
    		 7 14 21
        negative
    		 281 282 563
        unknown
    		 3 0 3
    Previous AIDS-defining illness
    Units: Subjects
        yes
    		 59 57 116
        no
    		 232 239 471
    Undetectable baseline HIV viral load
    Units: Subjects
        yes
    		 276 279 555
        no
    		 14 17 31
        missing
    		 1 0 1
    On first ART combination
    Units: Subjects
        yes
    		 91 96 187
        no
    		 200 200 400
    NNRTI at entry
    Units: Subjects
        Efavirenz
    		 115 115 230
        Nevirapine
    		 42 39 81
        Etravirine
    		 0 3 3
        none
    		 134 139 273
    Protease inhibitor at entry
    Units: Subjects
        Atazanavir
    		 59 59 118
        Lopinavir
    		 28 49 77
        Darunavir
    		 24 13 37
        Saquinavir
    		 16 15 31
        Fosamprenavir
    		 7 3 10
        none
    		 157 157 314
    NRTIs at entry
    Units: Subjects
        Emtricitabine and tenofovir
    		 190 180 370
        Lamivudine and abacavir
    		 80 82 162
        Other
    		 21 34 55
    Resistance test result available before trial
    Units: Subjects
        yes
    		 181 165 346
        no
    		 110 131 241
    Intermediate-level or high-level resistance to NRTI or NNRTI before trial
    Units: Subjects
        yes
    		 4 7 11
        no
    		 287 289 576
    Nadir CD4 count
    Units: cells per μL
        median (inter-quartile range (Q1-Q3))
    		 181 (90 to 258) 170 (80 to 239) -
    CD4 count
    Units: cells per μL
        median (inter-quartile range (Q1-Q3))
    		 512 (386 to 658) 516 (402 to 713) -
    Duration of undetectable viral load
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 36 (17 to 62) 38 (22 to 66) -
    Years since ART started
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 3.9 (2.0 to 6.4) 4.2 (2.4 to 6.9) -
    Number of drugs ever received
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 5 (3 to 6) 4 (3 to 6) -

    End points

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    End points reporting groups
    Reporting group title
    Ongoing triple therapy
    Reporting group description
    		 Patients randomised to the control arm will continue to take their standard-of-care triple-therapy regimen. Changes of therapy can be made for virological failure or drug-related toxicity as clinically indicated, but patients will be expected to remain on the strategy of receiving standard-of-care triple-therapy for the duration of the trial. The choice of drugs for use in the triple-therapy strategy is left to the discretion of the physician and patient.

    Reporting group title
    PI monotherapy
    Reporting group description
    		 Treatment with a single ritonavir-boosted protease inhibitor (PI). PIVOT was a strategic trial and hence the choice of protease inhibitor was left to physician and patient discretion. Any licensed, ritonavir-boosted PI was permitted. Switches to alternative PIs were permitted during the trial to avoid or minimise drug-related toxicity, to minimise the risk of interactions with any necessary concomitant medication, to create a more acceptable treatment schedule, or to take account of changes in current opinion of the relative merits of protease inhibitors in this therapeutic setting.

    Primary: Loss of future drug options

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    End point title
    		 Loss of future drug options
    End point description
    The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs in contemporary use to which we deemed patient’s virus to be sensitive at trial entry (assessed at 3 years). We defined contemporary use on the basis of inclusion in present UK treatment guidelines, with saquinavir added because this drug was taken by some participants during the trial.
    End point type
    Primary
    End point timeframe
    any time from randomisation to 3 years after randomisation
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    291
    296
    Units: Subjects
        Reached endpoint
    2
    6
        Did not reach endpoint
    289
    290
    Statistical analysis title
    		 Primary analysis of the primary endpoint
    Statistical analysis description
    We estimated the absolute difference between groups in reduction of future drug options using Kaplan-Meier analysis, with the 95% CI (two-sided) derived with bootstrap methods. Participants were censored at the time of death, loss to follow-up, or withdrawal. This analysis and all other analyses in PIVOT were made according to the intention-to-treat principle.
    Comparison groups
    PI monotherapy v Ongoing triple therapy
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 3.4
    Notes
    [1] - We defined non-inferiority of the PI-mono group by the upper limit of the two-sided 95% CI for the difference in proportions of patients who maintain all future drug options during 3 years (OT group minus the PI-mono group) being less than 10%.

    Secondary: Confirmed viral load rebound

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    End point title
    		 Confirmed viral load rebound
    End point description
    End point type
    Secondary
    End point timeframe
    Any time from randomisation to the end of follow-up
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    291
    296
    Units: Subjects
        Reached endpoint
    8
    95
        Did not reach endpoint
    283
    201
    Statistical analysis title
    		 Analysis of confirmed viral load rebound
    Statistical analysis description
    The proportion of patients who had viral load rebound was estimated with Kaplan-Meier analysis and compared groups by use of a log-rank test.
    Comparison groups
    Ongoing triple therapy v PI monotherapy
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Risk difference (RD)
    Point estimate
    31.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.6
         upper limit
    		 39

    Secondary: Death

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    End point title
    		 Death
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until the end of follow-up
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    291
    296
    Units: Subject
        Died
    1
    6
        Did not die
    290
    290
    Statistical analysis title
    		 Analysis of death
    Comparison groups
    PI monotherapy v Ongoing triple therapy
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Fisher exact
    Confidence interval

    Secondary: AIDS-defining event

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    End point title
    		 AIDS-defining event
    End point description
    End point type
    Secondary
    End point timeframe
    Any time from randomisation to the end of follow-up
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    291
    296
    Units: Subjects
        Reached endpoint
    1
    1
        Did not reach endpoint
    290
    295
    Statistical analysis title
    		 Analysis of AIDS-defining events
    Comparison groups
    Ongoing triple therapy v PI monotherapy
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Serious non-AIDS event

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    End point title
    		 Serious non-AIDS event
    End point description
    End point type
    Secondary
    End point timeframe
    Any time from randomisation to the end of follow-up
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    291
    296
    Units: Subjects
        Reached endpoint
    7
    12
        Did not reach endpoint
    284
    284
    Statistical analysis title
    		 Analysis of Serious non-AIDS event
    Comparison groups
    Ongoing triple therapy v PI monotherapy
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Fisher exact
    Confidence interval

    Secondary: CD4 change from baseline

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    End point title
    		 CD4 change from baseline
    End point description
    Patients without data at week 144 visit or a later time-point were excluded
    End point type
    Secondary
    End point timeframe
    Groups were compared by use of mean change from baseline and linear regression; we estimated change from baseline to the last available visit at which a measurement was done at or after week 144 (we did not include patients without such data).
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    283
    287
    Units: cells per mm³
        arithmetic mean (standard error)
    93 ± 10
    109 ± 9
    Statistical analysis title
    		 Analysis of CD4 change from baseline
    Comparison groups
    Ongoing triple therapy v PI monotherapy
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 42

    Secondary: Estimated glomerular filtration rate change

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    End point title
    		 Estimated glomerular filtration rate change
    End point description
    Groups were compared by use of mean change from baseline and linear regression.
    End point type
    Secondary
    End point timeframe
    From randomisation to the last available visit at which a measurement was done at or after week 144.
    End point values
    		 Ongoing triple therapy PI monotherapy
    Number of subjects analysed
    283
    286
    Units: mL/min per 1.73 m²
        arithmetic mean (standard error)
    -5.1 ± 0.7
    -3.8 ± 0.7
    Statistical analysis title
    		 Analysis of eGFR change from baseline
    Statistical analysis description
    Groups were compared by use of mean change from baseline and linear regression; we estimated change from baseline to the last available visit at which a measurement was done at or after week 144 (we did not include patients without such data).
    Comparison groups
    Ongoing triple therapy v PI monotherapy
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 3.15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any time from randomisation to the patient's last visit at or before 1. Nov 2013
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Ongoing triple therapy
    Reporting group description
    		 Active control

    Reporting group title
    PI monotherapy
    Reporting group description
    		 Experimental arm

    Serious adverse events
    		 Ongoing triple therapy PI monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 291 (15.46%)
    56 / 296 (18.92%)
         number of deaths (all causes)
    1
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiosarcoma metastatic
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carcinoma in situ
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal transplant
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depression suicidal
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric symptom
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Diverticulitis Meckel's
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphogranuloma venereum
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (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
    Ear infection
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoid abscess
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Keratoconus
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer stage IV
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 291 (0.69%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         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: 0%
    Non-serious adverse events
    		 Ongoing triple therapy PI monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 291 (8.93%)
    31 / 296 (10.47%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Meningioma
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Prostate cancer
         subjects affected / exposed
    2 / 291 (0.69%)
    1 / 296 (0.34%)
         occurrences all number
    2
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 291 (0.69%)
    0 / 296 (0.00%)
         occurrences all number
    2
    0
    Hypertension
         subjects affected / exposed
    3 / 291 (1.03%)
    0 / 296 (0.00%)
         occurrences all number
    3
    0
    Surgical and medical procedures
    Peripheral nerve decompression
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Crohn's disease
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Erythema nodosum
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Myasthenia gravis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 291 (0.34%)
    4 / 296 (1.35%)
         occurrences all number
    1
    4
    Depression suicidal
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    2
    Stress
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Suicidal ideation
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences all number
    1
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 291 (0.69%)
    0 / 296 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Wrist fracture
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Drug rash
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Jaundice
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Viral labyrinthitis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Oesophageal perforation
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Hepatitis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Hepatitis C
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Basal cell carcinoma
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Skin oedema
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Urethral stenosis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    1 / 291 (0.34%)
    1 / 296 (0.34%)
         occurrences all number
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Polyarthritis
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 291 (0.00%)
    2 / 296 (0.68%)
         occurrences all number
    0
    2
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 291 (0.00%)
    1 / 296 (0.34%)
         occurrences all number
    0
    1
    Facial wasting
         subjects affected / exposed
    1 / 291 (0.34%)
    0 / 296 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Dec 2008
    Protocol version 2.0: The amendment to the trial protocol was proposed following the first meeting of the PIVOT IDMC and TSC in September 2008. At this meeting and after ongoing discussions with the site investigators, several changes were agreed with the aim to facilitate recruitment, clarify management strategy and maximise the generalisability and importance of the trial findings.
    23 Apr 2010
    Protocol version 3.0: Most changes were minor editorial and procedural changes that do not impact in any significant way on the conduct of the trial. Two major changes were made: Firstly, the sections of the protocol concerning the definition and management of viral load rebounds was re-written to clarify the language and to make the procedures more explicit. This arose as a result of a request from the Independent Data Monitoring Committee (meeting on 11 February 2010) to re-consider procedures and definitions around virological rebound in order to address the considerable diversity of practice at clinical sites that frequently did not follow the protocol. The changes will improve the quality of the data that will be gathered from the trial, and will not adversely impact patient safety. Secondly, we have revised the sample size of the trial. From the emerging literature on PI monotherapy and observations within the trial so far, we believe that the event rate (10% over 3 years) that we originally projected for the primary endpoint of the trial is too high. Based on several recently presented studies, we now believe the event rate is likely to be closer to 3%. We have therefore reviewed the sample size calculations for the trial, and the Trial Steering Committee recommended at its meeting on 2 March 2010 that the sample size be increased from 400 to 560 in order that the trial will be able to fulfil its primary objective of demonstrating non-inferiority of PI monotherapy to standard of care.
    22 Jul 2013
    Protocol version 4.0: Most changes were minor editorial and procedural changes that do not impact in any significant way on the conduct of the trial. However, in one area the protocol has changed substantially: The Trial Management Group proposed that the PIVOT trial be extended for up to a further 5 years. This would be in the form of an annual review of the clinical case sheets of PIVOT patients (both arms, and irrespective of treatment changes). Following the last trial visit, this proposed extension phase will continue for up to a further 5 years in which basic treatment and clinical outcome data will continue to be collected. Patients will not be required to attend any specific visits as part of this extension phase, the data will be collected via retrospective review of routine clinic notes. No reporting of serious adverse events will be required during this extension phase. The rational for the trial extension is that PIVOT is by far the largest and longest randomised controlled trial of PI monotherapy ever done, but even if the trial clearly shows that this treatment option is non-inferior to standard of care, questions may still remain about additional potential longer term advantages or disadvantages of PI monotherapy.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26423649
    http://www.ncbi.nlm.nih.gov/pubmed/26966125
    http://www.ncbi.nlm.nih.gov/pubmed/27456983
    http://www.ncbi.nlm.nih.gov/pubmed/29428459
    For support, Contact us.
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    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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