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    Clinical Trial Results:
    CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY AND ECONOMIC IMPACT OF REDUCING DOSES OF DARUNAVIR IN PATIENTS INFECTED WITH HIV TREATED WITH DARUNAVIR / RITONAVIR ONCE A DAY

    Summary
    EudraCT number
    		 2011-006272-39
    Trial protocol
    		 ES  
    Global end of trial date
    26 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2016
    First version publication date
    30 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DRV600
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundació Lluita contra la Sida
    Sponsor organisation address
    Crta de Canyet s/n, Badalona, Spain, 08916
    Public contact
    Ensayos Clínicos, Fundació Lluita contra la Sida, +34 934978849, sgel@flsida.org
    Scientific contact
    Ensayos Clínicos, Fundació Lluita contra la Sida, +34 934978849, jmolto@flsida.org
    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
    30 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the proportion of patients maintaining HIV viral load in plasma <50 copies / mL after 48 weeks of follow-up.
    Protection of trial subjects
    No specific measures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2012
    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
    Spain: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    96
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited at four hospitals in the urban area of Barcelona, Spain. Eligible participants were HIV-infected patients aged ≥18 years who were on ART including 800/100 mg of darunavir/ritonavir once daily plus two NRTIs and who had had HIV-1 RNA levels in plasma ,50 copies/mL for at least 12 weeks.

    Pre-assignment
    Screening details
    		 Out of 105 patients screened from May 2012 to February 2013, a total of 100 fulfilled eligibility criteria and were enrolled and randomized (50 to each arm).

    Period 1
    Period 1 title
    Overall 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
    		 DRV600
    Arm description
    		 Darunavir (Prezista600®)/ ritonavir (Norvir®): 1 tablet 600mg/1 tablet 100mg QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    DARUNAVIR ETHANOLATE
    Investigational medicinal product code
    Other name
    Prezista
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Darunavir (Prezista600®) 1 tablet of 600mg daily

    Investigational medicinal product name
    RITONAVIR
    Investigational medicinal product code
    Other name
    NORVIR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ritonavir (Norvir®): 1 tablet 100 mg daily

    Arm title
    		 DRV800
    Arm description
    		 Darunavir (Prezista400®)/ ritonavir (Norvir®): 2 tablets 800mg/1 tablet 100mg QD
    Arm type
    		 Active comparator

    Investigational medicinal product name
    DARUNAVIR ETHANOLATE
    Investigational medicinal product code
    Other name
    Prezista
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Darunavir (Prezista 800®) 2 tablets of 400mg daily

    Investigational medicinal product name
    RITONAVIR
    Investigational medicinal product code
    Other name
    NORVIR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ritonavir (Norvir®): 1 tablet 100 mg daily

    Number of subjects in period 1
    		DRV600 DRV800
    Started
    50
    50
    Completed
    45
    47
    Not completed
    5
    3
         Adverse event, serious fatal
    1
    -
         Lost to follow-up
    1
    1
         Lack of efficacy
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DRV600
    Reporting group description
    		 Darunavir (Prezista600®)/ ritonavir (Norvir®): 1 tablet 600mg/1 tablet 100mg QD

    Reporting group title
    DRV800
    Reporting group description
    		 Darunavir (Prezista400®)/ ritonavir (Norvir®): 2 tablets 800mg/1 tablet 100mg QD

    Reporting group values
    		 DRV600 DRV800 Total
    Number of subjects
    		 50 50 100
    Age categorical
    Date of birth
    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)
    		 47 49 96
        From 65-84 years
    		 3 1 4
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.6 ± 10.8 44.8 ± 10.5 -
    Gender categorical
    Units: Subjects
        Female
    		 10 9 19
        Male
    		 40 41 81
    HIV transmission route
    Units: Subjects
        homosexual/bisexual contact
    		 21 25 46
        heterosexual contact
    		 18 16 34
        intravenous drug user
    		 8 6 14
        other/unknown
    		 3 3 6
    Hepatitis C virus coinfection
    Hepatitis C virus coinfection
    Units: Subjects
        Hepatitis C virus coinfection
    		 13 7 20
        Hepatitis C virus non coinfection
    		 37 43 80
    NRTI backbone
    NRTI backbone
    Units: Subjects
        TDF/FTC (tenofovir/emtricitabine)
    		 32 34 66
        ABC/3TC (abacavir/lamivudine)
    		 17 16 33
        Non NRTI backbone
    		 1 0 1
    Time since HIV infection diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 8.2 ± 6.8 8.9 ± 7.2 -
    Number of prior ART regimens
    Units: number
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 1.5 (0 to 3.75) 1 (0 to 2.75) -
    CD4+ T cell count
    Units: cells/mm3
        arithmetic mean (standard deviation)
    		 523 ± 331 591 ± 272 -
    Nadir CD4+ T cell count
    Units: cells/mm3
        arithmetic mean (standard deviation)
    		 197 ± 157 201 ± 136 -
    Time since last HIV-1 RNA<50 copies/mL
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 106.9 (40.3 to 252.4) 107.4 (55.4 to 219) -
    Body mass index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 25.3 ± 3.4 24.9 ± 3.5 -

    End points

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    End points reporting groups
    Reporting group title
    DRV600
    Reporting group description
    		 Darunavir (Prezista600®)/ ritonavir (Norvir®): 1 tablet 600mg/1 tablet 100mg QD

    Reporting group title
    DRV800
    Reporting group description
    		 Darunavir (Prezista400®)/ ritonavir (Norvir®): 2 tablets 800mg/1 tablet 100mg QD

    Primary: Absence of treatment failure

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    End point title
    		 Absence of treatment failure
    End point description
    Compare the proportion of patients maintaining HIV viral load in plasma <50 copies / mL after 48 weeks of follow-up. Absence of treatment failure was achieved by 45/50 (90%) and by 47/50 (94%) patients in the DRV600 and DRV800 groups, respectively (difference –4%; 95% CI lower limit, –12.9%).
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 DRV600 DRV800
    Number of subjects analysed
    50
    50
    Units: Percentatge
        Absence of treatment failure
    45
    47
        No absence of treatment failure
    5
    3
    Statistical analysis title
    		 ITT comparative analysis
    Statistical analysis description
    The primary efficacy endpoint (absence of treatment failure) was evaluated considering all the patients randomized (ITT analysis).
    Comparison groups
    DRV600 v DRV800
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 > 0.05
    Method
    		 comparing proportions
    Confidence interval
    Notes
    [1] - Proportion of absence of treatment failure per group and confidence interval 95% of the difference between groups was reported

    Secondary: Incidence of adverse events

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    End point title
    		 Incidence of adverse events
    End point description
    Compare the incidence of adverse events after 4, 12, 24, 36 and 48 weeks follow up
    End point type
    Secondary
    End point timeframe
    4, 12, 24, 36 and 48 weeks follow up
    End point values
    		 DRV600 DRV800
    Number of subjects analysed
    50
    50
    Units: Number of patients
    5
    11
    No statistical analyses for this end point

    Secondary: Darunavir plasma concentration

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    End point title
    		 Darunavir plasma concentration
    End point description
    The mean of DRV trough concentration
    End point type
    Secondary
    End point timeframe
    4, 12, 24, 36 and 48 weeks follow up
    End point values
    		 DRV600 DRV800
    Number of subjects analysed
    50
    50
    Units: mg/L
        number (not applicable)
    2.19
    2.21
    Statistical analysis title
    		 Pharmacokinetic study
    Statistical analysis description
    For the pharmacokinetic substudy, individual darunavir pharmacokinetic parameters [Cmax, AUC 0–24 and concentration at the end of the dosing interval (Ctrough)] were calculated using non-compartmental analysis (Winnonlin version 2.0; Pharsight, Mountain View, CA, USA) and the two study arms were compared with the geometric mean ratio and its 90% CI.
    Comparison groups
    DRV800 v DRV600
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 > 0.05
    Method
    		 geometric mean ratio and its 90% CI.
    Confidence interval
    Notes
    [2] - Full darunavir plasma concentration–time curves were determined in 15 patients in each arm

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS AE Grading Tab
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    DRV600
    Reporting group description
    		 Darunavir (Prezista600®)/ ritonavir (Norvir®): 1 tablet 600mg/1 tablet 100mg QD

    Reporting group title
    DRV800
    Reporting group description
    		 Darunavir (Prezista400®)/ ritonavir (Norvir®): 2 tablets 800mg/1 tablet 100mg QD

    Serious adverse events
    		 DRV600 DRV800
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 50 (4.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Headache
    Additional description: Hospitalisation for headache post lumbar punction
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
    Additional description: Hospitalisation for respiratory infection with bronchial hiperreactivity
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Hospitalization for right pneumonia (basal)
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Died of refractory septic shock
    Additional description: Patient with liver cirrhosis developed spontaneous Escherichia coli bacteraemia during the trial and died of refractory septic shock
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic function abnormal
    Additional description: Hospitalization due to hepatic decompensation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erisipela facial
    Additional description: Erisipela facial
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Autolitic fact by pharmacologic ingest
    Additional description: Autolitic fact by pharmacologic ingest
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         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
    		 DRV600 DRV800
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 50 (8.00%)
    11 / 50 (22.00%)
    Cardiac disorders
    Lipids increased
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Gastrointestinal disturbances grade 2
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 50 (12.00%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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