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    Clinical Trial Results:
    A phase II, open-label trial, to evaluate pharmacokinetics, safety, tolerability and antiviral activity of DRV/rtv once daily in treatment-naïve HIV-1 infected adolescents aged between 12 and < 18 years. Week-48 Final analysis. This trial is referred to as DIONE.

    Summary
    EudraCT number
    		 2008-004631-37
    Trial protocol
    		 IE   GB   FR   ES   IT   Outside EU/EEA  
    Global end of trial date
    31 Mar 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Jun 2016
    First version publication date
    29 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC114-TiDP29-C230
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00915655
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tibotec Pharmaceuticals
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Tibotec Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Tibotec Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000038-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the pharmacokinetics, safety, tolerability, and efficacy of darunavir with low-dose ritonavir (DRV/rtv) administered at 800/100 mg once daily (q.d.) in combination with an investigator-selected background regimen, consisting of either zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC, over a 24-week treatment period in antiretroviral (ARV) treatment-naïve HIV-1 infected adolescents aged between 12 and < 18 years and weighing ≥ 40 kg.
    Protection of trial subjects
    Safety and tolerability of subjects were evaluated by monitoring of the incidence and type of adverse events (AEs)/ HIV-Related Events, performing Clinical Laboratory Tests ( Hematology and Coagulation, Biochemistry, Urinalysis, Hepatitis Serology/Viremia) , Cardiovascular Safety tests (Electrocardiogram, Vital Signs) and other safety evaluations including Physical examination and Pubertal Development - Tanner Stage throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Aug 2009
    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: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    12
    EEA total number of subjects
    4
    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)
    12
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 21-Aug-2009 to 31-March-2011 and subjects from 6 countries were enrolled.

    Pre-assignment
    Screening details
    		 In total 12 subjects were screened, and all 12 subjects were treated and completed the entire study.

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

    Arms
    Arm title
    		 DRV/rtv 800/100 mg q.d.
    Arm description
    		 Subjects were administered with Darunavir in combination with low-dose of ritonavir (DRV/rtv) at 800/100 mg once daily (q.d.) in combination with an investigator-selected background regimen, consisting of either zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    TMC114
    Other name
    Prezista
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with two Darunavir 400 milligrams (mg) film coated tablets (2x400mg=800mg) orally once in a day.

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    RTV
    Other name
    Norvir
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with Ritonavir 100 milligrams (mg) capsule orally once in a day.

    Number of subjects in period 1
    		DRV/rtv 800/100 mg q.d.
    Started
    12
    Completed
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DRV/rtv 800/100 mg q.d.
    Reporting group description
    		 Subjects were administered with Darunavir in combination with low-dose of ritonavir (DRV/rtv) at 800/100 mg once daily (q.d.) in combination with an investigator-selected background regimen, consisting of either zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC.

    Reporting group values
    		 DRV/rtv 800/100 mg q.d. Total
    Number of subjects
    		 12 12
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 12 12
        Adults (18-64 years)
    		 0 0
        From 65 to 84 years
    		 0 0
        85 years and over
    		 0 0
    Title for AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 14.6 ± 1.69 -
    Title for Gender
    Units: subjects
        Female
    		 8 8
        Male
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    DRV/rtv 800/100 mg q.d.
    Reporting group description
    		 Subjects were administered with Darunavir in combination with low-dose of ritonavir (DRV/rtv) at 800/100 mg once daily (q.d.) in combination with an investigator-selected background regimen, consisting of either zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC.

    Primary: Virological Response[Viral Load <50 Copies/mL, (Time to Loss of Virologic Response) TLOVR]

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    End point title
    		 Virological Response[Viral Load <50 Copies/mL, (Time to Loss of Virologic Response) TLOVR] [1]
    End point description
    The analysis is based on virologic response defined as percentage of patients with confirmed plasma viral load less than (<) 50 HIV-1 RNA copies/mL at Week 24 calculated according to the Food and Drug Administration (FDA) Time to Loss of Virologic Response (TLOVR) algorithm.
    End point type
    Primary
    End point timeframe
    Week 24
    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: Descriptive statistics were done, no inferential statistical analyses were performed
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
        Yes
    11
        No
    1
    No statistical analyses for this end point

    Secondary: Virological Response [Viral Load <50 Copies/mL, FDA-SNAPSHOT]

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    End point title
    		 Virological Response [Viral Load <50 Copies/mL, FDA-SNAPSHOT]
    End point description
    The analysis is based on the last observed viral load (VL) data within the Week 24 window. Virologic response is defined as a VL less than (<) 50 copies/mL (observed case). Virologic Failure includes a) patients who had greater than or equal to (>=) 50 copies/millilitre (mL) in the Week 24 window, b) patients who discontinued prior to Week 24 for lack or loss of efficacy, c) patients who had a switch in their background regimen that was not permitted by the protocol, and d) patients who discontinued for reasons other than adverse events (AEs)/death, and lack or loss of efficacy (provided their last available viral load was detectable).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
    12
    No statistical analyses for this end point

    Secondary: Virologic response-Other parameters

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    End point title
    		 Virologic response-Other parameters
    End point description
    Virologic response defined as the percentage of subjects with (1) a confirmed plasma viral load <400 copies/mL, and (2) a confirmed ≥ 1 log10 decrease in plasma viral load versus baseline, calculated according to the TLOVR algorithm
    End point type
    Secondary
    End point timeframe
    Week 2 to Week 48
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
    12
    No statistical analyses for this end point

    Secondary: Change in plasma viral load versus baseline

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    End point title
    		 Change in plasma viral load versus baseline
    End point description
    The change in plasma log10 viral load from baseline was calculated using the NC = F algorithm.
    End point type
    Secondary
    End point timeframe
    Upto Week 48
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
    12
    No statistical analyses for this end point

    Secondary: Time to first virologic response

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    End point title
    		 Time to first virologic response
    End point description
    The time to first virologic response (defined as plasma viral load < 50 copies/mL, < 400 copies/mL, and ≥ 1 log10 decrease in plasma viral load versus baseline) was calculated according to the TLOVR algorithm. In this algorithm, subjects who never achieved virologic response were censored at their last available assessment time point during the treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
    12
    No statistical analyses for this end point

    Secondary: Immunologic response

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    End point title
    		 Immunologic response
    End point description
    CD4+ cell count was calculated using the NC = F algorithm.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 DRV/rtv 800/100 mg q.d.
    Number of subjects analysed
    12
    Units: Subjects
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline upto week 52.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    DRV/rtv 800/100 mg q.d.
    Reporting group description
    		 darunavir with low-dose ritonavir (DRV/rtv) administered at 800/100 mg once daily (q.d.) in combination with an investigator-selected background regimen, consisting of either zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC

    Serious adverse events
    		 DRV/rtv 800/100 mg q.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Traumatic Brain Injury
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 DRV/rtv 800/100 mg q.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Uterine Cervical Erosion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    3
    Rhinitis Allergic
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Attention Deficit/Hyperactivity Disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nail Injury
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    3
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    4
    Eye disorders
    Conjunctival Hyperaemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Keratitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Conjunctivitis Allergic
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vision Blurred
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Abdominal Pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Asymptomatic Bacteriuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Herpes Simplex
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Furuncle
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Herpes Zoster
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Otitis Media Acute
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Tooth Abscess
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

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

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