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    Clinical Trial Results:
    A Phase II, open-label trial to evaluate the safety, tolerability and antiviral activity of TMC125 in antiretroviral experienced HIV-1 infected children and adolescents

    Summary
    EudraCT number
    2007-007086-21
    Trial protocol
    GB   DE   BE   PT   ES   FR   NL   IT  
    Global end of trial date
    30 Aug 2011

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jun 2016
    First version publication date
    16 May 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
    TMC125-TiDP35-C213
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00665847
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Tibotec Pharmaceuticals
    Sponsor organisation address
    Eastgate Village, Eastgate, Little Island, Co Cork, Ireland,
    Public contact
    Tibotec Pharmaceuticals, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Tibotec Pharmaceuticals, Clinical Registry Group, 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-000222-PIP01-08
    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
    30 Aug 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate safety and tolerability of etravirine in combination with other antiretroviral (ARVs) over a 24-week treatment period in children and adolescents.
    Protection of trial subjects
    The safety assessments included laboratory measurements (for example hematology and coagulation, biochemistry, urinalysis, hepatitis serology/Viremia), cardiovascular safety, vital sign measurements and electrocardiograms (ECGs). Adverse events and vital signs were monitored throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Thailand: 20
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    South Africa: 10
    Worldwide total number of subjects
    101
    EEA total number of subjects
    27
    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)
    41
    Adolescents (12-17 years)
    60
    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
    In total, 41 investigators in 13 countries enrolled participants in study TMC125-C213.

    Pre-assignment
    Screening details
    A total of 103 participants were documented as being enrolled in the study. Among those, 101 participants were treated with etravirine (ETR) also known as TMC125 and were included in the intent-to-treat (ITT) population.

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

    Arms
    Arm title
    TMC125
    Arm description
    TMC125 dosed according to body weight (kilogram) from 100 milligram (mg) to 200 mg twice a day
    Arm type
    Experimental

    Investigational medicinal product name
    TMC125
    Investigational medicinal product code
    TMC125 (formulation F060 and F066)
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TMC125 dosed according to body weight (kilogram) from 100 milligram (mg) to 200 mg twice a day

    Number of subjects in period 1
    TMC125
    Started
    101
    Completed
    76
    Not completed
    25
         Resistance to TMC125
    1
         Subject reached a virologic endpoint
    4
         Adverse event
    8
         Consent withdrawn by subject
    2
         Subject non-compliant
    8
         Switch to commercial medication
    1
         Subject ineligible to continue the trial
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TMC125
    Reporting group description
    TMC125 dosed according to body weight (kilogram) from 100 milligram (mg) to 200 mg twice a day

    Reporting group values
    TMC125 Total
    Number of subjects
    101 101
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    41 41
        Adolescents (12-17 years)
    60 60
        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)
    12.2 ± 2.99 -
    Title for Gender
    Units: subjects
        Female
    64 64
        Male
    37 37

    End points

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    End points reporting groups
    Reporting group title
    TMC125
    Reporting group description
    TMC125 dosed according to body weight (kilogram) from 100 milligram (mg) to 200 mg twice a day

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    The percentage of participants with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged [i.e. started or worsened in severity, relation, or other attribute], and not in the subsequent study periods, even if the event continued to be present] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen.
    End point type
    Primary
    End point timeframe
    48 weeks
    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
    TMC125
    Number of subjects analysed
    101
    Units: Percentage of Participants
    number (not applicable)
        Any TEAE
    88.1
        TEAEs that were fatal
    0
        TEAEs that were serious
    5
        TEAEs that were grade 3 or 4 in severity
    13.9
        TEAEs leading to temporary ETR discontinuation
    7.9
        TEAEs leading to permanent ETR discontinuation
    7.9
        TEAEs possibly related to ETR
    22.8
        TEAEs probably related to ETR
    13.9
        TEAEs very likely related to ETR
    3
        TEAEs at least possibly related to ETR
    32.7
        TEAEs possibly related to OBR
    26.7
        TEAEs probably related to OBR
    11.9
        TEAEs very likely related to OBR
    5
        TEAEs at least possibly related to OBR
    35.6
        TEAEs of at least grade 2 in severity
    20.8
        TEAEs of at least grade 3 in severity
    3
        TEAEs of interest: Skin event
    30.7
        TEAEs of interest: Rash
    22.8
        TEAEs of interest: severe cutaneous reactions
    6.9
        TEAEs of interest: angioedema
    4
        TEAEs of interest: neuropsychiatric events
    2
        TEAEs of interest: hepatic events
    0
        TEAEs of interest: cardiac events
    0
        TEAEs of interest: bleeding events
    0
        TEAEs of interest: pancreatic events
    1
        TEAEs of interest: lipid-related events
    5.9
        TEAEs of interest: neoplasms
    1
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve Over 12 Hours at Steady-state (AUC12h) of Etravirine

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    End point title
    Area Under the Plasma Concentration-Time Curve Over 12 Hours at Steady-state (AUC12h) of Etravirine
    End point description
    The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample.
    End point type
    Secondary
    End point timeframe
    Weeks 4-48
    End point values
    TMC125
    Number of subjects analysed
    101
    Units: ng.h/mL
        arithmetic mean (standard deviation)
    5216 ± 4305
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (C0h) of Etravirine

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    End point title
    Trough Plasma Concentration (C0h) of Etravirine
    End point description
    Trough plasma concentration is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    TMC125
    Number of subjects analysed
    101
    Units: ng/mL
        arithmetic mean (standard deviation)
    346 ± 342
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Etravirine

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    End point title
    Maximum Plasma Concentration (Cmax) of Etravirine
    End point description
    Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    TMC125
    Number of subjects analysed
    66
    Units: ng/mL
        arithmetic mean (standard deviation)
    589 ± 486
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Virologic Response at Week 24

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    End point title
    Percentage of Participants With Virologic Response at Week 24
    End point description
    Virologic response was defined as the percentage of participants with plasma viral load less than (< ) 50 copies/ milliliter (mL) at Week 24 calculated according to the non-completer=failure (NC=F) imputation method.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    TMC125
    Number of subjects analysed
    101
    Units: Percentage of Participants
        number (not applicable)
    52.5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time

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    End point title
    Change From Baseline in Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time
    End point description
    Human Immunodeficiency Virus – Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    TMC125
    Number of subjects analysed
    101
    Units: log10 copies/mL
        arithmetic mean (standard error)
    -1.53 ± 0.132
    No statistical analyses for this end point

    Secondary: Change From Baseline in CD4 Cell Counts Over Time

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    End point title
    Change From Baseline in CD4 Cell Counts Over Time
    End point description
    CD4 cells (a type of white blood cells) are circulating in blood and gives an idea of how strong the HIV positive person's immune system really is. The values of CD4 cell counts were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    TMC125
    Number of subjects analysed
    101
    Units: 10E6 cells/L
        arithmetic mean (standard error)
    156 ± 22.7
    No statistical analyses for this end point

    Secondary: The Emergence of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Mutations (NNRTI RAMs) in Participants Classified as Virologic Failures

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    End point title
    The Emergence of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Mutations (NNRTI RAMs) in Participants Classified as Virologic Failures
    End point description
    Virologic failure (lack of response) was defined as: plasma viral load decline of < 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of <1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load greater than (>) 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients).
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (up to Week 48)
    End point values
    TMC125
    Number of subjects analysed
    41
    Units: Participants
        V90I
    3
        L100I
    3
        E138A
    3
        Y181C
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 52
    Adverse event reporting additional description
    Only participants who had at least one of the TEAEs listed in the Other (non Serious) AE table are included in the Total no. participants with Non-Serious Adverse Events.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    TMC125
    Reporting group description
    TMC125 dosed according to body weight (kilogram) from 100 milligram (mg) to 200 mg twice a day

    Serious adverse events
    TMC125
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 101 (4.95%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug toxicity
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Immunoglobulins
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphocyte morphology abnormal
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Treatment noncompliance
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Ulcerative keratitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Drug resistance
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    TMC125
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 101 (69.31%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 101 (5.94%)
         occurrences all number
    10
    Cough
         subjects affected / exposed
    13 / 101 (12.87%)
         occurrences all number
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 101 (8.91%)
         occurrences all number
    12
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    6 / 101 (5.94%)
         occurrences all number
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 101 (8.91%)
         occurrences all number
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 101 (15.84%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    11 / 101 (10.89%)
         occurrences all number
    11
    Nausea
         subjects affected / exposed
    10 / 101 (9.90%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 101 (10.89%)
         occurrences all number
    12
    Rash maculo-papular
         subjects affected / exposed
    9 / 101 (8.91%)
         occurrences all number
    10
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    6 / 101 (5.94%)
         occurrences all number
    8
    Bronchitis
         subjects affected / exposed
    9 / 101 (8.91%)
         occurrences all number
    10
    Rhinitis
         subjects affected / exposed
    6 / 101 (5.94%)
         occurrences all number
    8
    Pharyngitis
         subjects affected / exposed
    8 / 101 (7.92%)
         occurrences all number
    11
    Sinusitis
         subjects affected / exposed
    6 / 101 (5.94%)
         occurrences all number
    9
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 101 (26.73%)
         occurrences all number
    41

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2008
    The overall reason for the amendment was to address feedback provided by the United States Food and Drug Administration (US FDA) and modify inclusion criterion.
    30 Jan 2009
    The overall reason for the amendment was to modify inclusion criterion.
    24 Mar 2010
    The overall reason for the amendment was to adjust body weight criterion, definition Serious Adverse Events (SAE) and criterion regarding co-enrollment of participants in another study.

    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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