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    Clinical Trial Results:
    A Phase I/II, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-experienced HIV-1 Infected Infants and Children, Aged >= 2 Months to <6 Years

    Summary
    EudraCT number
    		 2012-002630-36
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    26 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2021
    First version publication date
    31 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TMC125-TIDP35-C234
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01504841
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Division of the National Institute of Allergy and Infectious Diseases (DAIDS)
    Sponsor organisation address
    5601 Fishers Lane, Rockville, United States,
    Public contact
    Clinical Registry Group, Janssen Research and Development, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research and Development, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the steady-state pharmacokinetics (PK), safety and tolerability and appropriate dose of etravirine (ETR) in combination with an optimized background regimen (OBR) for human immunodeficiency virus (HIV)-1 infected children aged greater than or equal to (>=) 2 years to less than (<) 6 years.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon adverse events (AEs) reported throughout the study, clinical laboratory test results, changes in physical examination including vital signs and electrocardiogram (ECGs) results.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    South Africa: 13
    Worldwide total number of subjects
    26
    EEA total number of subjects
    0
    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)
    6
    Children (2-11 years)
    20
    Adolescents (12-17 years)
    0
    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
    		 A total of 26 subjects were enrolled in the study and received at least 1 dose of etravirine (ETR). Out of those 26, 17 subjects completed the study.

    Pre-assignment
    Screening details
    		 3 sequential age cohorts were planned with 20 subjects in cohort 1, 6 subjects in cohort 2 and no enrollments occurred in cohort 3 during the 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
    		 Etravirine
    Arm description
    		 Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etravirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ETR 25mg and/or 100mg was administered orally twice daily either swallowed as a whole tablet or dispersed in an appropriate liquid.

    Number of subjects in period 1
    		Etravirine
    Started
    26
    Completed
    17
    Not completed
    9
         Consent withdrawn by subject
    2
         Completion of protocol
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etravirine
    Reporting group description
    		 Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

    Reporting group values
    		 Etravirine Total
    Number of subjects
    		 26 26
    Title for AgeCategorical
    Units: subjects
        infants and toddlers(28 days-23 months)
    		 6 6
        Children (2-11 years)
    		 20 20
        Adolescents (12-17 years)
    		 0 0
        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)
    		 3.2 ± 1.52 -
    Title for Gender
    Units: subjects
        Female
    		 12 12
        Male
    		 14 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 10 10
        Not Hispanic or Latino
    		 5 5
        Unknown or Not Reported
    		 11 11
    Race
    Units: Subjects
        Black or African American
    		 13 13
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Multiple
    		 4 4
        Other
    		 2 2
        Missing
    		 5 5
        Unknown
    		 1 1
        Not Reported
    		 1 1
    Region of Enrollment
    Units: Subjects
        Brazil
    		 9 9
        South Africa
    		 13 13
        United States
    		 4 4
    CD4 Count
    Units: Subjects
        <200 cells/μL
    		 1 1
        >=200 - <500 cells/μL
    		 4 4
        >=500 - <1000 cells/μL
    		 11 11
        >=1000 cells/μL
    		 10 10
    CD4 Percent
    Units: Subjects
        <25%
    		 12 12
        >=25%
    		 14 14

    End points

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    End points reporting groups
    Reporting group title
    Etravirine
    Reporting group description
    		 Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

    Subject analysis set title
    Cohort 1: >=2 to <6 years age
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. ETR was administered as 25 mg scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

    Subject analysis set title
    Cohort 2: >=1 to <2 years age
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. ETR was administered as 25 mg scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

    Primary: Termination From Treatment due to a Suspected Adverse Drug Reaction (SADR)

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    End point title
    		 Termination From Treatment due to a Suspected Adverse Drug Reaction (SADR) [1]
    End point description
    An event judged to be at least possibly related to the study treatment was considered to be a SADR. Number of subjects who discontinued treatment due to a SADR by Cohort were reported. Intent to treat (ITT) population consisted of all subjects who had taken at least one dose of etravirine (ETR).
    End point type
    Primary
    End point timeframe
    Up to 5.77 years
    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 was done, no inferential statistical analysis was performed.
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    20
    6
    Units: subjects
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events of Grade 3 or Higher Severity

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    End point title
    		 Number of Subjects With Adverse Events of Grade 3 or Higher Severity [2]
    End point description
    An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Number of subjects with grade 3 or higher severity adverse events were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Primary
    End point timeframe
    Up to 5.77 years
    Notes
    [2] - 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 was done, no inferential statistical analysis was performed.
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    20
    6
    Units: subjects
    10
    5
    No statistical analyses for this end point

    Primary: Number of Deaths

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    End point title
    		 Number of Deaths [3]
    End point description
    Number of deaths on study, by cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Primary
    End point timeframe
    Up to 5.77 years
    Notes
    [3] - 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 was done, no inferential statistical analysis was performed.
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    20
    6
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR

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    End point title
    		 Area Under the Plasma Concentration-Time Curve Over 12 Hours of ETR [4]
    End point description
    AUC12h was defined as area under curve from time of administration of ETR to 12 hours post dosing. AUC12h was determined at initial dose and recommended dose of ETR. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Primary
    End point timeframe
    Pre-dose, 1, 2, 4, 6, 9, and 12 hours post-dose measured at intensive PK visit (within 7-10 days after last dose of study drug administration)
    Notes
    [4] - 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 was done, no inferential statistical analysis was performed.
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    10
    4
    Units: nanogram*hour per mililiter
        geometric mean (standard deviation)
    5512.85 ± 3615.36
    4821.76 ± 3167.11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications

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    End point title
    		 Number of Subjects With Adverse Events of Grade 3 or Higher Severity Judged to be at Least Possibly Attributable to the Study Medications
    End point description
    An AE is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Number of subjects with grade 3 or higher severity adverse events possibly related to study treatment were reported by cohort. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Up to 5.77 years
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    20
    6
    Units: subjects
    3
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Confirmed Virologic Failure at Weeks 24 and 48

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    End point title
    		 Number of Subjects With Confirmed Virologic Failure at Weeks 24 and 48
    End point description
    Number of subjects with confirmed Virologic Failure, defined as: failure to suppress plasma human immunodeficiency virus (HIV)-1 ribosenucleic acid (RNA) to fewer than 400 copies per milliliter (copies/mL) and failure to achieve at least a 2-log10 reduction (from baseline) in HIV-1 RNA at Weeks 24 or 48, by Cohort, with Clopper-Pearson confidence intervals. The initial HIV-1 RNA results that met the Virologic Failure definition were each confirmed by a second result obtained within 1 to 4 weeks of the initial result obtained at Week 24 and/or 48. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 48
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    11
    4
    Units: subjects
        Week 24
    2
    1
        Week 48
    3
    3
    No statistical analyses for this end point

    Secondary: Treatment Discontinued due to Toxicity or Virologic Failure

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    End point title
    		 Treatment Discontinued due to Toxicity or Virologic Failure
    End point description
    Number of subjects who discontinued study treatment (ETR) due to a toxicity or Virologic Failure (VF), by cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    From baseline to occurrence of event, up to Week 48
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    20
    6
    Units: subjects
    1
    0
    No statistical analyses for this end point

    Secondary: Change in Optimized Background Regimen Due to Virologic Failure

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    End point title
    		 Change in Optimized Background Regimen Due to Virologic Failure
    End point description
    Number of subjects who initiated a change in their optimized background regimen (OBR) due to virologic failure, by Cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Measured at entry and at Weeks 8, 12, 24, and 48
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    11
    4
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: New Onset Opportunistic Infection (OI) or AIDS Diagnosis

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    End point title
    		 New Onset Opportunistic Infection (OI) or AIDS Diagnosis
    End point description
    Number of subjects with a new onset opportunistic infection (OI) or Acquired immunodeficiency syndrome (AIDS) diagnosis, by Cohort were reported. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    From baseline to occurrence of event, up to Week 48
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    11
    4
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ and CD8+ Cell Count

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    End point title
    		 Change from Baseline in CD4+ and CD8+ Cell Count
    End point description
    Change from baseline in cluster of differentiation (CD)4 and CD8 cell counts was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    19
    6
    Units: cells per microliter
    arithmetic mean (standard error)
        CD4 count
    82.6 ± 111.01
    -36.2 ± 262.50
        CD8 count
    -571.7 ± 165.82
    -591.2 ± 224.53
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ and CD8+ Cell Percentage

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    End point title
    		 Change from Baseline in CD4+ and CD8+ Cell Percentage
    End point description
    Change from baseline in CD4 and CD8 cell percentage was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    19
    6
    Units: percentage
    arithmetic mean (standard error)
        CD4 percentage
    9.52 ± 1.857
    4.27 ± 3.816
        CD8 percentage
    -10.44 ± 2.137
    -3.22 ± 2.806
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4/CD8 Ratio

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    End point title
    		 Change from Baseline in CD4/CD8 Ratio
    End point description
    Change from baseline in CD4/CD8 count ratio was reported to assess the immunologic change. ITT population consisted of all subjects who had taken at least one dose of ETR.
    End point type
    Secondary
    End point timeframe
    Every 12 Weeks from Baseline, up to 5.77 years or early discontinuation
    End point values
    		 Cohort 1: >=2 to <6 years age Cohort 2: >=1 to <2 years age
    Number of subjects analysed
    19
    6
    Units: ratio
        arithmetic mean (standard error)
    0.5171 ± 0.10223
    0.1323 ± 0.12798
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5.77 years
    Adverse event reporting additional description
    Safety set included all subjects who have taken at least 1 dose of etravirine (ETR), regardless of their compliance with the protocol and adherence to the dosing regimen.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Etravirine
    Reporting group description
    		 Subjects were divided into 2 age-based cohorts: Cohort 1 (greater than or equal to [>=] 2 years to less than [<] 6 years age) and Cohort 2 (>= 1 year to <2 years age). Subjects received etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. ETR was administered as 25 milligrams (mg) scored tablets and/or 100 mg tablets twice daily, swallowed whole or dispersed in an appropriate liquid vehicle 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

    Serious adverse events
    		 Etravirine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 26 (30.77%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Investigations
    Lipase Increased
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 26 (3.85%)
         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
    		 Etravirine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin Papilloma
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 26 (53.85%)
         occurrences all number
    32
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Bronchospasm
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    5
    Childhood Asthma
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    19 / 26 (73.08%)
         occurrences all number
    73
    Dyspnoea
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    8
    Nasal Congestion
         subjects affected / exposed
    20 / 26 (76.92%)
         occurrences all number
    47
    Pharyngeal Erythema
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Pharyngeal Inflammation
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Rales
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    10
    Rhinorrhoea
         subjects affected / exposed
    15 / 26 (57.69%)
         occurrences all number
    34
    Sneezing
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Wheezing
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    4
    Investigations
    Blood Pressure Diastolic Increased
         subjects affected / exposed
    7 / 26 (26.92%)
         occurrences all number
    21
    Blood Pressure Systolic Increased
         subjects affected / exposed
    5 / 26 (19.23%)
         occurrences all number
    11
    Weight Decreased
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    8
    Lethargy
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    6
    Lymphadenopathy
         subjects affected / exposed
    10 / 26 (38.46%)
         occurrences all number
    16
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Otorrhoea
         subjects affected / exposed
    7 / 26 (26.92%)
         occurrences all number
    7
    Eye disorders
    Eye Discharge
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    5
    Anal Pruritus
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    11 / 26 (42.31%)
         occurrences all number
    16
    Mouth Ulceration
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Oral Disorder
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    5 / 26 (19.23%)
         occurrences all number
    12
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Dry Skin
         subjects affected / exposed
    5 / 26 (19.23%)
         occurrences all number
    8
    Eczema
         subjects affected / exposed
    5 / 26 (19.23%)
         occurrences all number
    7
    Macule
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Papule
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Rash Papular
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    13 / 26 (50.00%)
         occurrences all number
    34
    Rash Pruritic
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Acarodermatitis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    4
    Acute Sinusitis
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    5
    Body Tinea
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Bronchitis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    4
    Impetigo
         subjects affected / exposed
    7 / 26 (26.92%)
         occurrences all number
    8
    Lice Infestation
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Molluscum Contagiosum
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Oral Candidiasis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Otitis Media Acute
         subjects affected / exposed
    6 / 26 (23.08%)
         occurrences all number
    7
    Parotitis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    8 / 26 (30.77%)
         occurrences all number
    10
    Pneumonia Bacterial
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Tinea Capitis
         subjects affected / exposed
    7 / 26 (26.92%)
         occurrences all number
    9
    Tinea Faciei
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    7
    Urinary Tract Infection
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Varicella
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    6 / 26 (23.08%)
         occurrences all number
    12
    Failure to Thrive
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2012
    The first amendment was issued to remove Cohorts IIB and IIIB (greater than or equal to [>=] 2-month to less than [<] 2-year old treatment-naive children, with or without exposure to antiretrovirals (ARVs) as part of a regimen to prevent mother-to-child transmission). Consequently, the number of cohorts was changed from 5 to 3, the sample size was updated from 80 to 50 subjects, and stratification by ARV exposure was deleted. All sections throughout the protocol were updated accordingly, including the protocol title and study objectives.
    04 Oct 2013
    The second amendment was issued to revise the criteria for individual and cohort dose evaluations and adjustments. Intensive pharmacokinetic (PK) sampling was to be performed on Day 14 (plus minus [+-] 4 days) of the study to allow etravirine (ETR) plasma concentrations to reach steady-state. In order to meet the PK criteria, at least 10 of 12 subjects per cohort were to have an area under plasma concentration-time curve over 12 hours of ETR (AUC12h) greater than (>) 2,350 nanograms * hour per milliliter (ng*h/mL) (>10th percentile of the adult AUC12h in the DUET studies) and a geometric mean AUC12h in the cohort to fall within 80 percent (%) to 130% of the geometric mean AUC12h in adults (that is, between 3,618 and 5,879 ng*h/mL). For individual PK-determined dose adjustments, a stepwise approach was introduced aimed at obtaining an ETR AUC12h around the 20th percentile of the adult AUC12h (instead of the median adult AUC12h) and with a first dose adjustment capped at 200 milligrams (mg) twice daily (bid).
    05 Dec 2014
    The third amendment was issued to incorporate revisions related to a change in the starting ETR dose (as per the new weight-banded ETR dosing table) for the study cohorts and a change in the overall PK criteria for evaluation of the (mini-)cohorts. Based on the high interindividual variability for apparent ETR clearance in the population PK model (62%), the target range for the geometric mean ETR AUC12h ratio (pediatric/adults) per age cohort was revised to be between 60% and 150% (instead of between 80% and 130%) of the geometric mean AUC12h in adults in the DUET studies (between 2,713 and 6,783 ng*h/mL). Since 2 subjects of the original mini-cohort already passed PK and safety criteria on the dose per amendment #2, and based on their body weight the same ETR dose would apply for them per amendment #3, it was agreed that these 2 subjects could be considered toward the new Cohort I minicohort under the amended protocol. Therefore, only 4 additional subjects needed to be enrolled to complete enrollment into that new mini-cohort. It was also agreed that subjects of the failed mini-cohort could be dose adjusted after an additional truncated intensive PK evaluation. The number of subjects to be enrolled was updated to account for the number of subjects needed to complete the dose-finding stage of the study and considering the number of subjects who were started on the final recommended ETR dose according to PK and safety criteria for that cohort.
    10 Mar 2016
    The fourth amendment was issued to revise the cohort management plan to allow early opening of the mini-cohort of Cohort III (while the first mini-cohort of Cohort II could still be enrolling) provided that the available Cohort II safety and PK were acceptable. Subjects <6 months of age could only be enrolled after initial safety and PK data from subjects between 6 months and 1 year of age were available. A go/no-go decision for further recruitment of study subjects was set approximately 2 years following the opening of Cohort II. At that time, an analysis was to be performed across all age cohorts (the Week-24 analysis). The accrual rate, and all relevant safety and PK data, were to be examined for determination of safety and value in continuing recruitment.

    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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