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    Clinical Trial Results:
    An open-label, multiple dose, Phase I, cross-over study to evaluate the steady-state pharmacokinetic parameters of nevirapine extended release tablets in HIV-1 infected children, with an optional extension phase.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2008-005855-61
    Trial protocol
    		 DE   Outside EU/EEA  
    Global end of trial date
    10 Sep 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Jul 2016
    First version publication date
    26 Jul 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT-Results

    Trial information

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    Trial identification
    Sponsor protocol code
    1100.1518
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00905489
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000391-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
    22 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish pharmacokinetic (PK) parameters at steady-state of once-daily (QD) Viramune extended release (XR) in children 3-<18 years of age (previously reported) and to evaluate the safety and efficacy profile in children who completed the PK phase and continued Viramune XR in the optional extension phase (OEP).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be randomised to trial treatment. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 Other ARVs were continued as chosen by the investigator.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    04 Jun 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Botswana: 64
    Country: Number of subjects enrolled
    Germany: 12
    Worldwide total number of subjects
    91
    EEA total number of subjects
    12
    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)
    56
    Adolescents (12-17 years)
    35
    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
    		 Multicenter study with one treatment group and no randomization process. Overall, 90 pediatric patients were enrolled. Five patients were not entered and 85 patients entered the study. Patients were stratified to the following three age groups: (26 in the 3 -<6 year age group, 26 in the 6 -< 12 year age group and 33 in the 12 -< 18 year age group).

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Pharmaco-kinetic (PK) Phase by age
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 3-<6 yr
    Arm description
    		 3-<6 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Investigational medicinal product name
    Viramune ®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Viramune ® 200 mg tablets or 50mg/5ml oral suspension. Dose depending on body surface or body weight: Body Surface Area (BSA): 150mg/m2 twice a day (BID) OR Body Weight (BW): 4 or 7 mg/kg BW BID depending on patient age (7 mg/kg BID if age is 3 to 8 years and 4 mg/kg BID if age is > 8 years)

    Arm title
    		 6-<12 yr
    Arm description
    		 6-<12 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Investigational medicinal product name
    Viramune ®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Viramune ® 200 mg tablets or 50mg/5ml oral suspension. Dose depending on body surface or body weight: Body Surface Area (BSA): 150mg/m2 twice a day (BID) OR Body Weight (BW): 4 or 7 mg/kg BW BID depending on patient age (7 mg/kg BID if age is 3 to 8 years and 4 mg/kg BID if age is > 8 years)

    Arm title
    		 12-<18 yr
    Arm description
    		 12-<18 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Investigational medicinal product name
    Viramune ®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Viramune ® 200 mg tablets or 50mg/5ml oral suspension. Dose depending on body surface or body weight: Body Surface Area (BSA): 150mg/m2 twice a day (BID) OR Body Weight (BW): 4 or 7 mg/kg BW BID depending on patient age (7 mg/kg BID if age is 3 to 8 years and 4 mg/kg BID if age is > 8 years)

    Number of subjects in period 1 [1]
    		3-<6 yr 6-<12 yr 12-<18 yr
    Started
    26
    26
    33
    Completed
    25
    24
    31
    Not completed
    1
    2
    2
         Other reason not defined above
    1
    1
    1
         Protocol deviation
    -
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Period 2
    Period 2 title
    Optional Extension Phase (OEP) by age
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 3-<6 yr
    Arm description
    		 3-<6 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Arm title
    		 6-<12 yr
    Arm description
    		 6-<12 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Arm title
    		 12-<18 yr
    Arm description
    		 12-<18 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nevirapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of various doses: 200 mg (100mg x 2 tablets), 300 mg (100mg x 3 tablets), 400 mg (1 tablet) of Nevirapine extended release (XR) once daily.

    Number of subjects in period 2 [2]
    		3-<6 yr 6-<12 yr 12-<18 yr
    Started
    12
    16
    12
    Completed
    11
    16
    12
    Not completed
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Extension Phase (OEP) includes only subjects who chose to continue treatment with nevirapine XR after completing the PK phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pharmaco-kinetic (PK) Phase by age
    Reporting group description
    		 -

    Reporting group values
    		 Pharmaco-kinetic (PK) Phase by age Total
    Number of subjects
    		 85 85
    Age Categorical
    Units: participants
    Age continuous
    Full analysis set (FAS): All patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
    Units: years
        arithmetic mean (standard deviation)
    		 9.3 ( 4.6 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 47 47
        Male
    		 38 38

    End points

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    End points reporting groups
    Reporting group title
    3-<6 yr
    Reporting group description
    		 3-<6 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).

    Reporting group title
    6-<12 yr
    Reporting group description
    		 6-<12 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).

    Reporting group title
    12-<18 yr
    Reporting group description
    		 12-<18 years-old subjects initially receive nevirapine immediate release (IR) and then they were switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dose of 200mg, 300mg or 400mg. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).
    Reporting group title
    3-<6 yr
    Reporting group description
    		 3-<6 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.

    Reporting group title
    6-<12 yr
    Reporting group description
    		 6-<12 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.

    Reporting group title
    12-<18 yr
    Reporting group description
    		 12-<18 years-old subjects who chose to continue treatment with nevirapine XR after completing the PK phase.

    Subject analysis set title
    NVP XR
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nevirapine XR (extended release)

    Subject analysis set title
    NVP IR
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nevirapine IR (immediate release)

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 200 mg, 300 mg or 400 mg QD. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).

    Primary: Trough Cpre,N.

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    End point title
    		 Trough Cpre,N.
    End point description
    Trough Nevirapine concentration immediately prior to the next scheduled dose. Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. The measure of dispersion presented is the coefficient of variation (%) rather than the geometric coefficient of variation. PK analysis set (PKS): This patient set includes all patients in the Full Analysis Set (FAS) set that have no protocol violations excluding them from PK analyses.
    End point type
    Primary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    74 [1]
    78 [2]
    Units: (ng/mL/mg)
        geometric mean (geometric coefficient of variation)
    15.47 ( 64.34 )
    16.66 ( 75.03 )
    Notes
    [1] - PKS
    [2] - PKS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted geometric means were estimated from the mixed model for intra-individual comparison. The actual number of subjects analyzed is 78. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (152) does not reflect the actual number. Ratio calculated as NVP XR: NVP IR.
    Comparison groups
    NVP XR v NVP IR
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.008
    Method
    		 Mixed models analysis
    Parameter type
    		 Ratio [NVP XR: NVP IR]
    Point estimate
    91.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 83.47
         upper limit
    		 99.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.05
    Notes
    [3] - No formal hypothesis testing.

    Secondary: AUCt,ss

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    End point title
    		 AUCt,ss
    End point description
    Area under the concentration-time curve of the Nevirapine (NVP) in plasma at steady state over the time dosing interval t. All patients received nevirapine IR for 10 days prior to collection of 12-hour Area Under the Curve (AUC) data. Then, all patients were switched to nevirapine XR for 9 days prior to collection of 24-hour AUC data. The treatments of IR and XR are summarized separately using geometric means and geometric coefficients of variation. For NVP IR AUC measured over hours: 0,1,2,3,4,8 and 12, For NVP XR AUC measured over hours: 0,1,2,3,4,8,10,12 and 24. Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [4]
    49 [5]
    Units: ng*h/ml
    geometric mean (geometric coefficient of variation)
        200mg NVP XR QD (175-249 mg IR/day), n=23/22
    99300 ( 37.7 )
    57900 ( 45.7 )
        300mg NVP XR QD (250-349 mg IR/day), n=11/12
    144000 ( 50.1 )
    58100 ( 35 )
        400mg NVP XR QD (≥350 mg IR/day), n=11/15
    108000 ( 60.7 )
    73400 ( 39.8 )
    Notes
    [4] - Intensive PK analysis set (IPK)
    [5] - Intensive PK analysis set (IPK)
    No statistical analyses for this end point

    Secondary: Cmin,ss (for IR and XR formulations by nevirapine XR dose group)

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    End point title
    		 Cmin,ss (for IR and XR formulations by nevirapine XR dose group)
    End point description
    Minimum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ by nevirapine XR dose group patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 21. Intensive PK analysis set (IPK): This patient set includes all patients in the PK set that underwent intensive PK sampling.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [6]
    49 [7]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    3090 ( 37.9 )
    3280 ( 57.6 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    4160 ( 62.6 )
    3620 ( 34.7 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    3410 ( 63 )
    4960 ( 39.1 )
    Notes
    [6] - IPK
    [7] - IPK
    No statistical analyses for this end point

    Secondary: Cmax,ss (for IR and XR formulations by nevirapine XR dose group)

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    End point title
    		 Cmax,ss (for IR and XR formulations by nevirapine XR dose group)
    End point description
    Maximum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ. Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [8]
    49 [9]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    5350 ( 43.1 )
    6850 ( 52.6 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    7970 ( 53.5 )
    6580 ( 31.4 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    5890 ( 50.5 )
    7790 ( 43.2 )
    Notes
    [8] - IPK
    [9] - IPK
    No statistical analyses for this end point

    Secondary: Ratio Cmax,ss/Cmin,ss

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    End point title
    		 Ratio Cmax,ss/Cmin,ss
    End point description
    Ratio of (maximum measured concentration of the Nevirapine in plasma at steady state over the time dosing interval τ)/(minimum measured concentration of the analyte in plasma at steady state over the time dosing interval τ). Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR.
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [10]
    49 [11]
    Units: Ratio
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    1.73 ( 23.7 )
    2.09 ( 32.3 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    1.91 ( 39.4 )
    1.82 ( 17.8 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    1.73 ( 21.8 )
    1.57 ( 21.1 )
    Notes
    [10] - IPK
    [11] - IPK
    No statistical analyses for this end point

    Secondary: %PTF

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    End point title
    		 %PTF
    End point description
    Percentage peak-trough Nevirapine fluctuation, % fluctuation (degree of peak to trough fluctuation). Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [12]
    49 [13]
    Units: percentage fluctuation
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    49.7 ( 47.3 )
    67.9 ( 49.8 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    54.6 ( 61.1 )
    59.1 ( 29.4 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    51 ( 47.6 )
    41.5 ( 55.7 )
    Notes
    [12] - IPK
    [13] - IPK
    No statistical analyses for this end point

    Secondary: Tmax,ss

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    End point title
    		 Tmax,ss
    End point description
    Time from dosing to the maximum concentration of the Nevirapine in plasma at steady state over the time dosing interval τ Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22. The measure of dispersion presented is the coefficient of variation (%) rather than the standard deviation.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [14]
    49 [15]
    Units: hours
    arithmetic mean (standard deviation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    6.34 ( 104 )
    2.46 ( 57.9 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    7.28 ( 121 )
    2.49 ( 50.4 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    5.73 ( 129 )
    4.41 ( 94.2 )
    Notes
    [14] - IPK
    [15] - IPK
    No statistical analyses for this end point

    Secondary: CL/F,ss

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    End point title
    		 CL/F,ss
    End point description
    Apparent clearance of the Nevirapine in the plasma after extravascular administration at steady-state Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [16]
    49 [17]
    Units: mL/h
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    2010 ( 37.7 )
    1780 ( 44.3 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    2080 ( 50.1 )
    2240 ( 32.9 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    3700 ( 60.7 )
    2640 ( 39.3 )
    Notes
    [16] - IPK
    [17] - IPK
    No statistical analyses for this end point

    Secondary: Cavg

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    End point title
    		 Cavg
    End point description
    Average measured concentration of the Nevirapine in plasma at steady state Patients took Nevirapine (NVP) Immediate Release (IR) up to day 10 and had PK measurements taken on Day 11. This was followed by 9 days (from day 12 to day 20) taking NVP Extended Release (XR) with PK measurements taken on Day 22.
    End point type
    Secondary
    End point timeframe
    Day 11 prior to the next scheduled dose of Nevirapine IR and day 22 prior to the next scheduled dose of Nevirapine XR
    End point values
    		 NVP XR NVP IR
    Number of subjects analysed
    45 [18]
    49 [19]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        200 mg XR QD (175-249 mg IR/day), n=23,22
    4140 ( 37.7 )
    4820 ( 45.7 )
        300 mg XR QD (250-349 mg IR/day), n=11,12
    6010 ( 50.1 )
    4840 ( 35 )
        400 mg XR QD (≥350 mg IR/day), n=11,15
    4510 ( 60.7 )
    6120 ( 39.8 )
    Notes
    [18] - IPK
    [19] - IPK
    No statistical analyses for this end point

    Secondary: Efficacy: Patients maintaining a VL < 50 copies/mL

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    End point title
    		 Efficacy: Patients maintaining a VL < 50 copies/mL
    End point description
    Patients maintaining a viral load < 50 copies/mL at Day 22. Full analysis set (FAS): This analysis set includes patients with available viral load data at day 22
    End point type
    Secondary
    End point timeframe
    Day 22
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr Total
    Number of subjects analysed
    25 [20]
    23 [21]
    31 [22]
    79 [23]
    Units: percentage of patients
        number (not applicable)
    96
    100
    100
    98.7
    Notes
    [20] - FAS
    [21] - FAS
    [22] - FAS
    [23] - FAS
    No statistical analyses for this end point

    Secondary: Efficacy: Patients Maintaining a VL < 400 Copies/mL

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    End point title
    		 Efficacy: Patients Maintaining a VL < 400 Copies/mL
    End point description
    Patients maintaining a viral load < 400 copies/mL at Day 22. Full analysis set (FAS) including patients with available viral load data at day 22.
    End point type
    Secondary
    End point timeframe
    Day 22
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr Total
    Number of subjects analysed
    25 [24]
    23 [25]
    31 [26]
    79 [27]
    Units: percentage of patients
        number (not applicable)
    100
    100
    100
    100
    Notes
    [24] - FAS
    [25] - FAS
    [26] - FAS
    [27] - FAS
    No statistical analyses for this end point

    Secondary: Change from baseline in mean CD4+ count (absolute)

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    End point title
    		 Change from baseline in mean CD4+ count (absolute)
    End point description
    Change in mean CD4+ count (absolute) from baseline to Day 22 and from baseline to Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 22 and Week 24
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr
    Number of subjects analysed
    24 [28]
    24 [29]
    31 [30]
    Units: cells/mm^3
    arithmetic mean (standard deviation)
        Day 22
    -115.6 ( 320.5 )
    24.2 ( 184.8 )
    60.3 ( 171.2 )
        Week 24 (n=8; 10; 9)
    -214.5 ( 397.5 )
    -51.2 ( 179.4 )
    31.1 ( 66.4 )
    Notes
    [28] - PKS
    [29] - PKS
    [30] - PKS
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in mean CD4+ count

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    End point title
    		 Percentage change from baseline in mean CD4+ count
    End point description
    ((Day 22 value-Baseline value)/Baseline value)*100. ((Week 24 value-Baseline value)/Baseline value)*100. Optional Extension Phase Treated Set (OEP TS), all patients that complete PK phase and enroll in Extension phase, and had available data at either day 22 or week 24.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 22 and baseline to Week 24
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr
    Number of subjects analysed
    24 [31]
    24 [32]
    31 [33]
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 22
    -2.1 ( 6.7 )
    0 ( 2.5 )
    0.5 ( 3.6 )
        Week 24 (n=8; 10; 9)
    -2.1 ( 4 )
    -2.1 ( 3.4 )
    -1 ( 2.9 )
    Notes
    [31] - OEP TS
    [32] - OEP TS
    [33] - OEP TS
    No statistical analyses for this end point

    Secondary: Efficacy: Patients maintaining a VL < 50 copies/mL at week 24 of Optional Extension Phase

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    End point title
    		 Efficacy: Patients maintaining a VL < 50 copies/mL at week 24 of Optional Extension Phase
    End point description
    Patients maintaining a viral load < 50 copies/mL at week 24 (approximately 168 days) of Optional Extension Phase (OEP). Full analysis set including patients with available viral load data at week 24.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr Total
    Number of subjects analysed
    8 [34]
    10 [35]
    9 [36]
    27 [37]
    Units: percentage of patients
        number (not applicable)
    100
    100
    100
    100
    Notes
    [34] - FAS
    [35] - FAS
    [36] - FAS
    [37] - FAS
    No statistical analyses for this end point

    Secondary: Efficacy: Patients Maintaining a VL < 400 Copies/mL in Optional Extension Phase

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    End point title
    		 Efficacy: Patients Maintaining a VL < 400 Copies/mL in Optional Extension Phase
    End point description
    Patients maintaining a viral load < 400 copies/mL at week 24 of the Optional Extension Phase (OEP). Full analysis set including patients with available viral load data at week 24
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr Total
    Number of subjects analysed
    8 [38]
    10 [39]
    9 [40]
    27 [41]
    Units: percentage of patients
        number (not applicable)
    100
    100
    100
    100
    Notes
    [38] - FAS
    [39] - FAS
    [40] - FAS
    [41] - FAS
    No statistical analyses for this end point

    Other pre-specified: Efficacy: Patients Maintaining a VL < 50 Copies/mL at Last Available Visit

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    End point title
    		 Efficacy: Patients Maintaining a VL < 50 Copies/mL at Last Available Visit
    End point description
    Patients maintaining a viral load < 50 copies/mL at the last available visit. Optional Extension Phase Treated Set (OEP TS), all patients that complete PK phase and enroll in Extension phase with VL data available.
    End point type
    Other pre-specified
    End point timeframe
    Last available visit, up to 155 weeks
    End point values
    		 3-<6 yr 6-<12 yr 12-<18 yr Total
    Number of subjects analysed
    12 [42]
    16 [43]
    12 [44]
    40 [45]
    Units: percentage of patients
    100
    100
    100
    100
    Notes
    [42] - OEP TS
    [43] - OEP TS
    [44] - OEP TS
    [45] - OEP TS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 14 days after the last drug administration, up to 157 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Total
    Reporting group description
    		 All patients enrolled in study. All patients initially receive nevirapine immediate release (IR) and then all patients are switched to nevirapine extended release (XR) 100mg or 400mg tablets for a once daily dosing of 200 mg, 300 mg or 400 mg QD. After completing the PK phase patients had the option of continuing treatment with nevirapine XR in the Optional Extension Phase (OEP).

    Serious adverse events
    		 Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 85 (3.53%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Coxsackie viral infection
         subjects affected / exposed
    1 / 85 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 85 (1.18%)
         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
    		 Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 85 (65.88%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 85 (16.47%)
         occurrences all number
    18
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 85 (9.41%)
         occurrences all number
    11
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    11 / 85 (12.94%)
         occurrences all number
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 85 (5.88%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    7 / 85 (8.24%)
         occurrences all number
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 85 (32.94%)
         occurrences all number
    39
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    20 / 85 (23.53%)
         occurrences all number
    24
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 85 (5.88%)
         occurrences all number
    9
    Body tinea
         subjects affected / exposed
    5 / 85 (5.88%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    5 / 85 (5.88%)
         occurrences all number
    12
    Respiratory tract infection
         subjects affected / exposed
    6 / 85 (7.06%)
         occurrences all number
    8
    Rhinitis
         subjects affected / exposed
    8 / 85 (9.41%)
         occurrences all number
    12
    Tinea capitis
         subjects affected / exposed
    7 / 85 (8.24%)
         occurrences all number
    12
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 85 (38.82%)
         occurrences all number
    46
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 85 (10.59%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2009
    Clarification of the PK analyses including primary and secondary endpoints
    08 Sep 2009
    1. To change the definition of virologic failure 2. Inclusion of Vital Status for patients who discontinue early after entering the OEP 3. To increase the number patients assigned to post-dose PK sampling in the 3-<6 years age group 4. Clarification of the PK analyses including the primary and secondary endpoints 5. To allow flexibility in the method of calculating the dose of Viramune IR during the run-in phase 6. To update the dose adjustment methodology of Viramune XR during the OEP

    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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