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    Clinical Trial Results:
    A Phase 1, Single-dose Study to Evaluate the Relative Bioavailability of Cobicistat (COBI) Age-Appropriate Pediatric Tablet Formulations Compared with Adult COBI 150-mg Tablets in Healthy Adult Volunteers

    Summary
    EudraCT number
    		 2015-000466-57
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 Jan 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-216-0127
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 101283
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000969-PIP01-10
    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
    05 Jan 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was to evaluate the relative bioavailability of 2 age-appropriate pediatric formulations (immediate release tablet or dispersible tablet as suspension) of cobicistat (COBI) in healthy adult participants.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    62
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    62
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at a single study site in the United States. The first participant was screened on 13 November 2012. The last study visit occurred on 05 January 2013.

    Pre-assignment
    Screening details
    		 120 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 3 x 50 mg age-appropriate pediatric immediate release tablet (Treatment B)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobicistat
    Investigational medicinal product code
    Other name
    Tybost®, GS-9350
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    COBI 150 mg adult immediate release tablet, 50 mg age-appropriate pediatric immediate release tablet, or 20 mg age-appropriate pediatric dispersible tablet as suspension formulation administered orally in the morning immediately after a standard meal

    Arm title
    		 Cohort 2
    Arm description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet (Treatment C)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobicistat
    Investigational medicinal product code
    Other name
    Tybost®, GS-9350
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    COBI 150 mg adult immediate release tablet, 50 mg age-appropriate pediatric immediate release tablet, or 20 mg age-appropriate pediatric dispersible tablet as suspension formulation administered orally in the morning immediately after a standard meal

    Number of subjects in period 1
    		Cohort 1 Cohort 2
    Started
    32
    30
    Completed
    30
    29
    Not completed
    2
    1
         Subject withdrew consent
    1
    -
         Protocol violation
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 3 x 50 mg age-appropriate pediatric immediate release tablet (Treatment B)

    Reporting group title
    Cohort 2
    Reporting group description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet (Treatment C)

    Reporting group values
    		 Cohort 1 Cohort 2 Total
    Number of subjects
    		 32 30 62
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28 ( 6.9 ) 29 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 8 21
        Male
    		 19 22 41
    Race
    Units: Subjects
        Asian
    		 0 2 2
        Black or African American
    		 23 14 37
        White
    		 9 14 23
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 5 7
        Not Hispanic or Latino
    		 30 25 55

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 3 x 50 mg age-appropriate pediatric immediate release tablet (Treatment B)

    Reporting group title
    Cohort 2
    Reporting group description
    		 COBI 1 x 150 mg adult immediate release tablet (Treatment A) or COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet (Treatment C)

    Subject analysis set title
    Cohort 1, Treatment A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 1 who received Treatment A (COBI 1 x 150 mg adult immediate release tablet) on Day 1 or 8

    Subject analysis set title
    Cohort 1, Treatment B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 1 who received Treatment B (COBI 3 x 50 mg age-appropriate pediatric immediate release tablet) on Day 1 or 8

    Subject analysis set title
    Cohort 2, Treatment A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 2 who received Treatment A (COBI 1 x 150 mg adult immediate release tablet) on Day 1 or 8

    Subject analysis set title
    Cohort 2, Treatment C
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 2 who received Treatment C (COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet) on Day 1 or 8

    Subject analysis set title
    Treatment A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohorts 1 and 2 who received Treatment A (COBI 1 x 150 mg adult immediate release tablet) were analyzed.

    Subject analysis set title
    Treatment B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 1 who received Treatment B (COBI 3 x 50 mg age-appropriate pediatric immediate release tablet) were analyzed.

    Subject analysis set title
    Treatment C
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in Cohort 2 who received Treatment C (COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet) were analyzed.

    Primary: Plasma Pharmacokinetics of COBI as measured by AUClast and AUCinf

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    End point title
    		 Plasma Pharmacokinetics of COBI as measured by AUClast and AUCinf
    End point description
    AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration. AUCinf is defined as the concentration of drug extrapolated to infinite time. Participants in the COBI PK Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20, 24, 28, 36, and 48 hours post-dose on Days 1 and 8
    End point values
    		 Cohort 1, Treatment A Cohort 1, Treatment B Cohort 2, Treatment A Cohort 2, Treatment C
    Number of subjects analysed
    30
    30
    30
    30
    Units: ng*h/mL
    geometric mean (confidence interval 95%)
        AUClast
    4705.1 (3906.5 to 5667)
    4468.6 (3776.3 to 5287.7)
    5664.3 (4720.7 to 6796.4)
    5471.5 (4490.7 to 6666.7)
        AUCinf
    4748.7 (3942.6 to 5719.6)
    4509.4 (3813.2 to 5332.6)
    5707.4 (4761.3 to 6841.6)
    5513.6 (4529.6 to 6711.4)
    Statistical analysis title
    		 Cohort 1: Treatment B/Treatment A for AUClast
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 1: Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment B.
    Comparison groups
    Cohort 1, Treatment B v Cohort 1, Treatment A
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    94.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.94
         upper limit
    		 101.42
    Notes
    [1] - Intergroup comparison
    Statistical analysis title
    		 Cohort 1: Treatment B/Treatment A for AUCinf
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 1: Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment B.
    Comparison groups
    Cohort 1, Treatment B v Cohort 1, Treatment A
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    94.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.93
         upper limit
    		 101.39
    Notes
    [2] - Intergroup comparison
    Statistical analysis title
    		 Cohort 2: Treatment C/Treatment A for AUClast
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 2: Treatment C/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment C.
    Comparison groups
    Cohort 2, Treatment A v Cohort 2, Treatment C
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    96.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.01
         upper limit
    		 103.67
    Notes
    [3] - Intergroup comparison
    Statistical analysis title
    		 Cohort 2: Treatment C/Treatment A for AUCinf
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 2: Treatment C/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment C.
    Comparison groups
    Cohort 2, Treatment A v Cohort 2, Treatment C
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    96.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.07
         upper limit
    		 103.62
    Notes
    [4] - Intergroup comparison

    Primary: Plasma Pharmacokinetics of COBI as measured by Cmax

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    End point title
    		 Plasma Pharmacokinetics of COBI as measured by Cmax
    End point description
    Cmax is defined as the maximum observed concentration of drug in plasma. Participants in the COBI PK Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20, 24, 28, 36, and 48 hours post-dose on Days 1 and 8
    End point values
    		 Cohort 1, Treatment A Cohort 1, Treatment B Cohort 2, Treatment A Cohort 2, Treatment C
    Number of subjects analysed
    30
    30
    30
    30
    Units: ng/mL
        geometric mean (confidence interval 95%)
    803.7 (707.5 to 913)
    804.1 (699.9 to 923.8)
    924.2 (800.6 to 1066.8)
    849.5 (725.5 to 994.7)
    Statistical analysis title
    		 Cohort 1: Treatment B/Treatment A for Cmax
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 1: Treatment B/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment B.
    Comparison groups
    Cohort 1, Treatment B v Cohort 1, Treatment A
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    100.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 92.8
         upper limit
    		 107.86
    Notes
    [5] - Intergroup comparison
    Statistical analysis title
    		 Cohort 2: Treatment C/Treatment A for Cmax
    Statistical analysis description
    A parametric mixed effect analysis of variance (ANOVA) model was used to estimate the geometric mean ratio (Cohort 2: Treatment C/Treatment A) of the PK parameter and the corresponding 90% CI. "Subjects in this analysis" states 60; however, only 30 unique participants were analyzed, each reported for Treatment A and Treatment C.
    Comparison groups
    Cohort 2, Treatment A v Cohort 2, Treatment C
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    91.92
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 86.77
         upper limit
    		 97.37
    Notes
    [6] - Intergroup comparison

    Secondary: Plasma Pharmacokinetics of COBI as measured by %AUCexp

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    End point title
    		 Plasma Pharmacokinetics of COBI as measured by %AUCexp
    End point description
    %AUCexp is defined as the percent area under the plasma concentration-time curve. Participants in the COBI PK Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20, 24, 28, 36, and 48 hours post-dose on Days 1 and 8
    End point values
    		 Cohort 1, Treatment A Cohort 1, Treatment B Cohort 2, Treatment A Cohort 2, Treatment C
    Number of subjects analysed
    30
    30
    30
    30
    Units: percent
        arithmetic mean (standard deviation)
    0.9 ( 0.51 )
    0.9 ( 0.38 )
    0.8 ( 0.37 )
    0.8 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI as measured by Tmax and t1/2

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    End point title
    		 Plasma Pharmacokinetics of COBI as measured by Tmax and t1/2
    End point description
    Tmax is defined as the time of Cmax. t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Participants in the COBI PK Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20, 24, 28, 36, and 48 hours post-dose on Days 1 and 8
    End point values
    		 Cohort 1, Treatment A Cohort 1, Treatment B Cohort 2, Treatment A Cohort 2, Treatment C
    Number of subjects analysed
    30
    30
    30
    30
    Units: hours
    median (inter-quartile range (Q1-Q3))
        Tmax
    2.5 (2 to 3.05)
    2.51 (2.5 to 3.02)
    2.5 (2.5 to 3.5)
    3.25 (2.5 to 4.5)
        t1/2
    3.27 (2.74 to 3.86)
    3.16 (2.73 to 3.8)
    3.36 (3 to 3.58)
    3.2 (2.76 to 3.72)
    No statistical analyses for this end point

    Secondary: Acceptability for COBI formulations as measured by palatability rating

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    End point title
    		 Acceptability for COBI formulations as measured by palatability rating
    End point description
    Palatability ratings were assessed using a scale of 1 (dislike very much) to 7 (like very much). Participants in the Safety Analysis Set were analyzed by treatment received.
    End point type
    Secondary
    End point timeframe
    Days 1 and 8
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    62
    31
    30
    Units: units on a scale
        arithmetic mean (standard deviation)
    5 ( 1.5 )
    6 ( 1.6 )
    4 ( 1.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 15 days plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Participants in Cohorts 1 and 2 who received Treatment A (COBI 1 x 150 mg adult immediate release tablet) were analyzed.

    Reporting group title
    Treatment B
    Reporting group description
    		 Participants in Cohort 1 who received Treatment B (COBI 3 x 50 mg age-appropriate pediatric immediate release tablet) were analyzed.

    Reporting group title
    Treatment C
    Reporting group description
    		 Participants in Cohort 2 who received Treatment C (COBI 7.5 x 20 mg age-appropriate pediatric dispersible tablet) were analyzed.

    Serious adverse events
    		 Treatment A Treatment B Treatment C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment A Treatment B Treatment C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    2
    3
    1

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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