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    Clinical Trial Results:
    Bioavailability and Food Effect of Experimental Glecaprevir + Pibrentasvir Pediatric Formulation in Healthy Adult Subjects

    Summary
    EudraCT number
    		 2019-003736-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2020
    First version publication date
    03 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M17-142
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    1 North Waukegan Road, North Chicago, IL, United States, 60064
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001832-PIP01-15
    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 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the bioavailability of the experimental glecaprevir (GLE) + pibrentasvir (PIB) pediatric formulation relative to the reference Phase 3 adult formulation under fasting and non-fasting conditions.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2017
    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: 39
    Worldwide total number of subjects
    39
    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)
    39
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was an open-label, randomized, crossover study conducted in 2 parts that enrolled healthy males and females between 18 and 55 years of age, inclusive.

    Pre-assignment
    Screening details
    		 Part 1: 4-sequence, 4-period crossover design to evaluate bioavailability of GLE+PIB pediatric formulation relative to commercial adult formulation under fasting/non-fasting conditions. Part 2: 3-sequence, 3-period crossover design to evaluate effect of high-fat and low-fat meals on GLE+PIB pediatric formulation relative to fasting conditions.

    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
    		 Part 1: Regimen Sequence ABCD
    Arm description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Investigational medicinal product name
    glecaprevir (GLE)/pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adult formulation, GLE 100 mg / PIB 40 mg per tablet

    Arm title
    		 Part 1: Regimen Sequence BDAC
    Arm description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Investigational medicinal product name
    glecaprevir (GLE)/pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adult formulation, GLC 100 mg / BIB 40 mg per tablet

    Arm title
    		 Part 1: Regimen Sequence CADB
    Arm description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Investigational medicinal product name
    glecaprevir (GLE)/pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adult formulation, GLE 100 mg / PIB 40 mg per tablet

    Arm title
    		 Part 1: Regimen Sequence DCBA
    Arm description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Investigational medicinal product name
    glecaprevir (GLE)/pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adult formulation, GLE 100 mg / PIB 40 mg per tablet

    Arm title
    		 Part 2: Regimen Sequence EFG
    Arm description
    		 In Part 2, subjects received 3 doses of GLE+PIB pediatric formulations with a washout interval of 5 days between doses: Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Arm title
    		 Part 2: Regimen Sequence FGE
    Arm description
    		 In Part 2, subjects received 3 doses of GLE +PIB pediatric formulations with a washout interval of 5 days between doses: Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Arm title
    		 Part 2: Regimen Sequence GEF
    Arm description
    		 In Part 2, subjects received 3 doses of GLE + PIB pediatric formulations with a washout interval of 5 days between doses: Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glecaprevir (GLE)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation,15.67% (w/w) strength

    Investigational medicinal product name
    pibrentasvir (PIB)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated pellets, pediatric formulation, 8.25% (w/w) strength

    Number of subjects in period 1
    		Part 1: Regimen Sequence ABCD Part 1: Regimen Sequence BDAC Part 1: Regimen Sequence CADB Part 1: Regimen Sequence DCBA Part 2: Regimen Sequence EFG Part 2: Regimen Sequence FGE Part 2: Regimen Sequence GEF
    Started
    6
    6
    6
    6
    5
    5
    5
    Completed
    6
    6
    5
    6
    5
    5
    5
    Not completed
    0
    0
    1
    0
    0
    0
    0
         Adverse event
    -
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Regimen Sequence ABCD
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence BDAC
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence CADB
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence DCBA
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions.

    Reporting group title
    Part 2: Regimen Sequence EFG
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE+PIB pediatric formulations with a washout interval of 5 days between doses: Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions.

    Reporting group title
    Part 2: Regimen Sequence FGE
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE +PIB pediatric formulations with a washout interval of 5 days between doses: Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions.

    Reporting group title
    Part 2: Regimen Sequence GEF
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE + PIB pediatric formulations with a washout interval of 5 days between doses: Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions.

    Reporting group values
    		 Part 1: Regimen Sequence ABCD Part 1: Regimen Sequence BDAC Part 1: Regimen Sequence CADB Part 1: Regimen Sequence DCBA Part 2: Regimen Sequence EFG Part 2: Regimen Sequence FGE Part 2: Regimen Sequence GEF Total
    Number of subjects
    		 6 6 6 6 5 5 5 39
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 6 6 6 5 5 5 39
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.5 ± 6.16 34.0 ± 7.51 44.2 ± 7.31 40.2 ± 10.53 39.4 ± 10.21 32.4 ± 4.16 32.6 ± 9.71 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3 4 3 1 0 0 14
        Male
    		 3 3 2 3 4 5 5 25
    Race
    Units: Subjects
        White
    		 4 3 3 4 3 4 4 25
        Black or African American
    		 2 3 3 2 1 0 0 11
        Multi-race
    		 0 0 0 0 1 1 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 0 0 1 1 2 6
        None of the above
    		 5 5 6 6 4 4 3 33

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Regimen Sequence ABCD
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence BDAC
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence CADB
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions. Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions.

    Reporting group title
    Part 1: Regimen Sequence DCBA
    Reporting group description
    		 In Part 1, subjects received 2 doses of GLE + PIB pediatric formulations and 2 doses of GLE/PIB adult formulation with a washout interval of at least 4 days between doses: Regimen D: single dose of GLE/PIB 300 mg/120 mg tablets administered under non-fasting conditions. Regimen C: single dose of GLE/PIB 300 mg/120 mg tablets administered under fasting conditions. Regimen B: single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions. Regimen A: single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions.

    Reporting group title
    Part 2: Regimen Sequence EFG
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE+PIB pediatric formulations with a washout interval of 5 days between doses: Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions.

    Reporting group title
    Part 2: Regimen Sequence FGE
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE +PIB pediatric formulations with a washout interval of 5 days between doses: Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions. Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions.

    Reporting group title
    Part 2: Regimen Sequence GEF
    Reporting group description
    		 In Part 2, subjects received 3 doses of GLE + PIB pediatric formulations with a washout interval of 5 days between doses: Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions. Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions. Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions.

    Subject analysis set title
    Regimen A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions.

    Subject analysis set title
    Regimen B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions.

    Subject analysis set title
    Regimen C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of GLE /PIB 300/120 mg tablets administered under fasting conditions.

    Subject analysis set title
    Regimen D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of GLE /PIB 300/120 mg tablets administered under non-fasting conditions.

    Subject analysis set title
    Regimen E
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Regimen E: Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions.

    Subject analysis set title
    Regimen F
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Regimen F: Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions.

    Subject analysis set title
    Regimen G
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Regimen G: Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions.

    Primary: Number of Subjects Treatment-Emergent Adverse Events

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    End point title
    		 Number of Subjects Treatment-Emergent Adverse Events [1]
    End point description
    An AE is defined as any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is an event that: results in death; is life-threatening; results in hospitalization or prolongation of hospitalization; is a congentical anomaly; results in significant disability/incapacity; is an important medical event.
    End point type
    Primary
    End point timeframe
    Part 1: From first dose of study treatment through the end of the last treatment (up to 19 days) plus 30 days. Part 2: From first dose of study treatment through the end of the last treatment (up to 11 days) plus 30 days.
    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 are presented per protocol.
    End point values
    		 Regimen A Regimen B Regimen C Regimen D Regimen E Regimen F Regimen G
    Number of subjects analysed
    24
    23
    24
    23
    15
    15
    15
    Units: subjects
        Any adverse event (AE)
    2
    1
    2
    1
    0
    0
    0
        Any AE possibly related to regimen A
    0
    0
    0
    0
    0
    0
    0
        Any AE possibly related to regimen B
    0
    0
    0
    0
    0
    0
    0
        Any AE possibly related to regimen C
    0
    0
    0
    0
    0
    0
    0
        Any AE possibly related to regimen D
    0
    0
    0
    0
    0
    0
    0
        Any serious AE
    0
    0
    0
    0
    0
    0
    0
        Any AE leading to discontinuation of study drug
    1
    0
    0
    0
    0
    0
    0
        Any fatal AE
    0
    0
    0
    0
    0
    0
    0
        Deaths
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Part 1 GLE Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Part 1 GLE Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax)
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    236 ± 144
    621 ± 51
    399 ± 97
    946 ± 83
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below) Comparison groups: Regimen A vs. Regimen C (not Regimen C vs. Regimen A, per below)
    Comparison groups
    Regimen C v Regimen A
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.591
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.447
         upper limit
    		 0.782
    Notes
    [2] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.664
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.524
         upper limit
    		 0.842
    Notes
    [3] - Bioequivalence

    Primary: Part 1 GLE Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax)

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    End point title
    		 Part 1 GLE Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) [4]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: hours
        median (full range (min-max))
    1.5 (1.0 to 6.0)
    3.0 (1.5 to 6.0)
    3.0 (2.0 to 6.0)
    4.0 (2.0 to 6.0)
    No statistical analyses for this end point

    Primary: Part 1 GLE Pharmacokinetics: Terminal Phase Elimination Half-Life (t1/2)

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    End point title
    		 Part 1 GLE Pharmacokinetics: Terminal Phase Elimination Half-Life (t1/2) [5]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [5] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: hours
        median (full range (min-max))
    7.78 (2.85 to 9.51)
    7.10 (4.77 to 10.3)
    7.11 (4.23 to 9.50)
    6.67 (4.00 to 9.69)
    No statistical analyses for this end point

    Primary: Part 1 GLE Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUCt)

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    End point title
    		 Part 1 GLE Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUCt)
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1110 ± 118
    2700 ± 50
    1830 ± 78
    3410 ± 76
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below)
    Comparison groups
    Regimen A v Regimen C
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.606
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.478
         upper limit
    		 0.768
    Notes
    [6] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.794
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.664
         upper limit
    		 0.949
    Notes
    [7] - Bioequivalence

    Primary: Part 1 GLE Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinite Time (AUCinf)

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    End point title
    		 Part 1 GLE Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinite Time (AUCinf)
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1110 ± 118
    2710 ± 50
    1830 ± 78
    3420 ± 76
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below)
    Comparison groups
    Regimen A v Regimen C
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.607
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.479
         upper limit
    		 0.769
    Notes
    [8] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.795
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.665
         upper limit
    		 0.95
    Notes
    [9] - Bioequivalence

    Primary: Part 1 PIB Pharmacokinetics: Cmax

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    End point title
    		 Part 1 PIB Pharmacokinetics: Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    102 ± 61
    213 ± 51
    124 ± 63
    189 ± 58
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below)
    Comparison groups
    Regimen A v Regimen C
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.822
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.659
         upper limit
    		 1.025
    Notes
    [10] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.137
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.908
         upper limit
    		 1.424
    Notes
    [11] - Bioequivalence

    Primary: Part 1 PIB Pharmacokinetics: Tmax

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    End point title
    		 Part 1 PIB Pharmacokinetics: Tmax [12]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [12] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: hours
        median (full range (min-max))
    4.0 (3.0 to 5.0)
    5.0 (3.0 to 6.0)
    5.0 (2.0 to 6.0)
    5.0 (2.0 to 8.0)
    No statistical analyses for this end point

    Primary: Part 1 PIB Pharmacokinetics: t1/2

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    End point title
    		 Part 1 PIB Pharmacokinetics: t1/2 [13]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [13] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: hours
        median (full range (min-max))
    14.4 (11.5 to 23.2)
    14.1 (11.5 to 16.1)
    14.3 (10.5 to 17.6)
    14.0 (11.6 to 17.5)
    No statistical analyses for this end point

    Primary: Part 1 PIB Pharmacokinetics: AUCt

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    End point title
    		 Part 1 PIB Pharmacokinetics: AUCt
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    869 ± 65
    1490 ± 52
    1010 ± 67
    1240 ± 60
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below)
    Comparison groups
    Regimen A v Regimen C
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [14]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.859
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.07
    Notes
    [14] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.223
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.977
         upper limit
    		 1.531
    Notes
    [15] - Bioequivalence

    Primary: Part 1 PIB Pharmacokinetics: AUCinf

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    End point title
    		 Part 1 PIB Pharmacokinetics: AUCinf
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen A Regimen B Regimen C Regimen D
    Number of subjects analysed
    24
    23
    24
    23
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    924 ± 64
    1580 ± 52
    1070 ± 68
    1310 ± 59
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 24 (not 48, per below)
    Comparison groups
    Regimen A v Regimen C
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [16]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    0.862
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.695
         upper limit
    		 1.07
    Notes
    [16] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 23 (not 46, per below)
    Comparison groups
    Regimen B v Regimen D
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [17]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.219
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.978
         upper limit
    		 1.52
    Notes
    [17] - Bioequivalence

    Primary: Part 2 GLE Pharmacokinetics: Cmax

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    End point title
    		 Part 2 GLE Pharmacokinetics: Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    284 ± 64
    387 ± 50
    134 ± 40
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [18]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.119
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.732
         upper limit
    		 2.592
    Notes
    [18] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.888
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.361
         upper limit
    		 3.533
    Notes
    [19] - Bioequivalence

    Primary: Part 2 GLE Pharmacokinetics: Tmax

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    End point title
    		 Part 2 GLE Pharmacokinetics: Tmax [20]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [20] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: hours
        median (full range (min-max))
    4.0 (1.5 to 6.0)
    3.0 (1.0 to 6.0)
    1.5 (1.0 to 2.0)
    No statistical analyses for this end point

    Primary: Part 2 GLE Pharmacokinetics: t1/2

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    End point title
    		 Part 2 GLE Pharmacokinetics: t1/2 [21]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [21] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: hours
        median (full range (min-max))
    6.02 (2.95 to 8.76)
    5.85 (5.15 to 10.5)
    5.83 (3.04 to 8.35)
    No statistical analyses for this end point

    Primary: Part 2 GLE Pharmacokinetics: AUCt

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    End point title
    		 Part 2 GLE Pharmacokinetics: AUCt
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1350 ± 48
    1560 ± 46
    585 ± 48
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [22]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.31
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.985
         upper limit
    		 2.688
    Notes
    [22] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [23]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.676
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.299
         upper limit
    		 3.114
    Notes
    [23] - Bioequivalence

    Primary: Part 2 GLE Pharmacokinetics: AUCinf

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    End point title
    		 Part 2 GLE Pharmacokinetics: AUCinf
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1360 ± 48
    1570 ± 46
    589 ± 48
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [24]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.305
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.981
         upper limit
    		 2.681
    Notes
    [24] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [25]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.666
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.292
         upper limit
    		 3.101
    Notes
    [25] - Bioequivalence

    Primary: Part 2 PIB Pharmacokinetics: Cmax

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    End point title
    		 Part 2 PIB Pharmacokinetics: Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    189 ± 54
    151 ± 58
    82.2 ± 46
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [26]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.867
         upper limit
    		 2.834
    Notes
    [26] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [27]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.834
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.489
         upper limit
    		 2.26
    Notes
    [27] - Bioequivalence

    Primary: Part 2 PIB Pharmacokinetics: Tmax

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    End point title
    		 Part 2 PIB Pharmacokinetics: Tmax [28]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [28] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: hours
        median (full range (min-max))
    5.0 (2.0 to 6.0)
    3.0 (2.0 to 5.0)
    4.0 (2.0 to 5.0)
    No statistical analyses for this end point

    Primary: Part 2 PIB Pharmacokinetics: t1/2

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    End point title
    		 Part 2 PIB Pharmacokinetics: t1/2 [29]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    Notes
    [29] - 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: Statistical analyses of pharmacokinetic parameters are presented in the data table per protocol.
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: hours
        median (full range (min-max))
    12.5 (11.2 to 15.9)
    13.1 (10.6 to 15.7)
    13.0 (11.8 to 17.2)
    No statistical analyses for this end point

    Primary: Part 2 PIB Pharmacokinetics: AUCt

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    End point title
    		 Part 2 PIB Pharmacokinetics: AUCt
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1400 ± 52
    1020 ± 63
    653 ± 49
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per the below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [30]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.145
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.75
         upper limit
    		 2.629
    Notes
    [30] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [31]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.566
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.277
         upper limit
    		 1.919
    Notes
    [31] - Bioequivalence

    Primary: Part 2 PIB Pharmacokinetics: AUCinf

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    End point title
    		 Part 2 PIB Pharmacokinetics: AUCinf
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose
    End point values
    		 Regimen E Regimen F Regimen G
    Number of subjects analysed
    15
    15
    15
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1470 ± 52
    1070 ± 63
    686 ± 49
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below)
    Comparison groups
    Regimen E v Regimen G
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [32]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    2.138
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.75
         upper limit
    		 2.613
    Notes
    [32] - Bioequivalence
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Subjects in this analysis: 15 (not 30, per below) Comparison groups: Regimen F vs. Regimen G (not Regimen G vs. Regimen F, per below)
    Comparison groups
    Regimen G v Regimen F
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [33]
    Method
    Parameter type
    		 Relative bioavailability
    Point estimate
    1.562
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.278
         upper limit
    		 1.908
    Notes
    [33] - Bioequivalence

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: From first dose of study treatment through the end of the last treatment (up to 19 days) plus 30 days. Part 2: From first dose of study treatment through the end of the last treatment (up to 11 days) plus 30 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Regimen A
    Reporting group description
    		 Single dose of GLE 300 mg and PIB 120 mg pellets administered under fasting conditions.

    Reporting group title
    Regimen B
    Reporting group description
    		 Single dose of GLE 300 mg and PIB 120 mg pellets administered under non-fasting conditions.

    Reporting group title
    Regimen C
    Reporting group description
    		 Single dose of GLE /PIB 300/120 mg tablets administered under fasting conditions.

    Reporting group title
    Regimen D
    Reporting group description
    		 Single dose of GLE /PIB 300/120 mg tablets administered under non-fasting conditions.

    Reporting group title
    Regimen E
    Reporting group description
    		 Single dose of GLE 300 mg and PIB 120 mg administered under high-fat conditions.

    Reporting group title
    Regimen F
    Reporting group description
    		 Single dose of GLE 300 mg and PIB 120 mg administered under low-fat conditions.

    Reporting group title
    Regimen G
    Reporting group description
    		 Single dose of GLE 300 mg and PIB 120 mg administered under fasting conditions.

    Serious adverse events
    		 Regimen A Regimen B Regimen C Regimen D Regimen E Regimen F Regimen G
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Regimen A Regimen B Regimen C Regimen D Regimen E Regimen F Regimen G
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 23 (4.35%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Infectious mononucleosis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2017
    The purpose of this amendment is to incorporate changes summarized below: - Modify the study design for Part 2. Rationale: To add evaluation of the effect of low-fat meal on the experimental GLE + PIB pediatric formulation to Part 2. Evaluation of different meal types in addition to the standard meal studied in Part 1 will generate data on various types of dietary habits with the pediatric pellet formulation.
    14 Feb 2018
    Section 3.13, Meals Updated to specify low-fat meal content for Part 2 for the added regimen. Section 3.14, Confinement Updated confinement details for Part 2 to account for the updated study design. Section 3.15, Follow-Up Updated follow-up details for Part 2 to account for the updated study design. Section 5.1, Treatments Administered Added low-fat regimen in Part 2. Section 5.3, Method of Assigning Subjects to Treatment Groups Updated description for Part 2 to match updated study design.

    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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