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    Clinical Trial Results:
    A Phase 1 Relative Bioavailability and Food Effect Study of a Pediatric Oral Granule Formulation of Ledipasvir/Sofosbuvir in Healthy Adult Subjects

    Summary
    EudraCT number
    		 2017-003956-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    27 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Dec 2017
    First version publication date
    06 Dec 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-337-2091
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox , Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials 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-001411-PIP01-12
    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
    27 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the relative bioavailability of a pediatric oral granule formulation of ledipasvir/sofosbuvir (LDV/SOF) relative to tablet formulation in healthy participants and to evaluate the effect of concomitant food intake on the pharmacokinetics (PK) of a pediatric oral granule formulation of LDV/SOF.
    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
    24 May 2016
    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: 42
    Worldwide total number of subjects
    42
    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)
    42
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at one study site in the United States. The first participant was screened on 24 May 2016. The last study visit occurred on 27 July 2016.

    Pre-assignment
    Screening details
    		 58 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
    		 Treatment ABC
    Arm description
    		 Treatment A, 9-day washout, Treatment B, 9-day washout, and then Treatment C.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition

    Arm title
    		 Treatment ACB
    Arm description
    		 Treatment A, 9-day washout, Treatment C, 9-day washout, and then Treatment B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition

    Arm title
    		 Treatment BCA
    Arm description
    		 Treatment B, 9-day washout, Treatment C, 9-day washout, and then Treatment A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition

    Arm title
    		 Treatment BAC
    Arm description
    		 Treatment B, 9-day washout, Treatment A, 9-day washout, and then Treatment C.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition

    Arm title
    		 Treatment CBA
    Arm description
    		 Treatment C, 9-day washout, Treatment B, 9-day washout, and then Treatment A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition

    Arm title
    		 Treatment CAB
    Arm description
    		 Treatment C, 9-day washout, Treatment A, 9-day washout, and then Treatment B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    LDV/SOF, Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Granules, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment C = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition Treatment A = Single dose of LDV/SOF (90/400 mg tablet) under fasted condition Treatment B = Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition

    Number of subjects in period 1
    		Treatment ABC Treatment ACB Treatment BCA Treatment BAC Treatment CBA Treatment CAB
    Started
    7
    7
    7
    7
    7
    7
    Completed
    7
    7
    7
    7
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment ABC
    Reporting group description
    		 Treatment A, 9-day washout, Treatment B, 9-day washout, and then Treatment C.

    Reporting group title
    Treatment ACB
    Reporting group description
    		 Treatment A, 9-day washout, Treatment C, 9-day washout, and then Treatment B.

    Reporting group title
    Treatment BCA
    Reporting group description
    		 Treatment B, 9-day washout, Treatment C, 9-day washout, and then Treatment A.

    Reporting group title
    Treatment BAC
    Reporting group description
    		 Treatment B, 9-day washout, Treatment A, 9-day washout, and then Treatment C.

    Reporting group title
    Treatment CBA
    Reporting group description
    		 Treatment C, 9-day washout, Treatment B, 9-day washout, and then Treatment A.

    Reporting group title
    Treatment CAB
    Reporting group description
    		 Treatment C, 9-day washout, Treatment A, 9-day washout, and then Treatment B.

    Reporting group values
    		 Treatment ABC Treatment ACB Treatment BCA Treatment BAC Treatment CBA Treatment CAB Total
    Number of subjects
    		 7 7 7 7 7 7 42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32 ( 7.4 ) 29 ( 6.3 ) 29 ( 4.8 ) 29 ( 6.4 ) 26 ( 4.0 ) 31 ( 6.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 2 2 3 2 12
        Male
    		 6 5 5 5 4 5 30
    Race
    Units: Subjects
        Black or African American
    		 3 3 3 2 4 3 18
        Native Hawaiian or Pacific Islander
    		 0 0 0 0 1 0 1
        White
    		 4 4 4 5 2 4 23
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 6 4 5 4 4 28
        Not Hispanic or Latino
    		 2 1 3 2 3 3 14

    End points

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    End points reporting groups
    Reporting group title
    Treatment ABC
    Reporting group description
    		 Treatment A, 9-day washout, Treatment B, 9-day washout, and then Treatment C.

    Reporting group title
    Treatment ACB
    Reporting group description
    		 Treatment A, 9-day washout, Treatment C, 9-day washout, and then Treatment B.

    Reporting group title
    Treatment BCA
    Reporting group description
    		 Treatment B, 9-day washout, Treatment C, 9-day washout, and then Treatment A.

    Reporting group title
    Treatment BAC
    Reporting group description
    		 Treatment B, 9-day washout, Treatment A, 9-day washout, and then Treatment C.

    Reporting group title
    Treatment CBA
    Reporting group description
    		 Treatment C, 9-day washout, Treatment B, 9-day washout, and then Treatment A.

    Reporting group title
    Treatment CAB
    Reporting group description
    		 Treatment C, 9-day washout, Treatment A, 9-day washout, and then Treatment B.

    Subject analysis set title
    Treatment A
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Single dose of LDV/SOF (90/400 mg tablet) under fasted condition (Treatment A)

    Subject analysis set title
    Treatment B
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition (Treatment B).

    Subject analysis set title
    Treatment C
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition (Treatment C)

    Primary: Pharmacokinetic (PK) Parameter: Cmax of SOF, GS-566500, and GS-331007

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    End point title
    		 Pharmacokinetic (PK) Parameter: Cmax of SOF, GS-566500, and GS-331007
    End point description
    Cmax is defined as the maximum concentration of drug.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    42
    42
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    1221.0 ( 469.99 )
    1266.7 ( 589.77 )
    1236.3 ( 605.60 )
        GS-566500
    475.1 ( 160.89 )
    511.3 ( 178.63 )
    593.9 ( 184.38 )
        GS-331007
    833.9 ( 197.11 )
    951.9 ( 257.01 )
    583.1 ( 141.01 )
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment B vs A)
    Statistical analysis description
    Percentage geometric least-squares mean (GLSM) ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    95.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 78
         upper limit
    		 118.11
    Notes
    [1] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    100.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 84.83
         upper limit
    		 118.65
    Notes
    [2] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 91.06
         upper limit
    		 116.6
    Notes
    [3] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    122.12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 108.28
         upper limit
    		 137.73
    Notes
    [4] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-331007 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    112.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 104.12
         upper limit
    		 122.22
    Notes
    [5] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-331007 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    62.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 56.9
         upper limit
    		 67.59
    Notes
    [6] - Statistical Comparison

    Primary: PK Parameter: Cmax of LDV

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    End point title
    		 PK Parameter: Cmax of LDV
    End point description
    Cmax is defined as the maximum concentration of drug.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    39 [7]
    40 [8]
    Units: ng/mL
        arithmetic mean (standard deviation)
    261.3 ( 113.55 )
    214.8 ( 82.05 )
    159.8 ( 46.17 )
    Notes
    [7] - 3 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    [8] - 2 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 81; however, only 42 unique participants were analyzed, each reported for Treatment B (N = 39) and Treatment A (N = 42).
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    84.59
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 74.69
         upper limit
    		 95.81
    Notes
    [9] - Statistical comparison
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 81; however, only 40 unique participants were analyzed, each reported for Treatment C (N = 40) and Treatment B (N = 39).
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    78.15
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 71.26
         upper limit
    		 85.71
    Notes
    [10] - Statistical comparison

    Primary: PK Parameter: AUClast of SOF, GS-566500, and GS-331007

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    End point title
    		 PK Parameter: AUClast of SOF, GS-566500, and GS-331007
    End point description
    AUClast is defined as the concentration of drug from time zero to the last observable concentration.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    42
    42
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF
    1559.8 ( 632.08 )
    1676.9 ( 732.07 )
    2577.2 ( 852.76 )
        GS-566500
    1846.6 ( 579.71 )
    1952.9 ( 654.54 )
    2931.7 ( 559.29 )
        GS-331007
    11146.3 ( 2999.47 )
    11525.8 ( 3037.01 )
    11653.6 ( 2197.58 )
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    102.13
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 87.16
         upper limit
    		 119.67
    Notes
    [11] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    166.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 145
         upper limit
    		 190.3
    Notes
    [12] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    100.59
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88.89
         upper limit
    		 113.83
    Notes
    [13] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    163.23
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 144.62
         upper limit
    		 184.23
    Notes
    [14] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-331007 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 96.71
         upper limit
    		 110
    Notes
    [15] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 97.61
         upper limit
    		 108.94
    Notes
    [16] - Statistical Comparison

    Primary: PK Parameter: AUClast of LDV

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    End point title
    		 PK Parameter: AUClast of LDV
    End point description
    AUClast is defined as the concentration of drug from time zero to the last observable concentration.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    39 [17]
    40 [18]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    7362.3 ( 3557.92 )
    6242.5 ( 2542.34 )
    5149.6 ( 1349.23 )
    Notes
    [17] - 3 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    [18] - 2 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 81; however, only 42 unique participants were analyzed, each reported for Treatment B (N = 39) and Treatment A (N = 42).
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    87.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 77.94
         upper limit
    		 98.82
    Notes
    [19] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 79; however, only 40 unique participants were analyzed, each reported for Treatment C (N = 40) and Treatment B (N = 39).
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    87.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 79.65
         upper limit
    		 96.39
    Notes
    [20] - Statistical Comparison

    Primary: PK Parameter: AUCinf of SOF, GS-566500, and GS-331007

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    End point title
    		 PK Parameter: AUCinf of SOF, GS-566500, and GS-331007
    End point description
    AUCinf is defined as the concentration of drug extrapolated to infinite time.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    42
    42
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF
    1580.8 ( 634.96 )
    1684.1 ( 733.08 )
    2597.7 ( 853.35 )
        GS-566500
    1894.9 ( 584.25 )
    2009.7 ( 663.88 )
    2988.8 ( 558.28 )
        GS-331007
    11720.0 ( 3058.58 )
    12095.0 ( 2947.17 )
    12220.6 ( 2238.27 )
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    101.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 86.67
         upper limit
    		 119.1
    Notes
    [21] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of SOF (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    166.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 145.56
         upper limit
    		 189.71
    Notes
    [22] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    101.37
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 90.17
         upper limit
    		 113.96
    Notes
    [23] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-566500 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    160.65
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 143.4
         upper limit
    		 179.99
    Notes
    [24] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-331007 (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment B and Treatment A.
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    103.64
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.48
         upper limit
    		 109.07
    Notes
    [25] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of GS-331007 (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 84; however, only 42 unique participants were analyzed, each reported for Treatment C and Treatment B.
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    102.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 98.18
         upper limit
    		 106.52
    Notes
    [26] - Statistical Comparison

    Primary: PK Parameter: AUCinf of LDV

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    End point title
    		 PK Parameter: AUCinf of LDV
    End point description
    AUCinf is defined as the concentration of drug extrapolated to infinite time.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    39 [27]
    40 [28]
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    8467.5 ( 4605.87 )
    7088.4 ( 3279.03 )
    5748.3 ( 1669.51 )
    Notes
    [27] - 3 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    [28] - 2 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment B vs A)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 81; however, only 42 unique participants were analyzed, each reported for Treatment B (N = 39) and Treatment A (N = 42).
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    88.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 78.43
         upper limit
    		 99.54
    Notes
    [29] - Statistical Comparison
    Statistical analysis title
    		 GLSM ratio of LDV (Treatment C vs B)
    Statistical analysis description
    Percentage GLSM ratio is being presented. "Subjects in this analysis" states 79; however, only 40 unique participants were analyzed, each reported for Treatment C (N = 40) and Treatment B (N = 39).
    Comparison groups
    Treatment C v Treatment B
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    Method
    Parameter type
    		 Geometric least-squares mean ratio
    Point estimate
    87.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 78.95
         upper limit
    		 96
    Notes
    [30] - Statistical Comparison

    Secondary: PK Parameter: Tmax of SOF, GS-566500, and GS-331007

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    End point title
    		 PK Parameter: Tmax of SOF, GS-566500, and GS-331007
    End point description
    Tmax is defined as the time (observed time point) of Cmax.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    42
    42
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    0.51 (0.50 to 1.50)
    2.00 (1.00 to 2.50)
    1.50 (1.00 to 3.00)
        GS-566500
    1.76 (1.00 to 2.00)
    2.50 (2.00 to 3.00)
    3.00 (2.50 to 4.00)
        GS-331007
    3.00 (2.00 to 4.00)
    3.00 (2.50 to 3.50)
    4.50 (4.00 to 5.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of LDV

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    End point title
    		 PK Parameter: Tmax of LDV
    End point description
    Tmax is defined as the time (observed time point) of Cmax.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96, 120 and 144 hours postdose
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    39 [31]
    40 [32]
    Units: hours
        median (inter-quartile range (Q1-Q3))
    4.50 (4.50 to 4.55)
    4.50 (4.50 to 5.00)
    5.00 (4.50 to 6.00)
    Notes
    [31] - 3 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    [32] - 2 participants were excluded since their LDV predose plasma concentration was > 5% of Cmax.
    No statistical analyses for this end point

    Secondary: Incidence of Adverse Events

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    End point title
    		 Incidence of Adverse Events
    End point description
    The percentage of participants experiencing treatment-emergent adverse events was summarized.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Day 21 plus 30 days
    End point values
    		 Treatment A Treatment B Treatment C
    Number of subjects analysed
    42
    42
    42
    Units: percentage of participants
        number (not applicable)
    9.5
    9.5
    14.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For Serious Adverse Events: From Screening until 30 days after last administration of study drug. For Non-Serious Adverse Events: From Baseline until 30 days after last administration of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Single dose of LDV/SOF (90/400 mg tablet) under fasted condition (Treatment A)

    Reporting group title
    Treatment B
    Reporting group description
    		 Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fasted condition (Treatment B)

    Reporting group title
    Treatment C
    Reporting group description
    		 Single dose of LDV/SOF (8 x 11.25/50 mg oral granules) under fed condition (Treatment C)

    Serious adverse events
    		 Treatment A Treatment B Treatment C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 42 (0.00%)
    0 / 42 (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 / 42 (4.76%)
    3 / 42 (7.14%)
    6 / 42 (14.29%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 42 (7.14%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    1
    0
    3

    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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